A Phase IB Study of Pembrolizumab in Combination With Pemetrexed and Oxaliplatin in Patients With Chemo-Refractory Metastatic Colorectal Cancer
Overview
- Phase
- Phase 1
- Intervention
- Pembrolizumab
- Conditions
- Metastatic Colorectal Cancer
- Sponsor
- NSABP Foundation Inc
- Enrollment
- 33
- Locations
- 15
- Primary Endpoint
- Objective Response Rate to pembrolizumab plus pemetrexed
- Last Updated
- 3 years ago
Overview
Brief Summary
This is a Phase Ib study to evaluate the safety and preliminary anti-tumor activity of pembrolizumab in combination with pemetrexed with or without oxaliplatin in patients with chemo-refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC) without any further standard treatment options.
Detailed Description
The co-primary endpoints of the study are to 1) establish the recommended Phase II dose (RP2D) of pembrolizumab in combination with pemetrexed and oxaliplatin and 2) evaluate the antitumor efficacy. The secondary aims of the study are to 1) evaluate the clinical benefit rate (CBR) of pembrolizumab in combination with pemetrexed and with pembrolizumab in combination with pemetrexed and oxaliplatin in patients with chemo-refractory MSS mCRC and 2) to estimate the progression free survival (PFS) and 3) overall survival (OS) in patients with MSS mCRC treated with pembrolizumab and pemetrexed or with pembrolizumab in combination with pemetrexed and oxaliplatin. Patients enrolled to Cohort 1 will receive: pembrolizumab 200mg IV and pemetrexed 500 mg/m2 on Day 1 of each 21 day cycle. Cohort 2 (the dose escalation portion of the study) will be a standard "3+3" design; 2 dose levels are planned. The first 3 to 6 patients in cohort 2 will be treated at dose level 1 and will receive pembrolizumab 200 mg IV, pemetrexed 500 mg/m2 IV and oxaliplatin 85 mg/ m2 on Day 1 of each 21 day cycle. If 1 of 3 patients in this cohort experiences a dose-limiting toxicity (DLT), see Section 6.4, 3 more patients will be added at the same dose level. If 0 of 3 initial patients or 1 of 6 patients in the cohort experiences a DLT, the dose for the next cohort will be escalated to dose level 2 and will receive pembrolizumab 200 mg IV, pemetrexed 500 mg/m2 IV and oxaliplatin 120 mg/ m2 on Day 1 of each 21 day cycle; otherwise, the combination will be considered too toxic. If ≥ 2 DLTs are experienced at any dose level, the combination will be considered too toxic and the next lower dose level will be considered the RP2D. A total of 12 patients will be treated at the RP2D as the expansion portion. Patients in both cohorts will continue to receive study therapy (maximum of 35 cycles) unless therapy is discontinued due to patient election, toxicity, or disease progression. Dose limiting toxicity (DLT) will be monitored during the first 21 days (Cycle 1) of each dose level in Cohort 2 and will be used for purposes of dose escalation and determination of RP2D. A DLT is defined as a non-hematologic adverse event (AE) of grade ≥ 3 or a hematologic toxicity of grade ≥ 4. Toxicity will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.0. The highest dose level tolerable without dose limiting toxicities (DLTs) in \< 2 of 6 patients will be considered the recommended phase 2 dose (RP2D) and be expanded to 12 patients. The maximum total enrollment of the study is 33 patients. In Cohort 1, a total of 15 patients with chemo-refractory MSS mCRC will be treated for further safety assessment and a preliminary signal. In Cohort 2, 3 to 6 patients will be accrued per dose level. A total of 12 patients with chemo-refractory MSS mCRC will be treated on the RP2D for further safety and preliminary efficacy signal. Cohort 1 and Cohort 2 will be analyzed separately. Efficacy will be evaluated as the individual best overall response as defined by a modified RECIST 1.1 (mRECIST 1.1). The objective response rate (complete response \[CR\] and partial response \[PR\]) will be determined. In either dose level cohort \> 3 patients (\> 3 of 18) with objective response (PR or CR) will warrant further investigation.
Investigators
Eligibility Criteria
Inclusion Criteria
- •The patient must have consented to participate and, prior to beginning specific study procedures, must have signed and dated an appropriate IRB-approved consent form that conforms to federal and institutional guidelines for study treatment.
- •The ECOG performance status must be 0 or
- •There must be histologic or cytologic confirmation of a diagnosis of microsatellite stable (MSS) colorectal adenocarcinoma using CLIA certified IHC or PCR-based MSI testing.
- •Metastatic or locally advanced disease not amenable to curative surgery and/or radiotherapy.
- •There must be documentation by PET/CT scan, CT scan, or MRI that the patient has evidence of measurable metastatic disease per RECIST 1.
- •Patients must have had prior treatment for metastatic or unresectable for cure of colorectal cancer with standard chemotherapy including fluoropyrimidine-, oxaliplatin- and irinotecan- based chemotherapy, and if RAS wild-type, an anti-EGFR therapy.
- •At the time of study entry, blood counts performed within 2 weeks prior to study entry must meet the following criteria:
- •ANC must be greater than or equal to 1500/mm3;
- •Platelet count must be greater than or equal to 100,000/mm3; and
- •Hemoglobin must be greater than or equal to 9 g/dL.
Exclusion Criteria
- •Diagnosis of anal or small bowel carcinoma.
- •Colorectal cancer other than adenocarcinoma, e.g., sarcoma, lymphoma, carcinoid.
- •Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study therapy.
- •Use and/or receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal anti-bodies) or radiation therapy within 4 weeks prior to receiving first dose of study therapy.
- •Prior monoclonal antibody therapy within 4 weeks prior to first dose of FC-10 study therapy or who has not recovered (i.e., less than or equal to grade 1 or at baseline) from adverse events due to a previously administered agent.
- •Neuropathy greater than grade
- •Active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease or a syndrome that requires systemic steroids or immunosuppressive agents. Note: steroid use is permitted only as indicated per protocol.
- •Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving study therapy. Administration of killed vaccines is allowed.
- •Known history of hepatitis B or hepatitis C.
- •Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 14 days prior to trial treatment.
Arms & Interventions
Cohort 1
Pembrolizumab + Pemetrexed every 21 days. Folic Acid 5 days prior to first dose of pemetrexed and daily including 21 days after last dose of pemetrexed. Dexamethasone twice daily on the day before, the day of, and the day after each dose of pemetrexed. Vitamin B-12 7 days prior to first dose of pemetrexed, every 9 weeks, continue until 3 weeks after last dose of pemetrexed.
Intervention: Pembrolizumab
Cohort 1
Pembrolizumab + Pemetrexed every 21 days. Folic Acid 5 days prior to first dose of pemetrexed and daily including 21 days after last dose of pemetrexed. Dexamethasone twice daily on the day before, the day of, and the day after each dose of pemetrexed. Vitamin B-12 7 days prior to first dose of pemetrexed, every 9 weeks, continue until 3 weeks after last dose of pemetrexed.
Intervention: Pemetrexed
Cohort 1
Pembrolizumab + Pemetrexed every 21 days. Folic Acid 5 days prior to first dose of pemetrexed and daily including 21 days after last dose of pemetrexed. Dexamethasone twice daily on the day before, the day of, and the day after each dose of pemetrexed. Vitamin B-12 7 days prior to first dose of pemetrexed, every 9 weeks, continue until 3 weeks after last dose of pemetrexed.
Intervention: Dexamethasone
Cohort 1
Pembrolizumab + Pemetrexed every 21 days. Folic Acid 5 days prior to first dose of pemetrexed and daily including 21 days after last dose of pemetrexed. Dexamethasone twice daily on the day before, the day of, and the day after each dose of pemetrexed. Vitamin B-12 7 days prior to first dose of pemetrexed, every 9 weeks, continue until 3 weeks after last dose of pemetrexed.
Intervention: Folic Acid
Cohort 1
Pembrolizumab + Pemetrexed every 21 days. Folic Acid 5 days prior to first dose of pemetrexed and daily including 21 days after last dose of pemetrexed. Dexamethasone twice daily on the day before, the day of, and the day after each dose of pemetrexed. Vitamin B-12 7 days prior to first dose of pemetrexed, every 9 weeks, continue until 3 weeks after last dose of pemetrexed.
Intervention: Vitamin B-12
Cohort 2
Pembrolizumab + Pemetrexed + Oxaliplatin every 21 days. Folic Acid 5 days prior to first dose of pemetrexed and daily including 21 days after last dose of pemetrexed. Dexamethasone twice daily on the day before, the day of, and the day after each dose of pemetrexed. Vitamin B-12 7 days prior to first dose of pemetrexed, every 9 weeks, continue until 3 weeks after last dose of pemetrexed.
Intervention: Pembrolizumab
Cohort 2
Pembrolizumab + Pemetrexed + Oxaliplatin every 21 days. Folic Acid 5 days prior to first dose of pemetrexed and daily including 21 days after last dose of pemetrexed. Dexamethasone twice daily on the day before, the day of, and the day after each dose of pemetrexed. Vitamin B-12 7 days prior to first dose of pemetrexed, every 9 weeks, continue until 3 weeks after last dose of pemetrexed.
Intervention: Pemetrexed
Cohort 2
Pembrolizumab + Pemetrexed + Oxaliplatin every 21 days. Folic Acid 5 days prior to first dose of pemetrexed and daily including 21 days after last dose of pemetrexed. Dexamethasone twice daily on the day before, the day of, and the day after each dose of pemetrexed. Vitamin B-12 7 days prior to first dose of pemetrexed, every 9 weeks, continue until 3 weeks after last dose of pemetrexed.
Intervention: Oxaliplatin
Cohort 2
Pembrolizumab + Pemetrexed + Oxaliplatin every 21 days. Folic Acid 5 days prior to first dose of pemetrexed and daily including 21 days after last dose of pemetrexed. Dexamethasone twice daily on the day before, the day of, and the day after each dose of pemetrexed. Vitamin B-12 7 days prior to first dose of pemetrexed, every 9 weeks, continue until 3 weeks after last dose of pemetrexed.
Intervention: Dexamethasone
Cohort 2
Pembrolizumab + Pemetrexed + Oxaliplatin every 21 days. Folic Acid 5 days prior to first dose of pemetrexed and daily including 21 days after last dose of pemetrexed. Dexamethasone twice daily on the day before, the day of, and the day after each dose of pemetrexed. Vitamin B-12 7 days prior to first dose of pemetrexed, every 9 weeks, continue until 3 weeks after last dose of pemetrexed.
Intervention: Folic Acid
Cohort 2
Pembrolizumab + Pemetrexed + Oxaliplatin every 21 days. Folic Acid 5 days prior to first dose of pemetrexed and daily including 21 days after last dose of pemetrexed. Dexamethasone twice daily on the day before, the day of, and the day after each dose of pemetrexed. Vitamin B-12 7 days prior to first dose of pemetrexed, every 9 weeks, continue until 3 weeks after last dose of pemetrexed.
Intervention: Vitamin B-12
Outcomes
Primary Outcomes
Objective Response Rate to pembrolizumab plus pemetrexed
Time Frame: From initiation of pembrolizumab and pemetrexed until disease progression, intolerable toxicity, or completion of 35 cycles (each cycle is 21 days), approximately 2 years.
Objective Response Rate using modified RECIST 1.1.
Objective Response Rate to pembrolizumab and pemetrexed plus oxaliplatin
Time Frame: From initiation of pembrolizumab and pemetrexed plus oxaliplatin until disease progression intolerable toxicity, or completion of 35 cycles (each cycle is 21 days), approximately 2 years.
Objective Response Rate using modified RECIST 1.1.
Secondary Outcomes
- Frequency of Adverse Events(From begining of study therapy until disease progression, intolerable toxicity, or completion of 35 cycles (each cycle is 21 days), approximately 2 years.)
- Clinical Benefit Rate(From initiation of study therapy until disease progression, approximately 2 years.)
- Progression-Free Survival(From initiation of study therapy until disease progression, approximately 2 years.)
- Overall Survival(Time of study entry through 1 year.)