| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Colorectal Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Colorectal Cancer |
|
| 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 | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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. To compare MK-4280A to standard of care (regorafenib or TAS-102) with respect to overall survival. |
|
| E.2.2 | Secondary objectives of the trial |
1. To compare MK-4280A to standard of care with respect to progression free survival per RECIST 1.1 as assessed BICR.
2. To compare MK-4280A to standard of care with respect to objective response rate per RECIST 1.1 as assessed by BICR.
3. To assess the efficacy of MK-4280A and standard of care with respect to duration of response per RECIST 1.1 by BICR.
4. To determine the safety and tolerability of MK-4280A and standard of care.
5. To compare the change from baseline in global health status/QoL, physical functioning, appetite loss and bloating for MK-4280A versus standard of care.
6. To compare the time to deterioration in global health status/QoL, physical functioning, appetite loss and bloating for MK-4280A versus standard of care.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The participant must have histologically confirmed colorectal adenocarcinoma that is metastatic and unresectable (Stage IV as defined by AJCC eighth edition) [National Comprehensive Cancer Network 2018]
2. Have measurable disease per RECIST 1.1 as assessed by the local site investigator. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
3. Has been previously treated for their disease and radiographically progressed 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.
d. Participants with BRAF v600E mutations must have been treated with a RAF inhibitor. with or without binimetinib. Participants with BRAF mutations that are not v600E are not required to have received RAF inhibitor therapy.
4. Submit an archival (≤ 5 years) or newly obtained tumor tissue sample that has not been previously irradiated, to enable central laboratory testing of PD-L1 and MMR status. FFPE blocks are preferred to slides.
5. Have an ECOG PS of 0 to 1 within 10 days prior to first dose of study intervention.
6. Have a life expectancy of at least 3 months, based on the investigator assessment.
7. Have the ability to swallow and retain oral medication and not have any clinically significant gastrointestinal abnormalities that might alter absorption.
8. Have adequate organ function as defined in the study protocol. Specimens must be collected within 10 days prior to the start of study intervention.
9. Is male or female, ≥18 years of age at the time of obtaining the documented informed consent.
10. Male participants are eligible to participate if they agree to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is as follows: TAS-102 (90 days) and regorafenib (90 days). No contraception requirements are needed for males receiving MK-4280A.
• Refrain from donating sperm
PLUS either:
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent
OR
• Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause). Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
• Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. 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), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle, as described in the protocol during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The length of time required to continue contraception for each study intervention is as follows: MK-4280A (120 days), TAS-102 (180 days), and regorafenib (180 days). The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) 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 or 72 hours, respectively, before the first dose of study intervention. Abstains from breastfeeding during the study intervention period and for at least 120 days after study intervention.
- 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.
11. 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.
|
|
| E.4 | Principal exclusion criteria |
1. Has previously been found to have dMMR/MSI-H tumor status determined by either IHC or PCR.
2. Has known active CNS metastases and/or carcinomatous meningitis or leptomeningeal disease. Participants with previously treated brain metastases may participate provided they are radiologically stable, ie, without evidence of progression for at least 28 days by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid intervention for at least 14 days prior to first dose of study intervention.
3. Has a history of acute or chronic pancreatitis.
4. Has neuromuscular disorders associated with an elevated creatine kinase (eg, inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
5. Has clinically significant cardiovascular disease within 12 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability.
6. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent, anti-LAG-3 antibody, with a TKI (eg, lenvatinib) other than RAF inhibitors (if appropriate), or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
7. Has previously received regorafenib or TAS-102.
8. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PDL2 agent, anti-LAG-3 antibody, with a TKI (eg, lenvatinib) other than RAF inhibitors (binimetinib is permitted if combined with a RAF inhibitor), or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
9. Has previously received regorafenib or TAS-102.
10. Has received prior systemic anticancer therapy including investigational agents within 28 days before randomization.
11. 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.
12. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.
13. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 28 days before the first dose of study intervention.
14. 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 10 days prior the first dose of study medication.
15. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
16. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
17. 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.
18. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung
disease.
19. Has an active infection requiring systemic therapy (eg, tuberculosis, known viral or bacterial infections).
20. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority.
21. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
22. 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.
23. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.
24. Has had an allogenic tissue/solid organ transplant. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Up to approximately 26 months |
|
| E.5.2 | Secondary end point(s) |
1. Progression-Free Survival (PFS) according per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR)
2. Objective Response Rate (ORR) per RECIST 1.1 as Assessed by BICR
3. Duration of Response (DOR) per RECIST 1.1 as Assessed by BICR
4. Number of Participants Who Experience at least One Adverse Event (AE)
5. Number of Participants Who Discontinue Study Treatment Due to an AE
6. Change from Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score
7. Change from Baseline in EORTC QLQ-C30 Physical Functioning (Items 1-5) Score
8. Change from Baseline in EORTC QLQ-C30 Appetite Loss (Item 13) Score
9. Change from Baseline in EORTC Quality of Life Questionnaire-Colorectal Cancer-Specific 29 Items (QLQ-CR29) Bloating (Item 37) Score
10. Time to Deterioration (TTD) in EORTC QLQ-C30 Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score
11. TTD in EORTC QLQ-C30 Physical Functioning (Items 1-5) Combined Score
12. TTD in in EORTC QLQ-C30 Appetite Loss (Item 13) Score
13. TTD in EORTC Quality of Life Questionnaire-Colorectal Cancer-Specific 29 Items (QLQ-CR29) Bloating (Item 37) Score |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 19 months
2. Up to approximately 19 months
3. Up to approximately 19 months
4. Up to approximately 27 months
5. Up to approximately 24 months
6. Baseline and up to approximately 24 months
7. Baseline and up to approximately 24 months
8. Baseline and up to approximately 24 months
9. Baseline and up to approximately 24 months
10. Baseline and up to approximately 24 months
11. Baseline and up to approximately 24 months
12. Baseline and up to approximately 24 months
13. Baseline and 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| 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 | 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 | 2 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| 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 |
| Chile |
| Ukraine |
| Taiwan |
| Australia |
| Canada |
| China |
| Czechia |
| France |
| Germany |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Russian Federation |
| South Africa |
| Spain |
| Turkey |
| United Kingdom |
| United States |
|
| 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
|
The overall study ends when the last participant completes the last study-related contact, withdraws consent, or is lost to follow-up
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the last laboratory test result or at the time of final contact with the last participant, whichever comes last |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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