| 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 (kind of breast cancer that does no have any receptor commonly found in breast cancer) and Liver 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 whose tumors express programmed cell death 1 ligand 1 (PD-L1) [combined positive score (CPS) ≥1)] 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 whose tumors express PD-L1 (CPS ≥1) enrolled in Cohort A1.
3. To evaluate MK-7684A alone or in combination with other anticancer therapies with respect to ORR per RECIST 1.1 as assessed by the investigator in participants with selected solid tumors, excluding those with cervical cancer whose tumors express PD-L1 (CPS ≥1) enrolled in Cohort A1.
|
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate MK-7684A alone or with other anticancer therapies for overall survival (OS).
2. To evaluate MK-7684A alone or with other anticancer therapies for PFS per RECIST 1.1 as assessed by investigator in participants with selected solid tumors except those enrolled in Cohort A1.
3. To evaluate MK-7684A alone for duration of response (DOR) per RECIST 1.1 as assessed by BICR in participants enrolled in Cohort A1.
4. To evaluate MK-7684A alone or with other anticancer therapies for DOR per RECIST 1.1 as assessed by investigator in participants with selected solid tumors, except those enrolled in Cohort A1.
5. To evaluate change from baseline in health-related quality-of-life (HRQoL) using the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-life questionnaire core 30 (QLQ-C30) in participants enrolled in Cohort A1.
6. 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:
Has histologically- or cytologically-confirmed, advanced (locally recurrent unresectable or metastatic) solid tumor as follows:
1. Cohort A: squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix which has progressed on standard of care chemotherapy with or without radiation but must not have been treated with prior anti-PD-1/PD L1 therapy. Chemotherapy given with radiation therapy will not be considered a first-line therapy.
- Cohort A1: participants whose tumors are PD-L1 positive (CPS ≥1) as determined by the central laboratory
- Cohort A2: participants whose tumors are PD-L1 negative (CPS <1) as determined by the central laboratory
2. Cohort B: endometrial cancer that has progressed after 1 prior systemic, platinum-based chemotherapy regimen for endometrial cancer but must not have been treated with prior anti-PD-1/ PD L1 therapy. Participants may have received up to 2 lines of platinum-based chemotherapy if 1 was given in the neoadjuvant or adjuvant treatment setting.
- Cohort B1: participants with endometrial cancer whose tumors are dMMR as determined by the central laboratory
- Cohort B2: participants with endometrial cancer whose tumors are pMMR as determined by the central laboratory
3. Cohort C: HNSCC that is considered incurable by local therapies and whose tumors express PD-L1 (CPS ≥1) as determined by the local laboratory using the PD-L1 IHC 22C3 pharmDx assay.
Note: participants may not have a primary tumor site of nasopharynx (any histology)
4. Cohort D: unresectable biliary adenocarcinoma (gallbladder or biliary tree [intrahepatic or extrahepatic] cholangiocarcinoma) that has progressed after 1 prior systemic therapy but must not have been treated with prior anti-PD-1/ PD L1 therapy.
5. Cohort E: adenocarcinoma or squamous cell carcinoma of the esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of the GEJ (defined as adenocarcinomas of the lower esophagus with the center located within 1 cm to 5 cm above the anatomic GEJ) that is unresectable and has not been previously treated with systemic therapy, including anti-PD-1/ PD L1 therapy, administered in the recurrent or metastatic setting.
6. Cohort F: locally confirmed TNBC, as defined by the most recent ASCO/CAP guidelines, that is either locally recurrent unresectable not previously treated with chemotherapy and that cannot be treated with curative intent or metastatic that has not been previously treated with chemotherapy.
7. Cohort G: HCC with any of the following criteria:
Radiologically, histologically, or cytologically-confirmed diagnosis of HCC, excluding fibrolamellar, sarcomatoid or mixed cholangio-HCC tumors that has not been previously treated with systemic therapy, including anti-PD-1/PD L1 therapy. Radiographic confirmation of the diagnosis must be confirmed by the study site.
8. Has measurable disease per RECIST 1.1 as assessed by the BICR (Cohort A1 only) or local site investigator/radiology (all other cohorts). Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
Note: For Cohort A1, BICR must confirm the presence of radiologically measurable disease based on RECIST 1.1 for the participant to be eligible for the study.
9. Can provide a newly obtained core or excisional biopsy of a tumor lesion or either an archival FFPE tumor tissue block or slides for determination of biomarker status (eg, PD L1, MMR, ER, PgR, BRCA, and HER2/neu). A newly obtained biopsy is preferred, but not required if archival tissue is available for analysis.
10. Has an ECOG performance status of either 0 or 1, as assessed within 7 days before starting study intervention.
11. Has a predicted life expectancy of at least 3 months.
12. Has adequately controlled BP with or without antihypertensive medications, defined as bp ≤150/90 mm hg at screening and no change in antihypertensive medications within 1 week before allocation.
Note: this criterion only applies to participants who will receive lenvatinib in either Cohort B2 or Cohort G.
|
|
| E.4 | Principal exclusion criteria |
The participant must be excluded from the study if the participant:
1. Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 3 years
Note: The time requirement does not apply to participants who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in-situ cervical cancer, or other in-situ cancers
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-TIGIT agent
3. Has received prior systemic anticancer therapy including investigational agents within 4 weeks before randomization/allocation
Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible. Participants with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may be eligible. Participants with Grade ≤2 alopecia are eligible
4. 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
Note: Participants who have entered the follow-up phase of an investigational study may participate if it has been 4 weeks after the last dose of the previous investigational agent
5. 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 (Note: The repeat imaging should be performed during study screening.), clinically stable, and without requirement of steroid treatment for at least 14 days before the first dose of study intervention
Note: Participants with known untreated, asymptomatic brain metastases (ie, no neurological symptoms, no requirement for corticosteroids, no or minimal surrounding edema, and no lesion >1.5 cm) may participate but will require regular imaging of the brain as a site of disease
6. Known severe hypersensitivity (≥Grade 3) to MK-7684A, pembrolizumab (Cohort A1 only), lenvatinib (Cohort B2 and Cohort G only), paclitaxel (Cohort F only), or 5-FU and cisplatin (Cohort E only) and/or any of their excipients.
7. Has an active autoimmune disease requiring 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 allowed
8. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
For participants who will receive lenvatinib in either Cohort B2 or Cohort G:
9. Has received previous treatment with lenvatinib
Note: Prior therapy with other kinase inhibitors that target VEGF are not exclusionary
10. Has had major surgery within 3 weeks before first dose of study interventions
Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility
11. Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula
12. Has urine protein ≥1 g/24 hours
Note: Participants with proteinuria ≥2+ (≥100 mg/dL) on urine dipstick testing (urinalysis) will undergo 24-hour urine collection for quantitative assessment of proteinuria
13. Has a LVEF below the institutional (or local laboratory) normal range, as determined by MUGA or ECHO
14. Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation
NOTE: The degree of proximity to major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis after lenvatinib therapy
15. Has prolongation of QTcF interval to >480 ms
NOTE: If the QTcF is prolonged to >480 ms in the presence of a pacemaker, contact the Sponsor to determine eligibility
16. Has clinically significant cardiovascular disease within 12 months from first dose of study intervention, including NYHA Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability. Note: Medically controlled arrhythmia would be permitted
17. Has serious nonhealing wound, ulcer, or bone fracture
18. Has GI malabsorption or any other condition that might affect the absorption of lenvatinib
19. Has active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks before the first dose of study intervention
20. Has a history of arterial thromboembolism within 12 months of start of study intervention
For participants who will receive paclitaxel in Cohort F:
21. Has a history of class II-IV congestive heart failure or myocardial infarction within 6 months of randomization |
|
| 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 36 months.
2. Up to approximately 36 months.
3. Up to approximately 36 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. 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).
6. Change from Baseline in Physical Functioning Score (EORTC QLQ-C30 Items 1-5).
7. Number of Participants Who Experienced One or More Adverse Events (AEs).
8. 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 36 months.
2. Up to approximately 36 months.
3. Up to approximately 36 months.
4. Up to approximately 36 months.
5. Baseline and up to approximately 36 months.
6. Baseline and up to approximately 36 months.
7. Up to approximately 36 months.
8. Up to approximately 35 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 | 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 | 6 |
| 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 | 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 |
| Canada |
| Chile |
| Colombia |
| Israel |
| Japan |
| Korea, Republic of |
| Taiwan |
| Turkey |
| United States |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
|
| 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 | 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 |
Print
