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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.

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.

Pembrolizumab 200 mg IV on Day 1 of each 21 day cycle until maximum of 35 cycles.

Pemetrexed 500 mg/m2 IV on Day 1 of each 21 day cycle until maximum of 35 cycles.

Oxaliplatin-Dose level1: 85 mg/m2 IV on Day 1 of each 21 day cycle until a maximum of 35 cycles or until discontinued due to patient election, toxicity, disease progression.

Dose level 2: 120 mg/m2 IV on Day 1 of each 21 day cycle until a maximum of 35 cycles or until discontinued due to patient election, toxicity, disease progression.

The MTD dose of oxaliplatin in the study combination of Cohort 2 will be the recommended Phase II dose (RP2D) for the cohort expansion.

Dexamethasone-4 mg by mouth twice daily on: the day before, the day of, and the day after each dose of pemetrexed.

Folic Acid-400 micrograms by mouth daily starting 5 days prior to first dose of pemetrexed and continue daily to include 21 days after the last dose of pemetrexed.

1000 micrograms administered intramuscularly 7 days prior to the first dose of pemetrexed, every 9 weeks, and should continue until 3 weeks after the last dose of pemetrexed.

Vitamin B-12

Norman Wolmark, MD

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.

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.

Study of Pembrolizumab With Pemetrexed and Oxaliplatin in Chemo-Refractory Metastatic Colorectal Cancer Patients

A Phase IB Study of Pembrolizumab in Combination With Pemetrexed and Oxaliplatin in Patients With Chemo-Refractory Metastatic Colorectal Cancer

Objective Response Rate using modified RECIST 1.1.

Frequency of adverse events in Cohort 1 categorized using the NCI Common Terminology Criteria for Adverse Events version 4.0.

Frequency of adverse events in Cohort 2 categorized using the NCI Common Terminology Criteria for Adverse Events version 4.0.

Rate of disease status by continuous tumor measurement using modified RECIST 1.1.

Progression-free survival (PFS). Percentage of patients alive with absence of progression assessed using RECIST 1.1 criteria.

Overall Survival. Percentage of patients alive after 1 year.

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