Study of Front Line Pembrolizumab and Valemetostat in PD-L1 Positive, HPV-Negative Recurrent/Metastatic Squamous Cell Carcinoma (SCC) of the Head and Neck: The PANTHERAS
- Conditions
- Squamous Non-small Cell Lung CancerLung CancerSinonasal CancerHead and Neck Squamous Cell CarcinomaHead and Neck CancerHead and Neck Carcnimona
- Interventions
- Registration Number
- NCT05879484
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide. These cancers have different causes, with smoking/tobacco exposure and human papilloma virus infection being the most common. . When HNSCC occurs in people who are not infected with HPV, the cancers are more likely to return after treatment; when this happens, overall survival is only about 10 months, thus better treatments are needed.
Objective:
To test a combination treatment using 2 drugs (valemetostat and pembrolizumab) in people with HNSCC. Phase 1b of the study will determine a recommended dose of the 2 drugs and evaluate how safe the combination is.; this will include patients with HPV-positive and HPV-negative HNSCC, as well as squamous cell NSCLC that have progressed on anti-PD-1/anti-PD-L1 therapies.Phase II will determine how effective the combination is and will focus on patients with HPV-negative HNSCC.
Eligibility:
People aged 18 years and older with HPV-negative HNSCC, sinonasal carcinoma of the head and neck, or squamous non-small cell lung cancer (NSCLC).
Design:
Participants will be screened. They will have a physical exam. They will have blood and urine tests and tests of their heart function. They will have imaging scans. They may have a biopsy: A small sample of tissue will be removed from the tumor.
Treatment will be given in 21-day cycles.
Pembrolizumab is administered through a tube attached to a needle inserted into a vein in the arm. Participants will receive pembrolizumab on the first day of each cycle.
Valemetostat is a tablet taken by mouth. Participants will take the tablet once a day at home. They will record the date and time of each dose in a diary. They will also write down any adverse effects they experience.
Participants may remain in the study up to 2 years.
- Detailed Description
Background:
* Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide, with approximately 60,000 patients diagnosed annually in the United States.
* Only 14% of HNSCC patients have structural defects in the genes encoding for the human leukocyte antigens (HLA) class I components, while a higher percentage of these tumors show downregulation of HLA class I components by immunohistochemistry supports those epigenetic mechanisms may be involved in the deregulation of these genes.
* Valemetostat (DS-3201) is an enhancer of zeste homolog 1 and 2 (EZH1/2) dual inhibitor that is actively being investigated in phase I and II trials for hematologic malignancies and is approved for adult T-cell leukemia/lymphoma (ATL) indication in Japan.
* Patients with recurrent or metastatic (R/M) pembrolizumab-na(SqrRoot) ve human papillomavirus (HPV)-negative HNSCC have a low 6-month progression-free survival (PFS) (28%) with pembrolizumab monotherapy, thus novel interventions are needed to increase the efficacy of pembrolizumab.
Objectives:
Phase Ib:
* To determine the recommended phase II dose (RP2D) of valemetostat in combination with pembrolizumab.
* To evaluate the safety of valemetostat in combination with pembrolizumab.
Phase II:
-To determine the disease control rate (DCR)=partial response (PR) + complete response (CR) + stable disease (SD).
Eligibility:
-Participants must have a diagnosis of locoregionally recurrent or metastatic (R/M) HPVnegative (Phase Ib and Phase II) or positive HNSCC (Phase Ib only): oral cavity, tonsil, pharynx, hypopharynx, larynx. Note: Nasopharyngeal carcinoma and cutaneous squamous cell carcinoma (SCC) are excluded
OR
(R/M) squamous non-small cell lung cancer (NSCLC) (Phase Ib only)
OR
(R/M) sinonasal carcinomas of the head and neck (Phase Ib only).
* Age \>18 years.
* Adequate organ and marrow function.
Design:
* This is an open-label multicenter phase Ib/II study to evaluate the safety and efficacy of the combined treatment of valemetostat and pembrolizumab.
* During phase Ib we will estimate the RP2D of the valemetostat in combination with pembrolizumab.
* During phase II we will examine the efficacy and continue to evaluate the safety of the study regimen at the RP2D of the valemetostat in combination with pembrolizumab.
* Participants will receive treatment in cycles consisting of 21 (+/- 3) days for 2 years.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 47
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Arm 1 valemetostat Pembrolizumab + de-escalating doses of valemetostat Arm 1 pembrolizumab Pembrolizumab + de-escalating doses of valemetostat Arm 2 valemetostat RP2D of valemetostat in combination with pembrolizumab Arm 2 pembrolizumab RP2D of valemetostat in combination with pembrolizumab
- Primary Outcome Measures
Name Time Method Phase Ib: Safety of valemetostat in combination with pembrolizumab Study start-30 days after last dose of study agents Any toxicities that occur during timeframe.
Phase Ib: Recommended phase II dose (RP2D) of valemetostat in combination with pembrolizumab 42 days Number of dose limiting toxicities (DLTs) that occur within the DLT period will determine RP2D.
Phase II: Disease control rate (DCR) Study start until progression or 2 years after treatment initiation Best confirmed response in participants with PD-L1 positive (CPS \>=1), HPV-negative relapsing/metatstic HNSCC treated with valemetostat and pembrolizumab compared to historical controls with pembrolizumab alone, by CT scan and brain MRI (PR+CR+SD)
- Secondary Outcome Measures
Name Time Method Pharmacokinetics of valemetostat in combination with pembrolizumab Phase Ib: C1D1, C1D8, C1D15, and C2D1Phase II: C0D1, C1D1, C1D8, C1D15, and C2D1 Valemetostat level in blood samples collected for PK analysis
Safety of the valemetostat and pembrolizumab combination (Phase II) Treatment start until 30 days after last dose of study agents. Any toxicities identified during evaluation timeframe.
Progression free survival (PFS) in participants treated with valemetostat and pembrolizumab compared to historical controls with pembrolizumab alone Phase Ib: Study start until progression or 2 years after treatment initiationPhase II: Study start until progression or 2 years after treatment initiation Participants will be assessed for survival until progression or 2 years after treatment start.
Clinical benefit rate (CBR) in participants treated with valemetostat and pembrolizumab compared to historical controls with pembrolizumab alone Phase 1b: Study start until progression or 2 years after treatment initiation.Phase II: Study start until progression or 2 years after treatment initiation. Stable disease \>= 6 months + complete response + partial response
Objective response rate (ORR) in participants treated with valemetostat and pembrolizumab compared to historical controls with pembrolizumab alone Phase 1b: Treatment start until progression or 2 years after treatment initiation.Phase II: Treatment start until progression or 2 years after treatment initiation. ORR will be evaluated with periodic CT imaging.
Overall survival (OS) in participants treated with valemetostat and pembrolizumab compared to historical controls with pembrolizumab alone Study start until progression or 2 years after treatment initiation. Participants will be assessed for survival while on study therapy and every 9 weeks before progression / every 6 weeks after progression.
6-month progression free survival (PFS) rate in participants treated with valemetostat and pembrolizumab compared to historical controls treated with pembrolizumab alone Phase Ib: Study start until progression or 6 months after treatment initiationPhase II: Study start until progression or 6 months after tx initiation Participants will be assessed for survival at 6 months after start of study, or until progression.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States