| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck, cervix, lung, anal, vulva, and penile. |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck, cervix, lung, anal, vulva, and penile. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10041823 |
| E.1.2 | Term | Squamous cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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, lung, anus, vulva, and penis, using the ORR during treatment (investigator assessment). |
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| E.2.2 | Secondary objectives of the trial |
SECONDARY OBJECTIVES:
•To determine, in each cohort, the anti-tumor activity in term of:
Centrally confirmed objective response rate (ORR), as per RECIST v1.1.
Centrally confirmed immune objective response rate (iORR), as per iRECIST.
Duration of response (DOR).
Progression-free survival (PFS), as per RECIST.
Immune-progression-free survival (iPFS), as per iRECIST.
Overall survival (OS).
•To evaluate the safety and tolerability of pembrolizumab in combination with vorinostat according to NCI CTCAE v5.0:
In each cohort.
In the overall study population.
TRANSLATIONAL OBJECTIVES:
The translational studies associated with this clinical study aim to assess the following:
•Link between the tumor molecular profile and immune parameters.
•Link between immune-related biomarkers and drug combination efficacy.
•Post-treatment modification of immune-related and molecular epigenetic biomarkers.
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•Predictive value of tumor microenvironment and epigenetic parameters.
•Predictive value of circulating biomarkers. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Aged ≥18 years old.
2.Patients with Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
3.Patients must have histologically confirmed recurrent and/or metastatic squamous cell carcinoma of the head and neck, cervix, lung, anus, vulva, or penis.
4.Patients must have radiologically confirmed progressive recurrent and/or metastatic disease.
5.Patients for which a treatment with an anti-PD1/PD-L1 agents and vorinostat is an acceptable option according to investigator.
6.Disease amenable to biopsy for study purpose.
7.Measurable disease according to RECIST v1.1.
8.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.
9.Adequate liver function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤3 × ULN (≤5 ULN when documented liver metastases) and total bilirubin level ≤1.5 × ULN, within 14 days prior inclusion.
10.Adequate bone marrow function: absolute neutrophil count (ANC) ≥1,000/mm³, platelet count ≥100,000/mm³, and hemoglobin ≥9 g/dL, within 14 days prior inclusion.
11.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.
12.Female of child-bearing potential must have a negative serum pregnancy test within 72 h before starting study treatment.
13.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.
14.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.
15.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.
16.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.
17.Patients able to swallow oral medications.
18.Patients must be affiliated to a Social Security System (or equivalent).
19.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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| E.4 | Principal exclusion criteria |
1.Prior treatment with anti-PD-1/PD-L1 agents or histone deacetylases (HDAC) inhibitors.
2.Patients with central nervous system involvement that has not been controlled for >3 months.
3.Patients with no other site for biopsy than bone lesions.
4.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.
5.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.
6.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).
7.History of allogeneic organ or bone marrow transplantation.
8.History of non-infectious pneumonitis that required steroids or has current pneumonitis.
9.Has an active infection requiring systemic therapy.
10.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 (eg, FluMist®) are live attenuated vaccines and are not allowed.
11.Known prior severe hypersensitivity to investigational products or its excipients,
12.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.
13.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.
14.Major surgery within 28 days prior to the first dose of study treatments.
Note: Local surgery of isolated lesions for palliative intent is acceptable.
15.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,
•Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
16. 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.
17.Pregnant women or women who are breast-feeding.
18.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.
19.Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons.
20.Persons deprived of their liberty or under protective custody or guardianship.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Investigators will assess the ORR. The ORR is defined in each cohort as the percentage of evaluable patients for ORR, designate as the proportion of patients with best response of complete response (CR) or a partial response (PR) during treatment according to RECIST v1.1. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
•Anti-tumor activity endpoints will be evaluated in each cohort:
ORR defined as the proportion of patients with best response of CR or PR during treatment, as assessed by a central radiological panel according to RECIST v1.1.
iORR defined as the proportion of patients with best response of CR or PR during treatment, as assessed by a central radiological panel according to immune-specific response criteria (iRECIST).
DOR will be evaluated in patients with either a complete response (CR) or partial response (PR). DOR is defined as the time from the first assessment of a CR or PR until the date of the first occurrence of progressive disease (PD) or death from any cause (if death occurred within predefined period), whichever occurs first.
PFS is defined per RECIST1.1 as the time from inclusion until disease progression (per RECIST v1.1) or death from any cause, whichever occurs first. At the time of analysis, a patient alive and without disease progression will be censored at the date of the last tumor assessment. Patients alive without disease progression who started a new anticancer therapy will be censored at the date of the last tumor assessment prior to the start of the new anticancer therapy.
iPFS is defined per iRECIST as the time from inclusion until confirmed disease progression (per iRECIST), or death from any cause, whichever occurs first. At the time of analysis, a patient alive and without progression will be censored at the date of the last tumor assessment. Patients alive without disease progression who started a new anti-cancer therapy will be censored at the date of the last tumor assessment prior to the start of the new anticancer therapy.
OS is defined as the time from inclusion until death from any cause. Patients who are alive at last follow-up news will be censored at this date.
The safety will be evaluated according to the incidence of adverse events (AEs) graded by NCI-CTCAE v5.0:
In each cohort.
In the overall study population.
TRANSLATIONAL ENDPOINTS:
•To assess the link between the tumor molecular profile including epigenetics features and immune parameters of the tumor microenvironment (TME) and in blood samples.
•To assess the link between immune-related biomarkers in the TME and in blood samples (including but not limited to tumor tissue PD-L1 expression by IHC, RNA gene expression profiling, and DNA mutation analysis), and measures of efficacy.
•To explore the modification of immune-related and molecular epigenetic biomarkers following treatment.
•To analyze the impact of TME and epigenetics parameters on sensitivity/response to treatment.
•To assess the predictive value of circulating biomarkers on sensitivity or resistance to treatment.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| basket study evaluating the efficacy of a combination of pembrolizumab and vorinostat |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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