A Phase 3 study of pembrolizumab (MK-3475) with or without lenvatinib (E7080/MK-7902) as 1L intervention in a PD-L1 selected population with Recurrent Metastatic Head and Neck Cancer (LEAP-010)

Phase 1

Conditions: Recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC)
MedDRA version: 27.0Level: LLTClassification code 10082179Term: Squamous cell carcinoma of head and neck metastaticSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2019-003717-34-PL

Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 500

Inclusion Criteria

1. Has histologically confirmed diagnosis of R/M HNSCC that is considered incurable by local therapies.
2. Has a primary tumor location of oropharynx, oral cavity, hypopharynx, or larynx.
3. Is male or female, and at least 18 years of age at the time of documented informed consent.
Male Participants
Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.
4. 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/placebo:
- 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.
- Please note that 7 days after lenvatinib is stopped, if the participant is on pembrolizumab only, no male contraception measures are needed.
Female Participants
Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.
5. 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/placebo 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 asrequired 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.
6. The participant (or legally acceptable representative) has provided documented informed consent for the study.
7. Has measurable disease per RECIST 1.1 as assessed by BICR.
8. Has provided an archival tumor tissue sample or newly obtained core, excisional 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.
9. Has a PD-L1 positive (CPS =1) tumor as determined by the central laboratory.
10. Participants with oropharyngeal cancer must have results fr

Exclusion Criteria

1. Has any evidence of symptoms or signs of active tumor bleeding within 6 months before randomization.
2. Has radiographic evidence of major blood vessel invasion/infiltration or tumor demonstrates >90 degree abutment or encasement of a major blood vessel.
3. Has a history of re-irradiation to any head and neck sites of disease including the cervical, infraclavicular or supraclavicular lymph nodes for head and neck cancer.
4. Has ulceration and/or fungation of disease onto the skin surface.
5. Has a life expectancy of less than 3 months and/or has rapidly progressing disease (eg, uncontrolled tumor pain) in the opinion of the treating investigator.
6. Has a history of any contraindication or has a severe hypersensitivity to any components of pembrolizumab (=Grade 3) or lenvatinib.
7. Has pre-existing =Grade 3 gastrointestinal or non-gastrointestinal fistula.
8. Has a history of a gastrointestinal condition or procedure that, in the opinion of the investigator, may affect oral study drug absorption.
9. Has clinically significant cardiovascular impairment within 12 months of the first dose of study intervention.
10. Has disease that is suitable for local therapy administered with curative intent.
11. Had PD within 6 months of completion of curatively intended systemic treatment for locoregionally advanced HNSCC.
12. Has had major surgery within 3 weeks before first dose of study interventions.
13. Has difficulty swallowing capsules or ingesting a suspension orally or by a feeding tube.
14. Has received prior therapy with lenvatinib or pembrolizumab.
15. Received last dose of systemic therapy for locoregionally advanced disease less than 6 months before signing consent
16. 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).
17. Has received prior systemic anticancer therapy including investigational agents within 4 weeks before randomization.
18. Has received prior radiotherapy within 2 weeks of start of study intervention.
19. Has received a live vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
20. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention.
21. Has urine protein =1 g/24 hours.
22. Has prolongation of QTc interval (calculated using Fridericia’s formula) to >480 msec.
23. Has a LVEF below the institutional (or local laboratory) normal range, as determined by MUGA or ECHO.
24. 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.
25. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
26. 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.
27. Has an active autoimmune disease that has required systemic treatment in pas

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: 1. To compare pembrolizumab + lenvatinib to pembrolizumab + placebo with respect to ORR per RECIST 1.1 as assessed by BICR.<br>2. To compare pembrolizumab + lenvatinib to pembrolizumab + placebo with respect to PFS per RECIST 1.1 as assessed by BICR.<br>3. To compare pembrolizumab + lenvatinib to pembrolizumab + placebo with respect to OS.;Secondary Objective: 1. To evaluate pembrolizumab + lenvatinib and pembrolizumab + placebo with respect to DOR per RECIST 1.1 as assessed by BICR.<br>2. To assess the safety and tolerability of study intervention with pembrolizumab + lenvatinib and pembrolizumab + placebo.;Primary end point(s): 1. Objective Response Rate per RECIST 1.1 as Assessed by BICR. <br>2. Progression Free Survival per RECIST 1.1 as Assessed by BICR. <br>3. Overall Survival ;Timepoint(s) of evaluation of this end point: 1. Up to approximately 24 months<br>2. Up to approximately 30 months<br>3. Up to approximately 44 months

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): 1. Duration of Response<br>2. Number of Participants Who Experienced an Adverse Event (AE)<br>3. Number of Participants Who Discontinued Study Drug Due to an AE;Timepoint(s) of evaluation of this end point: 1. Up to approximately 44 months<br>2. Up to approximately 44 months<br>3. Up to approximately 44 months<br>

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