341 Phase 1b/2 study of BXCL701, an oral activator of the systemic innate immunity pathway, combined with pembrolizumab (pembro), in men with metastatic castration-resistant prostate cancer (mCRPC)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A366-A366
Author(s):  
Rahul Aggarwal ◽  
Dan Costin ◽  
Jingsong Zhang ◽  
Paul Monk ◽  
Mark Linch ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Single Agent ◽  
Objective Response ◽  
Fixed Dose ◽  
Tumor Growth Inhibition ◽  
Low Grade ◽  
Phase 2 ◽  
Split Dose ◽  
Cytokine Activation ◽  
Phase 1B

BackgroundBXCL701 (talabostat) is an oral small molecule inhibitor of dipeptidyl peptidases (DPP) primarily DPP8 and DPP9, which triggers inflammasome mediated pyroptosis in macrophages leading to induction of IL-18 and IL-1beta, bridging between innate and adaptive immunity. PD-L1 expression correlates with amplification of DPP8 and DPP9. In syngeneic animal models, significant tumor growth inhibition was observed with BXCL701 plus checkpoint inhibition. In a prior clinical study, single-agent BXCL701 resulted in objective responses in patients (pts) with Stage IV melanoma (unpublished).MethodsIn Phase 1b portion of this multicenter study, eligible pts had progressing mCRPC (PCWG3), at least 1 prior systemic therapy, ≤ 2 lines of cytotoxicchemotherapy for mCRPC, no prior anti-PD-1/PD-L1 or other T-cell directed anticancertherapy. Using a 3+3 design, pts received fixed-dose pembro (200 mgIV q21-days) with escalating doses of BXCL701 on days 1–14. The primary endpoint was determination of the recommended Phase 2 dose (RP2D). Response (RECIST 1.1, PSA, CTC), plasma drug concentration and change in relevant immune effector cytokines were also evaluated.Results13 pts were treated in 3 cohorts of BXCL701: 0.4 mg qd (n = 3); 0.6 mg qd (n = 3) and 0.6 mg split dose (n=7). 7 pts had adenocarcinoma, 6 had small cell/neuroendocrine prostate cancer features. Prior treatment included ADT (n = 10), 2nd-generation androgen signaling inhibitors (n = 9), chemotherapy (n = 11), RT (n = 11). On-target AEs consistent with cytokine activation were seen at the highest dose levels. In the 0.6 mg qd cohort, all pts had events consistent with cytokine release: 3/3 had hypotension (including 1 grade 3 syncope (DLT)) and 2pts each had dizziness and LE edema. Splitting the 0.6 mg dose improved the tolerability while maintaining the TDD previously associated with objective response; 3/7 pts had fatigue, and 1pt each had low grade hypotension, dyspnea, chills, myalgia. Preliminary anti-tumor activity was seen with 1 pt achieving a PSA response and 3 pts with RECIST1.1 stable disease. BXCL701 was quantifiable in plasma. Consistent dose and time dependent increases in serum IL-18 levels were observed with 0.6 mg split dose.ConclusionsBXCL701 0.3 mg BID (0.6 mg TDD) administered on days 1–14 was identified as the RP2D when administered with pembro 200 mg every 21 days. Splitting the TDD was associated with improved tolerability as evidenced by no reported DLTs and lower rates of other adverse events of interest such as hypotension and peripheral edema. The Phase 2 portion of the study is enrolling.AcknowledgementsAll patients, their families, and caregivers who make this study possible; the participating investigators and their staff; Cedric Burg PhD and J. MacDougall PhD of BioXcel Therapeutics, Valery Chatikhine MD of Iqvia Biotech and the Iqvia Biotech team for assisting in the conduct of the study.Trial RegistrationNCT03910660EUDRACT 2018-003734-32Ethics ApprovalThis study was approved by Institution Review Boards or Ethics Committees affiliated with participating institutions.

BXCL701, first-in-class oral activator of systemic innate immunity pathway, combined with pembrolizumab (Keytruda) in men with metastatic castration-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 124-124
Author(s):  
Rahul Raj Aggarwal ◽  
Dan Costin ◽  
Jingsong Zhang ◽  
Lawrence Ivan Karsh ◽  
Diane I. Healey ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Single Agent ◽  
Objective Response ◽  
Fixed Dose ◽  
Low Grade ◽  
Phase 2 ◽  
2Nd Generation ◽  
Cytokine Activation ◽  
Signaling Inhibitors ◽  
Phase 1B

124 Background: BXCL701 (talabostat), oral small molecule inhibitor of dipeptidyl peptidases (DPP), primarily DPP8 and DPP9, triggers inflammasome mediated pyroptosis in macrophages, leading to induction of IL-18 and IL-1ß, bridging between innate and adaptive immunity. PD-L1 expression correlates with amplification of DPP8 and DPP9. In syngeneic animal models, significant tumor growth inhibition was observed with BXCL701 plus checkpoint inhibition. In a prior clinical study, single-agent BXCL701 resulted in objective responses in patients with Stage IV melanoma (unpublished). Methods: Eligible patients included in Phase 1b portion of this multicenter study, had progressing mCRPC (PCWG3), ≥1 prior systemic therapy, ≤2 lines of cytotoxic chemotherapy for mCRPC, no prior anti-PD-1/PD-L1 or other T-cell directed anticancer therapy. In Phase 2 portion, patients with adenocarcinoma must have received 1 or 2 2nd generation androgen signaling inhibitors; patients with SCNC/t-NEPC must have received ≥1 prior line of chemotherapy. Patients received fixed-dose pembrolizumab (200 mg IV q21-days) with BXCL701 on days 1-14 at recommended Phase 2 dose (RP2D)/schedule. Primary endpoint is Composite Response (RECIST 1.1, PSA, CTC). Change in relevant immune effector cells was also evaluated. Results: In Phase 1b portion 13 patients were treated with BXCL701 in 3 cohorts: 0.4 mg qd (n = 3); 0.6 mg qd (n = 3) and 0.6 mg split dose (n=7). 7 patients had adenocarcinoma, 6 had small cell/neuroendocrine prostate cancer phenotype. Prior treatment included androgen deprivation therapy (n = 10), 2nd-generation androgen signaling inhibitors (n = 9), chemotherapy (n = 11), radiation therapy (n = 11). On-target adverse events (AEs) consistent with cytokine activation were seen at highest dose levels. In 0.6 mg qd cohort, all patients had events consistent with cytokine release syndrome: 3/3 had hypotension, including 1 grade 3 syncope—dose-limiting toxicity (DLT)—and 2 patients each had dizziness and lower extremity edema. Splitting 0.6 mg dose improved tolerability while maintaining total daily dose (TDD) previously associated with objective response; 3/7 patients had fatigue, and 1 patient each had low grade hypotension, dyspnea, chills, myalgia. Preliminary anti-tumor activity was seen with 1 patient achieving a PSA response and 4 patients with RECIST1.1 stable disease. Consistent dose and time dependent increases in serum IL-18 levels were observed. Conclusions: BXCL701 0.3 mg BID (0.6mg TDD) administered on days 1-14 was identified as RP2D when administered with pembrolizumab 200 mg every 21 days. Splitting TDD was associated with improved tolerability as evidenced by no reported DLTs and lower rates of other AEs of interest e.g. hypotension and peripheral edema. Preliminary data from Phase 2 portion will be presented. Clinical trial information: NCT03910660.

A phase II, open label, randomized, noncomparative study of eFT508 (tomivosertib) alone or in combination with avelumab in subjects with relapsed/refractory microsatellite stable colorectal cancer (MSS CRC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14145-e14145 ◽  
Author(s):  
Joleen Marie Hubbard ◽  
Manish R. Patel ◽  
Tanios S. Bekaii-Saab ◽  
Gerald Steven Falchook ◽  
Bradley L. Freilich ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Objective Response ◽  
Mrna Translation ◽  
Fixed Dose ◽  
Low Grade ◽  
Target Engagement ◽  
Efficacy Evaluation ◽  
Open Label

e14145 Background: Dysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of solid tumors. Tomivosertib (T), a potent and highly selective small molecule inhibitor of MNK-1 and 2 blocks activation of eIF4E, a key regulator of mRNA translation, selectively regulating translation of a set of mRNAs. Preclinically, T triggers an anti-tumor immune response and enhances responses to checkpoint inhibitors. Avelumab is a fully human checkpoint inhibitor antibody directed against PD-L1. Methods: Part 1: In a 3+3 dose escalation patients (pts) with MSS CRC failing ≥2 prior therapies for metastatic disease received escalating doses of T, administered orally bid, with a fixed dose of 10 mg/kg avelumab q2w. Part 2: Pts were randomized (2:1) to combination therapy at the recommended phase 2 dose (RP2D) from part 1 or T alone. Primary endpoint is objective response rate. All pts have a pretreatment and on treatment biopsy to evaluate target engagement, tumor infiltrating lymphocytes and biomarkers of immune activation. Results: The RP2D for the combination was 200 mg bid T (single agent RP2D) with 10mg/kg avelumab q2w. At this dose level, 1 of 7 pts experienced a dose limiting toxicity being unable to complete the first 28 day cycle due to low grade (1/2) toxicities (nausea, fatigue, myalgia). In part 2, 30 pts were randomized to combination and 15 to monotherapy (25 male, 20 female: mean age 53.9 years, range 32-80 years). The most common adverse events, irrespective of causality were grade 1/2 gastrointestinal (including nausea, vomiting, abdominal pain, constipation and diarrhea) occurring in 77% (n = 23) of the combination and 67% (n = 10) of the monotherapy arm. Toxicities occurring more frequently in the combination arm included diarrhea, constipation, fatigue, myalgia/arthralgia, hypercalcemia and skin rash. Efficacy evaluation is pending from part 2. One pt with confirmed MSS status in part 1 treated at the RP2D achieved a confirmed Partial Response of greater than 8 months. Conclusions: Preliminary data suggest that the combination of T and avelumab has an acceptable safety profile with robust target engagement and demonstrated initial signs of activity. Updated efficacy and biological biopsy data will be presented at the conference. Clinical trial information: NCT03258398.

scholarly journals The CDK9 Inhibitor, Alvocidib, Potentiates the Non-Clinical Activity of Azacytidine or Decitabine in an MCL-1-Dependent Fashion, Supporting Clinical Exploration of a Decitabine and Alvocidib Combination

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4355-4355
Author(s):  
Wontak Kim ◽  
Clifford Whatcott ◽  
Adam Siddiqui-Jain ◽  
Stephen Anthony ◽  
David J. Bearss ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cell Viability ◽  
Single Agent ◽  
Xenograft Model ◽  
Complete Response ◽  
Tumor Growth Inhibition ◽  
Phase 2 ◽  
Phase 1B ◽  
Cdk9 Inhibitor

Abstract The hypomethylating agents (HMAs) azacytidine and decitabine exert biological activity via two distinct mechanisms, namely, DNA damage and inhibition of DNA methyltransferases. Azacytidine and decitabine are indicated in the treatment of patients with myelodysplastic syndromes (MDS). As a result of DNA methyltransferase inhibition, it is hypothesized that HMAs may function by inducing re-expression of key pro-apoptotic proteins such as NOXA, which sequesters the anti-apoptotic protein MCL-1, preventing its association with the mitochondrial pore-forming proteins BAX/BAK. Activity of the potent CDK9 inhibitor, alvocidib, is largely driven by targeting of CDK9-dependent MCL-1 expression. Alvocidib is under active clinical investigation, but has also has demonstrated high complete response rates in newly diagnosed AML patients, particularly when administered as part of a cytarabine and mitoxantrone containing regimen (ACM regimen). Given the dual NOXA/MCL-1-targeting ability of combining alvocidib and azacytidine or decitabine, the combination may synergize therapeutically in the treatment of non-clinical models of AML or MDS by means of transcriptional induction of NOXA and repression of MCL-1 expression. Cell viability and induction of apoptosis was assessed following treatment with alvocidib, azacytidine, and decitabine in cells using the Celltiter-Glo and Caspase-Glo assays. Gene expression changes following treatment were assessed using quantitative RT-PCR. Protein expression changes with treatment were also measured using standard immunoblotting technique. To assess the in vivo anti-tumor activity of these compounds, xenograft studies in the MOLM13 and additional models of MDS, exploring sequencing and scheduling of alvocidib administration with HMAs, were performed. Treatment of AML cell lines with alvocidib inhibited both mRNA and protein expression of MCL-1 in a time and concentration-dependent fashion. Pre-treatment of cells with alvocidib, to repress MCL-1 expression prior to azacytidine treatment, reduced the azacytidine cell viability EC50 more than 2.5-fold, from 1.8 µM to 0.6 µM in MV4-11 cells. The alvocidib/azacytidine combination also resulted in synergistic increases in caspase activity relative to either single agent within the combination, at multiple dose levels. The combination of azacytidine or decitabine with alvocidib was active in the MOLM13 xenograft model, yielding up to 65.7 or 91.1% tumor growth inhibition (%TGI) in the azacytidine or decitabine combination, respectively. Taken together, the in vitro and in vivo studies indicated that decitabine was more effective at re-expressing NOXA and potentiating alvocidib activity compared to azacytidine. These non-clinical data suggest that an alvocidib/HMA combination may constitute a viable therapeutic regimen whose rationale focuses on hypertargeting of NOXA/MCL-1. Based on these non-clinical results, a Phase 1b/2 clinical study of alvocidib administered in sequence after decitabine in patients with intermediate to high risk MDS is being conducted (Zella 102). Patients will be enrolled in cohorts of 3-6 patients with decitabine administered as a 1-hour IV infusion daily on days 1 to 5 at a dose of 20 mg/m2 followed by a single alvocidib treatment on day 8 as a loading dose over 30 minutes followed by a 4-hour infusion. Treatment will be repeated every 28 days until disease progression or unacceptable toxicity. Enrollment will include MDS patients (Phase 1b) with previously untreated MDS and patients who received fewer than six (6) cycles of previous HMAs, as well as (Phase 2) untreated patients with de novo or secondary MDS. The primary objective is to determine the maximum tolerated dose and recommended Phase 2 dose of alvocidib when administered in sequence with decitabine. Key Phase 2 endpoints will include complete response rate and improvement in transfusion dependency. Disclosures Kim: Tolero Pharmaceuticals, Inc: Employment. Whatcott:Tolero Pharmaceuticals, Inc: Employment. Siddiqui-Jain:Tolero Pharmaceuticals, Inc: Employment. Anthony:Tolero Pharmaceuticals, Inc: Employment. Bearss:Tolero Pharmaceuticals, Inc: Employment. Warner:Tolero Pharmaceuticals: Employment.

Phase 1b Results of a Phase 1b/2 Study of Obinutuzmab, Ibrutinib, and Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 639-639 ◽  
Author(s):  
Jeffrey A. Jones ◽  
Jennifer Woyach ◽  
Farrukh T. Awan ◽  
Kami J. Maddocks ◽  
Thomas Whitlow ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Objective Response ◽  
Response Assessment ◽  
Phase 2 ◽  
Advisory Committees ◽  
Once Daily ◽  
Phase 1B

Abstract BACKGROUND Venetoclax(VEN), a once daily oral inhibitor of BCL2, has demonstrated high response rates and acceptable toxicity in patients with relapsed or refractory (R/R) CLL both as a single agent and in combination with the anti-CD20 monoclonal antibodies rituximab and obinutuzumab (formerly GA-101, G), where minimal residual disease (MRD) negative responses have been observed in the majority of patients. Ibrutinib (IBR), a once daily oral inhibitor of the Brutontyrosine kinase, likewise induces remissions in the majority of treated patients, but complete response (CR) is uncommon even after prolonged administration. Early genetic studies have demonstrated that BCL2 over-expression rescues BTK deficient XID murine B-cells from spontaneous apoptosis (J Immunol 1996), so we hypothesized that combination therapy would more efficiently achieve deep response endpoints. We report phase 1b results of a single-institution phase 1b/2 study of G, IBR, and VEN to characterize the safety and preliminary efficacy of the combination. METHODS Patients with CLL relapsed after or refractory to ≥1 prior therapy and who required treatment were eligible. Enrolled patients had ECOG ≤1 and preserved end-organ function, including creatinine clearance ≥50 mL/min/m2. Patients with chronic viral hepatitis infection, uncontrolled autoimmunecytopenia, active Richter transformation, and known cysteine-481 BTK mutation or clinical disease progression during treatment with a cysteine-481-binding BTK inhibitor were excluded. G, IBR, and VEN were started sequentially over the first 3 of fourteen 28-day cycles as detailed in the table. To establish the safety of VEN in combination with OBIN and IBR, VEN dose was escalated in 3 x 3 cohorts (100, 200, 400 mg) to a maximum planned dose of 400 mg daily. Dose limiting toxicity (DLT) was defined during the third cycle. Risk assessment for VEN dose ramp-up was conducted according to US prescribing information. Adverse events were assessed and graded using CTCAE v4.03. Response assessment according to IWCLL 2008 criteria, including bone marrow biopsy with 4-colorimmunophenotyping of marrow and peripheral blood (PB) for MRD, occurs after cycles 8 and 14. RESULTS Twelve R/R patients have been treated in the phase 1b portion of the trial. Median age was 57 years (range: 42-70) and median prior therapies was 1 (range: 1-7). Baseline genetic risk features includedunmutatedIGHV in 11 (92%),del(17p) in 1 (8%), del(11q) in 8 (67%), and complex abnormal karyotype in 5 (42%) patients. Tumor lysis (TLS) risk was low in 1 (8%), medium in 7 (58%), and high in 4 (33%) patients at study entry. In general, observed toxicities for the combination were consistent with those reported for the single agents. DLTs were not observed at any VEN dose level, establishing VEN 400 mg daily as safe in combination with standard doses of G and IBR. The most common grade ≥3 adverse events (regardless of attribution) were neutropenia (50%), lymphopenia (33%),hypertension(25%), and fatigue (17%). Grade 1/2 adverse events occurring in over half the patients included bruising (all grade 1, 83%), infusion related reaction (75%), hypertension (67%), headache (67%), hyperuricemia (all grade 1, 75%), hypocalcemia (75%), and diarrhea (all grade 1, 67%), AST and/or ALT elevation (58%), and rash (50%). No cases of either clinical or laboratory TLS were observed. All patients remain on therapy and 6 have reached response assessment after completing 8 cycles of therapy. All 6 have achieved objective response: 5 PR, including 1 MRD-negative in PB (VEN 100) and 1 MRD-negative in both PB and marrow (VEN 100), and 1 CR with MRD-negative PB and marrow (VEN 200). CONCLUSIONS G, IBR, and VEN can be safely administered in combination at doses standard for the treatment of CLL. DLTs were not observed, establishing VEN 400 mg as the recommended phase 2 dose in combination with G and IBR. Adverse events were manageable and largely consistent with those reported in the single agent phase 2 studies. Objective responses, including MRD-negative responses, have been observed among all R/R patients from the first dose cohorts. Accrual continues to parallel phase 2 cohorts of R/R (n=25) and TN (n=25) patients. Updated phase 1b toxicity and response data will be presented. Table. Table. Disclosures Jones: Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan:Pharmacyclics: Consultancy; Novartis Oncology: Consultancy; Innate Pharma: Research Funding.

ProSTAR: A phase Ib/II study of CPI-1205, a small molecule inhibitor of EZH2, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration-resistant prostate cancer (mCRPC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS335-TPS335 ◽  
Author(s):  
Mary-Ellen Taplin ◽  
Arif Hussain ◽  
Satish Shah ◽  
Neal D. Shore ◽  
Manish Agrawal ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Primary Endpoint ◽  
Response Rate ◽  
Standard Dose ◽  
Phase 1 ◽  
Objective Response ◽  
Phase 2 ◽  
Once Daily ◽  
Phase 1B ◽  
Randomized Phase 2

TPS335 Background: EZH2 is frequently mutated and/or overexpressed in numerous cancers. High EZH2 expression is correlated with poor outcomes in prostate cancer patients (Varambally, 2002). EZH2 inhibition combines synergistically with anti-androgen therapies in preclinical models of advanced prostate cancer, suggesting epigenetic reprogramming as a pathophysiologic mechanism to enhance the combination therapy (Ku, 2017; Xiao 2018; Constellation, unpublished). CPI-1205 is a potent, selective, and cofactor-competitive inhibitor of wild type and mutant EZH2 catalytic activity, which demonstrates anti-proliferative effects in prostate and other cancer cell models. Methods: We present a Phase 1b/2 multicenter study of CPI-1205 combined with either E or A/P in patients with mCRPC, which includes phase 1 dose escalation, an expansion cohort in heavily pretreated patients (HPEC), and a randomized phase 2 study. Key eligibility criteria include progressive mCRPC in patients previously treated with a second-generation androgen inhibitor, ECOG 0-1, and measurable or non-measurable disease. During the phase 1b, patients will receive CPI-1205 continuously in 28-day cycles combined with the standard dose of either E (160mg PO once daily) or A/P (1000mg PO once daily/5 mg BID). The primary objective in Phase 1b is to determine the safety, tolerability, and recommended phase 2 dose (RP2D) of CPI-1205 combined with either E or A/P. Secondary objectives include safety, pharmacokinetic and pharmacodynamic profiles, and anti-tumor activity. The HPEC arm, with Simon’s 2-stage design, may begin with the regimen that is deemed safe by the study safety committee. The primary endpoint of the HPEC arm is objective response rate (ORR) per PCWG3, with a requirement ≥ 1 measurable lymph node at baseline. Once RP2D is established, we will start a randomized Phase 2 trial of E or A/P combined with CPI-1205 vs. E or A/P alone. The co-primary endpoint includes PSA50 and composite response rate (either CTC 30% reduction or ORR per PCWG3). Patient accrual in US sites began in December 2017. Clinical trial information: NCT03480646.

A first-in-man phase I/II study of OBI-3424, an AKR1C3-selective bis-alkylating agent prodrug, in subjects with advanced cancer, including hepatocellular carcinoma (HCC) and castrate-resistant prostate cancer (CRPC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3658-TPS3658
Author(s):  
Apostolia Maria Tsimberidou ◽  
Claire F. Verschraegen ◽  
Pei Hsu ◽  
Tillman E. Pearce
Keyword(s):  
Prostate Cancer ◽  
Alkylating Agent ◽  
Alkylating Agents ◽  
Single Agent ◽  
Objective Response ◽  
Unmet Need ◽  
Phase 2 ◽  
Clinical Safety ◽  
Toxic Dose ◽  
Tumor Expression

TPS3658 Background: Aldo-keto reductase family 1 member C3 (AKR1C3) modulates cellular differentiation and proliferation through indirect regulation of ligand access to hormone and nuclear receptor signaling. AKR1C3 is expressed at high levels in various human cancers, including HCC. In prostate cancer cells exposed to anti-androgen therapies, AKR1C3 is adaptively upregulated. CRPC is a potential indication for this targeted alkylating agent. AKR1C3 tumor expression is associated with poor patient survival and resistance to cancer therapies. OBI-3424 is a nitro-benzene prodrug of a nitrogen mustard that can be selectively cleaved in the presence of AKR1C3 enzyme into a bis-alkylating agent capable of forming intra- and inter-strand crosslinks with DNA, thereby resulting in cell death. The selectivity of OBI-3424 for AKR1C3 distinguishes it from traditional alkylating agents, which are nonselective. The primary objectives of the study are to evaluate the safety and tolerability of single-agent OBI-3424. The dose-escalation phase will determine the dose-limiting toxicities (DLT), maximum tolerable dose (MTD), and recommended Phase 2 dose (RP2D) of OBI-3424 through assessment of PK of OBI-3424 and OBI-2660 in plasma and urine. After determining the maximum tolerated dose (MTD), the study will enroll subjects with advanced HCC or CRPC, two tumor types with a high likelihood of overexpression of AKR1C3, into the dose expansion portion of the study according to a Simon two-stage phase 2 design. This phase is designed to assess the objective response rate, and progression-free survival in patients with HCC and CRPC. Immunohistochemistry assays are being developed to assess tumor expression of AKR1C3 for this study. The clinical safety and relationship of efficacy to AKR1C3 tumor expression will serve to guide further clinical development of OBI-3424 in these two unmet need settings. Methods: Based on the toxicology and PK results in cynomolgus monkeys, the starting dose is one sixth of the human equivalent dose of the highest non-severely toxic dose observed. Doses of 1, 2, 4, 6, 8, 12, and 14 mg/m2 will be used. OBI-3424 is administered intravenously (IV) over 30 minutes on days 1 and 8 of each 21-day cycle. Subjects without clinically significant disease progression may continue on treatment for up to 2 years, if they do not experience a DLT or other significant toxicity. Clinical trial information: NCT03592264 .

A phase Ib/II open-label study of tazemetostat (TAZ) plus enzalutamide (E) or abiraterone/prednisone (A/P) in chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS255-TPS255
Author(s):  
Wassim Abida ◽  
Thomas Paul Bradley ◽  
Arash Rezazadeh ◽  
Lawrence Ivan Karsh ◽  
Ashley Ross ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Second Generation ◽  
Response Rate ◽  
Objective Response ◽  
Specific Antigen ◽  
Phase 2 ◽  
Open Label ◽  
Open Label Study ◽  
Label Study ◽  
Phase 1B

TPS255 Background: The histone methyltransferase EZH2 is overexpressed in many cancers. In prostate cancer (PC), EZH2 inhibition may reverse acquired resistance to androgen inhibitors (AIs). Pts may initially respond to AIs, but pts who progress have limited treatment options. In phase 2 trials, TAZ, a selective, orally bioavailable, investigative small molecule EZH2 inhibitor, has demonstrated encouraging objective responses in B-cell lymphomas and molecularly defined solid tumors and a favorable safety profile. In PC preclinical models, TAZ + E or A/P showed a greater reduction in tumor growth than either drug alone. This study will evaluate the safety and efficacy of TAZ + E or A/P vs E or A/P alone in mCRPC. Methods: This phase 1b/2 study will enroll pts ≥18 years with progressive mCRPC, with or without prior second-generation AI treatment, and no prior chemotherapy. Phase 1b will identify the recommended phase 2 dose (RP2D) of TAZ when combined with E (160 mg/day) or A/P (A: 1000 mg/day; P: 5 mg twice-daily [BID]) and evaluate the safety and tolerability of each combination in treatment-naïve pts and pts previously treated with a second-generation AI. Using a modified 3+3 design (up to 48 pts: 18 for TAZ+A/P and 30 for TAZ+E), TAZ dosing will start at 400 mg BID, escalating to 800 mg BID in the TAZ+A/P group or 1600 mg BID in the TAZ + E group, if no dose-limiting toxicities are observed. Phase 2 will begin once the RP2D for each combination is determined. Efficacy and safety results from phase 1b will inform the final design for phase 2. Phase 2 will be an open label study where pts will be randomized to either E or A/P alone or in combination with TAZ. TAZ will be administered at the RP2D in continuous 28-day cycles for as long as pts tolerate treatment and continue AI therapy. Tumor assessments will be performed every 9 weeks for 6 months and every 12 weeks thereafter. Efficacy assessments include radiographic progression-free survival (primary endpoint), prostate-specific antigen (PSA) ≥50% response rate, time to PSA progression, time to subsequent systemic therapy, and objective response rate. Safety is a secondary endpoint.

scholarly journals A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Sébastien Perreault ◽  
Valérie Larouche ◽  
Uri Tabori ◽  
Cynthia Hawkin ◽  
Sarah Lippé ◽  
...  
Keyword(s):  
Single Agent ◽  
Objective Response ◽  
Plexiform Neurofibroma ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Low Grade ◽  
Erk Pathway ◽  
Phase 2 ◽  
Open Label ◽  
Phase 2 Study

Abstract Background Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. Up to 50% will be refractory to conventional chemotherapy. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. The same pathway is also activated in plexiform neurofibromas (PNs) which are low-grade tumors involving peripheral nerves in patients with neurofibromatosis type 1 (NF1). These lesions are known to be refractory to chemotherapy. Specific MEK inhibitors such as trametinib are now available and have been approved for other cancers harboring mutations in the MAPK/ERK pathway such as melanoma. We have observed significant responses to trametinib in patients with refractory PLGG in our institutions and results from the phase I study are promising. The treatment appears not only efficacious but is also usually well tolerated. We hypothesize that we will observe responses in the majority of refractory PLGG and PN treated with trametinib in this phase 2 study. Methods The primary objective is to determine the objective response rate of trametinib as a single agent for treatment of progressing/refractory tumors with MAPK/ERK pathway activation. The TRAM-01 study is a phase II multicentric open-label basket trial including four groups. Group 1 includes NF1 patients with progressing/refractory glioma. Group 2 includes NF1 patients with plexiform neurofibroma. Group 3 includes patients with progressing/refractory glioma with KIAA1549-BRAF fusion. Group 4 includes other patients with progressing/refractory glioma with activation of the MAPK/ERK pathway. Eligible patients for a given study group will receive daily oral trametinib at full dose for a total of 18 cycles of 28 days. A total of 150 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, overall survival, safety and tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment. Discussion Trametinib will allow us to target directly and specifically the MAPK/ERK pathway. We expect to observe a significant response in most patients. Following our study, trametinib could be integrated into standard treatment of PLGG and PN. Trial registration ClinicalTrials.gov Identifier: NCT03363217 December 6, 2017.

Tazemetostat (TAZ) in relapsed/refractory (R/R) follicular lymphoma (FL): Propensity-score matched analysis of E7438-G000-101 trial outcomes.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18627-e18627
Author(s):  
David Proudman ◽  
Deepshekhar Gupta ◽  
Dave Nellesen ◽  
Alex Wong ◽  
Jay Yang ◽  
...  
Keyword(s):  
Propensity Score ◽  
Single Agent ◽  
Objective Response ◽  
Prior History ◽  
Cell Transplant ◽  
Phase 2 ◽  
Matched Sample ◽  
Hematopoietic Stem ◽  
Disease Characteristics ◽  
Baseline Characteristics

e18627 Background: Oncology drug development often requires the use of non-randomized, open-label, phase 2 basket studies to better understand the early activity and safety of a potential new therapy. As such, baseline demographics and disease characteristics may differ between cohorts which can impact the perception of efficacy between cohorts. TAZ, a first-in-class, oral enhancer of zeste homolog 2 (EZH2) inhibitor was approved by the US FDA after demonstrating single-agent, antitumor activity in a phase 2 study in adults with wild-type (WT) or mutant (MT) EZH2 R/R FL who had received ≥2 prior systemic therapies (NCT01897571). Differences between the cohorts in baseline characteristics known to be prognostic for clinical outcomes were noted, with the WT EZH2 cohort enrolling more patients with poor-risk features. This analysis assessed outcomes in the 2 groups after minimizing differences in baseline characteristics by creating a matched sample of directly comparable WT and MT patients. Methods: Propensity scores for each WT (n = 54) and MT (n = 45) EZH2 patient in the study were generated, based on the likelihood of being selected given their baseline characteristics. Characteristics identified for inclusion in the model were chosen if they were prognostic based on peer-reviewed literature and where larger differences were observed between cohorts at baseline: ECOG performance status, number of prior lines of anticancer therapy, progression of disease within 24 months, double refractory status, and prior history of hematopoietic stem cell transplant. Patients were matched 1:1 on propensity score, using a nearest-neighbor approach with caliper restrictions. Baseline covariates between the two matched groups were found to be sufficiently balanced. Objective response rate (ORR) point estimates were measured for the matched WT and MT EZH2 groups, and progression-free survival (PFS) was described using Kaplan-Meier analyses. Results: The propensity-matched sample included 56 patients (28 WT and 28 MT). Prior to matching, ORR was 35% (95% CI [22%, 48%]) in the WT and 69% (95% CI [55%, 83%]) in MT EZH2 groups; after matching, the ORR was 50% (95% CI [31%, 69%]) and 71% (95% CI [54%, 88%]), respectively. Median PFS was 11.1 months (95% CI [5.4, 16.7]) in the WT and 13.8 months (95% CI [11.1, 22.1]) in the MT EZH2 groups prior to matching, and 14.3 months (95% CI [11.1, inf]) and 14.8 (95% CI [10.7, inf]) months in the WT and MT EZH2 matched groups, respectively. Conclusions: As expected, efficacy remained higher in the MT EZH2 group; however, after adjustment, the ORR and PFS improved in the WT EZH2 group. This hypothesis-generating analysis suggests that outcomes in patients with WT EZH2 R/R FL treated with TAZ may have been more similar to those in the MT EZH2 group in the phase 2 trial had the baseline disease characteristics been more equally matched.

Phase I study of BJ-001, a tumor-targeting interleukin-15 fusion protein, in patients with solid tumor.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14545-e14545
Author(s):  
Ki Y. Chung ◽  
Haeseong Park ◽  
Raghad Muhsin Abdul-Karim ◽  
Deborah Blythe Doroshow ◽  
Jorge Chaves ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Tumor Targeting ◽  
Single Agent ◽  
Adult Patients ◽  
Fixed Dose ◽  
Cell Counts ◽  
Phase 1B ◽  
Interleukin 15

e14545 Background: BJ-001 is the first tumor-targeting Interleukin-15 (IL-15) fusion protein, composed of an integrin-binding Arg-Gly-Asp (RGD)-4C motif, linked with a human IgG1 Fc, and then a modified sushi domain of human IL-15Rα unit and a human IL-15. Tumor-targeting is achieved with RGD-4C motif which binds to αvβ3, αvβ5, and αvβ6 integrins, commonly overexpressed in solid tumors. The molecule has shown an ability to activate Natural Killer (NK) and T cells in vitro and in pre-clinical in vivo studies. Methods: This first in-human (FIH) study has 2 phases: Phase 1a and Phase 1b. Phase 1a consists of 3 parts. In all 3 parts patients receive escalating doses of BJ-001 as a once weekly subcutaneous injection for 4 weeks in 6-week cycles. Part 1 utilizes an accelerated dose escalation design with single patient cohort for the first 3 dose levels. Part 2 uses a 3+3 dose escalation design. Part 3 uses a 3+3 dose escalation of BJ-001 but in combination with a fixed-dose PD-(L)1 inhibitor. Dose escalation will proceed based on clinical safety and tolerability data observed during the Dose Limiting Toxicity (DLT) period, i.e., Cycle 1 Days 1 through 28 for Part 1 and Cycle 1 Days 1 through 42 for Parts 2 and 3. Adult patients (ECOG PS ≤ 2) with locally advanced or metastatic solid tumors refractory to or intolerant of all existing therapies are eligible for Phase 1a. Phase 1b will enroll cohorts of adult patients with selected solid tumors known to have high levels of integrin expression at the Maximum Tolerated Dose or Recommended Phase 2 Dose of BJ-001 in combination with a PD-(L)1 inhibitor, as identified in Phase 1a, Part 3. Results: As of Jan 31, 2021, 9 patients have received BJ-001 dosing as a single agent at 0.21 µg/kg (n = 1), 0.9 µg/kg (n = 1), 3 µg/kg (n = 1), 6 µg/kg (n = 3), or 10 µg/kg (n = 3) in Phase 1a Parts 1 and 2, wherein 7 patients, including 1 patient in the 10 µg/kg cohort, have completed the DLT period. Among these 7 patients, 2 (1 in 3 µg/kg and 1 in 6 µg/kg cohorts) have stable disease and are still receiving BJ-001 treatment beyond Cycle 1. The longest duration in the study, to date, is approximately 4 cycles (over 5 months). Treatment Emergent Adverse Events (TRAEs) include injection site reactions (6/7, Grade 1-2), anorexia (2/7, Grade 1-2), cytokine release syndrome (1/7, Grade 1, resolved in 1 day), and temporal wasting (1/7, Grade 1). The AEs did not result in dose interruption or dose level adjustment. No DLTs observed to date. With escalating doses, a trend of increased post-dose NK cell counts observed, whereas Regulatory T cell (Treg) counts remained stable. Conclusions: To date, BJ-001 is well tolerated up to 6 µg/kg. The safety evaluation for 10 µg/kg is ongoing. The observed NK and Treg cell profiles are consistent with known IL-15 biology. Clinical trial information: NCT04294576.

Sign in / Sign up

Export Citation Format

Share Document