E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010036 |
E.1.2 | Term | Colorectal carcinoma |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Objective (Cohort A): To evaluate the Objective Response Rate (ORR) per RECIST 1.1 assessed by central imaging vendor of the 200 mg Q3W dose of pembrolizumab in subjects with locally advanced unresectable or metastatic MMR deficient or MSI high CRC and who have been previously treated with standard of care therapies, which must include fluoropyrimidine, oxaliplatin, and irinotecan.
Objective (Cohort B): To estimate the ORR per RECIST 1.1 assessed by central imaging vendor, of the 200 mg Q3W dose of pembrolizumab in subjects with locally advanced unresectable or metastatic MMR deficient or MSI high CRC and who have been previously treated with at least one line of systemic standard of care therapy (fluoropyrimidine + oxaliplatin or fluoropyrimidine + irinotecan +/- anti-VEGF/EGFR monoclonal antibody). |
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E.2.2 | Secondary objectives of the trial |
The secondary efficacy objectives of this study are to evaluate the ORR and DOR, DCR, PFS per RECIST 1.1 as assessed by the central imaging vendor, and OS in both Cohort A and Cohort B separately. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Merck will conduct Future Biomedical Research on DNA (blood and tissue) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time.
Additional biomarker research to identify factors important for MK-3475 therapy will be pursued in Cohort B and are optional in Cohort A.
On cohort B there will be a plasma Sample for Circulating Tumor DNA Study; A plasma sample will be collected prior to treatment at the Cycle 1, Cycle 3, and discontinuation visits for planned analysis of circulating tumor DNA. |
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E.3 | Principal inclusion criteria |
Subjects must: be male or female subjects who are ≥ 18 years of age on the day of signing the informed consent. Locally confirmed MMR deficient or MSI-h CRC. Have a histologically proven locally advanced unresectable or metastatic (Stage IV) CRC. Have been previously treated with standard therapies, which must include, for Cohort A, fluoropyrimidine, oxaliplatin and irinotecan and for Cohort B, at least 1 line of systemic standard of care therapy (fluoropyrimidine + oxaliplatin or fluoropyrimidine + irinotecan +/- anti-VEGF/EGFR monoclonal antibody). Subjects who have withdrawn from therapy standard treatment due to unacceptable toxicity warranting discontinuation of that treatment and precluding retreatment with the same agent before progression of disease will also be eligible. Regimens given with adjuvant intent will be counted as treatment for metastatic disease if the patient’s disease had progressed within 6 month following treatment. Have an ECOG performance status of 0 or 1. Have a life expectancy of greater than 3 months. Have at least one measurable lesion by RECIST 1.1 as determined by central review for response assessment. Provide an archival or newly obtained tumor
tissue sample (Cohort B). Subjects failing screening criteria in Cohort A may be rescreened for Cohort B only after consultation with the SPONSOR. |
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E.4 | Principal exclusion criteria |
Subjects will be excluded if he/she: is currently participating in another study and receiving trial treatment, has participated in a study of an investigational agent and received trial treatment within 4 weeks of the first dose of treatment in this study, or used an investigational device within 4 weeks of the first dose of treatment in this study. Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Has a 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 trial treatment.
Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they have stable brain metastases [without evidence of progression by imaging [confirmed by magnetic resonance imaging (MRI) if MRI was used at prior imaging, or confirmed by computed tomography (CT) imaging if CT used at prior imaging] for at least four weeks prior to the first dose of trial treatment; also, any neurologic symptoms must have returned to baseline], have no evidence of new or enlarging brain metastases, and have not used steroids for brain metastases for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis, as subjects with carcinomatous meningitis are excluded regardless of clinical stability. Has had prior monoclonal antibody (mAb), chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. Has received a live vaccine within 30 days of planned start of study therapy. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). Has known history of, or any evidence of interstitial lung disease or active, non-infectious pneumonitis.
Has an active infection requiring systemic therapy. |
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E.5 End points |
E.5.1 | Primary end point(s) |
ORR based on RECIST 1.1 assessed by central imaging vendor |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
There is one interim analysis planned in this study for Cohort A and no interim analysis planned for Cohort B. |
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E.5.2 | Secondary end point(s) |
Objective response rate (ORR) - irRECIST assessed by central imaging vendor
Disease Control Rate (DCR) - RECIST 1.1 and irRECIST assessed by central imaging vendor
Duration of Response (DOR) - RECIST 1.1 and irRECIST assessed by central imaging vendor
Progression-free Survival (PFS) - RECIST 1.1 and irRECIST assessed by central imaging vendor
Overall survival (OS) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Response assessments for endpoints are being evaluated throughout the study; imaging assessment to support the endpoints are obtained every 9 weeks for the first 12 months, then every 12 weeks thereafter, or more frequently if clinically indicated. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
Israel |
Japan |
Korea, Republic of |
United States |
Belgium |
France |
Germany |
Spain |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The overall trial ends when fewer than 25% of subjects are evaluable for OS or all subjects have discontinued trial treatment (including retreatment), whichever occurs earlier. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 24 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 24 |