| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient
(dMMR) Stage IV Colorectal Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10010035 |
| E.1.2 | Term | Colorectal cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10079619 |
| E.1.2 | Term | MSI-high |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
1. Objective (Cohort A): To compare MK-1308A and pembrolizumab with respect to Objective Response Rate per RECIST 1.1 as assessed by Blinded Independent Central Review
2. Objective (Cohorts B and C): To evaluate the efficacy of MK-1308A with respect to Objective Response Rate per RECIST 1.1 as assessed by Blinded Independent Central Review |
|
| E.2.2 | Secondary objectives of the trial |
1. Objective (Cohort A, B and C): To evaluate Duration of Response per RECIST 1.1 as assessed by Blinded Independent Central Review
2. Objective (Cohort A): To compare MK-1308A and pembrolizumab with respect to Progression-Free Survival per RECIST 1.1 as assessed by Blinded Independent Central Review
3. Objective (Cohorts B and C): To evaluate the Progression-Free Survival per RECIST 1.1 as assessed by Blinded Independent Central Review
4. Objective (Cohort A): To compare MK-1308A and pembrolizumab with respect to Overall Survival
5. Objective (Cohorts B and C): To evaluate Overall Survival
6. To evaluate the safety and tolerability of MK-1308A alone (Cohorts B and C) and compared to pembrolizumab (Cohort A)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has a histologically confirmed diagnosis of Stage IV CRC adenocarcinoma (as defined by AJCC version 8).
2. Has locally confirmed dMMR/MSI-H.
Cohort A:
3. Has been previously treated for their disease and radiographically progressed per RECIST 1.1 on or after or could not tolerate standard treatment, which must include ALL of the following agents if approved and locally available in the country where the participant is randomized:
a) Fluoropyrimidine, irinotecan and oxaliplatin.
b) With or without an anti-VEGF monoclonal antibody (eg, bevacizumab)
c) At least one of the anti-EGFR monoclonal antibodies (cetuximab or panitumumab) for RAS WT participants with left-sided tumors.
4. Must not have had prior exposure to PD-1 or PD-L1 therapies as treatment for this disease.
Cohort B:
5. Has untreated Stage IV dMMR/MSI-H CRC with no prior chemotherapy or immunotherapy for this disease.
Cohort C:
6. Has radiographically progressed on-treatment with an anti-PD-1 mAb administered either as monotherapy or in combination with other therapies. PD-1 treatment progression is defined by meeting all of the following criteria:
a. Has received at least 2 doses of an approved anti-PD-1 mAb.
b. Has shown disease progression after anti-PD-1 as defined by RECIST 1.1. The initial evidence of disease progression is to be confirmed by a second assessment no less than 4 weeks from the date of the first documented disease progression, in the absence of rapid symptom progression or clinical deterioration.
c. Has documented progressive disease within 12 weeks from the last dose of anti-PD-1 mAb.
◦ Progressive disease is determined according to RECIST 1.1.
◦ This determination is made by the investigator. Once disease progression is confirmed, the initial date of disease progression documentation will be considered the date of disease progression.
7. Has had 0 to 1 prior systemic fluoropyrimidine based chemotherapy regimens.
8. Must not have been treated in Cohort A.
9. Is male or female and at least 18 years of age at the time of providing documented informed consent.
10. Has a life expectancy of at least 3 months.
11. Has ECOG Performance Status of 0 to 1 at screening and within 3 days before Cycle 1 Day 1.
12. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a WOCBP
OR
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), during the intervention period and for at least 120 days after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure in relationship to the first dose of study intervention.
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours for a urine test and 72 hours for a serum test before the first dose of study intervention.
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
13. The participant (or legally acceptable representative) has provided documented informed consent/assent for the study. The participant may also provide consent/assent for FBR. However, the participant may participate in the study without participating in FBR.
14. Have measurable disease per RECIST 1.1 as assessed by BICR. Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions.
15. Submit an archival or newly obtained tumor tissue sample that has not been previously irradiated; FFPE blocks are preferred to slides. If a sufficient specimen does not exist, the participant must be willing to undergo a core or excisional biopsy during screening.
Newly obtained biopsies are preferred to archived tissue. For Cohort A, samples may predate chemotherapy. For Cohort B, the specimen may predate adjuvant chemotherapy (this cohort will have had no therapy for metastatic disease). For Cohort C, samples may have been taken prior to PD-1 therapy if taken within 3 months of allocation (i.e. primarily refractory disease); otherwise, a fresh biopsy will be required.
16. Have adequate organ function. Specimens must be collected within 7 days before the start of study intervention. |
|
| E.4 | Principal exclusion criteria |
1. Has received prior therapy with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137, PD-L1).
2. Has received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention.
3. If the participant had a surgery and they have not recovered adequately from the procedure and/or any complications from the surgery before starting study intervention.
4. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants 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.
5. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention.
6. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention.
7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication.
8. Has a known additional malignancy that is progressing or has required active treatment within the past 2 years.
9. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, (ie, without evidence of progression) for at least 4 weeks by repeat imaging, clinically stable and without requirement of steroid treatment for at least 14 days before the first dose of study intervention.
10. Has severe hypersensitivity (≥Grade 3) to pembrolizumab, quavonlimab and/or any of their excipients.
11. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, 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) is not considered a form of systemic treatment and is allowed.
Exception: Participants with a history of inflammatory bowel disease (eg, Crohn’s disease or ulcerative colitis) may not participate, regardless of treatment history.
12. Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis.
13. Has an active infection requiring systemic therapy (eg, tuberculosis, known viral or bacterial infections, etc.).
14. Has a known history of HIV infection.
15. Has known active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) or active Hepatitis C virus (defined as HCV RNA [qualitative] is detected or anti-HCV Ab positive) infection.
16. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
17. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
18. Is pregnant, or breastfeeding, or expecting to conceive children within the projected duration of the study, starting with the Screening Visit through 120 days after the last dose of study intervention.
19. Has had an allogenic tissue/solid organ transplant. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Up to approximately 39 months |
|
| E.5.2 | Secondary end point(s) |
1. Duration of Response (DOR) per RECIST 1.1 as assessed by BICR
2. Progression-Free Survival (PFS) per RECIST 1.1 as assessed by BICR
3. Overall Survival (OS)
4. Number of participants who experienced an Adverse Event (AE)
5. Number of participants discontinuing study treatment due to an AE
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 39 months
2. Up to approximately 39 months
3. Up to approximately 39 months
4. Up to approximately 27 months
5. Up to approximately 24 months
|
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| 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 |
| Canada |
| Korea, Republic of |
| Russian Federation |
| Turkey |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Poland |
| Spain |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
