A Phase 2, randomized, open-label three-arm clinical study to evaluate the safety and efficacy of lenvatinib (E7080/MK-7902) in combination with pembrolizumab (MK-3475) versus standard of care chemotherapy and lenvatinib monotherapy in participants with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) that have progressed after platinum therapy and immunotherapy (PD-1/PD-L1 inhibitors) (LEAP-009)
- Trial ID
- 2022-500820-31-00
- Protocol
- MK-7902-009
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the efficacy of **lenvatinib** in combination with **pembrolizumab** against standard of care (SOC) chemotherapy in terms of overall survival (OS) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M HNSCC) that has progressed following platinum-based therapy and immunotherapy with PD-1/PD-L1 inhibitors. This is clinically relevant as it aims to determine if the combination therapy can provide a survival advantage over existing treatment options, potentially leading to improved patient outcomes.
Secondary objectives include:
- Comparing the combination therapy and SOC chemotherapy with respect to progression-free survival (PFS) as per RECIST 1.1, assessed by blinded independent central review (BICR).
- Comparing the objective response rate (ORR) between the combination therapy and SOC chemotherapy, also assessed by BICR.
- Assessing the duration of response (DOR) for both treatment regimens according to RECIST 1.1, evaluated by BICR.
- Evaluating the safety and tolerability of the study interventions, including lenvatinib monotherapy, in addition to the combination therapy and SOC chemotherapy.
Participants
The clinical trial involves a total of **242 participants** diagnosed with **recurrent or metastatic squamous cell carcinoma of the head and neck**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific inclusion criteria, such as having pathologically confirmed recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) that is not amenable to curative treatment. The trial does not include a vulnerable population. Participants are required to have adequate organ function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Lifestyle considerations include the requirement for male participants to refrain from donating sperm and to use contraception or remain abstinent, while female participants must not be pregnant or breastfeeding and must use highly effective contraception or remain abstinent. The trial does not specify any particular dietary or physical activity requirements for participants.
Plans and Procedures
The clinical trial is a Phase 2, randomized, open-label, three-arm study designed to evaluate the safety and efficacy of **lenvatinib** in combination with **pembrolizumab** versus standard of care chemotherapy and lenvatinib monotherapy in participants with recurrent or metastatic squamous cell carcinoma of the head and neck. The trial aims to compare the combination therapy and standard chemotherapy with respect to overall survival. The study is expected to run from August 2020 to December 2025, with participants involved for a maximum treatment period of 78 weeks.
The trial design includes a screening visit to confirm eligibility based on criteria such as disease progression after platinum therapy and immunotherapy, adequate organ function, and measurable disease by CT or MRI. Participants will be randomly assigned to one of the three treatment arms. The study involves regular follow-up visits to monitor safety, efficacy, and any adverse events. The primary endpoint is overall survival, while secondary endpoints include progression-free survival, objective response rate, duration of response, and the number of participants experiencing adverse events.
Participants will be required to attend scheduled visits throughout the study, including an end-of-study visit to assess final outcomes. The expected length of participant involvement is up to 78 weeks, with conditions for early termination including significant adverse events or disease progression. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.
Treatment
The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Paclitaxel** is administered as an intravenous infusion with a pharmaceutical form designated as PHF00230MIG. The maximum daily dose is 80 mg/m², with a total maximum dose of 24,960 mg/m² over a treatment period of up to 78 weeks. Paclitaxel is a chemical substance used in the trial as a comparator treatment.
**Docetaxel** is also administered via intravenous infusion, sharing the same pharmaceutical form as Paclitaxel, PHF00230MIG. The maximum daily dose for Docetaxel is 75 mg/m², with a total maximum dose of 7,800 mg/m² over a 78-week period. It is used as a comparator treatment in the study.
**Lenvatinib** is provided in capsule form for oral use. The maximum daily dose is 24 mg, with a total maximum dose of 57,144 mg over a treatment period of up to 78 weeks. Lenvatinib is used both as an experimental medication and a comparator treatment, depending on the study arm.
**Pembrolizumab**, marketed as Keytruda, is administered as a concentrate for solution for infusion. The maximum daily dose is 200 mg, with a total maximum dose of 10,400 mg over a 36-week period. Pembrolizumab is a biological substance used as an experimental medication in the trial.
**Capecitabine** is administered orally, with a pharmaceutical form designated as PHF00009MIG. The maximum daily dose is 2,500 mg/m², with a total maximum dose of 3,640,000 mg/m² over a 78-week period. Capecitabine serves as a comparator treatment in the study.
**Cetuximab** is administered via intravenous infusion, with a pharmaceutical form designated as PHF00230MIG. The maximum daily dose is 400 mg/m², with a total maximum dose of 78,150 mg/m² over a 78-week period. Cetuximab is a biological substance used as a comparator treatment in the trial.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The trial aims to evaluate the safety and efficacy of these treatments in participants with recurrent/metastatic head and neck squamous cell carcinoma that have progressed after platinum therapy and immunotherapy.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Overall Survival (OS)**, which will be measured to determine the length of time from randomization until death from any cause. Secondary endpoints include **Progression-Free Survival (PFS)**, **Objective Response Rate (ORR)**, **Duration of Response (DOR)**, and the number of participants who experienced one or more adverse events (AEs) or discontinued the study intervention due to an AE.
These efficacy parameters will be collected and analyzed at various timepoints throughout the study. The trial will involve a randomized, open-label, three-arm design to evaluate the safety and efficacy of lenvatinib in combination with pembrolizumab versus standard of care chemotherapy and lenvatinib monotherapy in participants with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) that have progressed after platinum therapy and immunotherapy (PD-1/PD-L1 inhibitors). The study will utilize imaging techniques such as CT or MRI to assess measurable disease based on the Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1), verified by blinded independent central review (BICR).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Pathologically confirmed recurrent (not amenable to curative treatment with local and/or systemic therapies) or metastatic (disseminated) HNSCC of the oral cavity, oropharynx, hypopharynx, and/or larynx that is considered incurable by local therapies
- Disease progression at any time during or after treatment with a platinum-containing (e.g., carboplatin or cisplatin) regimen
- Disease progression on or after treatment with an anti-PD-1/PD-L1 mAb (programmed cell death protein 1/programmed death-ligand 1 monoclonal antibody)
- Pre-study imaging that demonstrates evidence of disease progression based on investigator review of at least 2 pre-study images per RECIST 1.1, following initiation of treatment with a PD-1/PD-L1 inhibitor
- Measurable disease by CT or MRI based on Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as verified by blinded independent central review (BICR). Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
- ECOG performance status of 0 or 1 assessed within 7 days of the first dose of study intervention
- Male participants are eligible to participate if they agree to the following during the intervention period and for at least 1 week after the last dose of lenvatinib, 3 months after the last dose of capecitabine and paclitaxel, and 6 months after the last dose of docetaxel: refrain from donating sperm; 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 azoospermia; contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
- 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 woman of childbearing potential (WOCBP); 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 1 month post lenvatinib, whichever occurs last (Arms 1 and 3), or during the intervention period and for at least 6 months after the last dose of capecitabine, docetaxel, paclitaxel; and 2 months after the last dose of cetuximab (Arm 2); female participants who randomize to Arm 2 must also agree not to donate or freeze/store eggs during the intervention period and for at least 6 months after the last dose of capecitabine, docetaxel, paclitaxel; and 2 months after the last dose of cetuximab
- Adequately controlled blood pressure (BP) with or without antihypertensive medications
- Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization
- Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening
- Adequate organ function
Exclusion Criteria
- Disease that is suitable for local therapy administered with curative intent
- Life expectancy of less than 3 months and/or has rapidly progressing disease in the opinion of the treating investigator
- History of (noninfectious) pneumonitis/interstitial lung disease that required steroids, or has current pneumonitis/interstitial lung disease
- Active infection requiring systemic therapy
- 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 to the first dose of study drug
- Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
- Known additional malignancy that is progressing or has required active systemic treatment within the past 3 years, except basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ that have undergone potentially curative therapy
- Active autoimmune disease that has required systemic treatment in the past 2 years
- Had an allogeneic tissue/solid organ transplant
- Known history of human immunodeficiency virus (HIV) infection
- History of any contraindication or has a severe hypersensitivity to any components of pembrolizumab, lenvatinib or SOC chemotherapy.
- Pre-existing ≥Grade 3 gastrointestinal or non-gastrointestinal fistula
- History of a gastrointestinal malabsorption or any other condition or procedure that may affect oral study drug absorption
- Had major surgery within 3 weeks prior to first dose of study interventions
- Clinically significant cardiovascular impairment within 12 months of the first dose of study drug
- Active tuberculosis
- Has difficulty swallowing capsules or ingesting a suspension orally, or by a feeding tube
- Prior treatment with lenvatinib
- Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Study Day 1 or has not recovered from adverse events (AEs) due to a previously administered agent. Participants with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may be eligible
- Has received a live or live attenuated vaccine within 30 days prior to the first dose of study intervention. Note: Administration of killed vaccines is allowed
- Previously treated with 4 or more systemic regimens given for recurrent/metastatic disease
- Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
- Known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Not Recruiting | 11 Aug 2020 | 7 |
 France | Not Recruiting | 11 Aug 2020 | 62 |
 Norway | Not Recruiting | 11 Aug 2020 | 5 |
 Portugal | Not Recruiting | 11 Aug 2020 | 11 |
 Romania | Not Recruiting | 11 Aug 2020 | 35 |
 Spain | Not Recruiting | 11 Aug 2020 | 38 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
DOCETAXEL | Comparator | PHF00230MIG | INTRAVENOUS INFUSION | 75 | 78 | SCP126226 |
PACLITAXEL | Comparator | PHF00230MIG | INTRAVENOUS INFUSION | 80 | 78 | SCP129816 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 200 | 36 | PRD4323105 |
CAPECITABINE | Comparator | PHF00009MIG | ORAL USE | 2500 | 78 | SCP131876 |
CETUXIMAB | Comparator | PHF00230MIG | INTRAVENOUS INFUSION | 400 | 78 | SCP185672 |
Lenvatinib | Test | CAPSULE | ORAL USE | 24 | 78 | PRD9414231 |
Lenvatinib | Test | CAPSULE | ORAL USE | 24 | 78 | PRD9414230 |