| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Previously untreated advanced or metastatic nccRCC |
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| E.1.1.1 | Medical condition in easily understood language |
| Non-clear Cell Renal Cell Carcinoma |
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| 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 | 26.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10038409 |
| E.1.2 | Term | Renal cell carcinoma NOS |
| 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 evaluate the objective response rate (ORR) of pembrolizumab + lenvatinib per response evaluation criteria in solid tumors 1.1 (RECIST 1.1) by blinded independent central review (BICR) |
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| E.2.2 | Secondary objectives of the trial |
1.To evaluate the duration of response (DOR) of pembrolizumab + lenvatinib in participants with a confirmed complete response (CR) or partial response (PR) per RECIST 1.1 by BICR
2.To evaluate progression-free survival (PFS) per RECIST 1.1 by BICR in participants receiving pembrolizumab + lenvatinib
3.To evaluate the overall survival (OS) of participants receiving pembrolizumab + lenvatinib
4.To evaluate the clinical benefit ratio (CBR) of pembrolizumab + lenvatinib per RECIST 1.1 by BICR
5.To evaluate the disease control rate (DCR) of pembrolizumab + lenvatinib per RECIST 1.1 by BICR
6.To evaluate the safety of pembrolizumab + lenvatinib
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Must have a histologically- confirmed diagnosis of non-clear cell RCC.
2. Has locally advanced/metastatic disease (ie, Stage IV per the American Joint Committee on Cancer).
3. Has received no prior systemic therapy for advanced nccRCC.
4. Is male or female, from 18 years to 120 years of age inclusive, at the time of providing the informed consent.
5. 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 study intervention)]:
• 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) 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.
• Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Please note that 7 days after lenvatinib is stopped, if the male participant is on pembrolizumab only, no male contraception measures are needed.
6. 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 (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.
• 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.
7. The participant (or legally acceptable representative) has provided documented informed consent/assent for the study.
8. Has measurable disease per RECIST 1.1 as assessed by BICR. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
9. Has submitted an archival tumor tissue sample or newly obtained core or incisional biopsy of a tumor lesion not previously irradiated. FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
10. Has KPS ≥70% as assessed within 10 days prior to the start of study intervention.
11. Has adequately controlled BP with or without antihypertensive medications, defined as BP ≤150/90 mm Hg with no change in antihypertensive medications within 1 week prior to allocation.
12. Have adequate organ function.
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| E.4 | Principal exclusion criteria |
1. Has collecting duct histology.
2. A WOCBP who has a positive urine pregnancy test within 24 hours before the first dose of study intervention. If the urine test cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
3. Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula.
4. Has urine protein ≥1 g/24 hours.
5. Has a left ventricular ejection fraction below the institutional (or local laboratory) normal range, as determined by multigated acquisition or echocardiogram.
6. Has radiographic encasement or invasion of a major blood vessel, or of intratumoral cavitation.
7. Has prolongation of QTcF interval to >480 msec.
8. 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.
9. Has gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib.
10. Has active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug
11. Has had major surgery within 3 weeks prior to first dose of study intervention.
12. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
13. Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to allocation.
14. 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.
15. Has received a live or attenuated vaccine within 30 days before the first dose of study intervention.
16. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.
17. 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.
18. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
19. 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 that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
20. Has severe hypersensitivity (≥Grade 3) to pembrolizumab, lenvatinib and/or any of their excipients.
21. 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.
22. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
23. Has an active infection requiring systemic therapy.
24. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority.
25. 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.
26. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
27. 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.
28. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
29. Has had an allogenic tissue/solid organ transplant.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1.Objective Response Rate (ORR) is defined as the percentage of participants with a complete response (CR) or partial response (PR) per response evaluation criteria in solid tumors 1.1 (RECIST 1.1) by blinded independent central review (BICR). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1.Up to approximately 5 years |
|
| E.5.2 | Secondary end point(s) |
1.Duration of Response (DOR) is defined for participants who demonstrate confirmed CR or PR as the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first.
2.Progression-free Survival (PFS) is defined as the time from the date of first dose to the first documented progressive disease (PD) per RECIST 1.1 by BICR or death from any cause, whichever occurs first.
3.Overall Survival (OS) is defined as the time from date of first dose until death from any cause.
4.Clinical Benefit Ratio (CBR) is defined as the percentage of participants who achieved CR, PR, or stable disease (SD) for at least 6 months per RECIST 1.1 by BICR.
5.Disease Control Rate (DCR) is defined as the percentage of participants who achieved CR, PR or SD per RECIST 1.1 by BICR.
6.Number of Participants Who Experienced One or More Adverse Events (AEs).
7.Number of Participants Who Discontinued Study Medication Due to an AE.
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.Up to approximately 4,5 years
2.Up to approximately 4,5 years
3.Up to approximately 4,5 years
4.Up to approximately 4,5 years
5.Up to approximately 4,5 years
6.Up to approximately 4,5 years
7.Up to approximately 4,5 years
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| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | 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 | 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 | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| 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 | 38 |
| 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 |
| Australia |
| Canada |
| China |
| United States |
| Russian Federation |
| Turkey |
| Ukraine |
| France |
| Hungary |
| Italy |
| Poland |
| Spain |
| Korea, Republic of |
| United Kingdom |
|
| 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
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| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 10 |
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