Status and phase
Conditions
Treatments
Study type
Funder types
Identifiers
About
This Phase Ib/IIa study comprises a Main Study and a Study Extension.
The Main Study has been designed according to a 3+3 dose escalation/dose expansion design in MSS mCRC patients. 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.
The Study Extension explores in other metastatic GI cancers the CR6086 recommended dose for expansion (RDE) obtained in the Main Study.
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.
Full description
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 in pMMR-MSS mCRC and other metastatic GI cancers. CR6086 (vorbipiprant) 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.
Enrollment
Sex
Ages
Volunteers
Inclusion and exclusion criteria
Diagnosis and Main Criteria for Inclusion/Exclusion:
Inclusion Criteria
Main Study - patients with MSS mCRC
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:
INR and PTT ≤ 1.5 × ULN.
Serum albumin ≥ 3.0 g/dL
Ability e and willingness to participate and comply with the requirements of the entire study
Study Extension - other metastatic GI cancers
Cohorts A and B - Gastric cancer
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:
INR and PTT ≤ 1.5 × ULN.
Serum albumin ≥ 3.0 g/dL
Ability e and willingness to participate and comply with the requirements of the entire study
Cohort C - GI cancers other than CRC and GC
Signed and dated informed consent obtained before undergoing any study-specific procedure
Male or female aged ≥18 years
Body weight > 40kg
Histologically proven advanced-stage unresectable GI cancer other than CRC and GC
Stage IV (according to the American Joint Committee on Cancer definition)
Failure to at least one prior line of chemotherapy for metastatic disease, given with or without trastuzumab, with or without anti-PD-1. In alternative, early disease recurrence after surgery with neo-adjuvant and/or adjuvant chemotherapy (within 6 months of the last administration of chemotherapy) or progression during neo-adjuvant and/or adjuvant chemotherapy (containing fluoropyrimidine and a platinum derivative).
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
Naïve to EP4 receptor antagonists
Availability of adequate and sufficient baseline tumour tissue sample (archival or newly obtained biopsy) Note: an adequate and sufficient sample is defined as formalin fixed paraffin embedded tumour tissue sample, preferably from the most recent biopsy of a tumour 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 tumour tissue is available, a fresh tissue from needle or excisional biopsy or from resection is required
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
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
Ability e and willingness to participate and comply with the requirements of the entire study
Exclusion Criteria
Exclusion criteria 1-37 are applicable to all patients to be enrolled in the study, in both Main Study and Study Extension.
Criteria 38-40 are applicable to patients to be enrolled in Study Extension only.
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 tumour, 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 tumour-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 (see Section 12.4), 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 (see Section 12.4) 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
Criteria for Study Extension only
Presence of portal hypertension
Presence of oesophageal varices
Presence of gastric infiltration, severe gastritis, duodenal or gastric ulcer, or any other condition that may lead to bleeding or perforation, as assessed by an EGDS performed during screening period.
Criteria referring to Cycle 1 D1, should be reassessed on study D1, before starting the study treatment.
Primary purpose
Allocation
Interventional model
Masking
55 participants in 4 patient groups
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Central trial contact
Clinical Operations Director Rottapharm Biotech
Data sourced from clinicaltrials.gov
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