| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable Stage III and Stage IV melanoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 progression-free survival (PFS) as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
2) 2) To compare the combination of pembrolizumab and lenvatinib to pembrolizumab and placebo with respect to overall survival. |
|
| E.2.2 | Secondary objectives of the trial |
1) To compare objective response rate (ORR) per RECIST 1.1 by BICR
2) To assess duration of response (DOR) per RECIST 1.1 by BICR
3) To assess safety and tolerability
4) To compare the mean change from baseline in PRO scores in global health status/quality of life (QoL) and physical functioning
5) To compare the time to true deterioration (TTD) in global health status/QoL and physical functioning
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have histologically or cytologically confirmed melanoma
2. Have unresectable Stage III or Stage IV melanoma, as per American Joint Committee on Cancer 8th edition guidelines, not amenable to local therapy
3. Have been untreated for advanced or metastatic disease except as follows:
a. BRAF V600 mutation-positive melanoma may have received standard of care targeted therapy as first-line therapy for advanced or metastatic disease (eg, BRAF/MEK inhibitor, alone or in combination); participants that do not have a BRAF V600 mutation but did receive BRAF or
BRAF/MEKi therapy are eligible to participate in this study after discussion with the medical monitor.
b. Prior adjuvant or neoadjuvant therapy, with targeted therapy or immunotherapy (such as anti-CTLA-4, anti-PD-1 therapy or Interferon). Immunotherapy will only be permitted if relapse did not occur during active treatment or within 6 months of treatment discontinuation. No other prior adjuvant or neoadjuvant therapy will be allowed
4. Have documentation of BRAF V600-activating mutation status or consent to BRAF V600 mutation testing during the screening period (participants with BRAF mutation positive melanoma as well as BRAF wild type or unknown are eligible)
5. Have an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1
6. Have the presence of at least 1 measurable lesion by CT or MRI per RECIST 1.1 criteria as determined by the local site investigator/radiology assessment. Measurable disease will be verified by central imaging vendor (CIV) prior to randomization. Cutaneous lesions and other superficial lesions are not considered measurable lesions for the purposes of this protocol, but may be considered as nontarget lesions. Photographs of cutaneous lesions do not need to be submitted to the CIV
7. Provide a tumor biopsy
8. Have resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia). If participant received major surgery or radiation therapy of >30 Gy, they must have recovered from the toxicity and/or complications from the intervention
9. individual of any sex/gender, from at least 18 years. if capable of producing sperm, agrees to the following during the intervention period and for at least 7 days after the last dose of lenvatinib/placebo. Please note that 7 days after lenvatinib/placebo is stopped, if the participant is
on pembrolizumab only, no male contraception measures are needed. Be abstinent from penile vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent
OR
use contraception, described in the protocol, unless confirmed to be azoospermic.
10. A participant assigned female sex at birth is eligible to participate if not pregnant, not breastfeeding, and at least 1 of the following conditions applies:
-Not a POCBP
OR
-POCBP Uses an acceptable contraceptive method or is abstinent from
penile-vaginal intercourse,
as described in the protocol, during the treatment period and for at least
120 days post pembrolizumab or 30 days post lenvatinib/placebo,
whichever occurs last.
-has a negative highly sensitive pregnancy test.
11. The participant (or legally acceptable representative) has provided documented informed consent for the study
12. Adequately controlled BP with or without antihypertensive medications, defined as BP ≤150/90 mmHg with no change in antihypertensive medications within 1 week prior to randomization.
13. Have adequate organ function |
|
| E.4 | Principal exclusion criteria |
1.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 before the first dose of study intervention
2.Has a known additional malignancy that is progressing or requires active treatment. Exceptions include early stage cancers (carcinoma in situ or stage1 non-ulcerated primary melanoma <1 mm in depth with no nodal involvement) treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, or in situ breast cancer that has undergone potentially curative therapy
3.Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks before the first dose of study intervention and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases confirmed by repeat imaging, and have not required steroids for at least 14 days before study intervention
4. Has ocular melanoma
5. Has known hypersensitivity to active substances or any of their excipients including previous clinically significant hypersensitivity reaction to treatment with another mAb
6.Has an active autoimmune disease that has required systemic treatment in past 2 years
7.Has an active infection requiring systemic therapy
8.Has known history of human immunodeficiency virus (HIV)(HIV 1/2 antibodies). No testing of HIV is required unless mandated by local health authority
9.Has known history of or is positive for hepatitis B(hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (HCV RNA[qualitative]is detected).No testing of hepatitis B or C is required unless mandated by local health authority
10.Has a history of (non-infectious) pneumonitis /interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
11. Has a history of active tuberculosis(Bacillus tuberculosis)
12. Gastrointestinal malabsorptionor any other condition that might affect the absorption of lenvatinib
13.Has had a major surgery within 3 weeks prior to first dose of study intervention.
14.Has a pre-existing Grade ≥3 gastrointestinal or nongastrointestinal fistula
15.Has radiographic evidence of encasement or invasion of a major blood vessel or of intratumoral cavitation
16. Has active hemoptysis(bright red blood of at least 0.5 teaspoon)within 3 weeks prior to the first dose of study intervention.
17. Has clinically significant cardiovascular disease within 12 months from of the 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
18.Has urine protein ≥1 g/24-hour
19.Prolongation of QTcF interval to >480 ms.
20.Has left ventricular ejection fraction (LVEF) below the institutional (or local laboratory) normal range as determined by multi-gated acquisition scan (MUGA) or echocardiogram
21.Has received prior systemic treatment for unresectable or metastatic melanoma other than targeted therapy
22.Has received prior therapy in the adjuvant setting
23. Has received prior therapy with a mAb, chemotherapy, or an investigational agent or device within 4 weeks or 5 half lives (whichever is longer) before administration of study intervention or not recovered(≤Grade 1 or at baseline) from AEs due to previously administered agents. Exception to this rule would be use of denosumab which is not excluded
24. Has received prior radiotherapy within 2 weeks of Cycle 1 Day 1. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis
25. Has received live vaccine within 30 days before the first dose of study intervention
26. 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
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. Had an allogeneic tissue/solid organ transplant
29. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1) Progression-free survival (PFS) as assessed by BICR per RECIST 1.1
2) Overall survival (OS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
As of Amendment 07, the prespecified final analysis of the study
described in the SAP will not be performed.
Interim analysis 1, PFS and OR: approximately 24 months after firs 1st participant randomized (after enrollment is completed, and ~369 PFS events observed and ~209 OS events observed)
Interim analysis 2, PFS and OR: approximately 34 months after 1st participant randomized (~397 PFS events observed, ~263 OS events observed)
Final OS analysis: approximately 62 months after 1st participant randomized (~316 OS events)
|
|
| E.5.2 | Secondary end point(s) |
1) Objective response (OR)
as assessed by BICR per RECIST 1.1
2) DOR as assessed by BICR per RECIST 1.1. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
OR: approximately 11-13 months after 1st participant randomized
DOR: will be evaluated on an ongoing basis
|
|
| 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 | 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) | 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 | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 46 |
| 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 |
| Switzerland |
| Australia |
| Brazil |
| Canada |
| China |
| Israel |
| Korea, Republic of |
| United Kingdom |
| United States |
| Austria |
| France |
| Germany |
| Italy |
| Poland |
| Spain |
| Sweden |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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