Phase II Basket Trial Evaluating Pembrolizumab and Vorinostat Efficacy in Recurrent/Metastatic Squamous Cell Carcinoma of Various Anatomical Sites

Trial ID: 2023-510320-71-00
Protocol: UC-GMP-1908
Sponsor: Unicancer

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Diseases & Conditions

Anal squamous cell carcinoma Squamous cell carcinoma of head and neck Squamous cell carcinoma of the cervix Squamous cell carcinoma of the vulva

Objectives

The primary objective of this trial is to evaluate the **antitumor activity** of pembrolizumab in combination with vorinostat in patients with recurrent and/or metastatic **squamous cell carcinoma** of the head and neck, cervix, anus, vulva/vagina, and penis. This is assessed using the objective response rate (ORR) during treatment, as determined by investigator assessment. The clinical relevance of this objective lies in its potential to provide evidence for the efficacy of this combination therapy in treating these specific types of cancer, which could inform future treatment protocols and improve patient outcomes.

Secondary objectives include: - Determining the anti-tumor activity in terms of centrally confirmed ORR, immune objective response rate (iORR), duration of response (DOR), progression-free survival (PFS), immune-progression-free survival (iPFS), and overall survival (OS) in each cohort. - Evaluating the safety and tolerability of pembrolizumab in combination with vorinostat according to NCI CTCAE v5.0, both in each cohort and in the overall study population. These secondary objectives are crucial for understanding the broader impact of the treatment on patient health and its potential side effects, thereby ensuring a comprehensive assessment of the therapy's clinical utility.

Participants

The clinical trial involves a study population comprising both **male** and **female** participants aged 18 years and older. The trial focuses on individuals with recurrent and/or metastatic **squamous cell carcinoma** of the head and neck, cervix, anus, vulva/vagina, or penis. Participants are required to have adequate bone marrow, coagulation, renal, and liver function, as well as a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale. The trial includes individuals who are either naive or previously treated for their recurrent and/or metastatic disease. Participants must have measurable disease according to RECIST v1.1 and be able to comply with the study protocol, including scheduled visits and procedures. The total number of participants is not provided, as the sponsor has not disclosed this information. The trial population was selected based on specific inclusion criteria, including the ability to swallow oral medications and affiliation with a Social Security System or equivalent. Lifestyle considerations such as diet and physical activity are not specified. The study does not provide information on the total number of participants or specific lifestyle factors.

Plans and Procedures

The clinical trial is designed as a **Phase II**, randomized, double-blind, controlled study to evaluate the efficacy of a combination therapy involving **pembrolizumab** and **vorinostat** in patients with recurrent and/or metastatic **squamous cell carcinoma**. The trial aims to assess the antitumor activity of this combination in various anatomical locations, including the head and neck, cervix, anus, vulva/vagina, and penis. The study is expected to run from October 27, 2020, to November 30, 2024, with a maximum treatment period of 105 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, adequate organ function, and disease status. Following successful screening, participants will be randomized to receive either the investigational combination therapy or a control. The treatment phase will involve regular follow-up visits to monitor response to therapy, assess safety, and manage any adverse events. These visits will include clinical assessments, laboratory tests, and imaging studies to evaluate the **objective response rate (ORR)** and other secondary endpoints such as progression-free survival (PFS) and overall survival (OS).

The end-of-study visit will occur after the completion of the treatment period or upon early termination. Conditions that may lead to early termination include disease progression, unacceptable toxicity, or withdrawal of consent. Participants are expected to be involved in the study for the duration of the treatment period and follow-up, with additional time allocated for safety monitoring post-treatment. The trial's primary endpoint is the ORR, defined as the proportion of patients achieving a complete or partial response, as assessed by investigators according to RECIST v1.1 criteria.

Treatment

The clinical trial involves the administration of two experimental medications: **vorinostat** and **pembrolizumab**. **Vorinostat**, also known by the sponsor product code MK-0683, is provided in a **capsule** form for oral administration. The maximum daily dose of vorinostat is 400 mg, with a total treatment period not exceeding 105 days. The active substance, vorinostat, is of chemical origin and is manufactured by Merck & Co. Inc. Participants are required to adhere to the dosing schedule, and compliance will be monitored throughout the study.

**Pembrolizumab** is administered as a **concentrate for solution for infusion**, specifically under the product name Keytruda 25 mg/mL. This medication is delivered via **intravenous injection**. The maximum daily dose for pembrolizumab is 200 mg, with a treatment duration also capped at 105 days. Pembrolizumab is a protein-based substance, produced by Merck Sharp & Dohme B.V. The administration of pembrolizumab will be conducted in a controlled clinical setting to ensure proper dosing and participant safety.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The primary objective is to evaluate the antitumor activity of the combination of pembrolizumab and vorinostat in patients with recurrent and/or metastatic squamous cell carcinoma. The study will monitor participant compliance with the dosing schedules to ensure the integrity of the trial data.

Efficacy

The efficacy of the combination of pembrolizumab and **vorinostat** in patients with recurrent and/or metastatic squamous cell carcinoma will be assessed primarily through the Overall Response Rate (ORR). The ORR is defined as the percentage of evaluable patients achieving a best response of complete response (CR) or partial response (PR) during treatment, as determined by investigators using RECIST v1.1 criteria. Secondary efficacy endpoints include ORR as assessed by a central radiological panel, immune-specific ORR (iORR) using iRECIST criteria, Duration of Response (DOR), Progression-Free Survival (PFS), immune-specific PFS (iPFS), and Overall Survival (OS).

The ORR will be measured by both investigator assessment and a central radiological panel, with the latter also evaluating iORR. DOR will be calculated from the first assessment of CR or PR until the occurrence of progressive disease or death. PFS and iPFS will be determined from inclusion until disease progression or death, with specific criteria for censoring patients who are alive without progression. OS will be measured from inclusion until death from any cause, with censoring at the last follow-up for patients who are alive.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Aged ≥18 years old.
Patients with Eastern Cooperative Oncology Group (ECOG) performance status ≤1
Patients must have histologically confirmed recurrent and/or metastatic squamous cell carcinoma of the head and neck, cervix, , anus, vulva/vagina, or penis.
Patients must have radiologically confirmed progressive recurrent and/or metastatic disease.
Patients naive or previously treated for their recurrent and/or metastatic disease.
Disease amenable to biopsy for study purpose.
Measurable disease according to RECIST v1.1.
Adequate renal function: serum creatinine ≤1.5 x upper limit of normal (ULN) (OR creatinine clearance [Cockcroft and Gault] ≥30 mL/min for participant with creatinine levels >1.5 × ULN) within 14 days prior inclusion.
Adequate liver function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤2.5 × ULN (≤5 ULN when documented liver metastases) and total bilirubin level ≤1.5 × ULN, within 14 days prior inclusion.
Adequate bone marrow function: absolute neutrophil count (ANC) ≥1,500/mm³, platelet count ≥100,000/mm³, and hemoglobin ≥9 g/dL, within 14 days prior inclusion.
Adequate coagulation: prothrombin time (PT)/international normalized ratio (INR) ≤1.5 × ULN within 14 days prior inclusion If participant is receiving anticoagulant therapy then the PT or activated partial thromboplastin time (aPTT) should be within the therapeutic range of intended use of anticoagulant.
Female of child-bearing potential must have a negative serum pregnancy test within 72 h before starting study treatment.
Female of childbearing potential, must use "highly effective" methods of contraception for the study duration and for 4 months following the last dose of pembrolizumab and 6 months following the last dose of vorinostat.
Male participants must agree to use an effective contraceptive for the duration of the trial and for at least 4 months after the last the last dose of pembrolizumab and 6 months following the last dose of vorinostat (to allow for effective elimination of the study drugs). Also, they should refrain from donating sperm during this period.
Patients must be willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, and laboratory tests.
Patients must be willing and able to comply with other study procedures, including a baseline tumor biopsy and a series of blood samples throughout the study.
Patients able to swallow oral medications.
Patients must be affiliated to a Social Security System (or equivalent).
Patients must have signed a written informed consent prior to any trial-specific procedures. When the patient is physically unable to give their written consent, a trusted person of their choice, independent from the investigator or the sponsor, can confirm in writing the patient’s consent.

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Exclusion Criteria

Prior treatment with anti-PD-1/PD-L1 or anti PD L2 agents or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137), or histone deacetylases (HDAC) inhibitors.
Patients with central nervous system involvement that has not been controlled for >3 months.
Patients with no other site for biopsy than bone lesions.
Patients with other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study, including uncontrolled diabetes, cardiac disease, uncontrolled hypertension, congestive cardiac failure, ventricular arrhythmias, active ischemic heart disease, myocardial infection within one year, chronic liver or renal disease, active gastrointestinal tract ulceration, severely impaired lung function.
Known history of human immunodeficiency virus (HIV), Hepatitis B virus (HBV; defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (HCV; defined as HCV RNA detected) virus infection.
History of autoimmune disease with the exception of: - (1) Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone; - (2) Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen, - (3) Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) provided that they meet the following conditions: (i) Rash must cover less than 10% of body surface area; (ii) Disease is well controlled at baseline and only requiring low potency topical steroids; (iii) No acute exacerbations of underlying condition within the previous 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoid, biologic agents, oral calcineurin inhibitors, high-potency or oral steroids).
History of allogeneic organ or bone marrow transplantation.
History of non-infectious pneumonitis that required steroids or has current pneumonitis.
Has an active infection requiring systemic therapy.
Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g, FluMist®) are live attenuated vaccines and are not allowed.
Known prior severe hypersensitivity to investigational products or its excipients,
Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks [could consider shorter interval for kinase inhibitors or other short half-life drugs] prior to first dose of study treatments. Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
Major surgery within 28 days prior to the first dose of study treatments. Note: Local surgery of isolated lesions for palliative intent is acceptable.
Current or prior use of immunosuppressive medication within 7 days before the first dose of pembrolizumab. The following are exceptions to this criterion: - Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection), - Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or its equivalent (see Appendix 5), - Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
Patients using drugs that could have pharmacokinetics interaction with investigational drugs. This includes, but is not limited to, valproic acid, coumarin-derivative anticoagulants, drugs that disrupt electrolyte levels, drugs that may prolong QT
Pregnant women or women who are breast-feeding.
Patients enrolled in another therapeutic study within 30 days prior to inclusion and during the treatment period. Patients can participate in an independent approved non-interventional studies.
Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons.
Persons deprived of their liberty or under protective custody or guardianship.