Evaluation of Pembrolizumab and Axitinib Combination Versus Sunitinib Monotherapy in First-line Treatment of Metastatic Renal Cell Carcinoma
- Trial ID
- 2023-507294-18-00
- Protocol
- MK-3475-426
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase III randomized, open-label study is to evaluate and compare **progression-free survival** (PFS) per RECIST 1.1 as assessed by blinded independent central review (BICR) in subjects with metastatic renal cell carcinoma treated with a combination of pembrolizumab plus axitinib versus sunitinib monotherapy. Additionally, the study aims to evaluate and compare overall survival (OS) in these treatment groups. These objectives are clinically relevant as they assess the efficacy of the combination therapy in delaying disease progression and improving survival outcomes, which are critical endpoints in the management of metastatic renal cell carcinoma.
Secondary objectives include:
- Comparing overall response rate (ORR) and disease control rate (DCR) per RECIST 1.1 as assessed by BICR, and evaluating duration of response (DOR) in subjects treated with pembrolizumab plus axitinib versus sunitinib monotherapy.
- Evaluating PFS rate per RECIST 1.1 at 12, 18, and 24 months, and OS rates at these time points based on data adequacy.
- Evaluating and comparing safety and tolerability profiles in the treatment groups.
- Comparing time to deterioration (TTD) based on the Functional Assessment of Cancer Therapy Kidney Symptom Index—Disease-Related Symptoms (FKSI-DRS) scale.
- Assessing longitudinal score changes from baseline to 42 weeks as measured by the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 global health status/quality of life scale.
Participants
The clinical trial involves a total of **592 participants** diagnosed with **metastatic renal cell carcinoma**. 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 criteria, including a histologically confirmed diagnosis of renal cell carcinoma with a clear cell component, locally advanced or metastatic disease, and no prior systemic therapy for advanced renal cell carcinoma. The trial population is characterized by a Karnofsky performance status of 70% or higher, indicating a relatively stable general health status. Lifestyle considerations such as the use of contraception for participants of childbearing potential and the initiation of bone resorptive therapy at least two weeks prior to randomization are noted. The trial includes a vulnerable population, ensuring comprehensive evaluation across diverse demographic groups.
Plans and Procedures
The clinical trial is a **Phase III** randomized, open-label study designed to evaluate the efficacy and safety of **pembrolizumab** in combination with **axitinib** versus **sunitinib** monotherapy as a first-line treatment for patients with locally advanced or **metastatic renal cell carcinoma**. The trial aims to compare progression-free survival (PFS) and overall survival (OS) between the two treatment groups. The study is expected to conclude by December 31, 2025, with recruitment having commenced on October 10, 2016.
Participants will be randomly assigned to receive either the combination therapy of pembrolizumab and axitinib or sunitinib monotherapy. The trial involves a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically confirmed diagnosis of renal cell carcinoma with a clear cell component, measurable disease per RECIST 1.1, and no prior systemic therapy for advanced RCC. Participants must also demonstrate adequate organ function and agree to use contraception if of childbearing potential.
Following the screening visit, participants will undergo regular follow-up visits to monitor treatment response and safety. These visits will include assessments of disease progression, adverse events, and overall health status. The primary endpoints of the study are progression-free survival and overall survival, with secondary endpoints including objective response rate, disease control rate, and duration of response, among others. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected length of participant involvement is up to 156 weeks, depending on the treatment arm and individual response to therapy. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or any other reason deemed appropriate by the investigator. The trial is conducted in accordance with ethical guidelines and regulatory requirements to ensure the safety and well-being of all participants.
Treatment
The clinical trial involves the administration of three distinct treatments for the evaluation of efficacy and safety in patients with locally advanced or metastatic renal cell carcinoma. The first treatment is **Sunitinib**, a chemical compound administered as an oral medication. The pharmaceutical form of Sunitinib is denoted as PHF00006MIG. The maximum daily dose is 50 mg, with a total maximum dose of 78,400 mg over a treatment period of 77 days. Sunitinib is classified under the ATC code L01EX01 and is used as a monotherapy in this study.
The second treatment is **Axitinib**, also a chemical compound, administered orally. Axitinib is provided in the pharmaceutical form PHF00009MIG. The maximum daily dose for Axitinib is 20 mg, with a total maximum dose of 46,841 mg over a 77-day treatment period. It is classified under the ATC code L01EK01. Axitinib is used in combination with Pembrolizumab in this study.
The third treatment is **Pembrolizumab**, a biological agent, administered as an intravenous infusion. The pharmaceutical form is a concentrate for solution for infusion, specifically Keytruda 25 mg/mL. The maximum daily dose is 200 mg, with a total maximum dose of 104,000 mg over a treatment period of 156 days. Pembrolizumab is used in combination with Axitinib in this study. The administration of Pembrolizumab is conducted under the authorization of Merck Sharp & Dohme B.V.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The study aims to compare the progression-free survival (PFS) and overall survival (OS) between the combination therapy of Pembrolizumab plus Axitinib and Sunitinib monotherapy.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Progression-Free Survival (PFS)** as per the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), assessed by Blinded Independent Central Imaging Review (BICR), and **Overall Survival (OS)**. These endpoints will provide a comprehensive evaluation of the treatment's impact on disease progression and patient survival.
Secondary endpoints will further assess efficacy through various measures, including the **Objective Response Rate (ORR)**, **Disease Control Rate (DCR)**, and **Duration of Response (DOR)**, all evaluated using RECIST 1.1 criteria by BICR. Additional secondary endpoints include the number of participants experiencing adverse events (AEs) and those discontinuing the study drug due to AEs. The trial will also measure PFS and OS rates at 12, 18, and 24 months, providing insights into the long-term benefits of the treatment. Patient-reported outcomes will be evaluated through the Functional Assessment of Cancer Therapy Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS) score and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (GHS) Scale Score, with specific attention to changes from baseline to week 54.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Has histologically confirmed diagnosis of renal cell carcinoma (RCC) with clear cell component with or without sarcomatoid features
- Has locally advanced/metastatic disease (i.e., newly diagnosed Stage IV RCC per American Joint Committee on Cancer) or has recurrent disease
- Has measurable disease per RECIST 1.1 as assessed by the investigator/site radiologist
- Has received no prior systemic therapy for advanced RCC.
- Has provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated.
- Has Karnofsky performance status (KPS) ≥ 70% as assessed within 10 days prior to randomization.
- If receiving bone resorptive therapy (including but not limited to bisphosphonate or receptor activator of nuclear factor-kappa B ligand [RANK-L] inhibitor) must have therapy initiated at least 2 weeks prior to randomization.
- Demonstrates adequate organ function.
- Female participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study drug.
- Male participants of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study drug through 120 days after the last dose of study drug.
Exclusion Criteria
- 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 randomization.
- Has had major surgery within 4 weeks, received radiation therapy within 2 weeks prior to randomization, or has not recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to prior treatment.
- Has had prior treatment with any anti-programmed cell death (anti-PD-1), or programmed cell death ligand 1 (PD-L1), or PD-L2 agent or an antibody targeting any other immune-regulatory receptors or mechanisms.
- Has received prior systemic anti-cancer therapy for RCC with vascular endothelial growth factor (VEGF)/VEGF receptors (VEGFR) or mechanistic target of rapamycin (mTOR) targeting agents.
- Has a history of severe hypersensitivity reaction (e.g., generalized rash/erythema, hypotension, bronchospasm, angioedema or anaphylaxis) to axitinib or sunitinib.
- Has a diagnosis of immunodeficiency OR is receiving a systemic steroid therapy exceeding physiologic corticosteroid dose or any other form of immunosuppressive therapy within 7 days prior to randomization, except in the case of central nervous system (CNS) metastases.
- Has an active autoimmune disease requiring systemic treatment with in the past 2 years OR a documented history of clinically severe autoimmune disease. Note: Participants with vitiligo, Sjøgren's syndrome, Type 1 diabetes, resolved childhood asthma/atopy, hypothyroidism or adrenal or pituitary insufficiency who are stable on hormone replacement, are not excluded.
- Has a known additional malignancy that has progressed or has required active treatment in the last 3 years. Note: Basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ such as breast cancer in situ are acceptable if they have undergone potentially curative therapy.
- Has known active CNS metastases and/or carcinomatous meningitis.
- Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
- Has an active infection requiring systemic therapy.
- Has a known history of Human Immunodeficiency Virus (HIV).
- Has known active Hepatitis B or Hepatitis C infection.
- Has received a live virus vaccine within 30 days of randomization.
- Has a clinically significant gastrointestinal (GI) abnormality including: malabsorption, total gastric resection, or any condition that might affect the absorption of orally taken medication; active GI bleeding, as evidenced by hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy; intraluminal metastatic lesion with suspected bleeding, inflammatory bowel disease, ulcerative colitis or other GI condition associated with increased risk of perforation.
- Has QT interval corrected for heart rate (QTc) ≥480 msec.
- Has a history of any of the following cardiovascular conditions within 12 months of randomization: myocardial infarction, unstable angina pectoris, cardiac angioplasty or stenting, coronary/peripheral artery bypass graft, class III or IV congestive heart failure per New York Heart Association, cerebrovascular accident or transient ischemic attack.
- Has a history of deep vein thrombosis or pulmonary embolism within 6 months of screening.
- Has poorly controlled hypertension defined as systolic blood pressure (SBP) ≥150 mm Hg and/or diastolic blood pressure (DBP) ≥90 mm Hg.
- Has evidence of inadequate wound healing.
- Has active bleeding disorder or other history of significant bleeding episodes within 30 days of randomization.
- Has hemoptysis within 6 weeks prior to randomization.
- Has current use (within 7 days of randomization) or anticipated need for treatment with drugs or foods that are known strong cytochrome P450 (CYP3A4/5) inhibitors.
- Has current use (within 7 days of randomization) or anticipated need for treatment with drugs that are known strong CYP3A4/5 inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort; or drugs that are known with proarrhythmic potential.
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
- Has had a prior solid organ transplant.
- 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 drug.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 10 Oct 2016 | 33 |
 France | Not Recruiting | 10 Oct 2016 | 85 |
 Germany | Not Recruiting | 10 Oct 2016 | 40 |
 Hungary | Not Recruiting | 10 Oct 2016 | 42 |
 Ireland | Not Recruiting | 10 Oct 2016 | 17 |
 Poland | Not Recruiting | 10 Oct 2016 | 32 |
 Spain | Not Recruiting | 10 Oct 2016 | 20 |
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 |
|---|---|---|---|---|---|---|
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 200 | 156 | PRD4323105 |
SUNITINIB | Comparator | PHF00006MIG | ORAL USE | 50 | 77 | SCP185293 |
AXITINIB | Test | PHF00009MIG | ORAL USE | 20 | 77 | SCP103387829 |