Toxicity Probability Interval Design Research Articles

A phase 1/2 study of favezelimab in combination with pembrolizumab for heavily pretreated anti–PD-1–refractory classical Hodgkin lymphoma (cHL): An updated analysis.

7056 Background: PD-1 inhibitors are standard of care for relapsed or refractory (R/R) cHL, but patients (pts) often progress after anti–PD-1 therapy. The immune checkpoint receptor lymphocyte-activation gene 3 (LAG-3) is proposed to contribute to anti–PD-1 resistance. In a phase 1/2 study (NCT03598608) evaluating favezelimab (anti–LAG-3) plus pembrolizumab (anti–PD-1) for R/R hematologic malignancies, the combination provided antitumor activity and manageable safety in pts with heavily pretreated anti–PD-1–refractory cHL (cohort 2). Updated results after additional follow-up are presented. Methods: Eligible pts were aged ≥18 years with R/R cHL; prior treatment with or ineligibility for autologous stem cell transplantation or no response to salvage chemotherapy; an ECOG performance status of 0 or 1; and disease progression after ≥2 doses of anti–PD-1–based therapy and within 12 weeks of the last dose of anti–PD-1 therapy. The study comprised a safety lead-in (pembrolizumab 200 mg IV Q3W + favezelimab 200-mg starting dose, then dose escalation to 800 mg IV Q3W per a modified toxicity probability interval design) and a dose expansion phase (pembrolizumab + favezelimab at the established recommended phase 2 dose of 800 mg Q3W for ≤35 cycles). Primary end point was safety. ORR per IWG 2007 criteria by investigator review was a secondary end point. DOR and PFS per IWG 2007 criteria by investigator review and OS were exploratory. Results: Cohort 2 enrolled 34 pts. Median time from first dose to data cutoff (August 15, 2023) was 40.7 months (range, 20.4-54.8). Treatment-related AEs occurred in 28 pts (82%); the most common (≥15%) were hypothyroidism (18%), nausea (18%), and fatigue (15%). Grade 3 or 4 treatment-related AEs occurred in 6 pts (18%). Discontinuation due to treatment-related AEs occurred in 6 pts (18%). No deaths due to treatment-related AEs were reported. AEs of clinical interest occurred in 17 pts (50%); 2 pts (6%) had grade 3 events (encephalitis, hepatitis) and 1 pt (3%) had a grade 4 event (type 1 diabetes mellitus). ORR was 29% (10/34; 95% CI, 15-48), with 3 (9%) complete responses and 7 (21%) partial responses. ORR was 35% (6/17; 95% CI, 14-62) in pts with anti–PD-1 and 24% (4/17; 95% CI, 7-50) in pts with non–anti–PD-1 as most recent therapy. Median DOR was 21.9 months (range, 0.0+ to 26.1+) and an estimated 17% of responders remained in response at 24 months. Median PFS was 9.7 months (95% CI, 5.1-14.7); 24-month PFS rate was 21%. Median OS was 39.0 months (95% CI, 25.7-not reached); 24-month OS rate was 73%. Conclusions: After additional follow-up, favezelimab + pembrolizumab continued to demonstrate manageable safety and antitumor activity in pts with heavily pretreated anti–PD-1–refractory cHL. The phase 3 KEYFORM-008 study (NCT05508867) will evaluate a coformulation of favezelimab and pembrolizumab in pts with anti–PD-1–refractory cHL. Clinical trial information: NCT03598608 .

BELLWAVE-010: A phase 3 study of nemtabrutinib plus venetoclax versus venetoclax plus rituximab (VR) in previously treated patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

TPS7089 Background: VR is a standard of care option for pts with CLL/SLL who have relapsed after ≥1 line of prior therapy. However, there is an unmet need for more effective treatments. Bruton tyrosine kinase (BTK) plays an important role in the pathogenesis of CLL. Nemtabrutinib is a BTK inhibitor that targets both wild type and C481-mutant forms of BTK. In the ongoing BELLWAVE-001 study, nemtabrutinib demonstrated manageable safety and durable antitumor activity in pts with R/R CLL/SLL with and without C481 mutations. The randomized, open-label, phase 3 BELLWAVE-010 study (NCT05947851) is designed to evaluate the efficacy and safety of nemtabrutinib + venetoclax versus VR as second-line or later treatment for pts with R/R CLL/SLL. Methods: Eligible pts are aged ≥18 years with active R/R CLL/SLL after ≥1 prior therapy per iwCLL 2018 criteria and an ECOG PS of 0-2. Approximately 720 pts will be enrolled in 2 parts. Part 1 is an open-label, nonrandomized dose escalation and confirmation phase to evaluate safety and determine the optimal dose of nemtabrutinib + venetoclax. Part 1 will enroll 30 pts to establish the dose of nemtabrutinib using a modified toxicity probability interval design. Pts will receive nemtabrutinib at 2 dose levels (45 mg PO QD starting dose, escalating to 65 mg PO QD) for 28 days, followed by nemtabrutinib + venetoclax (20-400 mg PO QD ramp up over 4 weeks). Part 2 is an open-label, parallel-group, randomized phase comparing the efficacy and safety of nemtabrutinib + venetoclax with VR. In part 2, approximately 690 pts will be randomly assigned 1:1 to receive either nemtabrutinib at the recommended dose for 28 days followed by the nemtabrutinib + venetoclax or venetoclax + rituximab (or rituximab biosimilar; 375 mg/m2 at week 6, followed by 500 mg/m2 every 4 weeks starting at week 10 until week 26 [total 6 doses]). Study treatment will continue for approximately 2 years or until unacceptable toxicity, disease progression, or other discontinuation criteria are met. Randomization will be stratified by BTK-C481 mutation status (detected vs not detected), geographic region (US/Canada vs Europe vs rest of world) and risk (high risk [del(17p) and/or TP53-mutated and/or IGHV-unmutated] vs low risk [absence of high-risk factors]). The primary end point for part 2 is progression-free survival by blinded independent central review (BICR) per iwCLL 2018 criteria. Secondary end points for part 2 are undetectable minimal residual disease in bone marrow at month 14 by central laboratory assessment, objective response rate (ORR), and duration of response by BICR per iwCLL 2018 criteria, overall survival, and safety. Exploratory end points are ORR including partial response with lymphocytosis, pharmacokinetics, and health-related quality of life. Recruitment is ongoing. Clinical trial information: NCT05947851 .

Updated efficacy and safety results of BCL-2 inhibitor lisaftoclax (APG-2575) alone or combined with ibrutinib or rituximab in patients (pts) with Waldenström macroglobulinemia (WM).

7078 Background: Lisaftoclax is a novel, oral, highly selective, potent BCL-2 inhibitor in development. In an ibrutinib-resistant patient-derived WM xenograft/preclinical model, lisaftoclax + ibrutinib has a strong synergistic effect. This report provides updated efficacy and safety data of lisaftoclax-based therapies (including combinations with ibrutinib) in pts with WM. Methods: In this global, open-label, phase 1b/2 multicenter study, pts with WM were enrolled in 3 arms: Arm A (lisaftoclax) included BTKi-resistant/intolerant pts; Arm B (lisaftoclax + ibrutinib), treatment-naïve pts; and Arm C (lisaftoclax + rituximab), BTKi-naïve relapsed/refractory pts. Lisaftoclax was escalated from 400 to 1,200 mg using a modified toxicity probability interval design. A 3-day ramp-up was used for pts at high risk of tumor lysis syndrome (TLS). Objectives were efficacy, safety, and pharmacokinetics (PK) assessments (responses assessed per IWWM criteria). Results: As of January 25, 2024, 46 pts were enrolled and treated at doses of up to 1,000 (Arm A), 1,200 (Arm B), and 800 mg (Arm C; Table). The median (range) treatment duration was 11 (1-28; Arm A), 23.5 (1-34; B), and 11.5 (5-33; C) months. Objective response rates (PR, VGFR, CR) were: 41.7% (Arm A), 90.9% (B), and 37.5% (C). In Arm A, pts with wild-type CXCR4 (n = 7) had better overall response to lisaftoclax than the CXCR4mut group (n = 3). No significant difference was observed between pts with/without CXCR4mut in Arms B and C. In Arm B, 1 DLT (grade 3 clinical TLS due to preexisting renal impairment) was reported at 1,200 mg; 1 grade 3 laboratory TLS, primarily attributed to dehydration and concomitant symptomatic therapies, occurred at 1,000 mg; abnormal electrolytes resolved after 1 day of drug interruption, without recurrence. Grade ≥ 3 lisaftoclax-related AEs included neutropenia (15.2%), thrombocytopenia (4.3%), decreased leukocytes (4.3%), TLS (4.3%), anemia (2.2%), weight loss (2.2%), and septic shock (2.2%). Ventricular arrhythmia was not observed. One pt required dose reduction because of neutropenia. The MTD was not reached. Lisaftoclax + ibrutinib showed a PK exposure comparable to lisaftoclax or ibrutinib alone, indicating no potential drug-drug interactions. Conclusions: Lisaftoclax alone and combined with ibrutinib or rituximab was well tolerated and demonstrated measurable effects in pts with naïve or BTKi-treatment-failed WM. (CT.gov: NCT04260217; Internal ID: APG2575WU101) *Co-first authors: ML and SA. Clinical trial information: NCT04260217 . [Table: see text]

Xevinapant with radiation and concurrent carboplatin and paclitaxel in patients ineligible for cisplatin with locoregionally advanced squamous cell carcinoma of the head and neck (EXtRaCT study).

TPS6126 Background: Locoregionally advanced (LA) head and neck cancer (HNC) patients undergoing chemoradiotherapy (CRT) who are ineligible for cisplatin have comparatively poor outcomes, with only ~40% alive at 5 years. There is an urgent unmet need to improve survival in these vulnerable patients with no standard therapeutic approach. Xevinapant, an oral inhibitor of XIAP and cIAP1/2, sensitizes cancer cells to apoptosis. Randomized phase II results in patients eligible for cisplatin combining xevinapant with CRT showed improved locoregional control, manageable toxicity, and promising survival outcomes. (Sun et al. Lancet Oncol. 2020) The current trial aims to extend these benefits to patients ineligible for cisplatin using xevinapant with carboplatin-paclitaxel-based CRT, hypothesizing safety and tolerability in this high-risk group. Methods: This phase I dose escalation/expansion study investigates xevinapant combined with carboplatin and paclitaxel to treat LA HNC in patients ineligible for cisplatin. Key eligibility includes previously untreated LA HNC and specific cisplatin ineligibility criteria, including >=70yo with moderate to severe comorbidity or vulnerability (Geriatric-8 score ≤ 14 and/or CARG score ≥ 30%) or <70yo with severe comorbidity and/or vulnerability, or >=18yo with an absolute contraindication to cisplatin. The treatment regimen comprises escalating doses of oral xevinapant (50-200 mg daily) on days 1-14 of a 21-day cycle for 3 cycles concurrent with CRT and 3 cycles adjuvant, weekly carboplatin AUC 1.5 IV, and paclitaxel 30 mg/m2 IV for 7 doses, and radiotherapy to 70 Gy in standard 2Gy fractions over 7 weeks with primary endpoint of tolerability and recommended phase 2 dose. A Bayesian-modified toxicity probability interval design will identify the maximum tolerated dose (MTD), targeting a 25% dose-limiting toxicity rate, with a sample size of 24 patients in dose-finding. 18 additional patients will be enrolled in the dose-expansion cohort at the MTD, totaling 42 patients. Secondary objectives include safety, response, progression-free, overall survival, and locoregional and distant control. Exploratory aims: in-clinic geriatric evaluations (Katz ADL, Lawton iADL, MMSE), QoL surveys, symptom tracking via smartphone, and wearable-derived steps and sarcopenia assessment. Recruitment began 02/2024. Clinical trial information: NCT06110195 .

Safety and Tolerability of AZD0466 As Monotherapy for Patients with Advanced Hematologic Malignancies. Results from a Phase I/II Trial

Background: Overexpressionof B-cell lymphoma 2 (BCL-2)-related pro-survival proteins allows cancer cells to evade apoptosis, and targeting these proteins has become important in anticancer therapy. BCL-2 inhibition by venetoclax (VEN) is beneficial in many patients (pts) with acute myeloid leukemia (AML), but resistance is common due to upregulation of other pro-survival proteins such as BCL-extra-large (BCL-xL) and myeloid cell leukemia-1. Dual inhibition of BCL-2/xL has potential for broader activity than agents such as VEN. However, BCL-xL is critical for platelet survival and inhibition can cause dose-limiting thrombocytopenia (Konopleva and Letai. Blood 2018). To broaden therapeutic activity, we developed AZD0466, a drug-dendrimer conjugate in which the BCL-2/xL dual inhibitor AZD4320 is covalently conjugated to a pegylated poly-L-lysine dendrimer and gradually released by hydrolysis. Preclinically, AZD4320 showed greater inhibition of tumor growth than VEN and navitoclax in VEN-resistant xenograft models (Balachander et al. Clin Cancer Res 2020). A first-in-human study (NCT04214093) in pts with advanced solid tumors indicated that AZD0466 is well tolerated with no reported dose-limiting toxicities (DLTs). We present preliminary data from NIMBLE, a Phase I/II trial of AZD0466 in pts with advanced hematologic malignancies (NCT04865419). Methods: Module 1, Part A of NIMBLE is a dose-escalation study of AZD0466 monotherapy investigating its preliminary safety and tolerability, pharmacokinetics (PK), and preliminary efficacy. Dose escalation and de-escalation of AZD0466 follow a modified toxicity probability interval (mTPI-2) design. Eligible pts are ≥18 years old with relapsed/refractory (R/R) AML, acute lymphoblastic leukemia (ALL), or high-risk myelodysplastic syndrome. AZD0466 is administered IV with a dose ramp-up on Days (D) 1, 4, and 8, reaching the target dose on D8 of Cycle 1, with weekly administrations thereafter. Cycle duration is 35 days for Cycle 1 and 28 days for subsequent cycles. Pts remain on study until disease progression, unacceptable toxicity, or withdrawal of consent. Resul ts: As of May 31, 2023, 31 pts (n=25 AML, n=6 ALL; median age 69 years) had received ≥1 dose of AZD0466 at target doses of 300 mg (n=4), 600 mg (n=4), 1200 mg (n=7), 2400 mg (n=5), 3600 mg (n=9), and 5400 mg (n=2). Median treatment duration was 4.1 weeks (range 0.1−29.6). Twenty-two pts (71%) had prior VEN and 11 (35%) had prior hematopoietic stem cell transplantation. Treatment-emergent adverse events (TEAEs) of any grade reported in >10% of pts are displayed in Table 1. One Grade 5 intracranial hemorrhage unrelated to AZD0466 was reported. Four pts experienced a serious adverse event (SAE) possibly related to AZD0466 (alanine aminotransferase [ALT] increase, pneumonia, troponin T increase, and uncoded SAE). Grade ≥3 TEAEs possibly related to AZD0466, reported in 12 pts (39%), included febrile neutropenia (n=3), platelet count decrease (n=2), diarrhea, thrombocytopenia, ALT increase, blood creatinine phosphokinase increase, pneumonia, gamma-glutamyltransferase increase, lipase increased, and troponin T increase (n=1, each). DLTs of asymptomatic troponin increase were observed in two pts (3600 mg [n=1], 5400 mg [n=1]). Evaluation of maximum concentration and area under the concentration-time curve revealed dose-proportional exposure to AZD4320. Released AZD4320 represented 1-5% of total AZD4320 and had a longer half-life than total AZD4320. Preclinical modeling and PK data predicted that 5400 mg may be required to drive efficacy. As a surrogate of BCL-xL on-target activity, transient aggravation of thrombocytopenia post-dosing was observed across all dose cohorts followed by platelet recovery prior to the next dose. Platelet reduction was in line with preclinical models showing a substantial reduction at lower doses with a ceiling effect at higher doses. As of July 6, 2023, no complete responses have been observed. However, preliminary bone marrow (BM) blast reductions of >50% were observed in four pts (1200 mg [n=1], 2400 mg [n=2], 3600 mg [n=1]), indicating antileukemia activity of AZD0466. Conclusions: Given the observed DLTs of asymptomatic increase in troponin levels, and the lack of significant clinical benefit, the study was terminated.

Favezelimab in Combination with Pembrolizumab in Patients with Heavily Pretreated Anti-PD-1-Refractory Classical Hodgkin Lymphoma: Updated Analysis of an Open-Label Phase 1/2 Study

Background: Programmed cell death protein 1 (PD-1) inhibitors are a standard of care for relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL), but better treatment options are needed for patients with anti-PD-1-refractory disease. Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor with a role in regulating T-cell function. Dual blockade of PD-1 and LAG-3 has demonstrated antitumor activity in patients with advanced melanoma. Combination therapy with favezelimab (anti-LAG-3) and pembrolizumab (anti-PD-1) is currently being investigated in a phase 1/2 study (NCT03598608) in patients with R/R hematologic malignancies. Prior analyses showed that the combination had antitumor activity and manageable safety in patients with heavily pretreated anti-PD-1-refractory cHL (cohort 2). Updated results for this cohort are presented. Methods: The study consisted of a safety lead-in (part 1) followed by a dose-expansion phase (part 2). Eligible patients were ≥18 y; had R/R cHL after autologous stem cell transplantation (ASCT), were ineligible for ASCT, or did not respond to salvage chemotherapy; had an ECOG performance status of 0 or 1; and had experienced disease progression after ≥2 doses of anti-PD-1-based therapy and within 12 weeks of the last dose of anti-PD-1 therapy. In part 1, patients received pembrolizumab 200 mg IV Q3W + favezelimab starting at 200 mg and escalating to 800 mg IV Q3W per a modified toxicity probability interval design. In part 2, patients received pembrolizumab + favezelimab at the established RP2D of 800 mg Q3W for ≤35 cycles (~2 y). The primary end point was safety. ORR per IWG 2007 criteria by investigator review was a secondary end point. DOR and PFS per IWG 2007 criteria by investigator review and OS were exploratory end points. Results: 34 patients with anti-PD-1-refractory cHL were enrolled in cohort 2. The median age was 37.5 y (range, 25-79), 16 patients (47%) were male, 21 (62%) had an ECOG performance status of 0, and 94% had received ≥4 prior lines of therapy. Seventeen patients (50%) had received an anti-PD-1-based regimen as their most recent therapy. At database cutoff (March 2, 2023), 8 patients (24%) had completed 35 cycles of treatment and 26 (76%) had discontinued treatment (14 [41%] progressive disease, 7 [21%] AEs, 5 [15%] other reasons). The median time from first dose to data cutoff was 35.3 mo (range, 15.0-49.4). Treatment-related AEs occurred in 28 patients (82%), of which the most common (≥15%) were hypothyroidism (18%), nausea (18%), and fatigue (15%). Grade 3/4 treatment-related AEs occurred in 6 patients (18%). 6 patients (18%) discontinued treatment because of treatment-related AEs. No deaths due to treatment-related AEs were reported. AEs of clinical interest occurred in 17 patients (50%); 2 patients (6%) had grade 3 events (encephalitis, hepatitis) and 1 patient (3%) had a grade 4 event (type 1 diabetes mellitus). Of the 2 patients who underwent allogeneic hematopoietic stem cell transplantation after discontinuation or completion of study treatment, 1 had a grade 3 AE (acute graft versus host disease) unrelated to study treatment that resolved. The ORR in cohort 2 was 29% (10/34; 95% CI, 15-48), with 3 (9%) complete responses (CR) and 7 (21%) partial responses (PR). Of the 10 responders, 7 had received ≥5 prior lines of therapy (3 CR/4 PR). The ORR in patients with anti-PD-1 as their most recent therapy was 35% (6/17; 95% CI, 14-62; 1 CR/5 PR); the ORR in patients with non-anti-PD-1 as their most recent therapy was 24% (4/17; 95% CI, 7-50; 2 CR/2 PR). Of 28 patients with a baseline and postbaseline assessment available, 25 (89%) had any reduction in target lesion size from baseline, and 12 (43%) had ≥50% reduction. Median DOR was 21.9 mo (range, 0.0+ to 26.1+) and an estimated 17% of responders remained in response ≥24 mo. Median PFS was 9.7 mo (95% CI, 5.1-14.7); 24-mo PFS rate was 21%. Median OS was 34.3 mo (95% CI, 25.7-NR); 24-mo OS rate was 76%. Conclusion: After additional follow-up, the combination of favezelimab + pembrolizumab continued to demonstrate manageable safety and antitumor activity in patients with heavily pretreated anti-PD-1-refractory cHL. Analyses are underway to identify biomarkers predictive of response to the combination of favezelimab and pembrolizumab. The phase 3 KEYFORM-008 study (NCT05508867) is being conducted to evaluate a coformulation of favezelimab and pembrolizumab in patients with anti-PD-1-refractory cHL.

Bellwave-010: Phase 3, Open-Label, Randomized Study of Nemtabrutinib Plus Venetoclax Versus Venetoclax Plus Rituximab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Following at Least One Prior Therapy

Background: Venetoclax + rituximab (VR) is a standard therapy among patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who have relapsed after at least 1 line of prior therapy. However, there is an unmet need for more effective treatments. Bruton's tyrosine kinase (BTK) is a critical signaling molecule in the pathogenesis of CLL, and inhibitors of BTK have resulted in significant improvements in survival for patients with CLL. Nemtabrutinib is a noncovalent, reversible, competitive inhibitor of BTK that does not require the C481 residue of BTK for binding and inhibition of kinase activity. As a result, nemtabrutinib can target both wild-type and C481-mutant forms of BTK. Results from the ongoing BELLWAVE-001 study have demonstrated manageable safety and durable antitumor activity of nemtabrutinib in patients with CLL/SLL with and without C481 mutations. The randomized, active-controlled, open-label, phase 3 BELLWAVE-010 study (NCT05947851) is designed to investigate the efficacy and safety of nemtabrutinib + venetoclax versus VR as second-line (2L) or later treatment for patients with relapsed/refractory (R/R) CLL/SLL. Study Design and Methods: Patients aged ≥18 years with active CLL/SLL that is relapsed/refractory to at least 1 prior therapy per the iwCLL 2018 criteria, an ECOG performance status of 0-2, and adequate organ function are eligible. Patients with Richter transformation, active central nervous system involvement, or severe bleeding disorder are excluded. Approximately 720 patients will be enrolled in 2 parts: an open-label, nonrandomized dose escalation and confirmation phase (part 1) to evaluate safety and determine the optimal dose of nemtabrutinib in combination with venetoclax and an open-label, parallel-group, randomized phase (part 2) comparing the efficacy and safety of nemtabrutinib + venetoclax with VR. In part 1, 30 patients will be enrolled to establish the dose of nemtabrutinib using a modified toxicity probability interval design. Patients will receive nemtabrutinib at 2 dose levels (45 mg PO QD starting dose, escalating to 65 mg PO QD) for 28 days followed by the combination of nemtabrutinib + venetoclax (20-400 mg PO QD ramp up over 4 weeks). In part 2, approximately 690 patients will be randomly assigned 1:1 to receive either nemtabrutinib at the recommended dose for 28 days followed by the combination of nemtabrutinib + venetoclax (20-400 mg PO QD ramp up over 4 weeks) or venetoclax (20-400 mg PO QD ramp up over 4 weeks) + rituximab (or rituximab biosimilar; 375 mg/m 2 at week 6 followed by 500 mg/m 2 Q4W starting at week 10 until week 26 [total 6 doses]). Patients will receive study treatment for ~2 years or until unacceptable toxicity, disease progression, or other discontinuation criteria are met. Randomization will be stratified by BTK-C481 mutation status (detected vs not detected; determined by droplet digital PCR with a limit of detection of approximately 0.01%-0.1%), geographic region (US/Canada vs Europe vs rest of world) and risk (high risk [del(17p) and/or TP53-mutated and/or IGHV-unmutated] vs low risk [absence of high-risk factors]). Response will be assessed (including imaging, physical examination, constitutional symptoms, hematological evaluations, and bone marrow biopsy as required) every 12 weeks up to week 97 and every 24 weeks thereafter or more frequently if clinically indicated. Adverse events will be monitored up to 30 days after treatment cessation (90 days for serious adverse events) and will be graded per NCI CTCAE, version 5.0. Hematologic toxicities will be evaluated according to iwCLL 2018 criteria. Patient-reported outcomes will be assessed using the EORTC QLQ-C30, EORTC QLQ-CLL17, and EQ-5D-5L questionnaires. The primary end points for part 1 are safety and tolerability, including dose-limiting toxicities, and to establish the recommended dose of nemtabrutinib in combination with venetoclax. The primary end point for part 2 is PFS as assessed per iwCLL 2018 criteria by blinded independent central review (BICR). Secondary end points for part 2 include undetectable minimal residual disease in bone marrow at month 14 as assessed by central laboratory, ORR, and DOR per iwCLL 2018 criteria by BICR, OS, and safety. Exploratory end points include ORR including partial response with lymphocytosis, pharmacokinetics, and health-related quality of life.

A Phase I/II Study to Investigate the Addition of Venetoclax to Dasatinib and Steroids in Patients with Newly Diagnosed or Relapsed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL): The Venda Trial, in Progress

Background: Acute Lymphoblastic Leukemia (ALL) is a hematologic malignancy of immature lymphocytes of either B cell or T cell origin. One particularly high -risk subset is Ph+ ALL, characterized by a translocation of chromosome 9 and 22, which generates the constitutively active BCR-ABL1 fusion tyrosine kinase capable of driving proliferation and survival of leukemic cells. Currently treatment options include multi-agent chemotherapy along with an ABL-specific tyrosine kinase inhibitor (TKI), though these regimens can lead to significant toxicity, particularly in older adults. Venetoclax is a potent and selective small molecule inhibitor of the B-cell lymphoma 2 (BCL-2) anti-apoptotic protein. Strong mechanistic and preclinical data have demonstrated strong synergistic activity between dasatinib and venetoclax I xenograft models and ex vivo patient samples, and provide an impetus to further explore the combination of BCR-ABL and BCL-2 inhibition in vivo. Based on these data, we designed a clinical trial to investigate the safety and preliminary efficacy of venetoclax in combination with the second generation TKI dasatinib in Ph+ ALL. Study Design and Methods This is an open label, Phase I/II investigator initiated trial evaluating the addition of venetoclax to dasatinib and steroids (with Rituximab in CD20+ patients). Phase I is the safety and dose-finding portion of the trial combining the BCL2 inhibitor venetoclax with dasatinib and steroids during the first 28 days of induction followed by dasatinib and venetoclax for the final 48 days of induction in newly diagnosed and relapsed Ph+ ALL and mixed phenotype acute leukemia (MPAL) patients, including patients with molecular only relapse. Primary inclusion criteria include a histologically confirmed diagnosis of Ph+ ALL or MPAL. Newly diagnosed Ph+ ALL or MPAL patients may not have received leukemia-directed therapy other than for steroids or hydrea, and relapsed patients must have not had prior dasatinib exposure. Key exclusion criteria include subjects with CML in myeloid blast crisis or Ph+ AML, ECOG < 2 and patients with a history of pleural effusions. n order to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), a Bayesian toxicity probability interval design applied to a pre-specified targeted dose limiting toxicity rate of 30%. Three dose cohorts investigating increasing doses of venetoclax will be enrolled. Once the RP2D dose has been identified, a Phase II expansion will examine preliminary efficacy of the combination. The primary endpoint is the rate of measureable residual disease (MRD) negative remission rate as assessed by both BCR-ABL RT-PCR and next generation sequencing (NGS) after induction. Secondary endpoints include relapse-free survival (RFS) and overall survival (OS). Correlative studies include BH3 profiling (measure of apoptosis) and ex vivo screening to dasatinib and venetoclax alone and in combination. Consolidation phase with blinatumomab plus dasatinib and venetoclax is planned for the cohort expansion group. Enrollment began in September 2022 and is expected to be complete by September 2025. This trial is registered at clinicaltrials.gov (NCT04872790).

Results of a Phase 1 Trial Testing the Novel Combination Therapy of Venetoclax and Ruxolitinib in Relapsed/Refractory Acute Myeloid Leukemia Patients

Introduction : A functional small molecule screen on a large cohort of primary AML patient samples revealed that the combination of Ruxolitinib (Rux) and Venetoclax (Ven) exhibited ex vivo efficacy and synergy in both newly diagnosed and R/R AML. This observation motivated a Phase I multi-center trial to evaluate Rux+Ven in R/R AML, for which we now report complete toxicity and efficacy data for 30 subjects. Methods: This study was designed to identify a maximum tolerated or recommended Phase II dose (RP2D) and evaluate the overall safety and preliminary efficacy of Rux+Ven therapy. Eligible subjects were ≥18 years old with R/R AML. There was no restriction on the number of previous therapies or prior exposure to Ven or Rux. We included subjects with prior allogeneic transplant if GVHD was controlled and prior MDS (≥75 years old or having poor cardiac or kidney function) who progressed on a hypomethylating agent (HMA) but had no primary AML therapy. In cohorts of 3 to 4, subjects were assigned to receive Rux+Ven at 1 of 6 dose levels according to the “keyboard” Bayesian toxicity probability interval design applied to a target dose-limiting toxicity (DLT) rate of 30%. DLTs were defined as non-disease-related, Grade ≥3 non-hematologic toxicities, with exceptions for nausea, vomiting, infections, febrile neutropenia episodes, and electrolyte abnormalities that resolved within 48 hours. Hematologic DLT was specified as Grade 4 neutropenia after 42 days in the absence of disease. The DLT evaluation period covered the first cycle. Subjects could continue study therapy after two 28-day cycles if they had a response (ie, CR/CRi or MLFS) or were otherwise deriving clinical benefit. Results : This Phase 1 study has completed enrollment (n=30), with all but one patient off-treatment as of June 2023. Baseline patient characteristics are summarized in Table 1. Median age was 69 (range 29-84), 40% of subjects had ≥3 prior therapies, and 43% had prior Ven. At enrollment, 30% had prior MDS, 24% had mutated TP53 (of 25 patients with available data), and 47% had CD56+ blasts. The numbers of patients treated by dose level (DL) were: 3 on DL0 (200 mg qd Ven; 10 mg bid Rux), 4 on DL1 (400 mg qd Ven; 10 mg bid Rux), 3 on DL2 (400 mg qd Ven; 20 mg bid Rux), and 20 on DL3 (400 mg qd Ven; 30 mg bid Rux), the highest dose level of the study. Per prescribing guidelines, the cycle 1 Rux doses of 15 subjects and Ven doses of 20 subjects were reduced because of a concomitant CYP3A inhibitor. The regimen was well-tolerated. As no DLTs were observed, DL3 is the RP2D. The median (interquartile range) duration of therapy was 55 (36-93) days. The most common grade ≥3 hematologic AEs, regardless of attribution, were thrombocytopenia (50%; which was 30% at study enrollment), anemia (40%; 40% at enrollment), neutropenia (37%; 10% at enrollment), febrile neutropenia (33%), and leukopenia (33%; 7% at enrollment). Six subjects had a Grade 5 AE: 4 were unrelated to study drug (2 death NOS, 1 lung infection, 1 respiratory failure) and 2 were potentially related to Ven (1 sepsis, 1 neutropenic pneumonia). Over the first 2 cycles of study therapy, the Clinical Benefit Rate (CBR; defined as the proportion of subjects obtaining at least stable disease) was 63% (95% CI: 44%-80%). Morphologic leukemia-free state (MLFS) was achieved in 20% (95% CI: 8%-39%) and Composite Complete Remission in 10% (95% CI: 2%-27%). Median overall survival (OS) was 3.7 months (95% CI: 2.3-6.5), with 23% (95% CI: 10%-39%) alive 1 year after commencing Rux+Ven. Two participants were exceptional responders: the first achieving MLFS and receiving 16 cycles of study therapy and the second having a complete remission and remaining on-treatment after 31 cycles. Pre-Rux+Ven CD56 expression on blasts correlated with worse response (all 6 ≥MLFS patients were CD56-; Fig 1) and overall survival (HR=2.37, p=0.044; Table 1). Correlative studies such as ex vivo drug assessment, genomic analysis, CyTOF, and single-cell imaging will be presented to enhance this finding. Conclusion: The novel, all-oral combination of Rux+Ven in R/R AML patients was well-tolerated with no DLTs and an encouraging 63% CBR over cycles 1-2. Negative CD56 was a biomarker of response, although additional work is required to determine if this is a broad association with Ven-based therapies or unique to the Rux+Ven combination. The tolerable toxicity profile of Rux+Ven makes it a promising combination to test with HMAs in high-risk AML patients.

LITESPARK-024: A randomized phase 1/2 study of belzutifan with or without palbociclib for previously treated advanced renal cell carcinoma

Abstract Background Immunotherapy is a standard-of-care first-line treatment for advanced clear cell renal cell carcinoma (ccRCC). However, many patients will develop resistance to first-line therapy, and effective second- and later-line treatment options are therefore needed. The von Hippel-Lindau (VHL) gene is inactivated in approximately 90% of patients with RCC and results in the constitutive activation of hypoxia-inducible factor 2α (HIF-2α), a key oncogenic driver in RCC. Belzutifan, a first-in-class HIF-2α inhibitor, has demonstrated antitumor activity with manageable safety in previously treated patients with advanced ccRCC. The cyclin-dependent kinase (CDK) pathway is also associated with poor clinical outcomes in ccRCC. In RCC cell lines, the CDK 4/6 inhibitor palbociclib inhibited cell growth. CDK 4/6 inhibition has shown synergistic antiproliferative effects with HIF-2α inhibition in HIF-2α–dependent VHL -/- RCC cell lines. Palbociclib could therefore potentially enhance the efficacy of belzutifan as combination therapy for previously treated pts with advanced RCC. Methods LITESPARK-024 is a 2-part, open-label, multicenter, phase 1/2 randomized study (NCT05468697). Part 1 is intended to establish the recommended phase 2 dose (RP2D) of belzutifan plus palbociclib using a modified toxicity probability interval design. After the RP2D is established, part 2 will directly compare the safety and efficacy of belzutifan monotherapy with belzutifan + palbociclib in patients with advanced ccRCC. In both parts, patients with measurable disease per RECIST v1.1, a Karnofsky Performance Status score of ≥70%, and histologically confirmed unresectable stage IV RCC with a clear cell component and disease progressing on or after receiving at least 2 systemic treatments (both an anti–PD-1/L1 monoclonal antibody and a VEGF receptor–targeted tyrosine kinase inhibitor, in sequence or in combination) will be enrolled. Up to 30 patients will be enrolled into 3 dose groups in part 1 and will receive belzutifan 120 mg once daily plus palbociclib (75, 100, or 125 mg) daily for 21 consecutive days followed by 7 days off. In part 2, approximately 150 patients will be randomly assigned 2:1 to receive belzutifan 120 mg once daily plus palbociclib RP2D (21 consecutive days/7 days off) or belzutifan 120 mg once daily. Patients will be stratified by International metastatic RCC Database Consortium risk (0 vs 1-2 vs 3-6) and sarcomatoid histology (yes vs no) at randomization in part 2. The primary end point for part 1 is to assess dose-limiting toxicities and adverse events and to determine the RP2D of belzutifan plus palbociclib. The primary end point for part 2 is objective response rate per RECIST v1.1 by investigator assessment. Secondary end points for part 2 are clinical benefit rate, duration of response, and progression-free survival per RECIST v1.1 by investigator assessment; overall survival, and safety and tolerability. Enrollment began in July 2022. ©2023 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO Genitourinary Cancers Symposium. All rights reserved. CDMRP DOD Funding: no

Initial results from a first-in-human, phase I study of immunomodulatory aryl hydrocarbon receptor (AhR) inhibitor BAY2416964 in patients with advanced solid tumors.

2502 Background: AhR activation is involved in tumor growth, immunomodulation, and resistance to immune checkpoint inhibitors. BAY2416964 is a novel, potent, oral AhR inhibitor (AhRi) that antagonizes AhR ligand-induced immunosuppressive effects, resulting in enhanced proinflammatory activity of antigen-presenting cells and T cells and reduced activity of immunosuppressive myeloid cells. Methods: A first-in-human, Phase I clinical trial of AhRi BAY2416964 (NCT04069026) is evaluating its safety, pharmacokinetics, pharmacodynamics, recommended Phase II dose, and anti-tumor activity per RECIST v1.1 and iRECIST. BAY2416964 was administered orally in patients with advanced solid tumors in a dose-escalation cohort using a modified toxicity probability interval (mTPI) design. The initial expansion cohorts enrolled patients with non-small-cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC). Results: As of November 4, 2022, 72 patients had been treated with BAY2416964: 39 patients in dose escalation and 33 patients in the initial dose expansion treated with 500 mg twice daily (25 NSCLC, 8 HNSCC). The most common tumor types enrolled in dose escalation were colorectal cancer ( n= 12), breast cancer ( n= 6), and pancreatic cancer ( n= 4). Median age was 61 years (range 35-80). 51/72 (70.8%) patients had received ≥3 lines of therapy (including 16 [22.2%] who had received ≥6 lines) and 47/72 (65.3%) had received immune checkpoint inhibitors. Drug-related treatment-emergent adverse events (TEAEs) of all grades reported in ≥10% of patients were nausea (13.9%; 1.4% grade 3) and fatigue (11.1%; 1.4% grade 3). Most drug-related TEAEs were grade 1 or 2; 9 (12.5%) patients experienced drug-related grade 3 TEAEs and no patients experienced drug-related grade ≥4 TEAEs. No dose-limiting toxicities were observed. Two patients in dose expansion discontinued treatment due to drug-related TEAEs. Plasma exposure to BAY2416964 increased according to dose and food intake. Analysis of biomarkers demonstrated evidence of target engagement and an increase in immune activation at the doses tested. Of 67 patients evaluable for response by RECIST, 22 (32.8%) had stable disease per RECIST v1.1, including 1 with thymoma in dose escalation achieving an iRECIST partial response. Conclusions: BAY2416964 was well tolerated across all dose levels and regimens tested. Initial evaluation of biomarkers shows BAY2416964 inhibits AhR and modulates immune functions. Encouraging preliminary anti-tumor activity was observed in heavily pretreated patients. The disease-specific dose-expansion part of this study is ongoing. The observed manageable safety profile also supports combination therapies. Clinical trial information: NCT04069026 .

LITESPARK-024: Randomized phase 1/2 study of belzutifan with or without palbociclib for treatment of advanced renal cell carcinoma (RCC).

TPS4603 Background: Immunotherapy is a standard-of-care first-line treatment for advanced clear cell RCC (ccRCC). However, many patients (pts) will develop resistance to first-line therapy, and effective second- and later-line treatment options are therefore needed. The von Hippel-Lindau ( VHL) gene is inactivated in approximately 90% of ccRCC cases and results in the constitutive activation of hypoxia-inducible factor 2α (HIF-2α), a key oncogenic driver in RCC. Belzutifan, a first-in-class HIF-2α inhibitor, has demonstrated antitumor activity with manageable safety in previously treated pts with advanced ccRCC. The cyclin-dependent kinase (CDK) pathway is also associated with poor clinical outcomes in ccRCC. In RCC cell lines, the CDK 4/6 inhibitor palbociclib inhibited cell growth. CDK 4/6 inhibition has shown synergistic antiproliferative effects with HIF-2α inhibition in HIF-2α–dependent VHL -/- RCC cell lines. Palbociclib could therefore potentially enhance the efficacy of belzutifan as combination therapy for previously treated pts with advanced RCC. Methods: LITESPARK-024 is a 2-part, open-label, multicenter, phase 1/2 randomized study (NCT05468697). Part 1 is intended to establish the recommended phase 2 dose (RP2D) of belzutifan + palbociclib using a modified toxicity probability interval design. After the RP2D is established, part 2 will directly compare the safety and efficacy of belzutifan monotherapy with belzutifan + palbociclib in pts with advanced ccRCC. In both parts, pts with measurable disease per RECIST v1.1, a KPS score of ≥70%, and histologically confirmed unresectable stage IV RCC with a clear cell component with disease progressing on or after receiving at least 2 systemic treatments (both an anti–PD-1/L1 monoclonal antibody and a VEGF receptor–targeted tyrosine kinase inhibitor, in sequence or in combination) will be enrolled. Up to 30 pts will be enrolled into 3 dose groups in part 1 and will receive belzutifan 120 mg once daily + palbociclib (75, 100, or 125 mg) daily for 21 consecutive days followed by 7 days off. In part 2, approximately 150 pts will be randomly assigned 2:1 to receive belzutifan 120 mg once daily + palbociclib RP2D (21 consecutive days/7 days off) or belzutifan 120 mg once daily. Pts will be stratified by IMDC risk (0 vs 1-2 vs 3-6) and sarcomatoid histology (yes vs no) at randomization in part 2. The primary end point for part 1 is to assess dose-limiting toxicities and adverse events and to determine the RP2D of belzutifan + palbociclib. The primary end point for part 2 is ORR per RECIST v1.1 by investigator assessment. Secondary end points for part 2 are CBR, DOR, and PFS per RECIST v1.1 by investigator assessment, OS, and safety and tolerability. Enrollment began in July 2022. Clinical trial information: NCT05468697 .

WaveLINE-007: Phase 2 study of zilovertamab vedotin (ZV) in combination with cyclophosphamide, doxorubicin, and prednisone plus rituximab (R-CHP) in previously untreated diffuse large B-cell lymphoma (DLBCL).

TPS7589 Background: The preferred first-line regimen for DLBCL is rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); but novel therapies are needed. A recent phase 3 study showed that replacing vincristine with an antibody-drug conjugate (ADC) is a viable approach (Tilly H et al. N Engl J Med. 2022;386:351-363). Receptor tyrosine kinase–like orphan receptor 1 (ROR1) is an oncofetal protein that is minimally expressed in adult tissues and overexpressed in DLBCL. ZV is an ADC comprising a humanized IgG1 monoclonal anti-ROR1, a proteolytically cleavable linker, and the antimicrotubule agent, monomethyl auristatin E. The single-arm, open-label, phase 2 waveLINE-007 study (NCT05406401) will investigate ZV combined with R-CHP in patients with previously untreated DLBCL. Part 1 is being conducted to determine safety and tolerability and recommended phase 2 dose (RP2D) of ZV in combination with R-CHP. Part 2 will be conducted to investigate efficacy of ZV at the RP2D with R-CHP. Methods: Eligible patients will be ≥18 years of age and have previously untreated histologically confirmed DLBCL, positron emission tomography (PET)–positive disease verified by blinded independent central review (BICR), an ECOG PS of 0 or 1, and adequate organ function. Patients diagnosed with primary mediastinal B-cell lymphoma, with a history of transformation of indolent disease to DLBCL, or active central nervous system lymphoma will be excluded. Approximately 60 patients will be enrolled (part 1, n = 45; part 2, n = 15). Part 1 will use a modified toxicity probability interval design to establish the RP2D of ZV when administered with R-CHP. The starting dose of ZV will be 1.75 mg/kg (modified to 1.5, 2.0, 2.25, or 2.5 mg/kg) administered as an intravenous infusion every 3 weeks (Q3W) in combination with R-CHP. In part 2, an additional 15 patients will receive ZV at RP2D plus R-CHP Q3W for up to 6 cycles until disease progression per Lugano 2014 criteria, unacceptable toxicity, or withdrawal. Disease response assessment, computed tomography, and PET will occur at baseline and cycles 3 and 6. Adverse events (AEs) will be monitored up to 30 days after cessation of treatment (90 days for serious AEs, or 30 days if new anticancer therapy is initiated). AEs will be graded per National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Primary end points are safety and tolerability and RP2D for ZV in combination with R-CHP, and complete response rate per Lugano 2014 criteria as assessed by the investigator. Secondary end points are objective response rate and duration of response per Lugano 2014 criteria by investigator review. Exploratory end points include progression-free survival per Lugano 2014 criteria by BICR and overall survival. Recruitment is currently underway. Clinical trial information: NCT05406401 .

Preliminary data of a phase 1b/2 study of BCL-2 inhibitor lisaftoclax (APG-2575) alone or combined with ibrutinib or rituximab in patients (pts) with Waldenström macroglobulinemia (WM).

7569 Background: B-cell lymphoma 2 inhibitors (BCL-2i) are well tolerated and effective in treating B-cell lymphoproliferative disorders such as CLL. Investigational agent lisaftoclax is a novel, oral, highly selective and potent BCL-2i. Preclinical data show a strong synergistic effect of lisaftoclax plus ibrutinib in an ibrutinib-insensitive PDXWM1 model. Methods: This global, open-label, multicenter study evaluates the safety and efficacy of lisaftoclax alone and combined with ibrutinib or rituximab in pts with WM. Pts were enrolled in 3 arms: Arm A (lisaftoclax), BTKi-resistant/intolerant pts; Arm B (lisaftoclax plus ibrutinib), treatment-naïve pts; and Arm C (lisaftoclax plus rituximab), BTKi-naïve relapsed/refractory pts. Lisaftoclax was escalated from 400 to 1,200 mg using a modified toxicity probability interval design. A 3-day ramp-up was used for pts at high TLS risk. Primary objectives were pharmacokinetics (PK), safety, and efficacy assessments; responses were assessed per IWWM criteria. Results: As of January 25, 2023, 46 pts were enrolled (Arm A [n = 14]; up to 1,000 mg; Arm B [n = 24]; up to 1,200 mg; Arm C [n = 8]; up to 800 mg). Baseline characteristics are shown in the table. Median (range) treatment duration was 6 (1-18; Arm A), 14 (1-27; B), and 8 (2-26; C) months. Overall response rates (ORRs) were: Arm A, 25% (median time to response [MTTR], 4.3 months); Arm B, 90.9% (MTTR, 1.9); Arm C, 37.5% (MTTR, 4.4). No significant difference was observed between pts with and without CXCR4-mut. At 1,200 mg, 1 DLT (grade 3 clinical TLS), due to pre-existing renal impairment, was reported. At 1,000 mg, 1 grade 3 laboratory TLS occurred in Arm B because of dehydration and active symptomatic therapies; abnormal electrolytes resolved after 1 day of drug interruption, without recurrence. Grade ≥ 3 lisaftoclax-related AEs included neutropenia (13%), leukocytopenia (4.3%), anemia (2.2%), weight loss (2.2%), and septic shock (2.2%). Ventricular arrhythmias were not observed. Only 1 pt required dose reduction (due to neutropenia). MTD has not been reached. A total of 14 pts discontinued study treatment because of disease progression (n = 5) and AE (n = 1). Lisaftoclax plus ibrutinib showed a PK exposure comparable to ibrutinib alone, indicating no potential DDI. Conclusions: Lisaftoclax alone or combined with ibrutinib/rituximab demonstrated measurable effects in pts with naïve or BTKi-treatment-failed WM. Internal study identifier: APG2575WU101. *SA and ML are co-first authors. Clinical trial information: NCT04260217 . [Table: see text]

Abstract CT031: A first-in-human, phase 1a/1b, open-label, dose-escalation and expansion study to investigate the safety, pharmacokinetics, and antitumor activity of the RAF dimer inhibitor BGB-3245 in patients with advanced or refractory tumors

Abstract Background: BGB-3245 is a RAF dimer inhibitor with preclinical activity in MAPK-altered tumor models harboring BRAF V600 mutations, atypical BRAF mutations/fusions, and RAS mutations. This study is investigating the safety, pharmacokinetics, and preliminary antitumor activity of BGB-3245 in patients (pts) with advanced or refractory MAPK-altered solid tumors. Methods: Eligible pts were ≥18 yrs old with ECOG 0-1 and had solid tumors harboring MAPK pathway alterations. Dose-escalation and cohort-size decisions were made using the Modified Toxicity Probability Interval Design. The starting dose was 5 mg QD. Treatment emergent adverse events (TEAEs) were graded per NCI CTCAE v5.0. Tumor responses were assessed by investigators using RECIST v1.1. Results: As of 1 Sep 2022, 42 pts were treated across 6 cohorts (5-60 mg QD). The median age was 60 yrs; pts had received a median of 3 prior lines of treatment. All pts had TEAEs; 79% had treatment-related (TR) AEs. The most common TRAEs (≥ 10%) were rash acneiform (33%), rash maculopapular (24%), fever (17%), ALT elevations and nausea (both 12%). Gr ≥3 TRAEs were reported in 29% of pts, events in ≥ 2 pts included decreased platelet count and rash maculopapular (3 each), ALT and AST elevations, and fever (2 each). Dose reductions occurred in 5 pts: rhabdomyolysis (1), LVEF decreased (1), hand-foot syndrome (1), rash maculopapular (1), and liver function abnormalities (1). Dose interruptions due to AEs occurred in 60% of pts. Dose discontinuations occurred in 79% of pts, 57% due to disease progression or death, 21% due to AE. Dose limiting toxicities were observed at 10 mg, 40 mg, and 60 mg. 40 mg QD was determined as the MTD. PK results showed generally dose-proportional increases in exposure. Tmax was at ~2 h; BGB-3245 had a long terminal half-life and 7.4-fold average accumulation in exposure at steady-state. 79% of pts were efficacy evaluable. The disease control rate was 48% with 1 CR, 5 cPR, 2 uPR and 8 SD≥24 wks. Objective responders included BRAF V600E melanoma pts post-BRAF/MEK and checkpoint inhibitors (2; 1 CR, 1 cPR), 1 NRAS G12S melanoma and 1 NRAS Q61K melanoma (post checkpoint inhibitors), 1 BRAF V600E LGSOC (progressed on BRAF inhibitor), 1 BRAF V600E cholangiocarcinoma (progressed on BRAF/MEK inhibitors), 1 BRAF K601E/PIK3CA endometrial cancer, and 1 KRAS G12D appendiceal cancer. Preliminary analysis of circulating tumor DNA showed correspondence to clinical response. Conclusions: BGB-3245 has a manageable safety profile and a generally dose-proportional PK. Antitumor activity was observed in pts with no approved targeted therapy options. The safety and early efficacy profile of BGB-3245 supports further investigation in selected MAPK-altered tumors. Citation Format: Alison M. Schram, Vivek Subbiah, Ryan Sullivan, Rasha Cosman, Jia Liu, Eric I. Sbar, Thuy Hoang, Jiarong Chen, Mark Johnson, Vincent Amoruccio, Todd Shearer, Adeela Kamal, Jocelyn Lewis, Wenlin Shao, Badreddin Edris, Lusong Luo, Jayesh Desai. A first-in-human, phase 1a/1b, open-label, dose-escalation and expansion study to investigate the safety, pharmacokinetics, and antitumor activity of the RAF dimer inhibitor BGB-3245 in patients with advanced or refractory tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT031.

Abstract CT120: The randomized phase 1/2 LITESPARK-024 study of belzutifan with or without palbociclib in patients with advanced renal cell carcinoma (RCC)

Abstract Background: First-line treatment with immunotherapy alone or in combination with antiangiogenic agents is a standard of care for advanced RCC. Many patients (pts) develop resistance to first-line treatment and effective second-line and beyond options are needed. The von Hippel-Lindau (VHL) gene is inactivated in approximately 90% of RCC cases, which results in the constitutive activation of hypoxia-inducible factor 2α (HIF-2α), a key oncogenic driver in RCC. The first-in-class HIF-2α inhibitor belzutifan has demonstrated promising antitumor activity with manageable safety in previously treated pts with advanced RCC. The cyclin-dependent kinase (CDK) pathway has also been implicated in RCC and is associated with poor clinical outcomes. In RCC cell lines, the CDK 4/6 inhibitor palbociclib inhibited cell growth. The addition of CDK 4/6 inhibition had synergistic antiproliferative effects with HIF-2α inhibition in HIF-2α-dependent VHL -/- RCC cell lines. Palbociclib could therefore potentially enhance the efficacy of belzutifan as combination therapy for previously treated pts with advanced RCC. Methods: The two-part, open-label, multicenter, phase 1/2 randomized LITESPARK-024 study (NCT05468697) is intended to establish the recommended phase 2 dose (RP2D) of belzutifan + palbociclib in combination with a modified toxicity probability interval design (Part 1), followed by a direct comparison of belzutifan monotherapy to the combination with respect to safety and efficacy in pts with advanced RCC (Part 2). Pts with histologically confirmed unresectable stage IV RCC with a clear cell component, whose disease progressed on or after having received at least 2 systemic treatments (both an anti-PD-1/PD-L1 monoclonal antibody and a VEGF receptor-targeted tyrosine kinase inhibitor, in sequence or in combination), have measurable disease per RECIST v1.1 by blinded independent central review, and have KPS score of ≥70% will be enrolled. Up to 30 pts will be enrolled into 3 dose groups in Part 1 and will receive belzutifan 120 mg once daily + palbociclib (75, 100, or 125 mg) daily for 21 consecutive days followed by 7 days off. In part 2, approximately 150 pts will be randomly assigned 2:1 to receive belzutifan 120 mg once daily + palbociclib RP2D (21 consecutive days/7 days off) or belzutifan 120 mg once daily. Pts will be stratified by IMDC risk (0 vs 1-2 vs 3-6) and sarcomatoid histology (yes vs no) at randomization in part 2. The primary end point for part 1 is to assess dose-limiting toxicities and adverse events to determine the RP2D of belzutifan + palbociclib. The primary end point for part 2 is ORR per RECIST v1.1 by investigator assessment. Secondary end points for part 2 are CBR, DOR, PFS, OS, and safety and tolerability. This abstract was accepted and previously presented at the 2023 ASCO Genitourinary Cancers Symposium. All rights reserved. Citation Format: David F. McDermott, Avivit Peer, Neeraj Agarwal, Michael B. Atkins, Jerry Cornell, Rodolfo F. Perini, Kenneth F. Grossmann, Howard Gurney. The randomized phase 1/2 LITESPARK-024 study of belzutifan with or without palbociclib in patients with advanced renal cell carcinoma (RCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT120.

LITESPARK-024: A randomized phase 1/2 study of belzutifan with or without palbociclib in patients with advanced renal cell carcinoma.

TPS747 Background: The combination of immunotherapy with antiangiogenic agents is a well-established first-line treatment option for patients (pts) with advanced renal cell carcinoma (RCC), but many pts develop resistance, and effective second- or subsequent-line options are needed. The von Hippel-Lindau ( VHL) gene is inactivated in approximately 90% of RCC cases, which results in the constitutive activation of hypoxia-inducible factor 2α (HIF-2α) signaling. HIF-2α is involved in angiogenesis, tumor growth, proliferation, and metastasis, and is a key oncogenic driver in RCC. The HIF-2α inhibitor belzutifan has demonstrated promising antitumor activity with manageable safety in pts with heavily pretreated RCC. The cyclin-dependent kinase (CDK) pathway is altered in several cancer types, including RCC, and is associated with poor clinical outcomes. The CDK 4/6 inhibitor palbociclib inhibited cell growth in RCC cell lines, and the antiproliferative effects of CDK 4/6 inhibition were synergistic with HIF-2α inhibition in HIF-2α–dependent VHL -/- clear cell RCC cell lines. We hypothesized palbociclib could potentially enhance the efficacy of belzutifan as combination therapy for previously treated pts with advanced RCC. Methods: LITESPARK-024 (NCT05468697) is an open-label, multicenter, phase 1/2 randomized study of belzutifan + palbociclib versus belzutifan monotherapy in pts with advanced RCC. Pts must have histologically confirmed unresectable stage IV RCC with a clear cell component, received at least 2 prior systemic regimens (both an anti–PD-1/PD-L1 monoclonal antibody and a VEGF receptor–targeted TKI, in sequence or in combination), have measurable disease per RECIST v1.1 by BICR, have KPS score of ≥70%, and have radiographic disease progression on or after the most recent regimen per investigator. Part 1 will evaluate the safety of belzutifan + palbociclib and determine the recommended phase 2 dose (RP2D) for the combination using a modified toxicity probability interval design. Part 2 will evaluate the safety and efficacy of belzutifan + palbociclib versus belzutifan alone. In part 1, ≤30 pts will be enrolled into 3 dose groups and receive belzutifan 120 mg once daily + palbociclib (75, 100, or 125 mg) daily for 21 consecutive days followed by 7 days off. In part 2, approximately 150 pts will be randomly assigned 2:1 to receive belzutifan 120 mg once daily + palbociclib RP2D (21 consecutive days/7 days off) or belzutifan 120 mg once daily. Pts will be stratified by IMDC risk (0 vs 1-2 vs 3-6) and sarcomatoid histology (yes vs no) at randomization in part 2. The primary end point for part 1 is to assess dose-limiting toxicities and adverse events to determine the RP2D of belzutifan + palbociclib. The primary end point for part 2 is ORR per RECIST v1.1 by investigator assessment. Secondary end points for part 2 are clinical benefit rate, DOR, PFS, OS, and safety and tolerability. Clinical trial information: NCT05468697 .

Phase 1b Trial of Cereblon-Modulating Agents Iberdomide and CC-99282 Plus R-CHOP in Previously Untreated Aggressive B-Cell Lymphoma

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive B-cell lymphoma (a-BCL). The standard of care for patients (pts) with DLBCL is chemo-immunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); however, up to 45%-50% of pts relapse after first-line (1L) R-CHOP. While pts who relapse have poor outcomes and limited treatment options, there is an opportunity to improve 1L response rates by building on the R-CHOP backbone. Lenalidomide (LEN) modulates cereblon E3 ligase, leading to antitumor effects and degradation of target proteins. The randomized, phase (ph) 3, ROBUST study evaluating LEN plus R-CHOP (R2-CHOP) in pts with activated B-cell like (ABC) DLBCL failed to demonstrate significant outcome improvements over R-CHOP alone (Nowakowski et al. J Clin Oncol 2021;39:1317-1328). A subsequent randomized ph 2 study showed significantly improved progression-free survival with R2-CHOP in all pts with untreated DLBCL, regardless of cell of origin (COO) (HR, 0.66; 95% CI, 0.43-1.01; one-sided P = 0.03) including those with ABC subtype (Nowakowski et al. J Clin Oncol 2021;39:1329-1338). These results reflect heterogeneity within COO subtypes, suggesting that COO alone does not support a precision medicine approach in DLBCL. Iberdomide (IBER, CC-220) and CC-99282 are novel cereblon E3 ligase modulating (CELMoD) agents designed to optimize degradation of target proteins Ikaros and Aiolos, and improve tissue distribution for lymphoma-specific needs. In preclinical studies, compared with LEN, IBER showed enhanced affinity for cereblon, with significantly faster and deeper degradation of target substrates and increased tumoricidal activity (Matyskiela et al. J Med Chem 2018). IBER and CC-99282 demonstrated rapid and extensive tumor killing in vitro and in mouse models independent of COO, and enhanced T and NK cell immunostimulatory activity (Lopez-Girona et al. Hematol Oncol 2021, Carrancio et al. Blood 2021, Nakayama et al. ASH 2021). Initial results from a ph 1 study of CC-99282 monotherapy in relapsed/refractory non-Hodgkin lymphoma (R/R NHL) (Michot et al. Blood 2021) and a ph 1 study of IBER as a single agent and in combination with rituximab in R/R NHL (Thieblemont et al. ASH 2022) showed a predictable and manageable safety profile with promising clinical activity independent of COO, consistent with preclinical data. CC-220-DBLCL-001 (NCT04884035) is a dose-finding and safety trial in progress that will assess CELMoD agents in combination with R-CHOP for the treatment of previously untreated a-BCL. Methods: CC-220-DLBCL-001 is a ph 1b, open-label, global, multicenter, dose-escalation (part 1), dose-expansion (part 2) study. Eligible pts aged ≥ 18 years must have untreated a-BCL with measurable disease per Lugano 2014 classification, with ECOG performance status ≤ 2. Part 1 includes pts with international prognostic index (IPI) scores 0-5; for part 2, pts must have IPI scores of 2-5. Primary objectives are to define the maximum tolerated dose and recommended ph 2 dose (RP2D) for IBER in combination with R-CHOP administered in 21-day cycles (R-CHOP-21), and CC-99282 in combination with R-CHOP-21, for pts with untreated a-BCL (part 1) and to evaluate safety and tolerability of these treatment combinations further at RP2D in pts with untreated a-BCL (part 2). Key secondary objectives include preliminary efficacy, pharmacokinetics, safety, and tolerability of the treatment combinations. In part 1, an estimated total of 36 pts will be enrolled who will receive escalating CELMoD dose levels guided by a modified toxicity probability interval design. Part 2 will enroll 40-80 pts who will be randomized to receive IBER or CC-99282 in combination with R-CHOP-21; further randomization may be introduced for dose optimization between RP2D and the next lower dose (Figure). Treatment will continue for 6 cycles or until disease progression, unacceptable toxicity, or study withdrawal. All pts will be followed for 28 days after the final dose for adverse event reporting. Pts who complete treatment will be assessed every 3 months during the first year and every 6 months for up to 2 years, with imaging at 9, 12, 18, and 24 months. The study opened on September 15, 2021 and is currently recruiting. Study support: This study is supported by Bristol Myers Squibb. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase 1b Trial of Anti-Immunoglobulin-like Transcript 3 Monoclonal Antibody MK-0482 Monotherapy in Relapsed/Refractory Acute Myeloid Leukemia and Chronic Myelomonocytic Leukemia

Background: Immunoglobulin-like transcript 3 (ILT3) is a cell surface inhibitory receptor expressed on various immune cells including dendritic cells, monocytic myeloid cells, and macrophages. The expression of ILT3 on dendritic cells and myeloid cells is thought to be involved in immune suppression and antigen-specific immune tolerance, contributing to an immunosuppressive tumor microenvironment. Acute myeloid leukemia (AML) is a type of cancer characterized by bone marrow that makes a large number of abnormal blood cells. In monocytic AML, ILT3 is highly expressed, and its signaling can mediate T-cell suppression and promote tumor infiltration (Deng M et al. Nature. 2018;562:605-609). Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm characterized by dysplasia, abnormal production and accumulation of monocytic cells, and with an elevated risk of transforming into AML. Based on the M2GEN database, ILT3 is also highly expressed in CMML. Thus, targeting ILT3 may exhibit antitumor activity in patients with AML and CMML. Currently, limited effective treatments are available for AML and CMML, especially in the relapse and refractory setting. MK-0482, a humanized IgG4 anti-ILT3 monoclonal antibody, has been evaluated as monotherapy and in combination with pembrolizumab at doses ≤2250 mg every 3 weeks (Q3W) in patients with advanced solid tumors. Patients treated with MK-0482 had a manageable safety profile, and modest antitumor activity was observed with MK-0482 plus pembrolizumab (Gutierrez M et al. J Clin Oncol. 2022;40. Abstract 2505). In this phase 1b study (NCT05038800), we are evaluating the safety and the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of MK-0482 in relapsed or refractory (r/r) AML and CMML. Study Design and Methods: Adult patients with AML with myelomonocytic or monoblastic/monocytic differentiation or CMML and with confirmed refractory or relapsed disease after treatment with available therapies will be eligible for enrollment. All patients must have an ECOG performance status of 0-2, adequate organ function, and a white blood cell count ≤20 × 109/L. Patients with active central nervous system leukemia, isolated extramedullary disease (ie no leukemic involvement), acute promyelocytic leukemia, or who have previously received allogeneic stem cell or organ transplant <60 days of treatment will be excluded. In part 1 (dose escalation), MK-0482 will be evaluated at dose levels ranging from 7.5 mg to 750 mg Q3W for ≤35 cycles with an accelerated titration design followed by a modified toxicity probability interval design in ~20 patients. After the recommended phase 2 dose (RP2D) is determined, 10 to 15 additional patients with AML with myelomonocytic or monoblastic/monocytic differentiation will be enrolled in part 2 (dose expansion). The primary objective of the study is to determine safety and tolerability and RP2D. Secondary objectives include characterizing the PK profile of MK-0482 monotherapy and antileukemia activities in AML as assessed by complete remission (CR), composite CR, and objective response per the 2017 European Leukemia Net AML response criteria. Exploratory objectives include assessment of receptor occupancy in peripheral blood and tumor biopsies, molecular biomarkers, and antileukemic activities in patients with CMML. Dose-limiting toxicities will be observed for 21 days after the first dose in cycle 1 and adverse events (AEs) will be assessed through 30 days after treatment discontinuation (90 days for serious AEs; 30 days if new anticancer therapy is initiated) per National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Disease assessment will be performed by investigator at baseline and prior to day 1 of cycles 3, 5, and 7, followed by every 3 cycles until disease progression or confirmed CR. Samples for PK analyses will be collected before and after treatment on day 1 of cycles 1-4, 6, 8, and every 4 cycles thereafter. The study is currently ongoing.

A hybrid design for dose-finding oncology clinical trials.

Identifying the maximum tolerated dose (MTD) and recommending a Phase II dose for an investigational treatment is crucial in cancer drug development. A suboptimal dose often leads to a failed late-stage trial, while an overly toxic dose causes harm to patients. There is a very rich literature on trial designs for dose-finding oncology clinical trials. We propose a novel hybrid design that maximizes the merits and minimizes the limitations of the existing designs. Building on two existing dose-finding designs: a model-assisted design (the modified toxicity probability interval) and a dose-toxicity model-based design, a hybrid design of the modified toxicity probability interval design and a dose-toxicity model such as the logistic regression model is proposed, incorporating optimal properties from these existing approaches. The performance of the hybrid design was tested in a real trial example and through simulation scenarios. The hybrid design controlled the overdosing toxicity well and led to a recommended dose closer to the true MTD due to its ability to calibrate for an intermediate dose. The robust performance of the proposed hybrid design is illustrated through the real trial dataset and simulations. The simulation results demonstrated that the proposed hybrid design can achieve excellent and robust operating characteristics compared to other existing designs and can be an effective model for determining the MTD and recommended Phase II dose in oncology dose-finding trials. For practical feasibility, an R-shiny tool was developed and is freely available to guide clinicians in every step of the dose finding process.