| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Triple negative breast cancer (TNBC), ovarian cancer, gastric cancer, colorectal cancer (CRC), glioblastoma (GBM), biliary tract cancers (BTC) or pancreatic cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Triple negative breast cancer (TNBC), ovarian cancer, gastric cancer, colorectal cancer (CRC), glioblastoma (GBM), biliary tract cancers (BTC) or pancreatic 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 | PT |
| E.1.2 | Classification code | 10028997 |
| E.1.2 | Term | Neoplasm malignant |
| 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. To evaluate objective response rate (ORR) of pembrolizumab (MK-3475) in combination with lenvatinib (MK-7902) per tumor cohort based on Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) by investigator assessments in initial cohorts and blinded independent central review (BICR) in cohorts that expand combining the initial and expansion cohorts (Cohorts A-F). In Cohort G, RECIST 1.1 by BICR will be utilized in all participants (for participants with glioblastoma [GBM], response will be assessed based on Response Assessment in Neuro-Oncology [RANO] criteria)
2. To assess safety and tolerability of treatment with pembrolizumab in combination with lenvatinib per tumor cohort assessed by the percentage of adverse events (AEs)
3. To assess safety and tolerability of treatment with lenvatinib monotherapy assessed by the proportion of AEs. |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate disease control rate (DCR), duration of response (DOR) and progression-free survival (PFS) of pembrolizumab in combination with lenvatinib per tumor cohort based on RECIST 1.1 (RANO for GBM) by investigator assessments in initial cohorts and BICR in cohorts that expand combining the initial and expansion cohorts (Cohorts A-F). In Cohort G, RECIST 1.1 by BICR will be utilized in all participants.
2. To evaluate overall survival (OS) of pembrolizumab in combination with lenvatinib per tumor cohort
3. To evaluate ORR, DCR, DOR, PFS, and OS of lenvatinib monotherapy based on RECIST 1.1 by BICR.
4. To characterize the population pharmacokinetics (PK) of lenvatinib when co-administered with pembrolizumab in participants per tumor cohort (Cohorts A-F only). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have a histologically or cytologically-documented, advanced metastatic and/or unresectable) solid tumor that is incurable and for which prior standard systemic therapy has failed in one of the following
cohorts:
Cohort A Triple-Negative Breast Cancer (TNBC)
Cohort B Ovarian Cancer
Cohort C Gastric Cancer
Cohort D Colorectal Cancer
Cohort E Glioblastoma (GBM)
Cohort F Biliary Tract Cancer (BTC) (intrahepatic, extrahepatic cholangiocarcinoma and gall bladder cancer; excludes Ampulla of Vater) Cohort G Pancreatic Cancer (ductal adenocarcinoma)
2. Participants must have fulfilled cohort-specific requirements regarding prior (line of therapy) treatments.
3. Participants must have progressed on or since the last treatment.
4. Have measurable disease per RECIST 1.1 (RANO for the GBM cohort) as assessed by the local site investigator/radiology and confirmed by BICR. Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions.
5. Have provided a PD-L1 evaluable archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. Fine-needle aspiration biopsies are not acceptable.
6. Participants are at least 18 years of age; male or female for gastric cancer, GBM, TNBC, CRC, BTC, and pancreatic cancer cohorts; female only for ovarian cancer.
7. Life expectancy of 12 weeks or more.
8. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 7 days after the last dose of lenvatinib:
a. 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
b. Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause) as detailed below:
- 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.
- 7 days after lenvatinib is stopped, if the participant is on pembrolizumab only, no male contraception measures are needed.
9. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies:
- Is not a woman of childbearing potential (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 (abstinent on a long term and persistent basis), during the intervention period and for at least 120 days post pembrolizumab or 30 days post lenvatinib, whichever occurs last. 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 hours 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.
10. The participant (or legally acceptable representative if applicable) has provided documented informed consent/assent for the study.
11. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 assessed within 3 days before allocation/randomization.
12. Have adequate organ function.
13. Have adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 mm Hg with no change in antihypertensive medications within 1 week before randomization.
Other cancer-specific inclusion criteria- please refer to the Protocol |
|
| E.4 | Principal exclusion criteria |
1. Has gastrointestinal malabsorption or any other condition that might affect the absorption of lenvatinib.
2. Has present or progressive accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks before enrollment. The participant can receive diuretic drugs as needed per the treating physician, outside of the above mentioned conditions.
3. Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation.
4. Has clinically significant hemoptysis or tumor bleeding within 2 weeks before the first dose of study intervention.
5. Has significant cardiovascular impairment within 12 months of the first dose of study intervention.
6. Has a history of arterial thromboembolism within 12 months of start of study intervention.
7. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
8. Has a serious nonhealing wound, ulcer or bone fracture.
9. Has had a major surgical procedure within 3 weeks before first dose of study interventions.
10. Has biologic response modifiers therapy (eg, granulocyte colonystimulating factor) within 4 weeks before study entry. Chronic erythropoietin therapy is permitted, provided that no dose adjustments were made within 2 months before first dose of study treatment.
11. Has pre-existing ≥Grade 3 gastrointestinal (GI) or nongastrointestinal fistula.
12. Has received prior therapy with lenvatinib, an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
13. Has received prior systemic anticancer therapy including investigational agents within 4 weeks before study treatment start.
14. Has not recovered adequately from the toxicity and/or complications from the intervention if participant received major surgical intervention before starting study treatment.
15. Has received prior radiotherapy within 2 weeks of start of study treatment.
16. Has received a live vaccine within 30 days before the first dose of study intervention.
17. Has known intolerance to lenvatinib (and/or any of the excipients).
18. Has participated or is currently participating in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention.
19. Has urine protein ≥1 g/24h. Participants with proteinuria >1+ on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria.
20. Has prolongation of QTc interval (calculated using Fridericia's formula) to >480 ms.
21. Has left ventricular ejection fraction (LVEF) <55% as determined by multigated acquisition scan (MUGA) or echocardiogram (ECHO).
22. 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 the first dose of study intervention.
23. Has known active CNS metastases and/or carcinomatous meningitis.
24. Has tumors involving the brain stem.
25. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
26. 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).
27. Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis.
28. Has an active infection requiring systemic therapy.
29. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority.
30. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
31. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
32. 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.
33. Has a known psychiatric or substance abuse disorder that would interfere with cooperating with the requirements of the study.
34. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study intervention.
35. Has had an allogenic tissue/solid organ transplant (large organ transplants, stem-cell transplant requiring chronic immunosuppressant therapy necessary to prevent graft rejection).
Other cancer-specific exclusion criteria- please refer to the Protocol |
|
| 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) or Response Assessment in Neuro-Oncology (RANO) criteria for glioblastoma (GBM) by investigator assessment in initial cohorts
2. ORR per RECIST 1.1 or RANO by blinded independent central review (BICR) in expanded cohorts
3. Percentage of participants receiving pembrolizumab plus lenvatinib who experience an adverse event (AE)
4. Percentage of participants receiving pembrolizumab plus lenvatinib who discontinue study treatment due to an AE
5. Percentage of participants receiving lenvatinib monotherapy who experience an AE
6. Percentage of participants receiving lenvatinib monotherapy who discontinue study treatment due to an AE |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 72 months
2. Up to approximately 72 months
3. Up to approximately 72 months
4. Up to approximately 72 months
5. Up to approximately 72 months
6. Up to approximately 72 months |
|
| E.5.2 | Secondary end point(s) |
1. Disease Control Rate (DCR) per RECIST 1.1 by investigator assessment in initial cohorts
2. Duration of Response (DOR) per RECIST 1.1 or RANO (GBM) by investigator assessment in initial cohorts
3. Progression Free Survival (PFS) per RECIST 1.1 or RANO (GBM) by investigator assessment in initial cohorts
4. Overall Survival (OS) in initial cohorts
5. DCR per RECIST 1.1 by BICR in expanded cohorts
6. DOR per RECIST 1.1 or RANO (GBM) by BICR in expanded cohorts
7. PFS per RECIST 1.1 or RANO (GBM) by BICR in expanded cohorts
8. OS in expanded cohorts
9. ORR per RECIST 1.1 by BICR in lenvatinib monotherapy arm
10. DCR per RECIST 1.1 by BICR in lenvatinib monotherapy arm
11. DOR per RECIST 1.1 by BICR in lenvatinib monotherapy arm
12. PFS per RECIST 1.1 by BICR in lenvatinib monotherapy arm
13. OS in lenvatinib monotherapy arm
14. Plasma concentration of lenvatinib |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 72 months
2. Up to approximately 72 months
3. Up to approximately 72 months
4. Up to approximately 72 months
5. Up to approximately 72 months
6. Up to approximately 72 months
7. Up to approximately 72 months
8. Up to approximately 72 months
9. Up to approximately 72 months
10. Up to approximately 72 months
11. Up to approximately 72 months
12. Up to approximately 72 months
13. Up to approximately 72 months
14. Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose and 2-12 hours post-dose; Cycle 2 Day 1: pre-dose, 0.5-4 hours, and 6-10 hours post-dose. Each cycle is 21 days. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 |
| Argentina |
| Chile |
| Colombia |
| Switzerland |
| Taiwan |
| Australia |
| Canada |
| Israel |
| Korea, Republic of |
| Russian Federation |
| Thailand |
| United Kingdom |
| United States |
| France |
| Germany |
| Italy |
| Spain |
|
| 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
|
| Receipt of 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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