| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
Cancer of the cervix, Uterine (endometrial), Head and Neck, Bile duct, Esophagus, Breast, Liver, Bladder, Ovarian and Gastric 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| 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-7684A to pembrolizumab alone with respect to objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by blinded independent central review (BICR) in participants with cervical cancer enrolled in Cohort A1.
2. To compare MK-7684A to pembrolizumab alone with respect to progression-free survival (PFS) per RECIST 1.1 as assessed by BICR in participants with cervical cancer enrolled in Cohort A1.
3. To evaluate MK-7684A alone or with anticancer therapies with respect to ORR per RECIST 1.1 as assessed by the investigator in participants with selected solid tumors.
4. To evaluate MK-7684A in combination with anticancer therapies with respect to PFS per RECIST 1.1 at 9 months (PFS-9) and 12 months (PFS-12) as assessed by the investigator in participants with previously untreated advancec epithelial ovarian cancer enrolled in Cohort I. |
|
| E.2.2 | Secondary objectives of the trial |
1.To evaluate MK-7684A alone or with other anticancer therapies for overall survival.
2.To evaluate MK-7684A alone or with other anticancer therapies for PFS per RECIST 1.1, per investigator in participants with selected solid tumors.
3.To evaluate MK-7684A alone for duration of response per RECIST 1.1 per BICR in participants in Cohort A1.
4.To evaluate MK-7684A alone or with other anticancer therapies for DOR per RECIST 1.1, per investigator in participants with selected solid tumors.
5.To compare MK-7684A to pembrolizumab for ORR per RECIST 1.1, per investigator in participants with cervical cancer enrolled in Cohort A1.
6.To compare MK-7684A to pembrolizumab for PFS per RECIST 1.1, per investigator in participants with cervical cancer enrolled in Cohort A1.
7.To evaluate change from baseline in health-related quality-of-life (HRQoL) in participants enrolled in Cohort A1.
8. To evaluate the safety and tolerability of MK-7684A alone or with other anticancer therapies.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A participant will be eligible for inclusion in the study if the participant:
1. Has histologically or cytologically confirmed, advanced (unresectable or metastatic) solid tumor as follows:
• Squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix
• Endometrial cancer
• Head and neck squamous cell carcinoma (HNSCC)
• Unresectable biliary adenocarcinoma (gallbladder or biliary tree [intrahepatic or extrahepatic] cholangiocarcinoma)
• Adenocarcinoma or squamous cell carcinoma of the esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of the gastroesophageal junction (GEJ).
• Triple-negative breast cancer (TNBC)
• Hepatocellular carcinoma (HCC)
• Urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra
• Ovarian cancer
• Gastric cancer
2. Has measurable disease per RECIST 1.1 as assessed by the BICR (Cohort A1 only) or local site investigator/radiology (all other cohorts).
3. Can provide a newly obtained core or excisional biopsy of a tumor lesion
4. Is male or female, who is at least 18 years of age at the time of providing informed consent.
Note: For Cohort I: participant must be female
5. Has an ECOG Performance Status of either 0 or 1 (ECOG PS of 2 allowed for Cohort H only), as assessed within 7 days before starting study intervention.
Note: For Cohort I: ECOG performance status must meet eligibility before start of lead-in chemotherapy and before C1D1
6. Has a predicted life expectancy of at least 3 months.
7. Male participants must agree to follow contraceptive guidance
8. Female participants are not pregnant or breastfeeding, not women of child-bearing potential (WOCBP) or are WOCBP and agree to follow contraceptive guidance.
9. The participant (or legally acceptable representative) has provided documented informed consent/assent for the study.
10. Has adequately controlled BP with or without antihypertensive medications,
Note: this criterion applies to participants who will receive lenvatinib or bevacizumab
11. HIV-infected participants must have well controlled HIV on ART
12. Participants who are HbsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load before randomization/allocation.
13. Participants with history of HCV infection are eligible if HCV viral load is undetectable at Screening.
14. Has adequate organ function
Note: For Cohort I: Adequate organ functions must meet eligibility before start of lead-in chemotherapy and before C1D1.
For the complete list of criteria, please refer to the protocol. |
|
| E.4 | Principal exclusion criteria |
1. Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 3 years
2. HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
3. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-TIGIT agent
4. Has received prior systemic anticancer therapy including investigational agents within 4 weeks. Note: This does not include leadin chemotherapy in Cohort I
5. Has received prior radiotherapy within 2 weeks or radiation-related toxicities requiring corticosteroids
6. Has received a live or live-attenuated vaccine within 30 days
7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days
8. Has known active CNS metastases and/or carcinomatous meningitis
9. Known severe hypersensitivity (≥Grade 3) to study medication or any of their excipients
10. Has an active autoimmune disease that has required systemic treatment in past 2 years
11. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
12. Has an active infection requiring systemic therapy
13. 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
14. Has present accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks
15. Has concurrent active hepatitis B and hepatitis C infection
16. Has not adequately recovered from major surgery
17. Participants unlikely to comply with the requirements of the study
18. Has had an allogenic organ transplant
19. Has received an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention
All Cohorts except B1:
20. Has known MSI-H or MMR deficient cancer
Cohort B1 and B2 only:
21. Greater than 1 prior systemic chemotherapy regimen
For participants who will receive Lenvatinib: Cohort B2 & G:
22. Has had major surgery within 3 weeks
23. Has current, clinically relevant ≥Grade 3 fistula
24. Has urine protein ≥1 g/24 hours
25. Has a LVEF below the normal range
26. Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation
27. Has prolongation of QTc interval to >480 ms
28. Has clinically significant cardiovascular disease within 12 months
29. Has serious nonhealing wound, ulcer, or bone fracture
30. Has GI malabsorption
31. Has active hemoptysis
32. Has had esophageal or gastric variceal bleeding within the last 6 months (G only)
Cohort D2:
33. Has had previous systemic therapy for advanced or unresectable biliary tract cancer
Cohort F:
34. Has a history of class II-IV congestive heart failure or myocardial infarction within 6 months
Cohort H:
35. Has disease suitable for local therapy administered with curative intent
36. Is receiving hemodialysis
Cohort I:
37. Has mucinous, germ cell, or borderline tumor of the ovary
38. Has ongoing Grade 3 or 4 toxicity, excluding alopecia, following chemotherapy administered during the Lead-in Period
39. Has received colony-stimulating factors within 4 weeks prior to receiving chemotherapy during the Lead-in Period
40. Is considered to be of poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection
41. Has had surgery <6 months prior to screening to treat borderline tumors, early stage EOC or early stage fallopian tube cancer.
42. Has uncontrolled hypertension
43. Has current, clinically relevant bowel obstruction (incl. subocclusive disease), abdominal fistula or gastrointestinal perforation, related to underlying EOC
44. Has a history of hemorrhage, hemoptysis or active gastrointestinal bleeding within 6 months prior to allocation
45. Has received prior treatment for any stage of OC
46. Is a participant for whom intraperitoneal chemotherapy is planned or has been administered as 1L therapy
47. Has severe hypersensitivity (≥Grade 3) to pembrolizumab, carboplatin, paclitaxel, or bevacizumab and/or any of their excipients
48. Has resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator or participant has congenital long QT syndrome
49. Had either major surgery within 3 weeks of allocation or has not recovered from major surgery
Cohort J
50. Has squamous cell or undifferentiated gastric cancer
51. Has preexisting peripheral neuropathy >Grade 1
52. Has had previous therapy for locally advanced, unresectable or
metastatic gastric cancer
53. Has received prior therapy with an agent directed to a stimulatory or coinhibitory T-cell receptor within 4 weeks of randomization/allocation |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Blinded Independent Central Review (BICR).
2. Progression-Free Survival (PFS) per RECIST 1.1 as Assessed by BICR.
3. ORR per RECIST 1.1 as Assessed by Investigator.
4. PFS per RECIST 1.1 as Assessed by Investigator at 9 months
5. PFS per RECIST 1.1 as Assessed by Investigator at 12 months |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 2 years.
2. Up to approximately 2 years.
3. Up to approximately 2 years.
4. 9 months
5. 12 months |
|
| E.5.2 | Secondary end point(s) |
1. Overall Survival (OS).
2. PFS per RECIST 1.1 as Assessed by Investigator.
3. Duration of Response (DOR) per RECIST 1.1 as Assessed by BICR.
4. DOR per RECIST 1.1 as Assessed by Investigator.
5. ORR per RECIST 1.1 as Assessed by Investigator
6. Change from Baseline in Global Health Status/Quality of Life Score (European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 [EORTC QLQ-C30] Items 29 and 30).
7. Change from Baseline in Physical Functioning Score (EORTC QLQ-C30 Items 1-5).
8. Number of Participants Who Experienced One or More Adverse Events (AEs).
9. Number of Participants Who Discontinued Study Intervention Due to an AE. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 5.5 years.
2. Up to approximately 2 years.
3. Up to approximately 2 years.
4. Up to approximately 2 years.
5. Up to approximately 2 years.
6. Baseline and up to approximately 2 years.
7. Baseline and up to approximately 2 years.
8. Up to approximately 2 years.
9. Up to approximately 2 years. |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Exploratory biomarker analysis |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 9 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 |
| Colombia |
| Taiwan |
| Canada |
| France |
| Germany |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Poland |
| Spain |
| Turkey |
| 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
|
| Receipt the last laboratory test result or LVLS, 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 | 5 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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