Refractory Metastatic Colorectal Cancer, Solid Tumor, Metastatic Microsatellite-stable Colorectal Cancer, Mismatch Repair Protein Proficient, Metastatic GI Cancers, Gastric Cancer
Conditions
Keywords
prostaglandin E2 (PGE2), EP4 antagonist, CR6086, Balstilimab, anti PD-1, immune checkpoint inhibitors, Immuno-Oncology, vorbipiprant
Brief summary
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 refractory pMMR-MSS mCRC patients. The fixed-dose Expansion phase will be conducted at the recommended dose for expansion (RDE), with the purpose of generating additional and more robust safety and efficacy data. 27 patients are predicted in the Dose Escalation phase and 52 in the Expansion phase, respectively. The Study Extension explores in other metastatic GI cancers the Vorbipiprant (CR6086) RDE obtained in the Main Study. 27 patients are predicted. 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
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 refractory 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.
Interventions
Sponsors
Agenus Inc.
Rottapharm Biotech
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Prospective, open label, non-randomized, single-arm (non-controlled), multiple ascending dose (Dose Escalation) in refractory pMMR-MSS mCRC patients, followed by a fixed-dose Expansion (at RDE) in refractory pMMR-MSS mCRC patients, and a fixed-dose (at RDE) Study Extension in other metastatic GI cancers
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Diagnosis and Main Criteria for Inclusion/Exclusion: Inclusion Criteria Main Study - patients with MSS mCRC These criteria are applicable for both Dose Escalation and Expansion part of the Main Study; criteria specific for each study part are identified with ESC=Escalation or EXP=Expansion. 1. Signed and dated informed consent obtained before undergoing any study-specific procedure 2. Male or female aged ≥18 years 3. ESC - Histologically confirmed diagnosis of adenocarcinoma originating from the colon or rectum, with known RAS and BRAF mutational status as assessed per standard practice. EXP - Histologically confirmed diagnosis of adenocarcinoma originating from the colon or rectum, with known RAS and BRAF mutational status as assessed per standard practice. For patients included in the Expansion part only: PD-L1 CPS or adequate tissue to perform PD-L1 CPS assessment should be available. 4. Stage IV (according to the American Joint Committee on Cancer definition) 5. 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 6. ESC - 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 EXP - Disease progression after at least two standard treatment lines for mCRC, including fluoropyrimidines, oxaliplatin and irinotecan and: 1. if RAS and BRAF wild type, cetuximab or panitumumab 2. if BRAFV600E mutated encorafenib and cetuximab 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 7. Naïve to any antibody/drug targeting T-cell co-regulatory proteins (immune checkpoints inhibitors) and EP4 receptor antagonists 8. ESC - 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 EXP - Availability of adequate and sufficient newly obtained fresh tumour tissue sample collected after ICF during the screening period and before the treatment starts. In case the biopsy collection is not feasible, according to Investigator judgement or patient decision, archival biopsy or surgical sample can be accepted after discussion with the Sponsor. Note: an adequate and sufficient sample is defined as formalin fixed paraffin embedded tumour tissue sample, collected from a site not previously irradiated. If the formalin fixed paraffin embedded tumor tissue sample obtained after the last treatment line and 90 days before the ICF signature, the patient is considered eligible, If the fresh tissue from needle or excisional biopsy/resection is not feasible according to the Investigator judgement, the patients may be eligible after discussion with the Sponsor. 9\. pMMR/MSS defined as CRC with all 4 MMR proteins intact and/or with instability at ≤1/5 locus (or 30% of loci if larger panel of markers are assayed) 10. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 11. Anticipated life expectancy ≥ 3 months 12. Adequate hematologic and end organ function, defined by the following laboratory results, obtained within 7 days before first dose of study drug treatment: 1. Hemoglobin ≥ 10 g/dL, platelet count ≥100,000/mm3, ANC ≥1500/mm3 2. Creatinine clearance ≥ 50 mL/min 3. Amylase and lipase ≤ 1.5 × ULN 4. Serum bilirubin ≤ 1.5× ULN 5. AST, ALT, and ALP ≤ 2.5 × ULN with the following exceptions: * Patients with documented liver metastases: AST and/or ALT ≤ 5 × ULN 6. INR and PTT ≤ 1.5 × 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. 7. Serum albumin ≥ 3.0 g/dL 13\. 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 1. Signed and dated informed consent obtained before undergoing any study-specific procedure 2. Male or female aged ≥18 years 3. Body weight \> 40kg 4. Histologically proven advanced-stage unresectable adenocarcinoma of the stomach or the GEJ 5. Stage IV (according to the American Joint Committee on Cancer definition) 6. Available CPS or available tissue to perform CPS assessment: Cohort A: CPS≥5 - Cohort B CPS\<5 7. 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). 8. 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 9. Naïve to EP4 receptor antagonists 10. 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 11. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 12. Anticipated life expectancy ≥ 3 months 13. Adequate hematologic and end organ function, defined by the following laboratory results, obtained within 7 days before first dose of study drug treatment: <!-- --> 1. Hemoglobin ≥ 10 g/dL, platelet count ≥100,000/mm3, ANC ≥1500/mm3 2. Creatinine clearance ≥ 50 mL/min 3. Amylase and lipase ≤ 1.5 × ULN 4. Serum bilirubin ≤ 1.5× ULN 5. AST, ALT, and ALP ≤ 2.5 × ULN with the following exceptions: * Patients with documented liver metastases: AST and/or ALT ≤ 5 × ULN 6. INR and PTT ≤ 1.5 × 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. 7. Serum albumin ≥ 3.0 g/dL 14\. Ability e and willingness to participate and comply with the requirements of the entire study Cohort C - GI cancers other than CRC and GC 1. Signed and dated informed consent obtained before undergoing any study-specific procedure 2. Male or female aged ≥18 years 3. Body weight \> 40kg 4. Histologically proven advanced-stage unresectable GI cancer other than CRC and GC 5. Stage IV (according to the American Joint Committee on Cancer definition) 6. 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). 7. 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 8. Naïve to EP4 receptor antagonists 9. 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 10. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 11. Anticipated life expectancy ≥ 3 months 12. Adequate hematologic and end organ function, defined by the following laboratory results, obtained within 7 days before first dose of study drug treatment: <!-- --> 1. Hemoglobin ≥ 10 g/dL, platelet count ≥100,000/mm3, ANC ≥1500/mm3 2. Creatinine clearance ≥ 50 mL/min 3. Amylase and lipase ≤ 1.5 × ULN 4. Serum bilirubin ≤ 1.5× ULN 5. AST, ALT, and ALP ≤ 2.5 × ULN with the following exceptions: * Patients with documented liver metastases: AST and/or ALT ≤ 5 × ULN 6. INR and PTT ≤ 1.5 × 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. 7. Serum albumin ≥ 3.0 g/dL 13\. Ability e and willingness to participate and comply with the requirements of the entire study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | up to 24 weeks of treatment | Proportion of patients who have achieved CR or PR per RECIST 1.1 / iRECIST during the Expansion part (Phase IIa) |
| Safety and Tolerability of CR6086 combined with AGEN2034 | From the time of the first dose up to 24 weeks of treatment | Incidence of TEAEs using NCI CTCAE v5.0 |
| Disease Control rate (DCR) | up to 24 weeks of treatment | Proportion of patients who have achieved CR, PR, or stable disease (SD) per RECIST 1.1 / iRECIST during the Dose Escalation part |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration Of Response (DOR) | throughout the study, up to 2 years | Time from first documentation of response (CR or PR) until the time of first documentation of disease progression per RECIST 1.1 / iRECIST |
| Progression-Free Survival (PFR) | throughout the study, up to 2 years | 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 |
| Overall Survival (OS) | throughout the study, up to 2 years | Time from the first dose of study drugs to the date of death by any cause |
| Safety and Tolerability of CR6086 combined with AGEN2034 | throughout the study, up to 2 years | Incidence of TEAEs |
| Progression-Free Survival Rate (PFSR) | throughout the study, up to 2 years | 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 |
| Disease Control Rate (DCR) | throughout the study | Proportion of patients who have achieved CR, PR, or stable disease (SD) per RECIST 1.1 / iRECIST during the Dose Escalation part |
| Objective Response Rate (ORR) | throughout the study | Proportion of patients who have achieved CR or PR per RECIST 1.1 / iRECIST during the Expansion part (Phase IIa) |
Other
| Measure | Time frame |
|---|---|
| Evaluate PD-L1 expression by CPS as predictor of response (Main Study/Expansion) | throughout the study |
Countries
Italy
Outcome results
None listed