Neoplasms

Digestive System Diseases

All Conditions

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Reproductive Control Agents

Immune Checkpoint Inhibitors

Dinoprostone

14-day cycles of combined AGEN2034 3 mg/Kg iv on D1 of each cycle, and oral CR6086 30 mg twice a day for 14 days

14-day cycles of combined AGEN2034 3 mg/Kg iv on D1 of each cycle, and oral CR6086 90 mg twice a day for 14 days

14-day cycles of combined AGEN2034 3 mg/Kg iv on D1 of each cycle, and oral CR6086 180 mg twice a day for 14 days

CR6086

AGEN2034 3 mg/Kg iv on D1 of each 14- day cycle

AGEN2034

Principal Investigator

This Phase Ib/IIa study has been designed according to a 3+3 dose escalation/dose expansion design. A dose expansion will be conducted at both the intermediate and high dose levels, if tolerated, with the purpose of generating additional and more robust safety and preliminary efficacy data. No control arm was included, as the target patient population of this study consists of patients in whom the overall survival is less than 6 months and treatment options are very limited and often poorly tolerated, making unlikely that the study results can be significantly biased.

In this study, the combination of the PGE2 inhibition (through the EP4 receptor antagonist CR6086) with the immune checkpoint blockade (through the anti-PD-1 AGEN2034) is being evaluated. CR6086 is a potent and selective, orally bioavailable, targeted immunomodulator small molecule acting as an EP4 receptor antagonist. AGEN2034 (balstilimab) is a novel, fully human monoclonal immunoglobulin G4 antibody, designed to block programmed cell death 1 (PD-1) from interacting with its ligands (PD-L) PD-L1 and PD-L2, currently being developed for the treatment of advanced malignancies. EP4 receptor antagonists turn the status of the tumor microenvironment into a favourable one, i.e. immune-responsive, representing thus a rational therapeutic approach in combination with ICIs in primarily refractory cancers.

Prospective, open label, non-randomized, single-arm (non-controlled), multiple ascending dose (dose escalation)

A Phase Ib/IIa Study of CR6086 in Combination With Balstilimab in pMMR-MSS Metastatic Colorectal Cancer Patients

An Open-label, Single-arm, Phase Ib/IIa Trial to Evaluate the Safety and Efficacy of the EP4 Receptor Antagonist CR6086 in Combination With the PD-1 Inhibitor Balstilimab (AGEN2034), in Patients With Pretreated Mismatch-repair-proficient and Microsatellite Stable Metastatic Colorectal Cancer

Proportion of patients who have achieved CR, PR, or stable disease (SD) per RECIST 1.1 / iRECIST

Proportion of patients who have achieved CR or PR per RECIST 1.1 / iRECIST

Time from first documentation of response (CR or PR) until the time of first documentation of disease progression per RECIST 1.1 / iRECIST

Time from the first dose of study drugs to the earlier date of assessment of progression per RECIST 1.1 / iRECIST, or death by any cause in the absence of progression

Proportion of patients alive and free of disease progression per RECIST 1.1 / iRECIST at specific timepoints, or death by any cause in the absence of progression

Time from the first dose of study drugs to the date of death by any cause

Agenus Inc.

Rottapharm Biotech

Antibodies

Antibodies, Monoclonal

Capecitabine

Bevacizumab

Pembrolizumab

Immunoglobulins

Immunoglobulin G

Endothelial Growth Factors

Mitogens

Immunoglobulins, Intravenous

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Immunologic Factors

Antimetabolites

Patients receive pembrolizumab IV over 30 minutes on day 1, bevacizumab IV over 30-90 minutes on day 1, and capecitabine PO BID on days 1-14. Treatment repeats every 3 weeks for up to 35 courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Chloe Atreya, MD, PhD

This phase II trial studies the side effects and best dose of capecitabine when given together with pembrolizumab and bevacizumab, and investigates how well they work in treating patients with microsatellite stable colorectal cancer that has spread to nearby tissues or lymph nodes, has spread to other places in the body, or that cannot be removed by surgery. Monoclonal antibodies, such as pembrolizumab and bevacizumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving capecitabine together with pembrolizumab and bevacizumab may work better in treating patients with colorectal cancer.

PRIMARY OBJECTIVES:

I. To determine the recommended phase 2 dose (RP2D)/maximum tolerated dose (MTD) of capecitabine when administered with pembrolizumab and bevacizumab. (Safety Lead-In Cohort) II. To evaluate the overall response rate (ORR) to pembrolizumab plus capecitabine and bevacizumab (complete or partial response rate per Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1) in subjects with metastatic or locally advanced unresectable microsatellite stable (MSS)/mismatch repair proficient (pMMR) colorectal carcinoma (CRC) that is stable or progressing on fluorouracil (5FU)-based therapy. (Phase II Expansion Cohort)

SECONDARY OBJECTIVES (Phase II Expansion Cohort):

I. To determine the safety and tolerability of pembrolizumab in combination with capecitabine and bevacizumab.

II. To evaluate ORR per immune-related RECIST (irRECIST). III. To evaluate duration of response (DOR), disease control rate (DCR) and progression-free survival (PFS) per RECIST 1.1 and irRECIST and overall survival (OS).

EXPLORATORY OBJECTIVES:

I. Correlation of outcomes to line of therapy; stable disease or progression on a prior regimen containing infusional 5-FU or capecitabine; prior exposure to bevacizumab; and primary tumor location.

II. To explore baseline immune profiles via PD-L1, and multiplex Immunohistochemistry (IHC) for identification of potentially predictive biomarkers in patients with metastatic or locally advanced, unresectable CRC treated with pembrolizumab-based combination therapy.

III. To characterize the change in the populations of tumor-infiltrating immune cells (TIICs) by IHC induced by pembrolizumab-based combination therapy in paired pre- and on-treatment tumor biopsies from patients with metastatic or locally advanced, unresectable MSS / pMMR CRC.

IV. To determine the change in T cell repertoire via next generation sequencing (NGS) within blood and tumor biopsy samples induced by pembrolizumab-based combination therapy in patients with metastatic or locally advanced, unresectable MSS/pMMR CRC.

V. To establish human immune system (HIS) patient-derived xenograft (PDX) models from pre-treatment biopsies to a) analyze change in immune cell profiles HIS PDX models using the same techniques as described for corresponding patients, above and b) correlate response to pembrolizumab-containing therapy in patients and HIS PDX.

OUTLINE:

An initial safety lead-in will be performed to define the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1, bevacizumab IV over 30-90 minutes on day 1, and capecitabine orally (PO) twice daily (BID) on days 1-14. Treatment repeats every 3 weeks for up to 35 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 9 weeks until disease progression, start of new anti-cancer therapy, death, or end of the study whichever comes first

Pembrolizumab, Capecitabine, and Bevacizumab in Treating Patients With Microsatellite Stable Colorectal Cancer That Is Locally Advanced, Metastatic, or Cannot Be Removed by Surgery

Phase II Study of Pembrolizumab Plus Capecitabine and Bevacizumab in Microsatellite Stable Metastatic Colorectal Cancer

A DLT evaluation of the first 6 patients will be conducted to confirm the safety of administering pembrolizumab at 200 mg (flat dosing) every three weeks with capecitabine and bevacizumab and follows the principles of standard 3+3 dose escalation studies. The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in this study. The ASaT population consists of all allocated subjects who received at least one dose of study treatment. At least one laboratory or vital sign measurement obtained subsequent to at least one dose of study treatment is required for inclusion in the analysis including a baseline measure. Dose-limiting toxicity (DLT) must be clinically-significant toxicities which are at least possibly treatment-related per the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4

ORR is defined as the proportion of the subjects in the analysis population who have a complete response (CR) or partial response (PR) assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The point estimate and 95% confidence interval, will be provided using exact binomial method proposed by Clopper and Pearson (1934).

DCR is defined as the percentage of subjects who have achieved confirmed CR or PR or have demonstrated stable disease (SD) for at least 24 weeks prior to any evidence of progression assessed by RECIST and immune-related RECIST (irRECIST). The point estimate and 95% confidence interval, will be provided using exact binomial method proposed by Clopper and Pearson (1934).

Duration of response is defined as the time from first documented evidence of CR or PR assessed by RECIST and irRECIST until disease progression or death due to any cause, whichever occurs first. Kaplan-Meier (KM) curves and median estimates from the KM curves will be provided as appropriate.

OS is defined as the time from first day of study treatment to death due to any cause. Subjects without documented death at the time of the final analysis will be censored at the date of the last follow-up. KM curves and median estimates from the KM curves will be provided as appropriate.

PFS is defined as the time from first day of study treatment to the first documented disease progression or death due to any cause, whichever occurs first. KM curves and median estimates from the KM curves will be provided as appropriate.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Phase Ib/IIa Study of CR6086 in Combination With Balstilimab in pMMR-MSS Metastatic Colorectal Cancer Patients	NCT05205330	Refractory Meta... Solid Tumor Metastatic Micr... Mismatch Repair...	CR6086 AGEN2034	18 Years -	Rottapharm Biotech
Pembrolizumab, Capecitabine, and Bevacizumab in Treating Patients With Microsatellite Stable Colorectal Cancer That Is Locally Advanced, Metastatic, or Cannot Be Removed by Surgery	NCT03396926	Microsatellite ... Mismatch Repair... Stage III Color... Stage IIIB Colo... Stage IIIC Colo... Stage IV Colore... Stage IVA Color... Stage IVB Color...	Bevacizumab Capecitabine Laboratory Biom... Pembrolizumab	18 Years -	University of California, San Francisco

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