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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Refractory Metastatic Colorectal Cancer, Solid Tumor, Metastatic Microsatellite-stable Colorectal Cancer, Mismatch Repair Protein Proficient

Intervention / Treatment
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* Drug: CR6086
* Biological: AGEN2034


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated informed consent obtained before undergoing any study-specific procedure Male or female aged ≥18 years Histologically confirmed diagnosis of adenocarcinoma originating from the colon or rectum, with known RAS and BRAF mutational status as assessed per standard practice Stage IV (according to the American Joint Committee on Cancer definition) Presence of measurable disease per RECIST v1.1 (based on imaging within 28 days from first study drug administration). Patients must have at least one target lesion to be used to assess response, as defined by RECIST v1.1 (Note: Subjects with lesions in a previously irradiated field as the sole site of measurable disease will be permitted to enroll provided the lesion(s) have demonstrated clear progression and can be measured accurately) Disease progression after at least two standard treatment lines for mCRC, including fluoropyrimidines, oxaliplatin and irinotecan and, if RAS and BRAF wild-type, cetuximab or panitumumab, or, intolerance or refusal of chemotherapy regimens for mCRC. Note: Previous oxaliplatin-based adjuvant treatment is considered as a treatment line if disease relapse occurred within 6 months from its completion Naïve to any antibody/drug targeting T-cell co-regulatory proteins (immune checkpoints inhibitors) and EP4 receptor antagonists Availability of adequate and sufficient baseline tumor tissue sample (archival or newly obtained biopsy). Note: an adequate and sufficient sample is defined as formalin fixed paraffin embedded tumor tissue sample, preferably from the most recent biopsy of a tumor lesion, collected either at the time of or after the diagnosis of metastatic disease has been made AND from a site not previously irradiated. If no tumor tissue is available, a fresh tissue from needle or excisional biopsy or from resection is required pMMR/MSS defined as CRC with all 4 MMR proteins intact AND with instability at ≤1/5 locus (or 30% of loci if larger panel of markers are assayed) Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 Anticipated life expectancy ≥ 3 months Adequate hematologic and end organ function, defined by the following laboratory results, obtained within 7 days before first dose of study drug treatment: Hemoglobin ≥ 10 g/dL, platelet count ≥100,000/mm3, ANC ≥1500/mm3 Creatinine clearance ≥ 50 mL/min Amylase and lipase ≤ 1.5 × ULN Serum bilirubin ≤ 1.5× ULN AST, ALT, and ALP ≤ 2.5 × ULN with the following exceptions: - Patients with documented liver metastases (AST and/or ALT ≤ 5 × ULN) INR and PTT ≤ 1.5 × ULN (Note: Patients who are on therapeutic doses of anti-coagulants should be on a stable dose for 28 days, with stable INR and PTT values). Serum albumin ≥ 3.0 g/dL Proteinuria ≤ 3.5 g/24 hours Ability and willingness to participate and comply with the requirements of the entire study Exclusion Criteria: Medical Condition/History: -Cancer and anti-cancer therapy: Additional malignancy that progressed or required active treatment within the last 2 years. Exceptions include basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin that has undergone potentially curative therapy with no evidence of recurrence for 5 years since initiation of that curative therapy, or carcinoma in situ (breast carcinoma, cervical cancer) Active brain tumor, metastasis or leptomeningeal metastases. Patients with brain metastases are eligible if these have been treated and there is no magnetic resonance imaging (MRI except where contraindicated in which CT scan is acceptable) evidence of progression for at least 8 weeks after treatment is complete and within 28 days prior to first dose of study drug administration. Cases should be discussed with the Sponsor. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (>10mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration Major surgery within 28 days before Cycle 1 Day 1 or anticipation of needing such procedure during the trial Treatment with any systemic or localized anti-cancer therapy, including chemotherapy, biological therapy, radiotherapy, or hormonal therapy within 28 days before initiation of Cycle 1 Day 1 or expected to required such a treatment during the trial Persistent toxicity related to prior therapy, Grade >1 according to NCI CTCAE Version 5.0. Note 1: Patients must have recovered from all AEs due to previous therapies, to CTCAE ≤Grade 1 or to baseline condition. Participants with CTCAE ≤Grade 2 neuropathy or alopecia may be eligible. Note 2: If patients received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment. Note 3: Patients must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease Uncontrolled tumor-related pain. Patients requiring narcotic pain medication must be on a stable regimen at study entry Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage more than once every 28 days. Indwelling drainage catheters are allowed -Cardiovascular: Unstable angina Myocardial infarction within 6 months before enrolment History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 6 months before enrolment Uncontrolled ventricular arrhythmia Congestive heart failure (New York Hearth Association class ≥II) Poorly controlled hypertension -Infections: Confirmed infection with SARS-CoV-2 as documented by molecular testing at nasopharyngeal swab HIV infection Active tuberculosis Acute or chronic viral hepatitis B or C infection Any severe infection within 14 days before Cycle 1 Day 1 -General Medical History: Active autoimmune disease in the past 2 years History of allogenic tissue/solid organ transplant (including allogeneic bone marrow transplantation) History of immunodeficiency History or presence of interstitial lung disease or history of pneumonitis that has required oral or iv corticosteroids. History of gastric/duodenal ulcers, colitis and/or gastrointestinal bleeding History of severe gastrointestinal adverse reactions History of hypersensitivity reactions to fully human monoclonal antibodies, Grade ≥ 3 according to NCI CTCAE Version 5.0 History of anaphylaxis, or uncontrolled asthma Allergy/hypersensitivity/intolerance to any component of CR6086 or AGEN2034 Any other clinically relevant disease and condition, including psychiatric or substance abuse disorders, that, in the opinion of the Investigator, may jeopardize efficacy or safety assessments, confound the result of the trial or may compromise the patient's safety during trial participation -Concomitant Treatments Administration of a live, attenuated vaccine within 28 days before Cycle 1 D1 Systemic steroid therapy or any other form of immunosuppressive therapy within 7 days before screening Note: Corticosteroid use for management of immune-related adverse events, and/or as a premedication for iv contrast allergies/reactions is allowed. Daily corticosteroid replacement therapy is allowed: permitted therapy are daily prednisone at doses of 5 to 7.5 mg or equivalent hydrocortisone dose, and steroid therapy administered by topical, intraocular, intranasal, and/or inhalation routes Regular use of any illicit drugs or recent history (within the last year) of substance abuse (including alcohol) -Others: Participation in a study with an investigational drug or medical device within 28 days before Cycle 1 Day 1 Note: Participants who have entered the follow-up phase of another investigational study may participate as long as at least 4 weeks have elapsed since the last dose of the investigational agent Inability to swallow medications Malabsorption conditions For women of childbearing potential: Pregnancy (i.e. positive pregnancy test at Screening) or breastfeeding Failure to agree to practice a highly effective method of contraception, from enrolment up to at least 120 days after the last IMP intake expecting to conceive within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of study treatment For sexually active men with a female partner of childbearing potential: failure to agree to use condom and refrain from donating sperm from enrolment up to at least 120 days after the last IMP intake. Patients who are legally incapacitated or has limited legal capacity

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Prospective, open label, non-randomized, single-arm (non-controlled), multiple ascending dose (dose escalation)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 30 mg (Dose Level 1)<br>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 | Drug: CR6086<br>* oral CR6086, twice a day for 14 days<br>Biological: AGEN2034<br>* AGEN2034 3 mg/Kg iv on D1 of each 14- day cycle<br>* Other names: Balstilimab;|
| Experimental: 90 mg (Dose Level 2)<br>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 | Drug: CR6086<br>* oral CR6086, twice a day for 14 days<br>Biological: AGEN2034<br>* AGEN2034 3 mg/Kg iv on D1 of each 14- day cycle<br>* Other names: Balstilimab;|
| Experimental: 180 mg (Dose Level 3)<br>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 | Drug: CR6086<br>* oral CR6086, twice a day for 14 days<br>Biological: AGEN2034<br>* AGEN2034 3 mg/Kg iv on D1 of each 14- day cycle<br>* Other names: Balstilimab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of CR6086 combined with AGEN2034 | Incidence of TEAEs using NCI CTCAE v5.0 | From the time of the first dose up to 24 weeks of treatment | 
| Disease Control rate (DCR) | Proportion of patients who have achieved CR, PR, or stable disease (SD) per RECIST 1.1 / iRECIST | up to 24 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Proportion of patients who have achieved CR or PR per RECIST 1.1 / iRECIST | throughout the study, up to 2 years | 
| Duration Of Response (DOR) | Time from first documentation of response (CR or PR) until the time of first documentation of disease progression per RECIST 1.1 / iRECIST | throughout the study, up to 2 years | 
| Progression-Free Survival (PFR) | 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 | throughout the study, up to 2 years | 
| Progression-Free Survival Rate (PFSR) | 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 | throughout the study, up to 2 years | 
| Overall Survival (OS) | Time from the first dose of study drugs to the date of death by any cause | throughout the study, up to 2 years | 
| Safety and Tolerability of CR6086 combined with AGEN2034 | Incidence of TEAEs | throughout the study, up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prostaglandin E2 (PGE2), EP4 antagonist, CR6086, Balstilimab, anti PD-1, immune checkpoint inhibitors, Immuno-Oncology