Phase 2 Multicenter Study of Pembrolizumab and Lenvatinib in Patients with Vulvar Cancer
- Trial ID
- 2023-509180-24-00
- Protocol
- MITO VULVA-01
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **activity** and safety of the combination of pembrolizumab and lenvatinib in patients with vulvar cancer, as assessed by the objective response rate for each study cohort. This is clinically relevant as it aims to determine the efficacy and tolerability of this therapeutic regimen, potentially offering a new treatment option for vulvar cancer, a condition with limited effective therapies.
Secondary objectives include:
- Describing progression-free survival (PFS) in the different single cohorts.
- Describing overall survival (OS) in each single cohort.
- Assessing the overall safety of pembrolizumab and lenvatinib in patients who receive more than four cycles of treatment.
- Evaluating response rate, PFS, and OS according to biomarker-based subpopulations and PDL1 expression.
Participants
The clinical trial focuses on evaluating the activity and safety of Pembrolizumab plus Lenvatinib in patients with **vulvar cancer**. The study population consists exclusively of female participants aged 18 years and older. The trial does not include male subjects or vulnerable populations. Participants are required to have a histologically or cytologically confirmed diagnosis of unresectable squamous cell carcinoma, adenocarcinoma, or mixed histology of the vulva. The trial population was selected based on specific inclusion criteria, including normal organ and bone marrow function, a life expectancy of at least 16 weeks, and an ECOG performance status of 0 to 1. Participants must also have adequately controlled blood pressure and be able to take oral medications. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the **activity** and safety of **Pembrolizumab** plus **Lenvatinib** in patients with **vulvar cancer**. This is a prospective, multi-cohort, multicenter, phase II study. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial is from September 2025 to September 2031, with recruitment expected to start in September 2025.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as normal organ and bone marrow function, and a life expectancy of at least 16 weeks. The inclusion visit will also confirm the absence of pregnancy in women of childbearing potential. Following the screening, participants will be randomized to receive either the investigational treatment or a control. The treatment period will involve regular follow-up visits to monitor the **objective response rate** and safety profile, as assessed by the **CTCAE** and **PRO-CTCAE** questionnaire. The primary endpoint will be evaluated after four cycles for Cohort A and throughout the treatment period for Cohorts B and C.
The expected length of participant involvement is up to 105 weeks, depending on the cohort assignment and response to treatment. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or failure to comply with the study protocol. The end-of-study visit will occur after the completion of the treatment period, where final assessments will be conducted to evaluate the long-term effects and safety of the treatment regimen.
Treatment
The clinical trial involves the administration of **Lenvatinib**, a chemical compound provided in **capsule** form. The active substance, lenvatinib, is manufactured by Merck & Co. Inc. The medication is administered **orally** with a maximum daily dose of 20 mg. The treatment period for lenvatinib is set at a maximum of 72 weeks. The dosing schedule is designed to ensure consistent administration, and participant compliance will be monitored throughout the trial to ensure adherence to the prescribed regimen.
Additionally, the trial includes the use of **KEYTRUDA**, a concentrate for solution for infusion containing the active substance **pembrolizumab**. This protein-based therapeutic is produced by Merck Sharp & Dohme B.V. and is administered via **intravenous infusion**. The maximum daily dose for pembrolizumab is 200 mg, with a treatment period extending up to 105 weeks. The infusion schedule is carefully structured to optimize therapeutic outcomes, and compliance will be closely monitored to maintain the integrity of the trial data.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this study. The trial is designed to evaluate the activity and safety of the combination of pembrolizumab and lenvatinib in patients with vulvar cancer, with the primary objective being the assessment of objective response rate and safety across different study cohorts.
Efficacy
The efficacy of the clinical trial involving Pembrolizumab plus **Lenvatinib** in patients with vulvar cancer will be assessed primarily through the **Objective Response Rate (ORR)**. This endpoint is defined as the proportion of patients achieving a complete response (CR) or partial response (PR) as evaluated by the Investigator using the RECIST 1.1 criteria. The ORR will be specifically evaluated after 4 cycles for patients in Cohort A and throughout the entire treatment period for patients in Cohorts B and C.
Additionally, the safety profile of the combination therapy will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and the PRO-CTCAE questionnaire across the overall study population. These assessments will provide comprehensive data on both the efficacy and safety of the treatment regimen in the specified patient cohorts.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed informed consent prior to any study specific procedures
- Female, age ≥ 18 years at time of signing informed consent
- Patients with histologically or cytologically confirmed unresectable squamous cell carcinoma, adenocarcinoma and mixed histology (adenosquamous) of the vulva, defined as: a. T2 or T3 primary tumors (N0-3, M0) not amenable to surgical resection by standard radical vulvectomy (Cohort A) OR b. patients with recurrent or de novo metastatic chemotherapy-naive vulvar squamous cell carcinoma, adenocarcinoma and mixed histology (adenosquamous) of the vulva, (Cohort B) OR c. patients with recurrent squamous cell carcinoma of the vulva after primary chemoradiation or patients with metastatic squamous cell carcinoma, adenocarcinoma and mixed histology (adenosquamous) of the vulva in progression to a chemotherapy based treatment (Cohort C)
- At least 1 measurable target lesion according to RECIST 1.1
- Patients must have a life expectancy ≥ 16 weeks
- ECOG performance status of 0 to 1
- Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤140/90 mmHg at Screening and no change in antihypertensive medications within 1 week before the Cycle 1/Day 1.
- Patient must provide formalin fixed paraffin embedded (FFPE) archival tumor sample, from primary surgery or from biopsy of primary tumor or metastases. Samples must be collected before any treatment (chemotherapy-naïve patients). A centralized quality control analysis of samples will be performed before patient’s enrollment. Only patients with adequate tumor sample for will be enrolled.
- Patient must be able to take oral medications
- Patients must have normal organ and bone marrow function measured as defined below: i. Haemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days ii. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L iii. Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be ≤ 5x ULN iv. Patients must have creatinine clearance estimated of ≥51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test: Estimated creatinine clearance = (140-age [years]) x weight (kg)(x F)a serum creatinine (mg/dL) x 72 (a where F=0.85 for females)
- INR or PT aPTT/PTT ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
- Patient is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: a. Is not a Women of Childbearing Potential (WOCBP) b. 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), as described in Appendix 1 during the intervention period and for at least 4 monts 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. Note 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
- Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
Exclusion Criteria
- Patients with vulvar melanomas, sarcomas, vulvar Paget's disease, or basal cell carcinoma
- Patients diagnosed with early-stage vulvar cancer that, according to the Investigator, can be treated with upfront curative surgery
- Patients who have received any systemic anticancer therapy for vulvar cancer, anti-VEGF therapy, or any systemic investigational anticancer agent including radiotherapy (Cohort A and B); Patients who have received any further systemic therapy for advanced disease after progression to a first-line platinum-based chemotherapy (Cohort C)
- Received a live vaccine or live attenuated within 30 days of planned start of study treatment (Cycle 1/Day 1). Note: The killed virus vaccines (ie seasonal influenza vaccines for injection are allowed)
- Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula
- Active infection (any infection requiring systemic treatment)
- Subjects known to be positive for Human Immunodeficiency Virus (HIV)
- Patients with known active hepatitis (i.e. Hepatitis B or C) i. Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible. ii. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
- Subjects with a diagnosis of immunodeficiency or who are receiving systemic steroid therapy (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 medications
- 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, etc.) is not considered a form of systemic treatment
- Patients unable to swallow orally administered medication
- Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment;
- Major surgery within 3 weeks of starting study treatment and patients must have recovered from any effects of major surgery. Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility;
- Breast feeding women;
- Known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, (i.e. without evidence of progression) for at least 4 weeks by repeat imaging (Note: The repeat imaging should be performed during study Screening.), clinically stable, and without requirement of steroid treatment for at least 14 days before the first dose of study intervention; Note: Participants with known untreated, asymptomatic brain metastases (ie, no neurological symptoms, no requirement for corticosteroids, no or minimal surrounding edema, and no lesion >1.5 cm) may participate but will require regular imaging of the brain as a site of disease;
- Other malignancy unless curatively treated with no evidence of disease for ≥5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS); Stage 1, grade 1 endometrial carcinoma
- Prolongation of QTcF interval to ≥480 msec
- LVEF below of the institutional (or local laboratory), normal range, as determined, by MUGA or ECHO
- Participation in another clinical study with an investigational product during the last 3 months
- Subjects who have not recovered adequately from any toxicity from other anti-cancer treatment regimens and/or complications from major surgery prior to starting therapy. Note: Withhold lenvatinib for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing
- Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction, cerebro vascular accident/stroke within 12 months of the first dose of study drug, or cardiac arrhythmia associated with hemodynamic instability. Medically controlled arrhytmia would be permitted
- Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage
- Radiographic evidence of tumor invasion/infiltration of major blood vessels (e.g. carotid artery) or intratumoral cavitation. Note: The degree of major blood vessel should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy
- History of arterial tromboembolism within 12 months of start the study
- Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug
- Has urine protein ≥1 g/24 hours. Note: Participants with proteinuria ≥2+ (≥100 mg/dL) on urine dipstick testing (urinalysis) will undergo 24-hour urine collection for quantitative assessment of proteinuria
- GI malabsorption or any other condition that might affect the absorption of Lenvatinib
- An allogenic tissue/solid organ transplant
- History of (non infectious) pneumonitis/interstizial lung disease that require steroids or current pneumonitis/ interstitial lung disease
- Known psychiatric disorder or substance abuse that would interfere with participant ability to cooperate with the requirement of the study
- Has received prior therapy with an anti-PD1, anti PD-L1 or anti PD-L2 agent 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)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 01 Sept 2025 | 80 |
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 | INTRAVENIOUS INFUSION | 200 | 105 | PRD4323105 |
Lenvatinib | Test | CAPSULE | ORAL | 20 | 72 | PRD9414230 |
Lenvatinib | Test | CAPSULE | ORAL | 20 | 72 | PRD9414231 |