Recommended Phase 2 Dose Research Articles

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

Introduction: Programmed cell death protein 1 (PD-1) inhibitors such as pembrolizumab play an important role in the treatment of patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL), but treatment failure remains a significant challenge. Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor that downregulates T-cell activity and plays a role in regulating T-cell function. Dual blockade of PD-1 and LAG-3 demonstrated antitumor activity in patients with advanced melanoma in the RELATIVITY-047 trial, which led to FDA approval in this setting. Favezelimab is a humanized IgG4 monoclonal antibody directed against LAG-3 that is being investigated in combination with pembrolizumab in patients with R/R hematologic malignancies in a multicohort phase 1/2 study (NCT03598608). Prior analyses of this study demonstrated that pembrolizumab 200 mg plus favezelimab 800 mg every 3 weeks (Q3W) exhibited sustained antitumor activity and acceptable safety in the cohort of patients with anti-PD-1-naive R/R cHL (cohort 1). We present updated results from this cohort. Methods: A safety lead-in phase to determine the recommended phase 2 dose (RP2D) was followed by a dose-expansion phase. Eligible patients were ≥18 years of age; had R/R cHL after autologous stem cell transplantation (ASCT), were ineligible for ASCT, or did not respond to salvage chemotherapy; had not received prior anti-PD-1 therapy; and had an ECOG performance status of 0 or 1. In the safety lead-in, patients received pembrolizumab 200 mg IV Q3W and favezelimab at a starting dose of 200 mg that was escalated to 800 mg IV Q3W using a modified toxicity probability interval method. In the dose-expansion phase, patients received pembrolizumab 200 mg Q3W plus favezelimab at the established RP2D of 800 mg Q3W for up to 35 cycles (~2 years). CT was performed every 12 weeks and PET at weeks 12 and 24. The primary end point was safety. Objective response rate (ORR) per IWG 2007 criteria by investigator review was a secondary end point. Duration of response (DOR) and progression-free survival (PFS) per IWG 2007 criteria by investigator review and overall survival (OS) were exploratory. Results: Thirty patients with anti-PD-1-naive cHL were enrolled in cohort 1. The median age was 40.5 years (range, 19-82), 17 patients (57%) were male, 16 (53%) had an ECOG performance status of 0, and 24 (80%) had received 3 or fewer prior lines of therapy. At data cutoff (March 2, 2023), 13 patients (43%) had completed 35 cycles of study treatment, 16 (53%) had discontinued treatment (10 [33%] progressive disease, 5 [17%] adverse event [AE], 1 [3%] noncompliance with study drug), and 1 (3%) was ongoing on treatment. The median time from first dose to data cutoff was 31.5 months (range, 24.0-43.2). Treatment-related AEs occurred in 27 patients (90%), of which the most common (≥20%) were hypothyroidism (27%), infusion-related reaction (23%), and fatigue (20%). Grade 3/4 treatment related AEs occurred in 9 patients (30%). Five patients (17%) discontinued treatment because of treatment-related AEs. No deaths due to treatment-related AEs were reported. AEs of clinical interest occurred in 20 patients (67%); 3 patients (10%) had grade 3 events (colitis, pneumonitis, severe skin reaction) and 1 patient (3%) had a grade 4 event (hepatitis). Of 5 patients who received allogeneic stem cell transplantation after discontinuation or completion of study treatment, 1 had a grade 3/4 AE (increased blood bilirubin) that was unrelated to study treatment and resolved. The ORR was 80% (n = 24; 95% CI, 61-92); 10 patients (33%) had a complete response and 14 (47%) had a partial response. Twenty-nine patients (97%) had any reduction in target lesions size from baseline, and 25 (83%) had a reduction of ≥50%. Median DOR was 17.0 months (range, 2.6-30.2), and an estimated 47% of responders remained in response ≥24 months. Median PFS was 19.4 months (95% CI, 9.0-28.5), and the 24-month PFS rate was 46%. Median OS was not reached (NR; 95% CI, NR-NR), and the 24-month OS rate was 93%. Conclusion: With additional follow-up, the combination of favezelimab and pembrolizumab continued to demonstrate sustained antitumor activity and manageable safety in patients with anti-PD-1-naive R/R cHL. Analyses are underway to identify biomarkers predictive of response to the combination of favezelimab and pembrolizumab. Further studies to investigate this combination are warranted.

Safety and Efficacy of Selinexor Sequential Azacytidine in Newly Diagnosed Patients with Myelodysplastic Syndromes EB1 or EB2: A Single-Center, Single-Arm, Phase Ib/II Trial

Background: Azacytidine is one of the hypomethylating agents (HMAs) for the treatment of higher-risk myelodysplastic syndromes (MDS). However, clinical outcomes of patients treated with azacytidine monotherapy were far from satisfactory with overall response rate (ORR) of 41%-59% and overall survival (OS) of 15-18 months. Selinexor is an oral, first-in-class selective inhibitor of nuclear export compound that inhibits exportin 1 (XPO1). Preclinical studies have shown that inhibition of XPO1 causes nuclear accumulation of p53 and disruption of NF-κB signaling, both relevant targets for myelodysplastic syndromes. Prior study reported an ORR of 26% and mOS of 8.7 months with selinexor in HMAs-refractory MDS patients. We therefore aimed to assess the safety and efficacy of selinexor sequential azacytidine in newly diagnosed patients with MDS-EB1 or EB2. Methods: The effectiveness of simultaneous and sequential treatment of azacytidine and selinexor was measured by cell death rate, cell cycle and colony formation rate in vitro. Western Blot was performed to detect the sublocation of p53. MOLM-13-luciferase xenograft murine model was established to verify the synergetic effect in vivo. Based on the experiments, we conducted a single-center, single-arm, phase Ib/II trial, which included newly diagnosed patients 18 years or older with MDS-EB1 or EB2. Eligible patients received 2-4 weeks long cycles of oral selinexor (40mg qw for 4 weeks; 40mg biw for 2 weeks; 60mg qw for 4 weeks). The primary endpoints were to find the recommended phase 2 dose (RP2D) and maximum tolerated dose (MTD). The secondary endpoint was ORR including complete remission (CR), partial remission (PR), marrow complete remission (mCR), and hematological improvement (HI). This trial was registered with the Chinese Clinical Trial Registry (#ChiCTR2200065167). Results: First we treated three AML cell lines: AML-OCI2, THP1, MV4-11 and three MDS cell lines: SKM-1, MOLM-13, MDSL with azacitidine and selinexor simultaneously or sequentially. Sequential treatment showed stronger synergetic effect (Figure 1A) and reduced colony formation by 90% in SKM-1 and MOLM-13 (Figure 1B). Cell cycle arrest were induced and the percentage of Annexin V cells obviously increased with sequential treatment (Figure 1C). Sequential treatment decreased leukemia burden and prolonged survival of MOLM-13-luciferase xenograft murine model (Figure 1D, E). Mechanistically, pretreatment of azacitidine on SKM-1 and MOLM-13 upregulated the expression level of p53, and selinexor led to massive nuclear accumulation of p53, resulted in better vulnerability lethal to MDS cells (Figure 1F). Secondly, 15 patients were enrolled in our trial with a median age of 57. 26.7% of patients were MDS-EB1, 73.3% were EB2. 93.3% of patients were high or very high risk by the Revised International Prognositic Scoring System (IPSS-R) (see the Table). At Phase Ib, the following selinexor dosages were administered: 40mg qw (n=3), 40mg biw (n=3) and 60mg qw (n=3). One patient in the 60mg qw group discontinued treatment because of nausea, vomiting, fatigue and Herpes simplex virus infection. Subsequently, in order to find RP2D, an extension cohort of 3 additional patients were treated with 40mg qw and 40mg biw, respectively. Therefore, 14 patients were evaluable for efficacy assessment. ORR was 78.6% in 11 patients including CR in 3 patients (21.4%); mCR+HI in 1 patient (7.1%); and mCR in 7 patients (50.0%) (see the swimmer plot). Especially, among the TP53 mutated patients (n=3), one achieved CR, the other two achieved mCR. The common adverse events were neutropenia (93.3%), anemia (86.7%), thrombocytopenia (80.0%), fatigue (53.3%), nausea (26.7%), dizziness (26.7%), vomiting (20.0%) and decreased appetite (20.0%). There were no treatment related deaths. Conclusion: We verified the activity of selinexor sequential azacytidine in MDS both in vitro and in vivo. The treatment showed with encouraging efficacy in newly diagnosed patients with MDS-EB1 or EB2. Adverse events were manageable with supportive care implementation. Enrollment is ongoing to assess the efficacy and safety of this sequential therapy, which may be a new treatment option for EB subjects.

BMS-986158, a Potent BET Inhibitor, in Combination with Ruxolitinib or Fedratinib in Patients (pts) with Intermediate- or High-Risk Myelofibrosis (MF): Updated Results from a Phase 1/2 Study

Introduction Bromodomain and extra-terminal (BET) inhibitors in combination with Janus kinase inhibitors (JAKi) have demonstrated clinical benefits in pts with MF. BMS-986158 is an orally bioavailable, potent, and selective small molecule BET inhibitor with a dose-proportional pharmacokinetic profile with linear increases in exposure, which has shown time- and dose-dependent modulation of BET target gene expression. BMS-986158 in combination with JAKi ruxolitinib (RUX) or fedratinib (FED) is being evaluated in pts with MF in the CA011-023 study (NCT04817007). Previous analyses showed that BMS-986158+RUX in first-line (1L; RUX-naïve) MF and BMS-986158+FED in second-line (2L; relapsed, refractory, or intolerant to prior RUX treatment) MF was well tolerated, with most pts remaining on treatment, and had promising preliminary efficacy (Ayala R et al. EHA 2023. S213). Updated results with longer follow-up will be presented. Methods Eligible pts had primary or secondary MF and were either RUX-naïve (1L) or relapsed, refractory, or intolerant to RUX (2L), with splenomegaly (spleen volume [SV] ≥ 450 cm 3), ECOG PS ≤ 2, and Dynamic International Prognostic Scoring System risk scores of intermediate-1 with symptoms, intermediate-2, or high. In dose escalation, pts with 1L MF received BMS-986158 2.0, 3.0, or 3.75 mg QD 5d on/2d off + RUX 15 mg BID; pts with 2L MF received BMS-986158 0.5, 0.75, 1.0, or 1.25 mg QD 5d on/2d off (alternative schedule for 1.0-mg dose: 5d on/2d off, 3 wks on/1 wk off) + FED 400 mg QD. Primary objectives in dose escalation were safety, tolerability, and determination of the maximum tolerated dose and/or recommended phase 2 dose (RP2D) of BMS-986158+RUX and BMS-986158+FED. Secondary objectives included spleen volume reduction (SVR) from baseline and response rate (SVR35) at wk 24. Assessment of JAK2 variant allele frequency (VAF) was an exploratory objective. JAK2V617 VAF was measured longitudinally in peripheral blood CD34+ stem cells using next-generation sequencing. Results As of May 18, 2023, 16 pts with 1L MF received BMS-986158+RUX (median age 66 y [range, 36-81]) and 24 pts with 2L MF received BMS-986158+FED (median age 68 y [range, 34-81]). At baseline, median SV was 1504 cm 3 (range, 524-4379) in pts treated with BMS-986158+RUX and 2222 cm 3 (range, 581-6598) in pts treated with BMS-986158+FED. Any grade (G) treatment-related adverse events (TRAEs) were reported in 15 (94%) pts treated with BMS-986158+RUX; G 3/4 TRAEs were thrombocytopenia (n = 7, 44%), neutropenia (n = 2, 13%), anemia, leukopenia, herpes zoster, hyperbilirubinemia, and hypertension (n = 1 each, 6%). Any G TRAEs were reported in 18 (75%) pts treated with BMS-986158+FED; G 3/4 TRAEs were thrombocytopenia and anemia (n = 6 each, 25%), hyperbilirubinemia (n=2, 8%), leukocytosis, and diarrhea (n = 1 each, 4%). No TRAEs led to discontinuation of BMS-986158+RUX; 2 TRAEs (G4 thrombocytopenia and G3 hyperbilirubinemia) led to discontinuation of BMS-986158+FED. SVR was observed at wk 12 in all evaluable pts in both treatment regimens and continued to deepen at wk 24 (Figure). Median SV at wk 24 was 603 cm 3 (range, 170-2532) and 1826 cm 3 (range, 1079-5288) in evaluable pts with 1L MF and 2L MF, respectively. In pts with 1L MF, 8/11 (73%) treated with BMS-986158 (2.0, 3.0 or 3.75 mg)+RUX met SVR35 at wk 12; 9/10 (90%) pts met SVR35 at wk 24. In pts with 2L MF, 7/12 (58%) pts treated with BMS-986158 (0.5, 0.75, 1.0, or 1.25 mg)+FED met SVR35 at wk 12; 3/7 (43%) pts met SVR35 at wk 24. At the time of reporting, 32/40 (80%) pts remained on treatment: 14/16 (88%) receiving BMS-986158+RUX and 18/24 (75%) receiving BMS-986158+FED. Available analysis of JAK2 VAF showed reductions in the frequency of JAK2V617F with BMS-986158+RUX (52% max. reduction by C10, n = 7) and BMS-986158+FED (29% max. reduction by C4, n = 4). Conclusions These updated analyses of study CA011-023 show that BMS-986158+RUX in 1L MF and BMS-986158+FED in 2L MF continue to be well tolerated, with most patients remaining on treatment. TRAEs were mostly low-grade and transient. Thrombocytopenia, an on-target effect, was manageable and did not result in clinically significant bleeding. Both treatment regimens produced early and deep SVR by wk 12, which continued and deepened at wk 24 and beyond. The reductions observed in JAK2 VAF provide promising preliminary data of potential disease modification. Dose expansion with BMS-986158+RUX in 1L MF has opened and is actively enrolling patients.

Phase 1 first-in-human dose-escalation study of ANV419 in patients with relapsed/refractory advanced solid tumors

BackgroundANV419 is a stable antibody–cytokine fusion protein consisting of interleukin-2 (IL-2) fused to an anti-IL-2 monoclonal antibody that sterically hinders binding of IL-2 to the α subunit of its receptor...

Results from a Phase 1 Study of ACTR707 in Combination with Rituximab in Patients with Relapsed or Refractory CD20+ B Cell Lymphoma

The antibody-coupled T cell receptor (ACTR) platform is an autologous engineered T cell therapy combining the cell-killing ability of T cells and the tumor-targeting ability of coadministered antibodies. Activation of the T cell product ACTR707 is dependent on the engagement of antibody bound to target cells via the CD16 domain of the chimeric receptor (CD16V-CD28-CD3ζ). ACTR707 in combination with the anti-CD20 monoclonal antibody rituximab was evaluated in the ATTCK-20-03 study, a multisite, single-arm, open-label phase I trial in B cell non-Hodgkin lymphoma (NHL). The primary objectives of this study were to evaluate the safety of the combination of ACTR707 and rituximab and to determine a recommended phase 2 dose (RP2D). Secondary objectives included evaluation of antitumor activity and ACTR T cell persistence. The study design included an ACTR707 cell dose escalation phase and an expansion phase at the RP2D. Escalating dose levels of ACTR707 in combination with rituximab were explored in 5 dose cohorts, with 25 subjects receiving study treatment. Subjects received lymphodepleting chemotherapy (cyclophosphamide 400 mg/m2/day and fludarabine 30 mg/m2/day) for 3 days, followed by rituximab 375 mg/m2 and, 24 to 48 hours later, a single dose of ACTR707. Additional doses of rituximab were administered every 3 weeks until disease progression, unacceptable toxicity, or investigator decision. Blood samples were collected at various time points to assess levels of rituximab, cytokines, inflammatory markers, and ACTR707 T cells. The overall response rate of ACTR707 plus rituximab was 56% (14 of 25) across all dose levels. Ten subjects (40.0%) achieved a complete response, with the longest duration of 586 days (range, 85 to 586 days), and 4 subjects (16.0%) experienced a partial response, with the longest duration of 130 days (range, 44 to 130 days). Only 1 case of cytokine release syndrome (grade 2) and no events of neurotoxicity were reported. There were no dose-limiting toxicities or events leading to death. ACTR707 plus rituximab resulted in only 1 adverse event (neutropenia), leading to study discontinuation of rituximab. The ATTCK-20-03 trial serves as proof of principle regarding the ACTR approach that potentially could be used with other antibodies targeting other markers in other malignancies. Although the ACTR707 program has been discontinued, these results may support other programs in the use of similar novel approaches of antibody-coupled T cell activation.

CLDN6-specific CAR-T cells plus amplifying RNA vaccine in relapsed or refractory solid tumors: the phase 1 BNT211-01 trial

The oncofetal antigen Claudin 6 (CLDN6) is highly and specifically expressed in many solid tumors, and could be a promising treatment target. We report dose escalation results from the ongoing phase 1/2 BNT211-01 trial evaluating the safety and feasibility of chimeric antigen receptor (CAR) T cells targeting the CLDN6 with or without a CAR-T cell-amplifying RNA vaccine (CARVac) at two dose levels (DLs) in relapsed/refractory CLDN6-positive solid tumors. The primary endpoints were safety and tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D). Secondary endpoints included objective response rate (ORR) and disease control rate. We observed manageable toxicity, with 10 out of 22 patients (46%) experiencing cytokine release syndrome including one grade 3 event and 1 out of 22 (5%) with grade 1 immune effector cell-associated neurotoxicity syndrome. Dose-limiting toxicities occurred in two patients at the higher DL, resolving without sequelae. CAR-T cell engraftment was robust, and the addition of CARVac was well tolerated. The unconfirmed ORR in 21 evaluable patients was 33% (7 of 21), including one complete response. The disease control rate was 67% (14 of 21), with stable disease in seven patients. Patients with germ cell tumors treated at the higher DL exhibited the highest response rate (ORR 57% (4 of 7)). The maximum tolerated dose and RP2D were not established as the trial has been amended to utilize an automated manufacturing process. A repeat of the dose escalation is ongoing and will identify a RP2D for pivotal trials. ClinicalTrials.gov Identifier: NCT04503278.

Combination of GT90001 and nivolumab in patients with advanced hepatocellular carcinoma: a multicenter, single-arm, phase 1b/2 study

BackgroundGT90001 (also known as PF-03446962) is an anti-ALK-1 monoclonal antibody and has shown activity in hepatocellular carcinoma (HCC). This phase 1b/2 study was designed to determine the recommended phase 2 dose (RP2D) of GT90001 plus nivolumab, and assess the safety and anti-tumor activity in patients with advanced HCC.MethodsPatients with advanced HCC were recruited from 3 centers. Eligible patients in the dose de-escalation stage received the GT90001 on day 1 of a 14-day cycle in a rolling-six design with a fixed dose of nivolumab (3.0 mg/kg). Patients in dose-expansion stage received the RP2D of GT90001 plus nivolumab. Primary endpoint was safety. Key secondary endpoint was objective response rate (ORR) as per RECIST 1.1.ResultsBetween July 9, 2019, and August 8, 2022, 20 patients were treated (6 in phase 1b; 14 in phase 2) and evaluable for analysis. In phase 1b, no dose-limiting toxicities were observed, and GT90001 7.0 mg/kg was confirmed as the RP2D. Common grade 3/4 adverse events (AEs) were platelet count decreased (15%). No deaths due to AEs were reported. Confirmed ORR and disease control rate were 30% (95% CI, 14.6%-51.9%) and 40% (95% CI, 21.9%-61.3%), respectively. Median duration of response was not calculated (95% CI, 7.39 months to not calculated). Median progression-free survival (PFS) was 2.81 months (95% CI, 1.71–9.33), with 6-month and 12-month PFS rates of 35% and 25%, respectively. One patient with multiple intra- and extra-hepatic metastases was diagnosed with pseudo-progression upon GT90001 plus nivolumab exposure.ConclusionsGT90001 plus nivolumab has a manageable safety profile and promising anti-tumor activity in patients with advanced HCC.Trial registration numberClinicalTrials.gov identifier NCT03893695.

The PD-1- and LAG-3-targeting bispecific molecule tebotelimab in solid tumors and hematologic cancers: a phase 1 trial

Tebotelimab, a bispecific PD-1×LAG-3 DART molecule that blocks both PD-1 and LAG-3, was investigated for clinical safety and activity in a phase 1 dose-escalation and cohort-expansion clinical trial in patients with solid tumors or hematologic malignancies and disease progression on previous treatment. Primary endpoints were safety and maximum tolerated dose of tebotelimab when administered as a single agent (n = 269) or in combination with the anti-HER2 antibody margetuximab (n = 84). Secondary endpoints included anti-tumor activity. In patients with advanced cancer treated with tebotelimab monotherapy, 68% (184/269) experienced treatment-related adverse events (TRAEs; 22% were grade ≥3). No maximum tolerated dose was defined; the recommended phase 2 dose (RP2D) was 600 mg once every 2 weeks. There were tumor decreases in 34% (59/172) of response-evaluable patients in the dose-escalation cohorts, with objective responses in multiple solid tumor types, including PD-1-refractory disease, and in LAG-3+ non-Hodgkin lymphomas, including CAR-T refractory disease. To enhance potential anti-tumor responses, we tested margetuximab plus tebotelimab. In patients with HER2+ tumors treated with tebotelimab plus margetuximab, 74% (62/84) had TRAEs (17% were grade ≥3). The RP2D was 600 mg once every 3 weeks. The confirmed objective response rate in these patients was 19% (14/72), including responses in patients typically not responsive to anti-HER2/anti-PD-1 combination therapy. ClinicalTrials.gov identifier: NCT03219268.

Determination and Confirmation of Recommended Ph2 Dose of Amivantamab in Epidermal Growth Factor Receptor Exon 20 Insertion Non-Small Cell Lung Cancer.

Amivantamab has demonstrated durable responses with a tolerable safety profile in non-small cell lung cancer with EGFR exon 20 insertions (Ex20ins) who progressed after prior platinum chemotherapy. Data supporting the amivantamab recommended phase II dose (RP2D) in this patient population are presented. Pharmacokinetic (PK) analysis and population PK (PopPK) modeling were conducted using serum concentration data obtained following amivantamab intravenous administration (140-1,750 mg). Pharmacodynamics (PDs) were evaluated using depletion of soluble EGFR and MET. Exposure-response (E-R) analyses were performed using the primary efficacy end point of objective response rate in patients with EGFR Ex20ins. The E-R relationship for safety was explored for adverse events of clinical interest. Amivantamab exhibited linear PKs at 350-1,750 mg dose levels following administration, with no maximum tolerated dose identified. A two-compartment PopPK model with linear clearance adequately described the observed PKs. Body weight was a covariate of clearance and volume of distribution in the central compartment. PopPK modeling showed that a weight-based, 2-tier (< 80 and ≥ 80 kg) dosing strategy reduces PK variability and provides comparable exposure across 2 weight groups, with 87% of patients achieving exposures above the target threshold. The final confirmed RP2D of amivantamab was 1,050 mg for < 80 kg (1,400 mg for ≥ 80 kg) weekly in cycle 1 (28 days) and every 2 weeks thereafter. No significant exposure-efficacy or safety correlation was observed. In conclusion, the amivantamab RP2D is supported by PK, PD, safety, and efficacy analyses. E-R analyses confirmed that the current regimen provides durable efficacy with tolerable safety.

Phase 1/1b open-label, dose-escalation study of fruquintinib in patients with advanced solid tumors in the United States

SummaryThis open-label, phase 1/1b study was conducted to evaluate the safety, tolerability, and pharmacokinetics (PK) of fruquintinib in United States (U.S.) patients to confirm the recommended phase 2 dose (RP2D) established in China. Patients with advanced solid tumors who had progressed on approved systemic therapy, were enrolled into 2 successive dose escalation cohorts, fruquintinib 3 mg (n = 7) or 5 mg (n = 7), orally, once daily (QD), 3 weeks on and 1 week off (3/1) with a 3 + 3 design followed by a dose expansion cohort at the RP2D 5 mg dose (n = 6). PK samples were collected on Days 1, 14, and 21 (Cycle 1). One of 6 dose-limiting toxicity (DLT)-evaluable patients in the 3 mg cohort had a DLT of grade 4 hypertension; there were no DLTs in the 5 mg cohort. The RP2D was confirmed to be 5 mg QD 3/1. All 20 patients experienced a treatment-emergent adverse event; grade ≥ 3 in 5 (71.4%; 3 mg dose) and 12 (92.3%; 5 mg dose) patients. Two patients had a confirmed partial response. After single and multiple doses, median peak plasma concentrations occurred at 2 h post-dose. Steady-state was achieved after 14 days of QD dosing with systemic exposure four-fold higher than that after a single dose. Fruquintinib was well tolerated, and the safety and PK profile at the 5 mg RP2D in U.S. patients with advanced solid tumors was consistent with dose-finding studies in China. Preliminary anticancer activity was observed. This study is registered at Clinicaltrials.gov NCT03251378.

A phase 1 trial of fuzuloparib in combination with apatinib for advanced ovarian and triple-negative breast cancer: efficacy, safety, pharmacokinetics and germline BRCA mutation analysis

BackgroundThe effect of the combination of an anti-angiogenic agent with a poly (ADP-ribose) polymerase (PARP) inhibitor in cancer treatment is unclear. We assessed the oral combination of fuzuloparib, a PARP inhibitor, and apatinib, a VEGFR2 inhibitor for treating advanced ovarian cancer (OC) or triple-negative breast cancer (TNBC).MethodsThis dose-escalation and pharmacokinetics-expansion phase 1 trial was conducted in China. We used a standard 3 + 3 dose-escalation design, with 7 dose levels tested. Patients received fuzuloparib orally twice daily, and apatinib orally once daily. The study objectives were to determine the safety profile, recommended phase 2 dose (RP2D), pharmacokinetics, preliminary efficacy, and efficacy in relation to germline BRCA mutation (gBRCAmut).ResultsFifty-two pre-treated patients were enrolled (30 OC/22 TNBC). 5 (9.6%) patients had complete response, 14 (26.9%) had partial response, and 15 (28.8%) had stable disease. Objective response rate (ORR) and disease control rate were 36.5% (95% CI 23.6–51.0) and 65.4% (95% CI 50.9–78.0), respectively. At the highest dose level of fuzuloparib 100 mg plus apatinib 500 mg, the ORR was 50.0% (4/8; 95% CI 15.7–84.3); this dose was determined to be the RP2D. Patients with gBRCAmut had higher ORR and longer median progression-free survival (PFS) than those with gBRCAwt, both in OC (ORR, 62.5% [5/8] vs 40.9% [9/22]; PFS, 9.4 vs 6.7 months) and TNBC (ORR, 66.7% [2/3] vs 15.8% [3/19]; PFS, 5.6 vs 2.8 months). Two dose-limiting toxicities occurred: grade 4 febrile neutropenia (fuzuloparib 100 mg plus apatinib 250 mg) and thrombocytopenia (fuzuloparib 100 mg plus apatinib 375 mg). Maximum tolerated dose was not reached. The most common treatment-related grade ≥ 3 toxicities in all patients were hypertension (19.2%), anaemia (13.5%), and decreased platelet count (5.8%). Exposure of apatinib increased proportionally with increasing dose ranging from 250 to 500 mg, when combined with fuzuloparib 100 mg.ConclusionsFuzuloparib plus apatinib had acceptable safety in patients with advanced OC or TNBC. Fuzuloparib 100 mg bid plus apatinib 500 mg qd was established as the RP2D. With the promising clinical activity observed, this combination is warranted to be further explored as a potential alternative to chemotherapy.Trial registrationClinicalTrials.gov, NCT03075462 (Mar. 9, 2017).

Anti-TIGIT Antibody Tiragolumab Alone or With Atezolizumab in Patients With Advanced Solid Tumors

Inhibition of the T-cell immunoreceptor with Ig and ITIM domains (TIGIT)/poliovirus receptor pathway may amplify the antitumor immune response of atezolizumab in programmed death ligand 1-selected tumors. To evaluate the safety and antitumor activity of the anti-TIGIT antibody tiragolumab and its combination with atezolizumab in patients with advanced solid tumors. The GO30103 open-label, first-in-human phase 1a/1b dose-escalation and dose-expansion nonrandomized controlled trial was conducted at 13 sites in 6 countries (Australia, Canada, France, Korea, Spain, and the US). The start dates were May 23, 2016, for phase 1a and October 11, 2016, for phase 1b. Patients were aged 18 years or older with measurable disease at baseline. The clinical cutoff date was October 1, 2021. Data analysis was performed on January 24, 2022. Patients received fixed-dose intravenous tiragolumab on day 1 of each 21-day cycle (2 mg escalating to 1200 mg) in phase 1a, plus fixed-dose intravenous atezolizumab (1200 mg every 3 weeks) in phase 1b. Patients were treated until disease progression, loss of clinical benefit, or development of unacceptable toxicity. The primary end points included the safety, tolerability, and recommended phase 2 dose (RP2D) of tiragolumab or combination tiragolumab plus atezolizumab. The secondary end point included the investigator-assessed objective response rate (ORR). Counts and percentages are used for categorical variables, and medians and ranges are used for continuous variables. Among the phase 1a (n = 24) and 1b (n = 49) dose-escalation cohorts, the median age was 60 (range, 40-77) and 54 (range, 25-81) years, respectively. More than half of patients were women (14 of 24 [58%] and 25 of 49 [51%]), and more than a third (10 [42%] and 18 [37%]) had received 4 or more prior cancer therapies. No dose-limiting toxicities occurred, and the maximum tolerated dose of tiragolumab was not reached (NR). The most frequent treatment-related adverse events (AEs) were fatigue (5 of 24 [21%]) in phase 1a and pruritus (5 of 49 [10%]) in phase 1b; the majority of AEs were grade 1 or 2. Immune-mediated AEs occurred in 4 of 24 (17%) and 29 of 49 (59%) patients during phases 1a and 1b, respectively (primarily grade 1 or 2). The RP2D of tiragolumab was 600 mg intravenously every 3 weeks, which was tested in phase 1b dose expansion. The confirmed ORR was 0% during phase 1a, with evidence of antitumor activity in 6% of patients (n = 3) during phase 1b. The safety profile of combination tiragolumab plus atezolizumab in phase 1b was similar in the dose-escalation and dose-expansion cohorts. The confirmed ORR was 46% (6 of 13) in the non-small cell lung cancer (NSCLC) cohort (median duration of response [DOR], NR) and 28% (5 of 18) in the esophageal cancer (EC) cohort (median DOR, 15.2 [95% CI, 7.0 to NR] months). In this nonrandomized controlled trial, tiragolumab was well tolerated with or without atezolizumab; no new safety signals were observed. Preliminary antitumor activity was demonstrated for the combination regimen in patients with cancer immunotherapy-naive metastatic NSCLC or EC. ClinicalTrials.gov Identifier: NCT02794571.

Phase 1/2 Study of Sorafenib Added to Cladribine, High-Dose Cytarabine, G-CSF, and Mitoxantrone in Untreated AML.

The multikinase inhibitor sorafenib improves event-free survival (EFS) when used with 7+3 in younger adults with newly diagnosed acute myeloid leukemia (AML) irrespective of FLT3 mutation status. Here, we evaluated adding sorafenib to CLAG-M (cladribine, high-dose cytarabine, G-CSF, mitoxantrone) in a phase 1/2 trial of 81 adults age ≤60 years with newly diagnosed AML or high-grade myeloid neoplasm. Forty-six patients were treated in phase 1 with escalating doses of sorafenib and mitoxantrone. No maximum tolerated dose was reached, and a regimen including mitoxantrone at 18 mg/m2/day and sorafenib 400 mg twice daily was declared the recommended phase 2 dose (RP2D). Among 41 patients treated at the RP2D, a measurable residual disease-negative complete remission (MRDneg CR) rate of 83% (95% confidence interval [CI]: 68-93%) was obtained. Four-week mortality was 2% (95% CI: 0-13%). One-year overall survival (OS) and EFS were 80% (95% CI: 69-94%) and 76% (95% CI 64-90%), without significant difference in MRDneg CR rates, OS, or EFS between patients with or without FLT3-mutated disease. Comparing outcomes with CLAG-M/sorafenib to a matched cohort of 76 patients treated with CLAG-M alone, multivariable adjusted survival estimates were improved for the 41 patients receiving CLAG-M/sorafenib at RP2D (OS: hazard ratio [HR]=0.24 [95% CI: 0.07-0.82], P=0.023; EFS: HR=0.16 [95% CI: 0.05-0.53], P=0.003). Statistically significant benefit was limited to patients with intermediate-risk disease (in univariate analysis, P=0.01 for OS and P=0.02 for EFS). These data suggest CLAG-M/sorafenib is safe and improves OS and EFS relative to CLAG-M alone, with benefit primarily for patients with intermediate-risk disease. The trial is registered on clinicialtrials.gov as NCT02728050.

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

Phase 1/2 study of PRO1160, a CD70-directed antibody-drug conjugate, in patients with advanced solid tumors and hematologic malignancies

Abstract Background: PRO1160 is a novel antibody-drug conjugate (ADC) directed to CD70, an antigen mediating immuno-suppression that is overexpressed in multiple solid tumors and hematologic malignancies, with limited distribution in normal tissues. PRO1160 comprises (1) a human monoclonal antibody specific for CD70, (2) a protease-cleavable proprietary hydrophilic linker, and (3) exatecan, a topoisomerase 1 inhibitor. Comprehensive prior work demonstrated that the hydrophilic linker confers excellent physicochemical properties and pharmacokinetics (PK) across a range of payload mechanisms and is superior to conventional linkers on these critical parameters for ADCs. In addition, exatecan is broadly active in many tumor types, is membrane permeable, and is not a substrate of multidrug resistance pumps, thus likely lending strong bystander effects and durable treatment responses. PRO1160 is highly potent in cell-derived xenograft models of renal cell carcinoma (RCC), non-Hodgkin lymphoma (NHL), and nasopharyngeal carcinoma (NPC). PRO1160 also demonstrates marked antitumor activity in patient-derived xenograft models of diverse tumor sites, histologies, molecular subtypes, target expression levels, and Epstein Barr Virus status. PRO1160 is stable in circulation and displays PK characteristics indistinguishable from the parent antibody in rats. In a GLP toxicity study in cynomolgus monkeys, the primary PRO1160-related toxicity resided in the thymus and bone marrow, was consistent with exatecan toxicities, and was reversible. PRO1160-001 is an ongoing, open-label Phase 1/2 study to evaluate the safety, tolerability, PK, and antitumor activity of PRO1160 in patients with metastatic RCC, metastatic or relapsed NPC, or advanced relapsed/refractory NHL. Patients must have measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or the Lugano Classification for NHL. Patients must also have previously received therapies known to confer clinical benefit unless considered ineligible, refused by the patient, or not available in the region. PRO1160 is given by intravenous infusion on Day 1 of a 21-day cycle and treatment may continue until disease progression, unacceptable toxicity, or other reason for discontinuation. The primary objectives are to evaluate the safety and tolerability of PRO1160 and to identify the maximum tolerated dose, if reached, and recommended phase 2 dose (RP2D). This study consists of 2 parts, Part A: dose-escalation and dose-level expansion, and Part B: 3 tumor-specific expansion cohorts (metastatic RCC, metastatic or relapsed NPC, or advanced relapsed/refractory NHL) treated at the RP2D. PK, immunogenicity, and antitumor activity will also be evaluated. The study is currently enrolling at sites in the US, with future enrollment in China planned (Clinicaltrials.gov: NCT05721222).

Palbociclib in combination with chemotherapy in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia and lymphoma: A Children's Oncology Group study (AINV18P1).

Cyclin D has been shown to play an essential role in acute lymphoblastic leukemia (ALL) initiation and progression, providing rationale for targeting the CDK4/6-cyclin D complex that regulates cell cycle progression. The Children's Oncology Group AINV18P1 phase 1 trial evaluated the CDK4/6 inhibitor, palbociclib, in combination with standard four-drug re-induction chemotherapy in children and young adults with relapsed/refractory B- and T-cell lymphoblastic leukemia (ALL) and lymphoma. Palbociclib (50mg/m2 /dose) was administered orally once daily for 21 consecutive days, first as a single agent (Days 1-3) and subsequently combined with re-induction chemotherapy. This two-part study was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D), followed by an expansion pharmacokinetic cohort. Twelve heavily pretreated patients enrolled, all of whom were evaluable for toxicity. One dose-limiting hematologic toxicity (DLT) occurred at the starting dose of 50mg/m2 /dose orally for 21days. No additional DLTs were observed in the dose determination or pharmacokinetic expansion cohorts, and overall rates of grade 3/4 nonhematologic toxicities were comparable to those observed with the chemotherapy platform alone. Five complete responses were observed, two among four patients with T-ALL and three among seven patients with B-ALL. Pharmacokinetic studies showed similar profiles with both liquid and capsule formulations of palbociclib. Palbociclib in combination with re-induction chemotherapy was well tolerated with a RP2D of 50mg/m2 /day for 21days. Complete responses were observed among heavily pretreated patients.

Targeted therapy with nanatinostat and valganciclovir in recurrent EBV-positive lymphoid malignancies: a phase 1b/2 study

AbstractLymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several subtypes. Nanatinostat is a class-I selective oral histone deacetylase inhibitor that induces the expression of lytic EBV BGLF4 protein kinase in EBV+ tumor cells, activating ganciclovir via phosphorylation, resulting in tumor cell apoptosis. This phase 1b/2 study investigated the combination of nanatinostat with valganciclovir in patients aged ≥18 years with EBV+ lymphomas relapsed/refractory to ≥1 prior systemic therapy with no viable curative treatment options. In the phase 1b part, 25 patients were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 dose (RP2D) for phase 2 expansion. Phase 2 patients (n = 30) received RP2D (nanatinostat 20 mg daily, 4 days per week with valganciclovir 900 mg orally daily) for 28-day cycles. The primary end points were safety, RP2D determination (phase 1b), and overall response rate (ORR; phase 2). Overall, 55 patients were enrolled (B–non-Hodgkin lymphoma [B-NHL], [n = 10]; T-cell/natural killer cell-NHL, [n = 21]; classical Hodgkin lymphoma, [n = 11]; and immunodeficiency-associated lymphoproliferative disorders, [n = 13]). The ORR was 40% in 43 evaluable patients (complete response rate [CRR], 19% [n = 8]) with a median duration of response of 10.4 months. For T-cell/natural killer cell-NHL (n = 15; all refractory to the last prior therapy), the ORR/CRR ratio was 60%/27%. The most common adverse events were nausea (38% any grade) and cytopenia (grade 3/4 neutropenia [29%], thrombocytopenia [20%], and anemia [20%]). This novel oral regimen provided encouraging efficacy across several EBV+ lymphoma subtypes and warrants further evaluation; a confirmatory phase 2 study (NCT05011058) is underway. This phase 1b/2 study is registered at www.clinicaltrials.gov as #NCT03397706.

AdvanTIG-105: Phase 1b dose-expansion study of ociperlimab (OCI) + tislelizumab (TIS) with chemotherapy (chemo) in patients (pts) with stage IV gastric/gastroesophageal adenocarcinoma (GC/GEJC).

31 Background: T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) inhibitor in combination with an anti-programmed cell death protein 1 (PD-1) antibody has shown antitumor activity in solid tumors. AdvanTIG-105 (NCT04047862) is a phase 1/1b open-label study designed to assess the safety and preliminary antitumor activity of OCI, an anti-TIGIT monoclonal antibody (mAb), + TIS, an anti-PD-1 mAb, in pts with unresectable, locally advanced or metastatic solid tumors. In the dose-escalation part, OCI + TIS was well tolerated with preliminary antitumor activity observed, and the recommended phase 2 dose (RP2D) of OCI 900 mg intravenously (IV) every three weeks (Q3W) + TIS 200 mg IV Q3W was established. We report results from the dose-expansion part (GC/GEJC Cohort 9) of the AdvanTIG-105 study. Methods: Eligible pts had histologically/cytologically confirmed stage IV GC/GEJC. Pts were excluded if they had squamous cell, undifferentiated or other histological types of GC, had GC/GEJC with positive HER2 expression, or if they had received any prior therapy for metastatic disease. Pts received either the RP2D of OCI + TIS with oxaliplatin + capecitabine Q3W for 6 cycles (C), followed by maintenance therapy with the RP2D of OCI + TIS, + capecitabine Q3W, or the RP2D of OCI + TIS with cisplatin + 5-fluorouracil Q3W for 6 C. Treatment continued until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DoR), disease control rate (DCR) per RECIST v1.1, and safety. Results: As of September 29, 2022, 60 pts with a median age of 61.5 years (range 35-82) were enrolled; 59 were efficacy evaluable. Median study follow-up was 31.1 weeks (range 1.4-78.4). ORR was 50.8% (95% CI: 37.5, 64.1); DCR was 84.7% (95% CI: 73.0, 92.8) with a median DoR of 8.1 months (95% CI: 4.5, not evaluable [NE]). Median PFS was 8.2 months (95% CI: 5.8, NE). In a subgroup analysis, ORR in pts with PD-L1 tumor area positivity (TAP) score ≥5% (n=27) was 59.3% (95% CI: 38.8, 77.6), and 50.0% (95% CI: 30.7, 69.4) in pts with PD-L1 TAP &lt;5% (n=28). All 60 pts reported ≥1 treatment-emergent adverse event (TEAE), the most common being anemia (43.3%) and platelet count decreased (41.7%). In total, 43 pts (71.7%) had ≥grade 3 TEAEs and 28 (46.7%) had serious adverse events. TEAEs leading to discontinuation of TIS and OCI occurred in 5 (8.3%) pts. TEAEs led to death in 2 (3.3%) pts; one event (neutropenic sepsis) was related to chemo, while the other (pulmonary embolism) was not treatment related. Conclusions: OCI 900 mg + TIS 200 mg + chemo was generally well tolerated and showed encouraging antitumor activity in pts with stage IV GC/GEJC. Clinical trial information: NCT04047862 .

Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Advanced Solid Tumors.

In this first-in-human, Phase 1, open-label, multicenter study, we evaluated JNJ-64619178, a selective and potent PRMT5 inhibitor, in patients with advanced malignant solid tumors or non-Hodgkin lymphomas (NHL). The primary objective was to evaluate the safety and to identify a recommended Phase 2 dose (RP2D) of JNJ-64619178. Adult patients with treatment-refractory advanced solid tumors or NHL and measurable disease received escalating doses of JNJ-64619178 following two schedules (Schedule A: 14 days on/7 days off; Schedule B: every day on a 21-day cycle). Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity were evaluated. Ninety patients received JNJ-64619178. Thrombocytopenia was identified as the only dose-limiting toxicity. JNJ-64619178 showed dose-proportional PK and robust target engagement, as measured by plasma symmetric dimethylarginine, across all dose levels. The objective response rate was 5.6% (5 of 90). Patients with adenoid cystic carcinoma (ACC) had an ORR of 11.5% (3 of 26) and a median progression-free survival of 19.1 months. JNJ-64619178 demonstrated manageable dose-dependent toxicity and preliminary evidence of antitumor activity in ACC and other tumor types. Plasma exposure was dose dependent, and target inhibition was maintained with intermittent and continuous dosing. On the basis of safety, clinical activity, PK, and PD findings, two provisional RP2Ds were selected: 1.5 mg intermittently and 1.0 mg once daily. Aside from ACC, clinical benefit was limited, and biomarkers to enrich for responsiveness to PRMT5 inhibition will be needed for further development.

Mesothelin-targeting T cell receptor fusion construct cell therapy in refractory solid tumors: phase 1/2 trial interim results

The T cell receptor fusion construct (TRuC) gavocabtagene autoleucel (gavo-cel) consists of single-domain anti-mesothelin antibody that integrates into the endogenous T cell receptor (TCR) and engages the signaling capacity of the entire TCR upon mesothelin binding. Here we describe phase 1 results from an ongoing phase1/2 trial of gavo-cel in patients with treatment-refractory mesothelin-expressing solid tumors. The primary objectives were to evaluate safety and determine the recommended phase 2 dose (RP2D). Secondary objectives included efficacy. Thirty-two patients received gavo-cel at increasing doses either as a single agent (n = 3) or after lymphodepletion (LD, n = 29). Dose-limiting toxicities of grade 3 pneumonitis and grade 5 bronchioalveolar hemorrhage were noted. The RP2D was determined as 1 × 108 cells per m2 after LD. Grade 3 or higher pneumonitis was seen in 16% of all patients and in none at the RP2D; grade 3 or higher cytokine release syndrome occurred in 25% of all patients and in 15% at the RP2D. In 30 evaluable patients, the overall response rate and disease control rate were 20% (13% confirmed) and 77%, respectively, and the 6-month overall survival rate was 70%. Gavo-cel warrants further study in patients with mesothelin-expressing cancers given its encouraging anti-tumor activity, but it may have a narrow therapeutic window. ClinicalTrials.gov identifier: NCT03907852.