Toxicity Probability Interval Design Research Articles

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 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.

PemBOv trial: Pembrolizumab plus bevacizumab with or without pegylated liposomal doxorubicin-based chemotherapy in patients with platinum-resistant ovarian cancer.

5575 Background: Few platinum resistant ovarian cancer (PROvC) patients respond to anti-PD1 monotherapy (ORR 7.6%) with little impact on survival (OS 10.1 mo). Among responders the median duration of response is impressive (18.7 mo) (Hamanishi 2021). Methods: We have evaluated the combination of pembrolizumab (200mg), with bevacizumab (400mg) for 6 cycles plus minus peglyated liposomal doxorubicin (PLD) q3w in PROvC patients with no limit in previous treatment lines, allowed to be previously treated with bevacizumab. An initial safety run evaluated the dual combination of pembrolizumab plus PLD (cohort A). The triple combination was evaluated at MTD-1 and at MTD of PLD (30mg/m2 q3w) (cohort C). The dual combination of pembrolizumab + bevacizumab was run in parallel (cohort B). This is an open label phase I trial with a modified toxicity probability interval design. The evaluation criteria endpoints were safety and efficacy. Pharmacokinetics of bevacizumab were evaluated. NCT03596281 Results: A total of 47 patients (pts) were enrolled between January 2019 and February 2021. Median age was 70 years (38-77). 30/12 pts (63.8/25.5%) had an initial FIGO stage III/IV, 44 pts (93.6%) had a HGSOC. 40 pts (85.1%) underwent surgery, out of which 13 pts (32.5%) had a primary debulking. BRCA mutations were present in 9 pts (19.1%). Pts had a median of 3 previous treatment lines (0-13), including pretreatment with antiangiogenic agents in 36 (76.6%) and PARP inhibitors in 21 pts (44.7%). No DLT was reported. Grade 3/4 treatment-related adverse events were reported in 2 pts (30%), 4 (20%) and 11 (50%) in cohorts A, B and C respectively. The ORR was 0, 26.3 (95% CI 6.5-46.1) and 30% (9.9-50.1) with a DCR of 0, 78.9 and 75% in cohorts A, B and C respectively. According to investigator assessment, the median PFS was 2.1, 4.7 and 4.8 mo (table). The blinded independent central review is currently under evaluation. A large inter-patient variability in bevacizumab plasma concentrations was observed among patients. The 400 mg flat dosing achieved residual concentrations similar to that of 5 mg/kg Q2W or 7.5 mg/kg q3w (51± 30 μg/ml in cohort B and 63 ± 55 μg/ml in cohort C (p>0.05) after C1). Overall, 22 % of pts of cohort B and 18 % of cohort C showed trough levels below the targeted threshold (i.e. < 25 μg/ml). Correlative studies are ongoing. Conclusions: Short-term flat dose bevacizumab potentiates the response to anti-PD1 therapy even in the absence of chemotherapy in heavily pre-treated PROvC patients. The long-term treatment with bevacizumab could potentially improve the outcome. The combination of anti-PD-1 plus anti-angiogenic agents should be a backbone for the treatment of PROvC patients. Clinical trial information: NCT03596281. [Table: see text]

Phase I study of AIC100 in relapsed and/or refractory advanced thyroid cancer and anaplastic thyroid cancer.

6093 Background: ICAM-1 is a cell surface glycoprotein that is typically expressed on endothelial cells and immune cells and a ligand for LFA-1 integrin. It is also overexpressed in several malignancies, in particular anaplastic and advanced thyroid cancer. We designed an affinity tuned ICAM-1-directed CAR T cell (micromolar affinity) that preferentially binds overexpressed ICAM-1 on tumor cells and spares normal cells. The CAR T cells also express somatostatin receptor 2 (SSTR2), which allows tracking of CAR T cells in vivo via DOTATATE PET/CT scan. Murine studies showed excellent responses in ICAM-1 expressing thyroid cancer without significant toxicities. We are conducting a first-in-human phase 1 clinical trial to evaluate the feasibility, safety and preliminary efficacy of ICAM-1 in patients with relapsed/refractory thyroid cancer or anaplastic thyroid cancer who are BRAF wild-type, or BRAF mutated after failure of BRAF specific therapy (NCT04420754). Methods: This is a dose-escalation study with modified toxicity probability interval design and cohorts of 3 Patients. Patients receive a single dose of 1x 107 (Cohort 1), 1 x 108 (Cohort 2) or 5 x 108 (Cohort 3) ICAM-1 CAR T cells after FLU/CY lymphodepleting (LD) chemotherapy. Additional CAR T infusion is allowed if patients achieve partial response or stable disease. Whole-body Fluorodeoxyglucose (FDG) and DOTATATE PET/CT is used to stage tumor and track CAR T cells in vivo, respectively. Results: All ICAM-1 CAR T infusion products met target transduction efficiency. Two patients with progressive anaplastic thyroid cancer received ICAM-1 CAR T therapy at dose-level I. Evaluation of CAR T cellular kinetics demonstrated transient peripheral blood CAR T cell expansion. One patient developed grade 1 cytokine release syndrome (CRS) with fever. Several tumor lesions from this patient showed DOTATATE avidity, indicating CAR T homing to the tumor, concomitant with decrease in FDG avidity, suggesting biological activity at ̃2 weeks post CAR T infusion. DOTATATE avidity at 2 weeks post CAR T infusion also appeared to match that of CAR T abundance in the blood. Updated results on additional patients and cohorts will be presented. Conclusions: Adoptive cellular therapy with ICAM-1 directed CAR T is safe and feasible at dose level 1 in patients with anaplastic thyroid cancer. DOTATATE PET allows visualization of expansion and homing of SSTR2 expressing CAR T cells, while concomitant FDG PET permits correlation with biological activity. Clinical trial information: NCT04420754.

Phase 2 open-label study of pembrolizumab plus lenvatinib and belzutifan in patients with advanced solid tumors.

TPS4173 Background: There is an unmet medical need in patients (pts) with advanced/metastatic hepatocellular carcinoma (HCC), colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and biliary tract cancer (BTC), that progresses after standard therapy. The combination of pembrolizumab (pembro; anti–PD-1 antibody) and lenvatinib (len; anti-angiogenic multikinase inhibitor) demonstrated antitumor activity and manageable toxicity in many tumor types. Hypoxia-inducible factor-2 alpha (HIF-2α) acts on multiple pathways including cell survival and proliferation, angiogenesis, genomic instability and treatment resistance. Monotherapy with the HIF-2α inhibitor belzutifan (MK-6482) impairs hypoxic signaling in cancer cells and has antitumor activity in clear cell renal cell carcinoma (RCC), von Hippel-Lindau (VHL) disease associated non-RCC tumors such as pancreatic neuroendocrine tumors. Based on the potential role of hypoxia signaling and HIF-2α in tumorigenesis and tumor progression, the combination of belzutifan with pembro and len may improve antitumor activity further in the selected tumor types. Methods: This phase 2, single-arm, open-label, multicenter study (NCT04976634) is evaluating pembro 400 mg IV Q6W + oral len 20 mg QD (8 or 12 mg QD for body weight < 60 or ≥60 kg, respectively, for pts with HCC) + oral belzutifan 120 mg QD. Eligible pts: ≥18 y old with histologically confirmed unresectable HCC (Child-Pugh A; 1L); previously treated unresectable, metastatic non–MSI-H/mismatch repair deficient CRC (3L+); metastatic PDAC (2L/3L); or locally advanced/metastatic BTC (includes intra/extrahepatic cholangiocarcinoma and gall bladder cancer; 2L+) with progressive disease (PD); measurable disease per RECIST v1.1 (verified by blinded independent central review [BICR]); ECOG PS ≤1 and archival/new tumor sample for biomarker analysis. All pts should be naïve to prior immune checkpoint inhibitor therapy, len or any HIF-2α inhibitor. The safety lead-in phase is based on the modified toxicity probability interval design with a target dose-limiting toxicity (DLT) rate of 30% and DLT-evaluable period of 21 days (3 wk/1 cycle) in ≤10 HCC pts and ≤15 pts with CRC, PDAC and BTC pooled for each dose level. The study will enroll 120 pts (30/tumor type) to receive triplet therapy for up to 2 y (for pembro) or until PD or discontinuation criteria are met. Enrollment may be expanded by an additional 70 pts/tumor type at the chosen dose level after safety and efficacy review with ≥6 mo follow-up. Primary endpoints are safety (DLTs [safety lead-in], AEs, and treatment discontinuation due to AEs) and ORR per RECIST v1.1 by BICR. Secondary endpoints include DOR, disease control rate and PFS per RECIST v1.1 (and mRECIST for HCC) by BICR, and OS. Efficacy analyses will report binomial proportion or Kaplan-Meier estimates with 95% CIs. Safety analyses will be descriptive. Enrollment began August 2021. Clinical trial information: NCT04976634.

First-in-human study of PC14586, a small molecule structural corrector of Y220C mutant p53, in patients with advanced solid tumors harboring a TP53 Y220C mutation.

3003 Background: The p53 tumor suppressor protein is a transcription factor that acts to maintain genome stability in response to cellular stress. Spontaneous mutation of the TP53 gene leading to inactivation of the p53 protein is the most common mutational event across all human cancers. PC14586 is a novel, small molecule structural corrector that binds selectively to p53 Y220C mutant protein and restores the p53 wildtype conformation and transcriptional activity, resulting in potent preclinical antitumor activity. This Phase 1 multicenter dose escalation study assesses PC14586 safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy in patients (pts) with advanced solid tumors that harbor the TP53 Y220C mutation. Methods: Eligible adult pts with locally advanced or metastastic TP53 Y220C mutant solid tumors received increasing doses of oral PC14586 using the modified Toxicity Probability Interval design to estimate toxicity and to determine maximum tolerated dose and recommended phase 2 dose. Plasma PK was characterized using standard methods. Preliminary efficacy was assessed by RECIST v1.1. Reporting of interim results was approved by the study’s Safety Review Committee. Results: As of 08 Feb 2022, 29 pts (62% female, median age 62 years) with a variety of TP53 Y220C mutant solid tumor types (median number of prior lines of therapy 3; range 1 to 8) were treated in 7 dose cohorts of PC14586: 150 mg QD (3 pts), 300 mg QD (3 pts), 600 mg QD (4 pts), 1150 mg QD (5 pts), 2000 mg QD (7 pts), 2500 mg QD (4 pts) and 1500 mg BID (3 pts). PC14586 was generally well-tolerated; treatment-related AEs were observed in 79% of pts that were all Grade 1/2 in severity except 2 Grade 3 AEs (alanine aminotransferase increased and neutrophil count decreased). The most common AEs (≥15% of pts) were nausea (34%), vomiting (24%), fatigue (21%), and aspartate aminotransferase increased (17%). There were no dose limiting toxicities and enrollment continues. PK analysis showed dose proportional increases in Cmax and AUC. Amongst 21 efficacy evaluable pts, PRs were observed in 5 pts: 1 small cell lung and 1 breast with confirmed PR (cPR), both ongoing; 1 colorectal with unconfirmed PR (uPR), and 2 prostate with uPR and ongoing. In the 3 highest dose cohorts (total daily dose 2000 to 3000 mg), there were 3 PRs (2 uPR, 1cPR) and 7 SD out of 10 efficacy evaluable pts (all ongoing). Observations of decreasing p53 Y220C circulating tumor DNA and decreasing numbers of circulating tumor cells in pts further support on-target anti-tumor activity of PC14586. Conclusions: Enrollment to a Phase 1 study is feasible in a TP53 mutation selective population. PC14586 is safe and tolerated up to 3000 mg daily. Preliminary efficacy was achieved in heavily pretreated pts. Additional safety, PK, PD and efficacy data will be reported at the annual meeting. Clinical trial information: NCT04585750.

A multi-modular phase I/II study of UCB6114, a first-in-class, fully human IgG4P anti-Gremlin-1 monoclonal antibody, as monotherapy and in combination with mFOLFOX6 or trifluridine/tipiracil, for patients with advanced gastrointestinal (GI) tumors.

TPS221 Background: Despite recent advances, effective treatment for GI cancers remains a significant unmet medical need. Gremlin-1 is secreted by the peri-tumoral stroma and down-regulates bone morphogenetic proteins (BMP) -2, -4, and -7 (members of the transforming growth factor-β superfamily), thereby allowing malignant cell expansion, renewal, and a more treatment-resistant mesenchymal phenotype. Gremlin-1 mRNA is highly expressed in multiple solid tumors including >60% of colorectal, pancreatic and esophageal cancers. UCB6114 is a first-in-class, fully human IgG4P monoclonal antibody optimized for neutralizing the activity of human Gremlin-1 thereby restoring BMP signaling. Preclinical studies have demonstrated that UCB6114 binds to Gremlin-1, inhibits its pharmacological activity, and has antitumor activity in several in vivo mouse models (including several GI cancers). Methods: ONC001 (clinicaltrials.gov: NCT04393298) is an ongoing multi-part, multicenter, nonrandomized, open-label, Phase I/II study evaluating the safety, pharmacokinetics (PK) and antitumor activity of UCB6114 administered intravenously as monotherapy or in combination with selected standard of care (SOC) regimens. Eligible patients (pts) are: aged ≥18 years; resistant or refractory to standard therapy; ECOG performance status 0/1; and have adequate renal, hepatic and bone marrow function. In the Phase I monotherapy dose escalation and adaption part (part A and A1; modified rolling 6 design), up to 66 pts with advanced solid tumors associated with high levels of Gremlin-1 mRNA expression will be recruited. In parts B and C (modified toxicity probability interval design), up to 54 pts with locally advanced or metastatic colorectal, gastric or gastroesophageal junction adenocarcinomas will receive UCB6114 in escalating doses in combination with either mFOLFOX6 (5-fluorouracil, leucovorin and oxaliplatin) or trifluridine/tipiracil, given at SOC dosing and schedules. The overarching objective of the phase I parts of the study (Parts A‒C) is to identify the recommended phase II dose of UCB6114 either as monotherapy or in combination. The primary objective is to characterize the safety profile of UCB6114; secondary and exploratory objectives include PK, antitumor activity (RECIST v1.1), and pharmacodynamics (including circulating Gremlin-1). Enrollment in ONC001 began in July 2020; as of Sept 2021, four dose escalation levels in the monotherapy dose-escalation module (Part A) have been completed without DLT. Recruitment to parts B and C is due to commence in Q4 2021. Clinical trial information: NCT04393298.

Phase 2 open-label study of pembrolizumab plus lenvatinib and belzutifan in patients with advanced solid tumors.

TPS669 Background: There is an unmet medical need in patients (pts) with advanced/metastatic hepatocellular carcinoma (HCC), colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and biliary tract cancer (BTC), that progresses after standard therapy. The combination of pembrolizumab (pembro; anti–PD-1 antibody) and lenvatinib (len; anti-angiogenic multikinase inhibitor) demonstrated antitumor activity and manageable toxicity in many tumor types. Hypoxia-inducible factor-2 alpha (HIF-2α) acts on multiple pathways including cell survival and proliferation, angiogenesis, genomic instability and treatment resistance. Monotherapy with the HIF-2α inhibitor belzutifan (MK-6482) impairs hypoxic signaling in cancer cells and has antitumor activity in clear cell renal cell carcinoma (RCC), von Hippel-Lindau (VHL) disease associated non-RCC tumors such as pancreatic neuroendocrine tumors. Based on the potential role of hypoxia signaling and HIF-2α in tumorigenesis and tumor progression, the combination of belzutifan with pembro and len may improve antitumor activity further in the selected tumor types. Methods: This phase 2, single-arm, open-label, multicenter study (NCT04976634) is evaluating pembro 400 mg IV Q6W + oral len 20 mg QD (8 or 12 mg QD for body weight < 60 or ≥60 kg, respectively, for pts with HCC) + oral belzutifan 120 mg QD. Eligible pts: ≥18 y old with histologically confirmed unresectable HCC (Child-Pugh A; 1L); previously treated unresectable, metastatic non–MSI-H/mismatch repair deficient CRC (3L+); metastatic PDAC (2L/3L); or locally advanced/metastatic BTC (includes intra/extrahepatic cholangiocarcinoma and gall bladder cancer; 2L+) with progressive disease (PD); measurable disease per RECIST v1.1 (verified by blinded independent central review [BICR]); ECOG PS ≤1 and archival/new tumor sample for biomarker analysis. All pts should be naïve to prior immune checkpoint inhibitor therapy, len or any HIF-2α inhibitor. The safety lead-in phase is based on the modified toxicity probability interval design with a target dose-limiting toxicity (DLT) rate of 30% and DLT-evaluable period of 21 days (3 wk/1 cycle) in ≤10 HCC pts and ≤15 pts with CRC, PDAC and BTC pooled for each dose level. The study will enroll 120 pts (30/tumor type) to receive triplet therapy for up to 2 y (for pembro) or until PD or discontinuation criteria are met. Enrollment may be expanded by an additional 70 pts/tumor type at the chosen dose level after safety and efficacy review with ≥6 mo follow-up. Primary endpoints are safety (DLTs [safety lead-in], AEs, and treatment discontinuation due to AEs) and ORR per RECIST v1.1 by BICR. Secondary endpoints include DOR, disease control rate and PFS per RECIST v1.1 (and mRECIST for HCC) by BICR, and OS. Efficacy analyses will report binomial proportion or Kaplan-Meier estimates with 95% CIs. Safety analyses will be descriptive. Enrollment began August 2021. Clinical trial information: NCT04976634.

Novel Combination Therapy of Venetoclax and Ruxolitinib in the Treatment of Patients with Relapsed/Refractory Acute Myeloid Leukemia

Novel Combination Therapy of Venetoclax and Ruxolitinib in the Treatment of Patients with Relapsed/Refractory Acute Myeloid Leukemia

FLT3-Mutated Acute Myeloid Leukemia Using a Novel Regimen of Gemtuzumab Ozogamicin and Midostaurin in Combination with Standard Cytarabine and Daunorubicin Induction Therapy

FLT3-Mutated Acute Myeloid Leukemia Using a Novel Regimen of Gemtuzumab Ozogamicin and Midostaurin in Combination with Standard Cytarabine and Daunorubicin Induction Therapy

355 Pembrolizumab and bevacizumab in platinum resistant epithelial ovarian cancer patients

BackgroundThere is a medical need in platinum resistant ovarian cancer patients. Median progression-free survival (PFS) is 3.4 months with chemotherapy and 6.7 months with chemotherapy-bevacizumab combination regimens.1 RECIST overall response rate (ORR) is 11.8% and 27.3%, respectively. The ORR is 15.9% for bevacizumab as a monotherapy with a median PFS of 4.4 months.2MethodsNCT03596281 An open-label phase 1b trial with a modified toxicity probability interval design to evaluate the combination of a flat dose of 400mg bevacizumab for 6 cycles and 200mg pembrolizumab until disease progression, unacceptable toxicity or completed 24 months of treatment in patients with platinum resistant ovarian cancer. The primary evaluation criteria is safety, the secondary endpoint is the efficacy.Results19 patients have been enrolled between January 2019 and February 2021 in 6 French centers. Patients‘ characteristics are reported (table 1). No dose limiting toxicities were observed. Grade 3 treatment related adverse events occurred in 3 patients (i.e. arterial thromboembolism, bowel perforation, proteinuria and sepsis). No grade 4/5 toxicities were induced. A median of 7 cycles (range 3–14) were administered. Median follow-up of patients was 4.1 months (1.8–23). The RECIST ORR was 26.3% (1 complete response and 4 partial responses) (table 2). The disease control rate was 78.9%. The time to progression was not yet reached in 6 patients. The ORR was equivalent whether patients have been pretreated or not with bevacizumab (27.3 and 25% respectively) (table 3). The ORR according to the combined positive score (CPS) for the evaluation of PD-L1 was 50.0% for CPS≥10% (n=4), 30.0% for a CPS≥1% (n=10) and 25.0% for CPS<1 (n=8) (table 4).ConclusionsA chemotherapy-free regimen combining pembrolizumab and bevacizumab was well tolerated and showed encouraging results in heavily pretreated platinum resistant ovarian cancer patients independent of their previous challenge with antiangiogenic agents.AcknowledgementsFunding for this research was provided by Fondation Cancer du Luxembourg and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationNCT03596281ReferencesPujade-Lauraine E, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Onco Off J Am Soc Clin Oncol 32,1302–1308 (2014).Cannistra SA, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol Off J Am Soc Clin Oncol 33,5180–5186 (2007).Ethics ApprovalThis study was approved by CPP Sud Méditerranée V institution’s Ethics Board; approval number 18.020 (EudraCT number 2017-004197-34).ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

A phase 1/2 open-label study of KY1044, an anti-ICOS antibody with dual mechanism of action, as single agent and in combination with atezolizumab, in adult patients with advanced malignancies.

2624 Background: KY1044, is a fully human IgG1 anti ICOS antibody designed to stimulate Teffs and to deplete ICOS high Tregs in the tumor microenvironment. Methods: Patients with advanced/metastatic malignancies received escalating doses of KY1044 as a single agent and in combination with atezolizumab 1200 mg by IV infusion every 3 weeks until disease progression or unacceptable toxicity. Dose escalation was guided by a modified toxicity probability interval design. The primary objective was to determine safety, tolerability, and maximum tolerated dose. Cohorts that were tolerated were later enriched with more subjects. AEs were classified according to CTCAE v5 and efficacy measures performed according to RECIST v1.1 every 8 weeks for the first 16 weeks and then every 12 weeks. Results: As of 16-Dec-2020, a total of 103 patients have been enrolled in the study (38 patients as monotherapy in 6 cohorts at doses ranging from 0.8 to 240 mg and 65 in combination with atezolizumab in 5 cohorts at doses 0.8 – 80 mg). 63% and 55% of patients received ≥4 prior anti-cancer therapies in the single agent and combination cohorts, respectively. All cohorts were completed without DLTs during the first 21 days of treatment. In the KY1044 single agent cohorts, 47.4% of patients experienced treatment-related AEs (TRAEs), all were grades 1 or 2. In the combination cohorts, TRAEs were observed in 58% of patients. Most of the TRAEs were grade 1 or 2 apart from 8 TRAEs that were ≥grade 3 occurring in <8% of patients. Infusion-related reactions, pyrexia and lymphopenia were the most commonly occurring TRAEs in ≥10% of patients. TRAE leading to dose interruptions occurred in 1 patient in the single agent cohort and in 4 patients in the combination cohort. Only 1 patient discontinued treatment due to myositis that was considered related to the combination. Preliminary KY1044 PK data from 69 patients agree with the PK model predictions. Median treatment duration for all enrolled patients was 9 weeks. Treatment duration ≥16 weeks was observed in 24% (9/38) and 27% (17/64) patients in the single agent and combination cohorts, respectively. Five objective responses, including 1 CR in triple negative breast cancer (TNBC) and 4 PRs in TNBC, head and neck squamous cell carcinoma, penile and pancreatic cancer were observed. Four of the 5 responding patients were still on treatment at the data cut, with 3 patients on treatment for >43 weeks (range 45 to 66 weeks). Conclusions: KY1044 is well tolerated as single agent and in combination with atezolizumab. Objective responses have been observed in this phase 1 part of the study. The phase 1 expansion and phase 2 part of the study is ongoing. Clinical trial information: NCT03829501.

Pembrolizumab in combination with bevacizumab and pegylated liposomal doxorubicin in patients with platinum-resistant epithelial ovarian cancer.

5522 Background: There is a medical unmet need for effective treatments in platinum resistant ovarian cancer patients. We assessed the safety and efficacy of a combination of pembrolizumab with bevacizumab and pegylated liposomal doxorubicin (PLD). Methods: This is an open-label phase 1b trial in patients ECOG 0 or 1 with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. The safety of the dual combinations of pembrolizumab with bevacizumab or with PLD were previously evaluated in 6 patients respectively. In the absence of dose limiting toxicities (DLT) the triple combination was evaluated at a maximum tolerated dose (MTD)-1 for PLD in 3 patients and in the absence of DLT at MTD. The sample size was calculated according to the modified toxicity probability interval design. The primary evaluation criteria was the safety, the secondary endpoint was the outcome. Pharmacokinetics of the flat dose of bevacizumab will be evaluated. Results: 22 patients were enrolled from September 2019 until June 2020 in six French centers. 3 initial patients have been treated at 20mg/m2 of PLD (MTD-1) and 19 patients were treated at the dose of 30mg/m2 of PLD (MTD) combined with 200mg of pembrolizumab until progression, unacceptable toxicity, or withdrawal of consent and 400mg of bevacizumab for a total of six cycles. The patients’ characteristics are reported in the table. No DLT occurred. Grade 3 palmar-plantar erythrodysesthesia were reported in 4 patients. The recommended phase II dose of PLD was 30mg/m2 in combination with pembrolizumab and bevacizumab. For patients treated at MTD, the overall response rate was 32% (6 partial responses) with 74% of clinical benefit with a durable response in 10 patients (53%). Median number of cycles was 7.5 (2 to not reached). Two patients are still on treatment. Correlative studies are ongoing. Conclusions: The combination was well tolerated and demonstrated clinical benefit in 74% platinum resistant ovarian cancer patients with durable response (>6 months) in 53% of patients. Clinical trial information: NCT03596281. [Table: see text]

UTPI: A utility-based toxicity probability interval design for phase I/II dose-finding trials.

Unlike chemotherapy, the maximum tolerated dose (MTD) of molecularly targeted agents and immunotherapy may not pose significant clinical benefit over the lower doses. By simultaneously considering both toxicity and efficacy endpoints, phase I/II trials can identify a more clinically meaningful dose for subsequent phase II trials than traditional toxicity-based phase I trials in terms of risk-benefit tradeoff. To strengthen and simplify the current practice of phase I/II trials, we propose a utility-based toxicity probability interval (uTPI) design for finding the optimal biological dose, based on a numerical utility that provides a clinically meaningful, one-dimensional summary representation of the patient's bivariate toxicity and efficacy outcome. The uTPI design does not rely on any parametric specification of the dose-response relationship, and it directly models the dose desirability through a quasi binomial likelihood. Toxicity probability intervals are used to screen out overly toxic dose levels, and then the dose escalation/de-escalation decisions are made adaptively by comparing the posterior desirability distributions of the adjacent levels of the current dose. The uTPI design is flexible in accommodating various dose desirability formulations, while only requiring minimum design parameters. It has a clear decision structure such that a dose-assignment decision table can be calculated before the trial starts and can be used throughout the trial, which simplifies the practical implementation of the design. Extensive simulation studies demonstrate that the proposed uTPI design yields desirable as well as robust performance under various scenarios.

Abstract PS10-18: Phase Ib trial of olinvacimab and pembrolizumab in patients with metastatic triple-negative breast cancer

Abstract Background: Metastatic TNBC (mTNBC) has a poor prognosis. Preclinical data suggests benefit for combination therapy of immune checkpoint inhibitor and anti-angiogenesis. Olinvacimab (O) is a fully humanised monoclonal antibody (MAB) which binds to Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) and antiangiogenic and antitumor effects have been demonstrated. Pembrolizumab (P) is an anti-PD1 MAB. This study aimed to identify the safety and tolerability of O and P to establish a phase 2 recommended dose of O. Methods: From December 2018 to September 2020, we conducted a two-site, single arm, open-label study of O and P in pts with mTNBC. Eligible patients (pts) were >18 years, had ER, PR & HER2-negative MBC with at least one measurable lesion and adequate organ function. Pts with history of serious thromboembolism, gastrointestinal haemorrhage and prior anti-VEGF therapy were excluded. A modified Toxicity Probability Interval design was used. Pts received O 12 mg/kg q7d (dose level 1) or 16mg/kg day q7d (dose level 2) in combination with P 200mg flat dose day 1 q21d. Treatment continued until dose limiting toxicity (DLT), disease progression (PD) or treatment intolerance. Results: 11 pts, median age 62 (range 39-67) were recruited and received at least one dose of treatment. 8 (73%) had ECOG PS 1 and 3 (27%) had ECOG PS 2. 5 pts had previous chemotherapy for mTNBC (with 3 pts also having received immunotherapy), 6 pts were treated in the first-line metastatic setting (with all pts having received anthracycline and taxane in the adjuvant setting). 5 pts received O at 12mg/kg with P, completing a median of 6 cycles (range 1-18). As no DLTs were seen, 6 pts were treated with O at 16mg/kg with median of 8 cycles (range 2-21), with no DLTs being observed. Treatment was ceased due to PD in 6 pts, 3 pts are receiving treatment at data cut-off. Haemangiomas were seen in 8 pts accounting for 47 events of CTCAE grade 1 and 21 events of grade 2. Treatment emergent adverse events (TEAEs) of ≥grade 3 was seen in 6 pts (27 events), with 8 events being related to treatment. 4 pts (36%) had partial response (PR) as best overall response 5 pts (45%) had clinical benefit (PR+SD≥24weeks). Conclusions: Combination therapy of O and P was well tolerated with evidence of efficacy in mTNBC pts who had all previously received anthracycline and taxanes, with 3 pts having previously received immunotherapy. These results support the combination entering into a phase 2 study. Citation Format: Arlene Chan, Eugene Moylan, Sally Jackson, Jeannette Devoto, Nicola Jones, Silvie Radmil, Kate Wilkinson, Aflah Roohullah, Tamiem Adam, Seon Young Lee, Weon Sup Lee, Jin-San Yoo. Phase Ib trial of olinvacimab and pembrolizumab in patients with metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-18.

The importance of loss functions: A note on the evolution of the Toxicity Probability Interval design

The Toxicity Probability Interval Design by Ji et al. (2007), which was subsequently modified by the mTPI (Ji et al., 2010), proposed a more efficient approach to early-phase dose-finding than conventional designs like 3 + 3. Subsequent authors reported issues with the method, finding that it tends to stay at a dose level when clinical intuition would suggest the toxicity level warrants decrease. Several iterations of refinement proceeded in an effort to address these issues, including the mTPI-2 and the keyboard method, as well as alternative approaches such as the BOIN. This author suggests the reason for these safety issues involves the underlying loss function. The TPI and mTPI used the identify function defined over wide intervals. As explained in this paper, this function and its domain can be problematic as a model of patients’ loss experience. Later refinements moved the loss function closer to one more consistent with clinical intuition, and this explains their improved safety performance. Greater attention to quality as defined by fitness for use, including early evaluation of patient-experience and clinical-intuition implications of proposed loss functions, may improve future design efforts.

Rationale for and Results of a Phase I Study of the TGF-β 1/3 Inhibitor AVID200 in Subjects with Myelofibrosis: MPN-RC 118 Trial

Rationale for and Results of a Phase I Study of the TGF-β 1/3 Inhibitor AVID200 in Subjects with Myelofibrosis: MPN-RC 118 Trial