Single-agent Phase Research Articles

Adverse Events During Single-Agent Phase of Venetoclax Therapy

Adverse Events During Single-Agent Phase of Venetoclax Therapy

CLL-533 Adverse Events During Single-Agent Phase of Venetoclax Therapy

CLL-533 Adverse Events During Single-Agent Phase of Venetoclax Therapy

HDAC I/IIb selective inhibitor purinostat mesylate in relapsed and refractory diffuse large B-cell lymphoma: A single agent phase IIa trial.

LBA7074 Background: Relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) has a poor prognosis. Double-expressor (DEL) or TP53 abnormal r/r DLBCL patients(pts) are associated with even worse outcomes. Class I and IIb histone deacetylases (HDACs) are overexpressed in DLBCL and have been identified as a therapy target. Purinostat Mesylate (PM) is a high selective HDAC I/IIb inhibitor. Phase I dose-escalation trial of PM (1.2, 2.4, 4.0, 6.0, 8.4, 11.2, 15 mg/m2) by i.v was conducted in 29 hematologic malignancies at day 1, 4, 8, 11 of a 21-day cycle. PM was generally well tolerated with no DLTs. 61.1% (11/18) ORR was observed in r/r lymphoma pts. Based on these data, we conducted a phase 2a to further explore efficacy and safety of PM and mechanism of actions. Methods: This randomized, multicenter, open-label, phase 2a study was conducted from Nov.2022 to the present(NCT05563844). Key eligibility include r/r DLBCL pts with prior therapy including anti-CD20 antibody and anthracycline-based chemotherapy; ECOG≤2. Thirty pts were randomized 1:1 received PM at 8.4 and 11.2 mg/m2 on Day 1, 4, 8, 11 of a 21-day cycle. Pts continued to receive PM until disease progression or unacceptable toxicity. Primary outcome was ORR and safety. Multiple cell lines and PDX mouse models were used to evaluate the PM activity and mechanism of action in vitro and in vivo. ATAC-seq, bulk RNA-seq, and scRNA-seq from both PDX models and pts were investigated for the activated immune response of PM. Results: Thirty patients were enrolled and 28 patients were evaluable. The ORR (20/28) was 71.4% (95%CI:51.3-86.8) with 5 CR and 15 PR. Fifteen pts at 8.4 mg/m2 achieved an ORR of 66.7%(95%CI:38.4-88.2) with 1 CR and 9 PR. Thirteen pts at 11.2 mg/m2 achieved ORR of 76.9%(95%CI:46.2-95.0) with 4 CR and 6 PR. As of the data cut off in Feb. 2024, 7 pts remained on treatment and the longest treatment has lasted 17 cycles. Median PFS was 4.3m (95%CI:2.8-8.5), OS were immature. In subgroup analyses, 7 DE DLBCL pts obtained 42.9%(3/7) ORR and 11 pts with TP53 abnormal by FISH or NGS test achieved 45.5%(5/11) ORR. Fifteen pts with non-DE or without TP53 abnormal achieved ORR of 86.7%(13/15). The most frequently reported Grade≥3 TRAE were thrombocytopenia, neutropenia, lymphocytopenia. No PM-related death was reported. PM monotherapy showed stronger and superior antitumor effects in DE DLBCL and TP53 mutations PDX models than selinexor and R-CHOP. PM significantly down-regulates the proteins c-MYC, EZH2, and mutated P53. ATAC-seq, bulk RNA-seq and scRNA-seq revealed that PM can stimulate the proliferation and activation of cytotoxic T cells and NKT cells, up-regulate the expression of B-cell tumor MHC I and II and inhibit tumor cell immune escape. Conclusions: This study further supports the recommended dose 11.2 mg/m2 PM as the phase 2b for r/r DLBCL. Currently, the phase 2b, open-label, multicenter study has enrolled in 37 sites in China. Clinical trial information: NCT05563844 .

Event-free survival in relapsed and refractory rhabdomyosarcoma treated on cooperative group phase II trials: A report from the Children's Oncology Group.

Novel therapies are needed for relapsed and refractory rhabdomyosarcoma (RRMS). Phase II clinical trials in RRMS have typically utilized radiologic response as the primary activity endpoint, an approach that poses several limitations in RRMS. In this analysis, we aimed to estimate an event-free survival (EFS) endpoint for RRMS that could be used as a benchmark for future studies. We performed a retrospective study of patients with RRMS enrolling on 13 single-agent phase II Children's Oncology Group and legacy group trials from 1997 to 2016. All included trials used radiographic response as their primary activity endpoint. Six-month EFS was estimated from time of trial enrollment with 95% confidence intervals. Clinical characteristics, including trial of enrollment, sex, age, race, histology, number of prior chemotherapies, and radiographic response were evaluated for their impact on 6-month EFS. We identified 175 patients across 13 trials. The 6-month EFS was 16.8% (11.6%-22.8%). No differences were seen in 6-month EFS based on age, sex, race, or histology. There were nonsignificant trends toward improved 6-month EFS for patients with less than or equal to two prior lines of therapy versus higher than two, for patients enrolled on trials that achieved their primary radiographic response endpoint versus trials that did not, and for patients who achieved complete or partial response compared to those achieving stable disease. The prognosis of RRMS enrolled on single-agent phase II trials is poor. This pooled 6-month EFS of RRMS on single-agent trials may be used as a RRMS-specific benchmark for future single-agent phase II trials.

Outcome of patients with relapsed or refractory nonrhabdomyosarcoma soft tissue sarcomas enrolled in phase 2 cooperative group clinical trials: A report from the Children's Oncology Group.

The aim of this study was to estimate the event-free survival (EFS) of children and young adults with relapsed or refractory nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) treated in nonrandomized phase 2 studies conducted by the Children's Oncology Group (COG) and predecessor groups to establish a benchmark EFS for future phase 2 NRSTS trials evaluating the activity of novel agents. A retrospective analysis of patients with recurrent or refractory NRSTS prospectively enrolled in nonrandomized phase 2 COG and predecessor group trials between 1994 and 2015 was conducted. EFS was defined as disease progression/relapse or death and calculated via the Kaplan-Meier method. The log-rank test and relative risk regression were used to compare EFS distribution by age at enrollment, sex, race, NRSTS histology, prior lines of therapy, calendar year of trial, and type of radiographic response. In total, 137 patients were enrolled in 13 phase 2 trials. All trials used radiographic response rate as a primary outcome, and none of the agents used were considered active on the basis of trial-specified thresholds. The estimated median EFS and 6-month EFS of the entire study cohort was 1.5 months (95% confidence interval [CI], 1.3-1.8 months) and 19.4% (95% CI, 12.7%-26%), respectively. No difference in EFS was observed by age at enrollment, sex, race, NRSTS histology subtype, prior lines of therapies, and trial initiation year. EFS significantly differed by radiographic response. The EFS for children and young adults with relapsed or refractory NRSTS remains suboptimal. Established EFS can be referenced as a benchmark for future single-agent phase 2 trials incorporating potentially active novel agents in this population.

Dose Escalation of ISB 1342, a Novel CD38xCD3 Bispecific Antibody, in Patients with Relapsed / Refractory Multiple Myeloma (RRMM)

Introduction: ISB 1342 is a humanized CD38xCD3 bispecific T-cell engager using Ichnos proprietary Bispecific Engagement by Antibodies based on the T cell receptor (BEAT ®) platform, designed to simultaneously bind CD38 on multiple myeloma (MM) cells and CD3ε on T cells, to induce tumor killing. This mechanism of action is different from existing monospecific CD38 targeting therapies and was designed to overcome resistance to daratumumab in MM. ISB 1342 exhibits potent killing of the primary MM cells and MM cell lines with low sensitivity to daratumumab ( Pouleau B. et al. Blood 2023; 142 (3): 260-273). We report here, the updated findings from the weekly dose-escalations of intravenous (IV) and subcutaneous (SC) injections of an ongoing, single-agent phase 1 study (NCT03309111) of ISB 1342 in patients with RRMM. Methods: Adult patients with RRMM that relapsed after or were refractory to prior therapies, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody; received ISB 1342 on a weekly (QW) schedule by IV or SC injection with a priming dose on the first day in 2 parallel dose-escalation schemas. Patients had measurable disease per the International Myeloma Working Group (IMWG) criteria (2016). Dose escalation in the QW schedule began at 0.2/0.3 mg/kg priming/treatment dose and followed a “3 + 3” design. The primary study objectives are to determine the maximum tolerated dose (MTD) and select a recommended phase 2 dose (RP2D) of ISB 1342. Secondary objectives includ evaluation of anti-myeloma activity, pharmacokinetics (PK), pharmacodynamics, and immunogenicity of ISB 1342. Results: As of July 18, 2023, based on ongoing clinical database, 39 subjects had received weekly IV infusions of ISB 1342 in 8 dose-escalation groups from 0.2/0.3 mg/kg to 4.0/16.0 mg/kg as priming/treatment dose; and 7 additional subjects had received weekly SC injections at 2.0/8.0 mg/kg. Two different formulations have been tested in SC group. Median number of cycles administered was 2. The majority were male (57%) and white (74%); 13% were Black or African American. The median age was 69 years (range, 54-76) and the median time since diagnosis was 6.6 years (range, 2.8-22.2). The median number of prior anti-myeloma lines of therapy was 6 (range 1-12). Twenty-one (67%) subjects were considered to be triple-class refractory and 18 (48%) penta-drug refractory. Forty-one (89%) subjects experienced treatment-related adverse events (TRAEs) of any grade. Most TRAEs were grade 1-2, including infusion related reactions (37%), cytokine release syndrome (CRS, 34%, all grade 1or 2), anemia (24%), neutropenia (24%), and thrombocytopenia (17%). Five subjects in SC group (71% of SC) had injection site reaction, all grade 1 or 2. Grade 3 or higher TRAEs occurring in more than 5% of subjects were infusion related reaction (no grade 4), anemia (no grade 4), neutropenia, leukopenia. No Grade 5 TRAE was observed. After QW IV infusion, ISB 1342 serum concentration peaked at the end of infusion and then showed bi-exponential decline. ISB 1342 serum exposures increased in a dose linear fashion across the tested IV infusion dose range. The limited PK data after SC injection suggest slow presentation of ISB 1342 into the systemic circulation leading to lower C max and delayed T max relative to IV. Transient increases in serum cytokines were observed within 24 hours after ISB 1342 dosing, including IFNg, TNFa, IL-2, IL-6 and IL-10. Transient increases in T-cell activation were observed by flow cytometry at 24-48 hours after ISB 1342 dosing at 1.0 / 4.0 μg/kg and above, based on increased expression of CD69 on peripheral blood CD4+ and CD8+ T-cell populations (Figure 1). Comparison of the available data from subjects treated at 2 / 8 μg/kg (Cohort 109) indicated reduced T-cell activation following SC compared to IV administration of ISB 1342. The efficacy signals observed in Cohorts 108 and 109 are consistent with the estimates of the lower boundary of the predicted efficacious dose range using a quantitative systems pharmacology (QSP) model based on preclinical data. Updated clinical data, including response rates and safety data, will be present at the meeting. Conclusions: Treatment with ISB 1342 was well tolerated at higher dose levels evaluated. Observed CRS events were moderate. No increased risk of infection has been observed . Updated safety, efficacy, biomarker and PK data will be presented.

Initial Dose Escalation of ISB 1442, a Novel CD38 Biparatopic x CD47 Bispecific Antibody, in Patients with Relapsed / Refractory Multiple Myeloma (RRMM)

Introduction: ISB 1442 is a fully human bispecific, biparatopic antibody that targets CD38 and CD47, generated using Ichnos' Bispecific Engagement by Antibodies based on the T cell receptor (BEAT ®) platform. ISB 1442 is designed to kill CD38-expressing tumor cells through multiple mechanisms of action including blocking CD47-signal regulatory protein alpha (SIRPα) axis to increase several antibody effector functions: antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) through optimized architecture, affinity to targets, and Fc engineering. ISB 1442 has 2 Fab domains binding to distinct CD38 epitopes that do not compete functionally with daratumumab. ISB 1442 is expected to have optimized tolerability with low potential for adverse effects on red blood cells (RBC) such as hemagglutination, platelet aggregation and RBC depletion (Sammicheli at al., ASH 2021, Blood (2021) 138 (Supplement 1): 73). We report here initial findings from the early dose-escalation portion of an ongoing, multi-center, open-label, single-agent phase 1/2 study (NCT05427812) of ISB 1442 in patients with RRMM. Methods: Adult patients with relapsed refractory multiple myeloma (RRMM) to prior therapies, including a proteasome inhibitors (PIs), an immunomodulatory drugs (IMiDs), and an anti-CD38 antibodies received subcutaneous (SC) doses of ISB 1442 weekly (QW) in 28-day cycles. Patients had measurable disease per the International Myeloma Working Group (IMWG) criteria (2016). Dose escalation began at 6 mg dose with single patient accelerated titration phase for the first 3 cohorts, followed by a standard titration phase with a “3 + 3” design. The primary study objective for phase 1 is to assess the safety and tolerability to determine the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D) of ISB 1442. For phase 2 the primary study objective is to evaluate efficacy of ISB 1442. Secondary objectives include evaluation of pharmacokinetics (PK) and immunogenicity of ISB 1442. Exploratory objectives include assessment of minimal residual disease (MRD), assessment of cellular biomarkers in blood and bone marrow, and soluble factors in blood, and their correlation with efficacy, safety and other clinical endpoints of interest. Results: As of July 18, 2023, based on preliminary data from ongoing clinical database, 10 subjects had received once weekly SC injections of ISB 1442 in 4 dose-escalation groups from 6 mg to 150 mg. The majority were male (60%) and white (90%). The median age was 67 years (range 57-79). The median number of prior anti-myeloma lines of therapy was 6 (range 3-7); 70% were exposed to 5 drugs (2PIs, 2IMiDs, and CD38). The median number of ISB 1442 cycles was 1(range 1-2). Eight subjects (80%) experienced treatment-related adverse events (TRAEs), all were grade 1 or 2: cytokine release syndrome (CRS) (50%), injection site reactions (injection site erythema 20%, injection site bruising 10%), anemia (10%, 1 subject, grade 2) (Table 1). No grade 5 TRAE was observed. Following QW SC injection, ISB 1442 was slowly absorbed into the systemic circulation with T max generally occurring on day 2 of dosing. The ISB 1442 serum concentrations generally remained quantifiable over the entire dosing duration from 20 mg and above. The available PK data suggest an approximately dose-linear increase in serum concentration up to DL 3 (60 mg), followed by a supra-proportional increase in serum levels in subjects treated at DL 4 (150 mg). To date, 5 subjects treated at DL4 (150 mg) have experienced clinical symptoms of CRS (Grade 1-2) following the first dose of ISB 1442. Assessment of a panel of 63 soluble factors (including multiple cytokines, chemokines and growth factors) in the peripheral blood revealed that several subjects at DL3-4 exhibited transient increases (>10-fold) in macrophage inflammatory protein-1b (MIP-1b/CCL4) within 24h after treatment with ISB 1442, consistent with a macrophage-associated mechanism of action. Conclusions: Treatment with ISB 1442 was well tolerated at the dose levels evaluated. The observed clinical CRS events were moderate and potentially related to macrophage activation following ISB 1442 administration. Updated clinical, biomarker and PK data will be presented for this ongoing study.

Abstract 4334: Clever-1/PD-L1 ratio predicts response to Bexmarilimab, a novel macrophage-guided immunotherapy, in immune deprived cancers

Abstract Introduction: Clever-1 is an immunosuppressive scavenger receptor expressed on tumor associated macrophages. High levels of Clever-1 are associated with poor survival, T-cell exclusion and dysfunction, and immunotherapy resistance. Bexmarilimab (FP-1305) is a novel humanized anti-Clever-1 IgG4-antibody capable of promoting an immune switch, potentially leading to intratumoral proinflammatory responses in patients. In a first-in-human all-comer single agent Phase I/II study in advanced solid tumors (NCT03733990) approximately 30% of patients in hepatocellular carcinoma, cutaneous melanoma and cholangiocarcinoma achieved immune activation, characterized by an IFNg response, which led to a survival benefit (ASCO 2022). Here, we show that patients getting a therapy benefit have immunologically cold tumors with low PD-L1 staining and high Clever-1 staining. Methods: Pre-treatment tumor samples were immunohistochemically stained for Clever-1 (4G9, Santa Cruz) using Ventana platform and scored by % of intratumoral positive cells out of all viable cells and PD-L1 (22C3, Agilent) with combined positivity scoring (CPS). Ratio (PD-L1/Clever-1) at baseline was compared using non-parametric Wilcoxon-test according to clinical benefit. Results: 23 successful baseline biopsies and stainings were obtained, 6 per cutaneous melanoma, 11 per cholangiocarcinoma and 1 per hepatocellular carcinoma, from patients treated with bexmarilimab. Patients had received an average of three previous lines of therapy. At baseline, patients that saw a clinical benefit (CBR) from bexmarilimab had average PD-L1/Clever-1 ratio of 0.2 compared to 4.4 (p=0.042, Wilcoxon nonparametric test) in patients that did not respond to the treatment. Conclusion: PD-L1/Clever-1 IHC staining ratio may be used to predict bexmarilimab responding patients. These patients have a low PD-L1 staining and low IFNg levels as reported previously, and are often refractory to checkpoint inhibitors and other T cell activating agents. Bexmarilimab provides a novel therapy option for a tumor group that is otherwise poorly responsive to immune therapies. Citation Format: Mari L. Björkman, Elisa M. Vuorinen, Juho Jalkanen, Marie-Louise Fjällskog, Jussi Koivunen, Teppo Huttunen, Maija Hollmén, Petri Bono. Clever-1/PD-L1 ratio predicts response to Bexmarilimab, a novel macrophage-guided immunotherapy, in immune deprived cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4334.

Initial Results of Dose Escalation of ISB 1342, a Novel CD3xCD38 Bispecific Antibody, in Patients with Relapsed / Refractory Multiple Myeloma (RRMM)

Introduction: ISB 1342 is a heterodimer based on the Ichnos proprietary Bispecific Engagement by Antibodies based on the TCR (BEAT®) platform and is a humanized CD3xCD38 bispecific antibody designed to simultaneously engage the CD3 molecule on T cells and the CD38 antigen on multiple myeloma (MM) cells. By co-engaging CD3ε on T cells and CD38 on tumor cells, ISB 1342 redirects T cells to kill CD38-expressing tumor cells. This mechanism of action is differentiated from existing monospecific CD38 targeting therapies and was designed to overcome resistance to daratumumab in MM. We report here, findings from the dose-escalation portion of an ongoing, multi-center, open-label, single-agent phase 1 study (NCT03309111) of ISB 1342 in patients with RRMM. Methods: Adult patients (≥18 years of age) with RRMM that relapsed after or were considered refractory to prior therapies, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody; received escalating, intravenous (IV) doses of ISB 1342 every two weeks (Q2W) or weekly (QW) with a priming dose administered on the first day. The focus of this report will be on patients enrolled in the QW schedule. Patients had measurable disease per the International Myeloma Working Group (IMWG) updated criteria 2016. Dose escalation began with 0.001mg/kg (prime) / 0.003 mg/kg in the Q2W schedule with single patient accelerated titration for the first four cohorts then a "3 + 3" design; dose escalation in the QW schedule began at 0.2/0.3 mg/kg and followed a "3 + 3" design. The primary study objectives are to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of ISB 1342. Secondary objectives included evaluation of anti-myeloma activity, pharmacokinetics (PK) and pharmacodynamics, and immunogenicity of ISB 1342. Results: As of July 7, 2022, 24 patients had received a once weekly, IV infusion of ISB 1342 in 6 dose-escalation groups from 0.2/0.3 mg/kg dose level to 1.0 / 4.0 mg/kg dose level. The majority were males (63%) and white (67%); 21% were black or African American. The median age was 67 years (range, 54-76) and the median disease duration since onset was 6.7 years (range, 2.8-22.2). The median number of prior anti-myeloma lines of therapy was 6 (range 1-10); 8 (33%) patients had received prior B cell maturation antigen (BCMA)-targeted therapy including bi-specifics, antibody drug conjugates (ADCs) and/or cell therapies. Twenty-one (88%) patients were considered to be triple-refractory and 18 (75%) were considered to be penta-refractory. Twenty-two (92%) patients experienced treatment-related adverse events (TRAEs) of any grade. Most TRAEs were grade 1-2, including infusion related reactions (42%), anemia (21%), cytokine release syndrome (CRS, 17%), thrombocytopenia (17%), and diarrhoea (13%). Nine (38%) patients had grade 3 or higher TRAEs with only infusion related reactions occurring in more than 5% of patients (17%, all grade 3 events). No grade 5 TRAE was observed. One dose limiting toxicity (DLT), a Grade 3 delirium was observed in a 73-year-old patient treated at 0.3/0.55 dose level after the third dose of ISB 1342, and who also presented with Grade 4 pneumonia; three additional patients were enrolled at that dose level, no other DLT was observed, and dose escalation continued. The median duration of treatment was 2 months (range, 1-5). The ISB 1342 serum concentration-time profiles showed Cmax near the end of infusion, followed by a biphasic decline. The serum exposures showed a dose-dependent increase following both Q2W and Q1W regimens. With the Q1W regimen, the serum Ctrough was higher than that with the Q2W regimen at similar dose levels. Transient increases in serum cytokine levels were observed within 24 hours following ISB 1342 administration, including IFNg, TNFa, IL-2, IL-6 and IL-10. Conclusions: Treatment with ISB 1342 was well tolerated at the dose levels evaluated. The observed CRS events were moderate. Dose escalation continues with additional dose cohorts accruing. The updated clinical, biomarker and PK data will be presented for this ongoing study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparative efficacy and tolerability of novel agents vs chemotherapy in relapsed and refractory T-cell lymphomas: a meta-analysis

AbstractOptimal treatment strategies for (relapsed and refractory [R/R]) peripheral T-cell lymphoma (PTCL) have not been well defined, and with the approval of several novel single agents (SA), the comparative efficacy of combination chemotherapy (CC) to single-agent strategies remains unclear. We conducted a meta-analysis to evaluate overall response rates (ORR) and toxicities of SA to CC. MEDLINE, Embase, Web of Science Core Collection, and Cochrane were systematically searched for phase I, phase II, and phase III trials investigating a defined SA or an anthracycline-, ifosfamide-, gemcitabine-, and platinum-based regimens. One hundred and fifty-one articles were included, encompassing single and combinations of 60 phase I trials involving 1075 patients, 95 phase II trials involving 3246, and 23 phase III trials involving 1888 patients. There was a high degree of heterogeneity in the trials. Using a random-effects model, the estimated ORR for SA in phase I trials were 40% (95% confidence interval [CI], 34.7%, 46.9%) relative to 41% for CC (95% CI, 27.4%, 56.1%; P = .97) and in phase II trials 34.4% (95% CI, 30.4%, 38.7%) for SA vs 55.3% (95% CI, 31%, 77.2%; P = .1) for CC. There were significant subgroup differences in ORR between histological subtypes of PTCL and drug classes. Our results highlight SA as an attractive outpatient option for R/R PTCL, and their incorporation in the development of upfront treatment paradigms merits urgent consideration. Our results underscore enrollment in clinical trials of SA as a critical strategy for R/R PTCL.

Abstract CT521: Phase 1b trial of the MNK1/2 inhibitor tomivosertib combined with paclitaxel in patients with metastatic breast cancer

Abstract MNK is a serine/threonine kinase signaling node in the MAPK pathway, which is phosphorylated and activated by ERK. MNK phosphorylates eIF4E to promote translation of a subset of mRNAs that encode oncogenically relevant proteins including c-Myc, Cyclin D1 and PD-L1. We conducted a phase 1B study [NCT04261218] of tomivosertib (T), an orally administered inhibitor of MNK, to assess target engagement in metastatic breast cancer tissue and tolerability and pharmacokinetics of co-administration with paclitaxel (P). There are no prior reports of co-administration of a MNK inhibitor with a cytotoxic agent. All patients underwent pre-treatment baseline and on-treatment (day ~7) core biopsy of metastatic disease during the T monotherapy lead-in phase; subsequently patients continued oral T 100mg bid (without or with meal) with the addition of IV P at 80mg/m2 day 1 and 8 every 21 days. Results: We report here interim data for the first 14 patients with MBC refractory to standard treatments. Pharmacokinetics: T plasma levels were 21+/- 40 ng/ml throughout the day, and were not influenced by infusion of P. Peak P levels following infusion were 600 +/- 220 ng/ml and fell to below detection limit by 24 hours post infusion, similar to prior reports for single-agent P. Pharmacodynamics: The main endpoint was assessment of T -induced eIF4E phosphorylation in MBC biopsy tissue, estimated by immunostaining with an antibody specific for eIF4E phosphorylated at S209. Phospho-eIF4E staining intensity was generally high in the pre-treatment samples (indicating baseline activation of eIF4E in MBC). In contrast, the on- T biopsies revealed undetectable phopho-eIF4E staining in all patients. These results were confirmed by mass cytometry analysis, which also included a characterization of the immune microenvironment. We performed ribo-seq analysis on 2 mg flash frozen cancer specimens, and this provided preliminary evidence for decreased translation of mRNAs encoding proteins relevant to neoplasia including TMSB4X and MUCL1 on exposure to T. Preliminary analysis of comparison of proteomic data for each patient, comparing baseline and on-drug biopsies, revealed upregulation of proteins involved in fatty acid catabolic processes, consistent with prior experimental work (PMID 32712434). Safety and Clinical: Of 14 initial patients, 1 left the study for adverse reaction (nausea), 1 left study at physician’s discretion, and 5 left the study for progressive disease. There were no indications of increased P toxicity, and T was generally well tolerated in keeping with prior single agent phase I data. Two patients showed a decrease (36% and 45%) in size of metastases, but others showed disease progression, despite evidence for absence of phospho-eIF4E. The results indicate feasibility of a future phase 2 study of the T - P combination. (Supported by a Dream Team grant from Stand Up To Cancer - Canada) Citation Format: Cristiano Ferrario, John Mackey, Karen Gelmon, Poul HB Sorensen, Htoo Zarni Oo, Gregg B. Morin, Sonia del Rincon, Mehdi Amiri, Premal Patel, Harvey W. Smith, Nahum Sonenberg, Michael N. Pollak. Phase 1b trial of the MNK1/2 inhibitor tomivosertib combined with paclitaxel in patients with metastatic breast 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 CT521.

The bi-steric mTORC1-selective inhibitor RMC-5552 in tumors with activation of mTOR signaling: Preclinical activity in combination with RAS(ON) inhibitors in RAS-addicted tumors, and initial clinical findings from a single agent phase 1/1b study.

3098 Background: RMC-5552 is a potent bi-steric mTORC1-selective inhibitor that activates the downstream tumor suppressor 4EBP1, thereby inhibiting initiation of protein translation. This novel therapeutic moiety addresses a key limitation of rapalogs, which do not effectively inhibit phosphorylation of 4EBP1. RMC-5552 has previously demonstrated significant anti-tumor activity in preclinical models of human cancers with mTOR pathway activation. Additionally, mTOR signaling plays a key role in therapeutic response and resistance in RAS-addicted cancers, which represent a significant unmet medical need. Methods: We examined the combination of bi-steric mTORC1 inhibitors (RMC-5552 and the research tool compound RMC-6272) with direct inhibitors of active RAS (RAS(ON) inhibitors) in mutant KRAS-driven models. To enable the clinical testing of RMC-5552 as a companion inhibitor for RAS(ON) inhibitors, a Phase 1/1b dose-escalation trial of RMC-5552 monotherapy is currently testing a once-a-week IV schedule. Results: RMC-5552 and RMC-6272 demonstrated marked combinatorial anti-tumor activity with RAS(ON) inhibitors across a series of preclinical models of KRAS mutated non-small cell lung cancer. The combination enhanced tumor apoptosis and resulted in durable tumor regressions as compared to tumor growth inhibition resulting from single agents alone. As of 13 January 2022, a total of 14 patients with solid tumors have been evaluated in an ongoing Phase 1/1b trial over 5 dose levels ranging from 1.6 to 12 mg IV weekly. Median age was 62 years and the majority received ≥3 prior therapies. The most common (> 25%) drug-related adverse events were mucositis/stomatitis (43%) and decreased appetite (29%). The most common grade 3 drug-related adverse events were mucositis/stomatitis observed in 3 patients in dose levels ≥ 10 mg (21%) and were dose-limiting. The dose of 6 mg IV weekly was well tolerated. Plasma exposures of RMC-5552 were dose-proportionate at lower dose levels up to 6 mg but increased above dose proportionality with higher dose levels. Plasma exposures at 6 mg and above were consistent with those resulting in inhibition of tumor p4EBP1 in preclinical models. Of 5 patients evaluable for efficacy at doses of 6 mg and higher, one confirmed PR was observed in a patient with head and neck cancer with a pathogenic mutation in PTEN (ORR 20%) and 3 patients had a best response of SD. Dose-optimization is ongoing. Conclusions: RMC-5552 is clinically active in tumors with mTORC1 signaling activation at a tolerable dose and schedule and has the potential to be a companion inhibitor of choice for RAS(ON) inhibitors in RAS-addicted tumors. Clinical trial information: NCT04774952.

BOIN Suite: A Software Platform to Design and Implement Novel Early-Phase Clinical Trials.

Using novel Bayesian adaptive designs has great potential to improve the efficiency of early-phase clinical trials. A major barrier for clinical researchers to adopt novel designs is the lack of easy-to-use software. Our purpose is to develop a user-friendly software platform to implement novel clinical trial designs that address various challenges in early-phase dose-finding trials. We used R Shiny to develop a web-based software platform to facilitate the use of recent novel adaptive designs. We developed a web-based software suite, called Bayesian optimal interval (BOIN) suite, which includes R Shiny applications to handle various clinical settings, including single-agent phase I trials with and without prior information, trials with late-onset toxicity, trials to find the optimal biological dose based on risk-benefit trade-off, and drug combination trials to find a single maximum tolerated dose (MTD) or the MTD contour. The applications are built using the same software architecture to ensure the best and a uniform user experience, and they are developed using a proven software development standard operating procedure to ensure accuracy, robustness, and reproducibility. The suite is freely available with internet access and a web browser without the need of installing any other software. The BOIN suite allows clinical researchers to design various types of early-phase clinical trials under a unified framework. This work is extremely important because it not only advances the clinical research and drug development by facilitating the use of novel trial designs with optimal performance but also enhances collaborations between biostatisticians and clinicians by disseminating novel statistical methodology to broader scientific communities through user-friendly software. The BOIN suite establishes a KISS principle: keep it simple, but smart.

CTNI-08. DB102-01 ENGAGE STUDY: A BIOMARKER-GUIDED, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTI-CENTER PHASE 3 CLINICAL TRIAL OF DB102 IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM)

Abstract Precision medicine is vital for treating many cancers. Lack of valid biomarkers might contribute to the failure of drug therapy for GBM. The Denovo Genomic Marker 1 (DGM1), a novel pharmacogenomic biomarker, has been discovered by a genome-wide screen of patients treated with DB102 (enzastaurin) in a trial for lymphoma. Similarly, retrospective analyses showed that DB102 significantly improved outcomes in the biomarker positive GBM patients treated with DB102, regardless of MGMT promoter methylation status. The ENGAGE Study (DB102-01, NCT03776071) is a global Phase 3 clinical trial to confirm clinical benefits in patients with newly diagnosed GBM who are DGM1 biomarker positive. This is a prospective, randomized, double-blind, placebo-controlled, multi-center study. A total of 318 patients with newly diagnosed GBM will be enrolled. After screening, patients will be randomized to receive radiation therapy (RT) and temozolomide (TMZ) plus either DB102 or a matched placebo for 6 weeks in the Concurrent Phase, followed by DB102 or placebo for approximately 5 weeks in the Single-Agent Phase and then TMZ plus DB102 or placebo in the Adjuvant Phase (up to 12 cycles). Thereafter DB102 or placebo may be continued as a single agent for up to 2 years. The primary endpoint is overall survival (OS). The secondary endpoints include progression free survival (PFS), objective response rate (ORR) and drug safety. By April 2021, the safety-run-in part was completed. The study is now open for enrollment in the US and soon in Canada and China.

Integrated exposure\u2013response analysis of efficacy and safety of lurbinectedin to support the dose regimen in small-cell lung cancer

PurposeThese exposure–response (E–R) analyses integrated lurbinectedin effects on key efficacy and safety variables in relapsed SCLC to determine the adequacy of the dose regimen of 3.2 mg/m2 1-h intravenous infusion every 3 weeks (q3wk).MethodsLogistic models and Cox regression analyses were applied to correlate lurbinectedin exposure metrics (AUCtot and AUCu) with efficacy and safety endpoints: objective response rate (ORR) and overall survival (OS) in SCLC patients (n = 99) treated in study B-005 with 3.2 mg/m2 q3wk, and incidence of grade 4 (G4) neutropenia and grade 3–4 (G ≥ 3) thrombocytopenia in a pool of cancer patients from single-agent phase I to III studies (n = 692) treated at a wide range of doses. A clinical utility index was used to assess the appropriateness of the selected dose.ResultsEffect of lurbinectedin AUCu on ORR best fitted to a sigmoid-maximal response (Emax) logistic model, where Emax was dependent on chemotherapy-free interval (CTFI). Cox regression analysis with OS found relationships with both CTFI and AUCu. An Emax logistic model for G4 neutropenia and a linear logistic model for G ≥ 3 thrombocytopenia, which retained platelets and albumin at baseline and body surface area, best fitted to AUCtot and AUCu. AUCu between approximately 1000 and 1700 ng·h/L provided the best benefit/risk ratio, and the dose of 3.2 mg/m2 provided median AUCu of 1400 ng·h/L, thus maximizing the proportion of patients within that lurbinectedin target exposure range.ConclusionsThe relationships evidenced in this integrated E–R analysis support a favorable benefit-risk profile for lurbinectedin 3.2 mg/m2 q3wk.Trial registrationClinicaltrials.gov: NCT02454972; registered May 27, 2015.

In Vitro andpre-Clinical In Vivo evidence Support MDMX/MDM2 As Common Vulnerabilities across TP53 -Wild-Type T-Cell Lymphomas That Are Targetable with the α-Helical p53 Stapled Peptide Alrn-6924

T-cell lymphomas (TCL) are a heterogeneous group of non-Hodgkin lymphomas with poor outcomes. Biological heterogeneity across TCLs has hampered the development of targeted therapies. Thus, we sought to identify common vulnerabilities that could be targeted across multiple TCL subtypes. We performed transcriptome and exome sequencing of 21 TCL cell lines and 8 TCL patient-derived xenografts (PDX), and a genome-wide CRISPR-Cas9 pooled screening in 7 TCL lines. Sequencing identified multiple genomic alterations of clinical significance and disease-specific recurrence, like activating JAK1 and STAT3 mutations in cell lines and a PDX-model of anaplastic large cell lymphoma (ALCL) or mutations of TET2, DNMT3A and RHOA in PDX-models of angioimmunoblastic TCL (AITL). Unsupervised hierarchical clustering of transcriptomes identified disease-specific gene-expression profiles across cell lines and PDX models. Ranking the genetic vulnerabilities of the CRISPR-Cas9 screen by z-score and recurrence across multiple cell lines, we identified both previously defined (e.g. IRF4) and novel vulnerabilities (e.g. PTPN2) within multiple TCL subtypes. The most consistent dependence in TP53- wild-type (WT) lines was the E3 ubiquitin ligase MDM2, which polyubiquitinates and targets p53 for degradation. Multiple TCL lines harbored copy number gains or amplifications of MDM2 and/or MDMX that correlated with high transcript levels. To address the therapeutic potential for targeting MDMX/MDM2 in TCL we tested ALRN-6924, a p53-derived stapled peptide that inhibits both MDMX and MDM2, and that is currently in multicenter phase I/Ib and phase II trials. ALRN-6924 was recently shown to induce objective responses in a variety of cancers as a single agent in phase 1 dose-escalation (Meric-Bernstam, F. et al, ASCO 2017). Our results showed that ALRN-6924 potently induced G1 cell cycle arrest and apoptotic cell death in WT TP53 TCL lines (n=8; IC50 100 nm-1 µM) while inducing expression of p21 and Annexin V. ALRN-6924 was inactive in TP53 -mutant lines (n=11; IC50 > 5 µM). Next, we performed a phase II-like trial in eight WT TP53 PDXs: hepatosplenic (HS-TCL), cutaneous (CTCL), NK/T, AITL (n=2), T-cell prolymphocytic leukemia (TPLL) and Alk+ ALCL (n=2). At the time of extensive lymphoma engraftment (e.g. >20% splenic involvement), mice were randomized to treatment with vehicle, ALRN-6924 or the 2nd line standard-of-care agent Romidepsin (n=3/arm/model) on days 1, 4 and 7, and sacrificed on day 8. ALRN-6924 had a favorable safety profile and significantly reduced tumor burden compared to vehicle in all 8 models, with superior efficacy to Romidepsin in the majority of models (Figure). Residual tumor cells collected from ALRN-6924-treated mice consistently had increased AAD/Annexin V staining and p21 induction, consistent with on-target p53 activation and apoptosis.In summary, we identified MDM2/MDMX as a targetable vulnerability that is effectively targeted by the stapled peptide ALRN-6924 in TP53 WT TCLs with promising activity across multiple subtypes, supporting further clinical development of ALRN-6924 in TCL for patients requiring 2nd or frontline treatment. A Phase IIa clinical trial of ALRN-6924 in PTCL patients is currently enrolling (NCT02264613). [Display omitted] DisclosuresHorwitz:Millenium/Takeda: Consultancy, Research Funding; HUYA: Consultancy; Forty-Seven: Consultancy, Research Funding; BMS: Consultancy; Seattle Genetics: Consultancy, Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Mundipharma: Consultancy; ADCT Therapeutics: Research Funding; Aileron Therapeutics: Research Funding; Infinity/Verastem: Consultancy, Research Funding. Santiago:Aileron: Employment. Ren:Aileron: Employment. Guerlavais:Aileron: Employment. Annis:Aileron: Employment. Aivado:Aileron: Employment.

Genetic Profiling and Deep IDH1 Mutation Clearance to ≤0.04% in Ivosidenib (AG-120)-Treated Patients with Mutant IDH1 Relapsed or Refractory and Untreated AML

Genetic Profiling and Deep IDH1 Mutation Clearance to ≤0.04% in Ivosidenib (AG-120)-Treated Patients with Mutant IDH1 Relapsed or Refractory and Untreated AML

The Novel, Irreversible FLT3 Inhibitor FF-10101 Demonstrates Broad in Vitro Activity Against FLT3 Inhibitor Resistance Mutations

Background: Small-molecule FLT3 tyrosine kinase inhibitors (TKIs) have improved remission rates in relapsed/refractory AML driven by FLT3 internal tandem duplication (ITD) mutations, although nearly all responders eventually relapse. Acquired clinical resistance to type II inhibitors such as quizartinib and sorafenib has largely been due to kinase domain (KD) mutations that destabilize drug binding. Early inhibitors, limited by short half-life and fluctuating plasma levels, were also only able to transiently inhibit FLT3. FF-10101 is a first-in-class, type I inhibitor that covalently binds FLT3 irreversibly, suggesting its activity should be limited by the half-life of FLT3 itself. In a profiling assay of 216 human recombinant kinases FF-10101 showed selectivity for wild type FLT3 and FLT3 D835Y. It also demonstrated potent activity against FLT3-ITD AML cell lines harboring TKI-resistant D835Y and Y842C/H mutations. Here, we report in vitro testing of FF-10101 against 19 additional FLT3 TKI-resistant mutations, as well as six cysteine-to-serine mutations within the KD that could impact covalent drug binding. Profiling of this activity is relevant as FF-10101 enters single-agent phase 1/2a clinical trial in relapsed/refractory FLT3 mutant AML.Results: FF-10101 was profiled in an in vitro viability assay against murine BaF3 and human AML cell lines harboring a spectrum of mutations. FF-10101 inhibited the proliferation of FLT3-driven Molm14 and MV4;11 cells (IC50 4.1 and 1.1 nM, respectively). BaF3 FLT3-ITD cells were comparably inhibited (IC50 3.1 ± 1.6 nM), while growth of BCR-ABL-driven K562 cells were unaffected. To confirm covalent binding of FF-10101, we then analyzed its activity against all cysteine residues in the FLT3 KD. Every C->S substitution except C695S remained sensitive to FF-10101, confirming C695 as the FF-10101 binding site and suggesting C695S may impart clinical resistance to FF-10101. We next assessed 10 BaF3 FLT3-ITD cell lines harboring mutations at D835 and the gatekeeper F691, given discovery of resistance mutations at these sites in patients treated with AC220 and sorafenib. FF-10101 inhibited F691L and all substitutions/deletions at the D835 residue. N676K, a mutation found in a patient at relapse on midostaurin, was also potently inhibited. Notably, F691L previously exhibited relative resistance to crenolanib, a reversible, type I FLT3 inhibitor. Beyond clinically described mutants, we also tested FF-10101 against six mutations previously identified in mutagenesis screening assays. A D698N mutation found in separate crenolanib and PLX3397 mutagenesis assays demonstrated relative resistance to crenolanib but was sensitive to FF-10101 (IC50 8.4 ± 7.8 nM), as were four D839 amino acid substitutions identified in the PLX3397 mutagenesis assay alone. Alternatively, a Y693C mutation found in a crenolanib mutagenesis screen remained relatively insensitive to FF-10101. Finally, two resistance mutations co-occurring in the same KD are well-described in chronic myelogenous leukemia (CML) patients treated with sequential TKI therapy. While not yet found in AML patients treated similarly, we hypothesize that analogous compound mutations could emerge. As such, we tested FF-10101 against BaF3 FLT3-ITD cells containing three compound mutations. Unlike crenolanib, FF-10101 potently inhibited D698N/D835V, but F691L/D835V and Y693C/D835V each exhibited relatively moderate resistance to both drugs. Analysis of additional activation loop (AL) mutations (N831H/K, R845G, G846R, Y842S) and biochemical studies of FLT3 phosphorylation and downstream effector pathways in response to FF10101 is ongoing and will be presented.Conclusions: FF-10101 is a type I, irreversible FLT3 inhibitor that has demonstrated potent activity against all mutations associated with clinical resistance to FLT3 TKIs. Expanded profiling shows anti-proliferative activity against nearly all mutations associated with FLT3 TKI resistance except for C695S (the site of FF-10101 binding) and the crenolanib-resistant Y693C mutation, which has yet to be associated with clinical TKI resistance. These data suggest FF-10101 has potential to be clinically active against the majority of FLT3 TKI resistant KD mutations. FF-10101 is currently beginning phase I/2a clinical assessment as a single agent in patients with relapsed/refractory AML harboring a FLT3 mutation. [Display omitted] DisclosuresSmith:Fujifilm: Research Funding; Astellas: Research Funding.

On the coherence of model-based dose-finding designs for drug combination trials.

The concept of coherence was proposed for single-agent phase I clinical trials to describe the property that a design never escalates the dose when the most recently treated patient has toxicity and never de-escalates the dose when the most recently treated patient has no toxicity. It provides a useful theoretical tool for investigating the properties of phase I trial designs. In this paper, we generalize the concept of coherence to drug combination trials, which are substantially different and more challenging than single-agent trials. For example, in the dose-combination matrix, each dose has up to 8 neighboring doses as candidates for dose escalation and de-escalation, and the toxicity orders of these doses are only partially known. We derive sufficient conditions for a model-based drug combination trial design to be coherent. Our results are more general and relaxed than the existing results and are applicable to both single-agent and drug combination trials. We illustrate the application of our theoretical results with a number of drug combination dose-finding designs in the literature.

RTID-09. A RANDOMIZED, DOUBLE-BLINDED, PHASE 3 STUDY OF ENZASTAURIN ADDED TO TEMOZOLOMIDE DURING AND FOLLOWING RADIATION THERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS WHO POSSESS THE NOVEL BIOMARKER, DGM1

Abstract BACKGROUND Limited progress has been made in improving therapeutic outcomes for glioblastoma (GBM) patients. Enzastaurin (enza) is an oral PKC-β inhibitor that suppresses signaling through the PKC and PI3K/AKT pathways. Although enza did not significantly improve survival in a prior Phase 1/2 study, we have identified a novel genomic biomarker, DGM1, that may predict a response to enza in GBM. PRIMARY OBJECTIVE To assess whether enza added to temozolomide and radiation therapy (RT) improves overall survival (OS) in newly diagnosed GBM patients who possess the DGM1 biomarker. POPULATION Adults with newly diagnosed GBM regardless of DGM1 status who have undergone surgical resection and are candidates for chemoradiation. Approximately 318 patients will be enrolled. DGM1 status will be determined prior to analysis. DESIGN This is a randomized, double-blinded, placebo-controlled study. Patients will be stratified by MGMT and IDH1 status and by geographic region. Treatment will be divided into 3 phases. In the Concurrent Phase (6 weeks), patients will receive RT plus temozolomide and either enzastaurin or placebo. Patients will then enter the Single-Agent Phase and receive either enza or placebo (21-35 days). Then, patients will enter the Adjuvant Phase and receive temozolomide with either enza or placebo (6-12 cycles) followed by enza or placebo alone (to 24 cycles total). ANALYSIS The primary efficacy endpoint of OS will be analyzed using stratified log-rank test for all DGM1-positive randomized patients. The study has approximately 90% power to detect a HR of 0.63 assuming 196 OS events based on a 2.5% one-sided false positive error rate. Statistical significance would be achieved with an estimated observed HR < 0.76. Safety evaluation will include all patients receiving at least one dose of enza or placebo. If OS in DGM1-positive patients is statistically significant, OS in the overall population will be assessed.