Modified Toxicity Probability Interval Research Articles

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 .

Phase I trial of KN046, a novel bispecific antibody targeting PD-L1 and CTLA-4 in patients with advanced solid tumors

BackgroundKN046 is a novel bispecific antibody targeting programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). This multicenter phase I trial investigated the safety, tolerability, pharmacokinetics (PK),...

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.

Interim Phase I Clinical Data of FT576 As Monotherapy and in Combination with Daratumumab in Subjects with Relapsed/Refractory Multiple Myeloma

Introduction: Despite the recent FDA approval of autologous chimeric antigen receptor (CAR) T-cell therapies targeting B-cell maturation antigen (BCMA), multiple myeloma (MM) remains incurable and relapsed/refractory (R/R) disease remains an area of high unmet medical need. Additionally, patient access to autologous CAR T-cell therapies is currently limited due to manufacturing constraints, the need for bridging therapy, and potentially life-threatening toxicities including cytokine release syndrome and neurologic toxicities (Munshi et al. 2021). Off-the-shelf natural killer (NK) cell therapies may offer an improved therapeutic profile and broader patient access than autologous CAR T-cell therapies. FT576 is a first-of-kind, multiplexed-engineered BCMA CAR NK cell therapy generated from a clonal master engineered induced pluripotent stem cell line, which can be used as a renewable source for the mass production of off-the-shelf NK cells of uniform composition. FT576 is engineered with 4 modalities to combine multifaceted innate immunity with multi-antigen-targeting capability: (1) high-affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor for augmented antibody-dependent cellular cytotoxicity; (2) IL-15/IL-15 receptor fusion that promotes NK cell persistence; (3) CD38 knockout to mitigate NK cell fratricide by CD38-directed monoclonal antibodies (mAbs) and that provides improved metabolic fitness and resistance to oxidative stress within the tumor microenvironment; and (4) a BCMA-directed CAR to target plasma cells. These modalities are designed to enhance the potency and persistence of FT576 and to enable multi-antigen targeting when combined with tumor-targeting mAbs. In preclinical studies, FT576 combined with the anti-CD38 mAb daratumumab demonstrated highly effective tumor control compared to either treatment alone or to primary CAR T cells in a disseminated MM xenograft model (Goodridge et al. 2021), suggestive that limitations in MM treatment confounded by clonal heterogeneity and antigen loss can be overcome with a dual antigen-targeting approach. Methods: This is a Phase I trial of FT576 in patients with R/R MM. The primary objectives are to assess safety and tolerability and to determine the recommended Phase II dose of FT576, given as single or multiple doses, as monotherapy and in combination with daratumumab in R/R MM. Key secondary objectives include anti-tumor activity and pharmacokinetics. The dose-escalation stage of the trial has the following 4 arms: single-dose FT576 monotherapy on Day 1 (Regimen A); multi-dose FT576 monotherapy on Days 1 and 15 (Regimen A1); single-dose FT576 + daratumumab on Day 1 (Regimen B); and multi-dose FT576 + daratumumab on Days 1 and 15 (Regimen B1). Dose levels of FT576 starting from 100 million cells/dose are being evaluated using a modified toxicity probability interval dose-escalation design. Daratumumab is administered per approved dose and schedule. Outpatient conditioning chemotherapy consists of 3 consecutive days of fludarabine and cyclophosphamide administered prior to the first dose of FT576. Results: As of a data cutoff date of 18 Jul 2022, 9 patients with R/R MM were treated and evaluable for safety and efficacy, in the first 2 dose levels of Regimen A (n = 6) and in the first dose level of Regimen B (n = 3). No dose-limiting toxicities, and no events of any grade of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome, or graft-versus-host disease (GvHD), were observed. Conclusions: Administration of a single dose of FT576 at 100 or 300 million cells/dose alone or in combination with daratumumab is safe and well tolerated thus far without CRS, neurotoxicity, or GvHD. Interim clinical data, including safety and tolerability and initial anti-tumor activity, from the ongoing Phase I dose-escalation study of FT576 will be presented at the conference.

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.

CUSUMIN: A cumulative sum interval design for cancer phase I dose finding studies.

Recently, model-assisted designs, including the Bayesian optimal interval (BOIN) design with optimal thresholds to determine the dose for the next cohort, have been proposed for cancer phase I studies. Model-assisted designs are useful because of their good performance as model-based designs in addition to their algorithm-based simplicity. In BOIN, escalation and de-escalation based on boundaries can be understood as a type of change point detection based on a sequential test procedure. Notably, the sequential test procedure is used in a wide range of fields and is known for its application to control charts, statistical monitoring methods used for detecting abnormalities in manufacturing processes. In control charts, abnormalities are detected if the control chart statistics are observed to be outside of the optimal boundaries. The cumulative sum (CUSUM) statistic, which is developed for control chart applications, derives higher power under the same erroneous judgment rate. Hence, it is expected that a more efficient model-assisted design can be achieved by the application of CUSUM statistics. In this study, a model-assisted design based on the CUSUM statistic is proposed. In the proposed design, the dose for the next cohort is decided by CUSUM statistics calculated from the counts of the dose-limiting toxicity and pre-defined boundaries, based on the CUSUM control chart scheme. Intensive simulation shows that our proposed method performs better than BOIN, and other representative model-assisted designs, including modified toxicity probability interval (mTPI) and Keyboard, in terms of controlling over-dosing rates while maintaining similar performance in the determination of maximum tolerated dose.

A phase Ib dose-escalation study of troriluzole (BHV-4157), an oral glutamatergic signaling modulator, in combination with nivolumab in patients with advanced solid tumors

BackgroundGlutamate signaling activates MAPK and PI3K/AKT pathways in tumor cells. Treatment with riluzole, a glutamate release inhibitor, has been previously shown to be safe in melanoma patients and produced biologic effects, but did not lead to radiographic responses, possibly due to poor pharmacokinetic properties. Therefore, we conducted a phase Ib trial to determine the safety and tolerability of the combination of the riluzole prodrug troriluzole (BHV-4157, trigriluzole) and the PD-1 antibody nivolumab in patients with advanced solid tumors.MethodsPatients with advanced or refractory solid tumors and measurable disease per RECIST 1.1 were treated with increasing doses of troriluzole using a semi-Bayesian modified toxicity probability interval dose escalation procedure. Troriluzole monotherapy was orally self-administered for a 14-day lead-in period followed by continuation of troriluzole in combination with nivolumab 240 mg IV every 2 weeks. Endpoints included safety, pharmacokinetics (PK) and efficacy.ResultsWe enrolled 14 patients with advanced solid tumors (melanoma = 3, NSCLC = 3, renal cell carcinoma = 2, bladder/urothelial = 2, ovarian cancer = 1, adenoid cystic carcinoma = 1, pleural mesothelial = 1, head and neck cancer = 1). Eleven patients had cancer progression on prior therapy with PD-1 or PD-L1 agent. Patients received troriluzole total daily doses from 140 to 560 mg (divided). The most common treatment-related adverse events (TRAE) occurring in ≥ 5 patients (> 35%) were transaminitis and increased lipase. DLT (dose-limiting toxicity) occurred in 3 patients: (1) grade 3 anorexia, (2) grade 3 fatigue and, (3) grade 3 atrial fibrillation. Six patients were treated at the MTD (maximum tolerated dose). No subjects discontinued treatment due to AEs. One response occurred (7%), which was a partial response in a subject who had PD-1 refractory disease. The 6-month PFS rate was 21%. PK data showed that the prodrug troriluzole was efficiently cleaved into riluzole by 2-h post-dosing in all dose cohorts tested.ConclusionThe combination of troriluzole and nivolumab was safe and well-tolerated. The MTD of troriluzole was determined to be 420 mg total daily dose. The observed antitumor activity, primarily disease stabilization, is of interest in patients with PD-1 resistant tumors.Trial Registration ClinicalTrials.gov Identifier NCT03229278.

A semi-mechanistic dose-finding design in oncology using pharmacokinetic/pharmacodynamic modeling.

While a number of phase I dose-finding designs in oncology exist, the commonly used ones are either algorithmic or empirical model-based. We propose a new framework for modeling the dose-response relationship, by systematically incorporating the pharmacokinetic (PK) data collected in the trial and the hypothesized mechanisms of the drug effects, via dynamic PK/PD modeling, as well as modeling of the relationship between a latent cumulative pharmacologic effect and a binary toxicity outcome. This modeling framework naturally incorporates the information on the impact of dose, schedule and method of administration (e.g., drug formulation and route of administration) on toxicity. The resulting design is an extension of existing designs that make use of pre-specified summary PK information (such as the area under the concentration-time curve [AUC] or maximum serum concentration [Cmax ]). Our simulation studies show, with moderate departure from the hypothesized mechanisms of the drug action, that the performance of the proposed design on average improves upon those of the common designs, including the continual reassessment method (CRM), Bayesian optimal interval (BOIN) design, modified toxicity probability interval (mTPI) method, and a design called PKLOGIT that models the effect of the AUC on toxicity. In case of considerable departure from the underlying drug effect mechanism, the performance of the design is shown to be comparable with that of the other designs. We illustrate the proposed design by applying it to the setting of a phase I trial of a γ-secretase inhibitor in metastatic or locally advanced solid tumors. We also provide R code to implement the proposed design.

P1086: FAVEZELIMAB (ANTI–LAG-3) AND PEMBROLIZUMAB CO-BLOCKADE IN ANTI–PD-1–NAIVE PATIENTS WITH RELAPSED OR REFRACTORY CLASSICAL HODGKIN LYMPHOMA: AN OPEN-LABEL PHASE 1/2 STUDY

Background: Programmed cell death 1 (PD-1) inhibitors are a standard of care in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL), but clinical interest persists for new approaches to deepen and lengthen responses. Dual blockade of PD-1 and lymphocyte-activation gene 3 (LAG-3) has demonstrated antitumor activity in preclinical models. Aims: The multicohort phase 1/2 MK-4280-003 study (NCT03598608) evaluated the safety and efficacy of favezelimab (MK-4280), a humanized Immunoglobulin G4 LAG-3 inhibitor, plus pembrolizumab (a PD-1 inhibitor) in patients with R/R hematologic malignancies. This analysis focused on anti–PD-1–naïve patients with R/R cHL (cohort 1). Methods: This study included a safety lead-in phase (part 1) to determine the recommended phase 2 dose (RP2D) followed by a dose-expansion phase (part 2). Eligible patients in cohort 1 must have had R/R cHL after autologous stem cell transplantation (ASCT) or been ineligible for ASCT and have had no prior anti–PD-1 therapy. In part 1, patients from all cohorts received intravenous (IV) pembrolizumab 200 mg every 3 weeks (Q3W) and favezelimab IV 200 mg or 800 mg Q3W. Dose-finding based on occurrence of dose-limiting toxicities (DLTs) was determined using a modified toxicity probability interval design. In part 2, patients received pembrolizumab + favezelimab at the established RP2D for up to 2 years (35 cycles), or until documented disease progression, adverse events (AEs), or withdrawal from the study. Primary end point was safety, including DLTs and AEs. Secondary end point was objective response rate (ORR). Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were exploratory end points. Results: Only 1 DLT (autoimmune hepatitis [grade 4]) was identified among the first 6 patients from all cohorts included in part 1 at the favezelimab 200 mg dose; thus, the dose was escalated to 800 mg. No DLTs were observed in the 15 additional patients treated at the 800 mg dose. The RP2D for the combination was defined as 800 mg Q3W + pembrolizumab 200 mg Q3W. In cohort 1, 30 patients were enrolled; median age was 40 years, 53% had ECOG PS 0, and 80% had no more than 3 prior lines of therapy. As of the database cutoff (Nov 1, 2021), 9 of 30 (30%) patients had discontinued treatment either due to adverse events (n=3) or disease progression (n=6). After a median follow-up of 13.5 months, ORR for cohort 1 was 73% (95% CI, 54-88; complete response, 7 patients [23%]; partial response, 15 patients [50%]). 28 of 30 patients (93%) had a reduction from baseline in target lesions. Median DOR was not reached ([NR]; 95% CI, 0+ to 23+ months) and 6 patients (51%) had response ≥12 months. The median PFS was 19 months (95% CI, 8-NR) and the 12-month PFS rate was 57%. The median OS was NR (95% CI, NR-NR) and the 12-month OS rate was 94%. Treatment-related AEs (TRAE) occurred in 26 patients (87%); most common (≥10%) were hypothyroidism (27%), fatigue (20%), infusion-related reactions (20%), headache (17%), and arthralgia, hyperthyroidism, myalgia, and nausea (10% each). Grade 3 or 4 TRAEs occurred in 6 patients (20%) and 10% of patients discontinued due to TRAEs. No treatment-related deaths occurred. Summary/Conclusion: Favezelimab 800 mg + pembrolizumab 200 mg Q3W demonstrated an acceptable safety profile and effective antitumor activity in anti–PD-1–naïve patients with R/R cHL. Further studies are merited to compare the activity of this combination to that of pembrolizumab alone.

P1087: FAVEZELIMAB (ANTI–LAG-3) AND PEMBROLIZUMAB CO-BLOCKADE IN PATIENTS WITH RELAPSED OR REFRACTORY CLASSICAL HODGKIN LYMPHOMA WHO PROGRESSED AFTER ANTI–PD-1 THERAPY: AN OPEN-LABEL PHASE 1/2 STUDY

Background: PD-1 inhibitors are a standard of care for relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL), but optimal therapy is yet to be defined for patients whose disease progresses after anti–PD-1 treatment. Dual blockade of PD-1 and lymphocyte-activation gene 3 (LAG-3) has demonstrated antitumor activity in preclinical models. Aims: This multicohort phase 1/2 study (NCT03598608) evaluated safety and efficacy of favezelimab (MK-4280), a humanized IgG4 LAG-3 inhibitor, plus the PD-1 inhibitor pembrolizumab in patients with R/R hematologic malignancies. Cohort 2 focused on patients with R/R cHL refractory to anti–PD-1 therapy. Methods: This study included a safety lead-in phase (part 1) to determine recommended phase 2 dose (RP2D) followed by a dose-expansion phase (part 2). Eligible patients in cohort 2 had R/R cHL, relapsed after or were ineligible for autologous stem cell transplantation (ASCT), and progressed after ≥2 doses of anti–PD-1 therapy (within 12 weeks of last dose). In part 1, patients from all cohorts received intravenous (IV) pembrolizumab 200 mg every 3 weeks (Q3W) and favezelimab IV 200 mg or 800 mg Q3W. Dose-finding based on occurrence of dose-limiting toxicities (DLT) was determined using a modified toxicity probability interval design. In part 2, patients received pembrolizumab + favezelimab at the established RP2D for up to 2 years (35 cycles), or until documented disease progression, adverse events (AEs), or withdrawal from study. Primary end point was safety, including DLTs and AEs. Secondary end point was objective response rate (ORR). Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were exploratory end points. Results: Only 1 DLT (autoimmune hepatitis [grade 4]) was observed among the first 6 patients from all cohorts included in part 1 at the favezelimab 200 mg dose; thus, the dose was escalated to 800 mg. No DLTs were observed in the 15 additional patients at the 800 mg dose. Favezelimab RP2D was defined as 800 mg Q3W + pembrolizumab 200 mg Q3W. In cohort 2, 33 patients were enrolled; median age was 37 years, 64% had ECOG PS 0, and 94% had at least 4 prior lines of therapy. At database cutoff (Nov 1, 2021), 20 patients had discontinued treatment due to adverse events (n=7); disease progression or clinical progression (n=11); or withdrawal/physician decision (n=2). After a median follow-up of 16.5 months, ORR for patients receiving favezelimab 800 mg (n=29) was 31% (95% CI, 15-51; complete response, 2 [7%]; partial response, 7 [24%]). 19 of 29 responders (66%) had an anti–PD-1–based regimen as their most recent line of therapy at study entry. 23 of 29 patients (79%) had a reduction from baseline in target lesions. Median DOR for patients who received favezelimab 800 mg was not reached ([NR]; 95% CI, 0+ to 14+ months). For all patients in cohort 2, the median PFS was 9 months (95% CI, 5-15); 12-month PFS rate was 39%. Median OS was 26 months (95% CI, 26-NR); 12-month OS rate was 91%. Treatment-related AEs (TRAE) occurred in 28 patients (85%); most common (>10%) were hypothyroidism (18%), nausea and fatigue (15% each), and arthralgia and diarrhea (12% each). Grade 3 or 4 TRAEs occurred in 6 patients (18%) and 18% of patients discontinued treatment due to TRAEs. No treatment-related deaths occurred. Summary/Conclusion: Favezelimab 800 mg + pembrolizumab 200 mg Q3W showed a tolerable safety profile and effective antitumor activity in heavily pretreated patients with R/R cHL whose disease had progressed after anti–PD-1 therapy, suggesting that the combination may reinduce a response in these patients.

Abstract CT242: KRYSTAL-16: A phase I/Ib trial of adagrasib (MRTX849) in combination with palbociclib in patients with advanced solid tumors with KRASG12C mutation

Abstract Background: KRAS is a key mediator of the RAS/MAPK signaling cascade and promotes cellular growth and proliferation. It is the most frequently mutated oncogene in cancer, and KRASG12C mutations occur in 3-4% of colorectal cancers (CRC) and in up to 14% of non-small-cell lung cancers (NSCLC). The investigational agent adagrasib, a potent, covalent inhibitor of KRASG12C, irreversibly and selectively binds to KRASG12C and locks it in its inactive state. Adagrasib was optimized for favorable pharmacokinetic (PK) properties, including long half-life (~24 h), dose-dependent PK, and central nervous system penetration. Initial results have shown encouraging antitumor activity and tolerability of adagrasib monotherapy or combination therapy in patients with CRC or NSCLC harboring KRASG12C mutations. Cyclin D1 and cyclin-dependent kinases (CDK) 4 and 6 are downstream of signaling pathways that lead to cellular proliferation. Palbociclib, a CDK4/6 inhibitor, disrupts cancer cell proliferation by inducing cell cycle arrest by preventing the G1 to S phase transition. Preclinical data in KRASG12C mouse models suggest enhanced antitumor activity when combining adagrasib and palbociclib compared with either agent as a monotherapy. Trial Design: KRYSTAL-16 (NCT05178888) is a multicenter phase I/Ib trial evaluating the safety, PK, pharmacodynamics, and preliminary clinical activity of adagrasib in combination with palbociclib in patients with solid tumors harboring a KRASG12C mutation previously treated with at least 1 standard therapy. The first stage of the trial will comprise a PK lead-in to evaluate potential drug-drug interactions. Exploration of the dose and regimen will continue for the combination of adagrasib (starting dose 400 mg BID) and palbociclib, with expansion cohorts implemented as applicable to further evaluate the safety and preliminary clinical activity of the combination. Decisions regarding dose escalation, expansion, or de-escalation will be determined using the modified Toxicity Probability Interval (mTPI-2) design. Study endpoints include safety, maximum tolerated dose (MTD) and/or recommended Phase II combination dose regimen (RP2D), plasma PK parameters, and preliminary clinical activity (objective response rate [RECIST v1.1], duration of response, progression-free survival, and overall survival). Patients will receive treatment until disease progression, unacceptable adverse events, patient withdrawal, or death. This study will be enrolling at sites in the United States. Citation Format: David Sommerhalder, Jeena Thevathasan, Xenophon Ianopulos, Weining Volinn, David Hong. KRYSTAL-16: A phase I/Ib trial of adagrasib (MRTX849) in combination with palbociclib in patients with advanced solid tumors with KRASG12C mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT242.

Abstract CT209: A first-in-human phase 1 trial of IO-108, an antagonist antibody targeting LILRB2 (ILT4), as monotherapy and in combination with pembrolizumab in adult patients with advanced relapsed or refractory solid tumors (NCT05054348)

Abstract Cancer immunotherapy has entered the mainstream with approval of T-cell checkpoint inhibitors. However, most patients with advanced solid tumors do not derive benefits, or relapse after T-cell checkpoint blockade. Myeloid checkpoint inhibition is a new approach to cancer immunotherapy. LILRB2 is primarily expressed by myeloid cells and its expression in tumors is associated with high macrophage infiltration. Several LILRB2 ligands (HLA-G, ANGPTL2, and SEMA4A) are known to contribute to the immune suppressive microenvironment of solid tumors. Blockade of the LILRB2 pathway has the potential to reactivate or enhance anti-tumor T cell immune responses. IO-108 is a IgG4 monoclonal antibody that specifically binds LILRB2 to block ligands interaction and activation of LILRB2. In vitro, IO-108 treatment of primary immune cells results increased pro-inflammatory responses and an enhanced antigen presenting cell phenotypes. A Good Laboratory Practice repeat-dose, 15-day toxicology study in Cynomolgus monkeys at 0 (control), 1, 10, or 100 mg/kg/dose administered intravenously once weekly for a total of 3 doses showed that IO-108 was well-tolerated at all dose levels, with only non-statistically significant reduction of thyroid glands weight. No-observed-adverse-effect-level (NOAEL) of 100 mg/kg provides a sufficient safety margin for the IO-108 starting dose of 60 mg, which was derived using a MABEL (minimum anticipated biological effect level) approach. This clinical trial is a first-in-human, Phase 1, multicenter, open-label, dose-escalation, safety, pharmacokinetic (PK), and pharmacodynamic evaluation of intravenously administered IO-108, both as monotherapy and in combination with pembrolizumab, in adult patients with solid tumors that have failed standard of care therapies (NCT05054348). It is estimated that up to 36 patients will be enrolled in the study. IO-108 will be administered every 21 days, with a dose-limiting toxicity (DLT) evaluation period of 21 days. Patients will be enrolled into sequential cohorts and treated with increasing doses of IO-108 using mTPI (modified Toxicity Probability Interval) method. Safety, PK, and clinical activity will be evaluated on an ongoing basis. The primary objective of the study is to assess safety and tolerability at increasing dose levels of IO-108 in successive cohorts of adult patients (treated with or without with pembrolizumab) with advanced relapsed or refractory solid tumors, to estimate the maximal tolerated dose (MTD) or maximum administered dose (MAD) and select the recommended phase 2 dose (RP2D). Secondary objectives include characterizing PK, immunogenicity, and preliminary anti-tumor activity. Biomarker evaluation will include changes in myeloid cell markers and T-cells, LILRB2 expression level and receptor occupancy. Statistical analyses will be primarily descriptive in nature. Tabulations will be produced for appropriate disposition, demographic, baseline disease characteristics, safety, PK, pharmacodynamic, and clinical activity parameters. Response to treatment as assessed by RECIST v1.1 will be tabulated. To date, five patients have been dosed without DLT. Citation Format: John Powderly, Manish Patel, Paul Woodard, Luke Chung, Hongyu Tian, Elizabeth Wieland, Kyu Hong, Maria Jose Costa, X. Charlene Liao, Matthew Taylor. A first-in-human phase 1 trial of IO-108, an antagonist antibody targeting LILRB2 (ILT4), as monotherapy and in combination with pembrolizumab in adult patients with advanced relapsed or refractory solid tumors (NCT05054348) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT209.

Abstract CT152: Phase I study of MT-6402, a novel engineered toxin body (ETB) targeting PD-L1, in patients with PD-L1 expressing advanced solid tumors

Abstract This is the first-in-human study of MT-6402, a unique, first-in-class potent PD-L1-targeted engineered toxin body (ETB) capable of direct killing of PD-L1 expressing cells via rapid PD-L1-mediated internalization of a fused Shiga-like toxin A subunit (SLTA) resulting in permanent ribosomal inactivation. MT-6402 also delivers an HLA-A*02 restricted pp65 cytomegalovirus (CMV) antigen into PD-L1 expressing tumor cells leading to MHC-I presentation to existing CMV-specific cytotoxic T cells (antigen seeding). MT-6402 functions by targeting tumor and inhibitory immune cells directly and altering tumor immunophenotype to re-direct antiviral cytotoxic T cells into the tumor microenvironment. MT-6402 shows picomolar cytotoxic activity across several PD-L1 expressing cancer cell lines and treatment of human PBMCs results in selective depletion of PD-L1 positive cells. MT-6402 was well tolerated in non-human primates at doses above those which induce pharmacodynamic (PD) effect (reduction of CD14+ monocytes) in humans. This first-in-human study in patients with PD-L1-expressing advanced solid tumors will employ a modified toxicity probability interval design to determine MTD and will then enroll additional subjects at the MTD, to further explore safety and efficacy and determine RP2D. Results of the first dose cohort (16 micrograms/kg) are presented. Six patients received MT-6402. A significant and sustained reduction in CD14+ monocytes starting in cycle 2 was observed in patients on therapy beyond one cycle and was maintained with each MT-6402 administration, indicating HLA-independent PD effect consistent with preclinical observations. One HLA-A*02 and CMV+ patient with osseous metastases from NSCLC showed marked CMV-specific T-cell extravasation at day 8 and serum cytokine signatures consistent with antigen dependent responses and T cell mobilizations, suggesting engagement of MT-6402 antigen seeding. This patient has reduced intensity of metastatic bone lesions with 3/4 lesions resolving; the remaining lesion showing reduced uptake. Two patients had cytokine elevations at day 15, manifested by transient (1-12h), grade 2 infusion-related reactions and grade 2 cytokine release syndrome, which were subsequently prevented by steroid premedication. These results describe a novel approach to checkpoint modulation, leveraging direct PD-L1 cell kill and antigen seeding technology by the ETB. The results support further dose escalation and hold promise for development of MT-6402 for solid tumors, including in the R/R setting. Citation Format: David R. Spigel, Eugene Ahn, Herbert L. Duvivier, Drew Rasco, Agnes Rethy, Chris Moore, Amy Yuet, Sandra Hankins, Swati Khanna, Joseph Dekker, Brian Van Tine. Phase I study of MT-6402, a novel engineered toxin body (ETB) targeting PD-L1, in patients with PD-L1 expressing advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT152.

Abstract 5579: First-in-human study of ICAM-1-specific affinity tuned CAR T cells against advanced thyroid cancer

Abstract Background: The use of chimeric antigen receptor (CAR) T cells for solid tumors has a number of challenges, such as lack of tumor-specific targets, CAR T cell exhaustion, and the immunosuppressive tumor microenvironment. To address these challenges, AffyImmune has developed technologies to affinity tune and track CAR T cells in patients. The targeting moiety is affinity tuned to preferentially bind to tumor cells overexpressing the target while leaving normal cells with low basal levels untouched, thereby increasing the therapeutic window and allowing for more physiological T cell killing. The CAR T cells are engineered to co-express somatostatin receptor 2 (SSTR2), which allows for the tracking of CAR T cells in vivo via PET/CT scan using FDA-approved DOTATATE. Methods: AIC100 was generated by affinity tuning the I-domain of LFA-1, the physiological ligand to ICAM-1. Various mutants with 106-fold difference in affinity were evaluated for structure activity relationships using targets with varying antigen densities. The AIC100 with micromolar affinity was clearly the most effective in non-clinical animal models. AIC100 is currently being evaluated to assess safety, CAR T expansion, tumor localization, and preliminary activity in patients with advanced thyroid cancer (ATC) in a phase I study (NCT04420754). Our study uses a modified toxicity probability interval design with three dosage groups of 10 × 106, 100 × 106, and 500 × 106 cells. Results: Preclinical studies demonstrated greater in vivo anti-tumor activity and safety with micromolar affinity CAR T cells. A single dose of AIC100 resulted in tumor elimination and significantly improved survival of animals bearing ATC xenografts. AIC100 activity was confirmed in other high ICAM-1 tumor models including breast cancer, gastric cancer, and multiple myeloma. In a Phase I patient given 10 × 106 CAR T cells, near synchronous imaging of FDG and DOTATATE revealed preliminary evidence of transient CAR T expansion and tumor reduction at multiple tumor lesions, with the peak of CAR T cell density coinciding with the spike in CAR T cell numbers in blood. Conclusion: We have developed affinity tuned CAR T cells designed to selectively target ICAM-1 overexpressing tumor cells and to spatiotemporally image CAR T cells. Near-synchronous FDG and DOTATATE scans will enhance patient safety by early detection of off-tumor CAR T activity and validation of tumor response. We anticipate that our “tune and track” technology will be widely applicable to developing potent yet safe CAR T cells against hard-to-treat solid cancers. Citation Format: Jingmei Hsu, Yen-Michael Hsu, Koen van Besien, Thomas J. Fahey, Jana Ivanidze, Janusz Puc, Karrie Du, Yanping Yang, Yogindra Vedvyas, Irene M. Min, Eric von Hofe, Moonsoo M. Jin. First-in-human study of ICAM-1-specific affinity tuned CAR T cells against advanced thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5579.