Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Symptoms and General Pathology

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Carcinoma, Squamous Cell

Recurrence

Head and Neck Neoplasms

Squamous Cell Carcinoma of Head and Neck

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Neoplasms, Squamous Cell

Antineoplastic Agents

All Drugs and Chemicals

Pembrolizumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Pembrolizumab + de-escalating doses of valemetostat

RP2D of valemetostat in combination with pembrolizumab

Phase Ib: Pembrolizumab 200mg will be administered by IV infusion every 3 weeks.

Phase II: Pembrolizumab 200mg will be administered by IV infusion every 3 weeks.

pembrolizumab

Phase Ib: Valemetostat will be given orally every day of every cycle (DL-1: 100mg, DL1: 150mg, DL2: 200mg).

Phase II: Valemetostat will be given orally daily at the recommended phase 2 dose.

valemetostat

Christine A Feierabend

Vassiliki Saloura, M.D.

National Cancer Institute Referral Office

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.

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.

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

A Phase Ib/II Multicenter 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

.All IPD recorded in the medical record will be shared with intramural investigators upon request. All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP. All collected IPD will be shared with collaborators under the terms of collaborative agreements.

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)

Any toxicities that occur during timeframe.

Number of dose limiting toxicities (DLTs) that occur within the DLT period will determine RP2D.

Valemetostat level in blood samples collected for PK analysis

Participants will be assessed for survival while on study therapy and every 9 weeks before progression / every 6 weeks after progression.

Participants will be assessed for survival at 6 months after start of study, or until progression.

Participants will be assessed for survival until progression or 2 years after treatment start.

Stable disease \>= 6 months + complete response + partial response

ORR will be evaluated with periodic CT imaging.

Any toxicities identified during evaluation timeframe.

Spots Global Cancer Trial Database for valemetostat + pembrolizumab