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

NCT05879484 | Withdrawn Phase 1 FDA Drug

• 2 other identifiers: 10001545001545-C
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

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.

Conditions

Sinonasal Cancer; Squamous Non-small Cell Lung Cancer; Lung Cancer; Head and Neck Squamous Cell Carcinoma; Head and Neck Carcnimona; Head and Neck Cancer

Keywords

Pd-L1 Inhibitor; Valemetostat + pembrolizumab; Pembrolizumab; Valemetostat

Outcome Measures

Primary Outcomes (3)

• Phase II: Disease control rate (DCR)

  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)

  Study start until progression or 2 years after treatment initiation

• Phase Ib: Safety of valemetostat in combination with pembrolizumab

  Any toxicities that occur during timeframe.

  Study start-30 days after last dose of study agents

• Phase Ib: Recommended phase II dose (RP2D) of valemetostat in combination with pembrolizumab

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

  42 days

Secondary Outcomes (7)

• Pharmacokinetics of valemetostat in combination with pembrolizumab

  Phase Ib: C1D1, C1D8, C1D15, and C2D1Phase II: C0D1, C1D1, C1D8, C1D15, and C2D1

• 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.

• 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

• 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

• 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.

Study Arms (2)

Arm 1

EXPERIMENTAL

Pembrolizumab + de-escalating doses of valemetostat

Drug: pembrolizumab; Drug: valemetostat

Arm 2

EXPERIMENTAL

RP2D of valemetostat in combination with pembrolizumab

Drug: pembrolizumab; Drug: valemetostat

Interventions

pembrolizumab DRUG

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.

Arm 1; Arm 2

valemetostat DRUG

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.

Arm 1; Arm 2

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must have a diagnosis of one of the following types of cancer:
• Phase Ib (Part A):
• Histologically or cytologically confirmed locoregionally recurrent or metastatic (R/M) human papillomavirus (HPV)-negative\* or -positive\* squamous cell carcinoma of the head and neck: oral cavity, tonsil, pharynx, hypopharynx, larynx. Note: Nasopharyngeal carcinoma and cutaneous squamous cell carcinoma (SCC) are excluded.
• Histologically or cytologically confirmed R/M sinonasal carcinomas of the head and neck.
• Histologically confirmed R/M squamous non-small cell lung cancer (NSCLC).
• \*HPV status will be determined by history of p16 IHC staining conducted per standard of care.
• Phase II (Part B):
• Histologically or cytologically confirmed locoregionally R/M HPV-negative\* squamous cell carcinoma of the head and neck: oral cavity, tonsil, pharynx, hypopharynx, larynx. Note: Nasopharyngeal carcinoma and cutaneous SCC are excluded.
• \*HPV status will be determined by history of p16 IHC staining conducted per standard of care.
• PD-L1 combined positive score (CPS) \>= 1, confirmed by Food and Drug Administration (FDA) approved 22C3 PharmDx test.
• Phase Ib only: Participants may be na(SqrRoot) ve or refractory to pembrolizumab or other PD- L1/PD-1 checkpoint inhibitors and may have had any number of lines of systemic therapy.
• Phase II only: Participants must be pembrolizumab-naive and not have received PD- L1/PD-1 checkpoint inhibitors and must not have had prior lines of systemic chemotherapy or immunotherapy for recurrent or metastatic HNSCC.
• Age \>=18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status \<=2 (Phase Ib) or \<= 1 (Phase II).
• Participants must have adequate organ and marrow function as defined below:

You may not qualify if:

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to valemetostat or pembrolizumab used in the study.
• Prior curative radiation therapy or major surgery within 4 weeks or palliative radiation therapy within 2 weeks prior to the first dose of study drug(s).
• Prior systemic therapy (e.g., chemotherapy, immunomodulatory therapy, monoclonal antibody therapy, or investigational therapy) within 4 weeks, or 5 half-lives of the drug, whichever is longer, prior to the first dose of the study drug(s).
• History of previous treatment with EZH2 inhibition.
• Participants currently receiving any medications or substances that are moderate or strong inducers or moderate or strong inhibitors of cytochrome P450 (CYP3A).
• Participants currently receiving any medications or substances that are P-gp inhibitors (e.g., amiodarone, clarithromycin, diltiazem, erythromycin, ketoconazole, itraconazole, propafenone, quinidine, and verapamil).
• Consumption of foods and beverages that are strong CYP3A inhibitors or inducers (star fruit, Seville orange, Seville orange-containing foods and beverages, grapefruit, grapefruit-containing food or beverages) within 3 days prior to the first dose of study drug(s).
• Active immunosuppressive treatment equivalent to\>10 mg of prednisone daily. Note: Short-course systemic corticosteroids (e.g., prevention/treatment for transfusion reaction) or use for a non-cancer indication (e.g., adrenal replacement) is acceptable.
• Cardiovascular diseases with the following criteria:
• Evidence of prolongation of QT/corrected (QTc) interval (e.g., repeated episodes of QT corrected for heart rate using Fridericia s method \[QTcF\] \>470 ms regardless of sex) (average of triplicate determinations) at screening
• Diagnosed or suspected long QT syndrome, or known family history of long QT syndrome
• History of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or Torsade de pointes
• Uncontrolled arrhythmia (participants with asymptomatic, controllable atrial fibrillation may be enrolled), or asymptomatic persistent ventricular tachycardia at screening
• Participant has clinically relevant bradycardia of less than 50 bpm at screening unless the participant has a pacemaker
• History of second- or third-degree heart block. Candidates with a history of heart block may be eligible if they currently have pacemakers, and have no history of fainting or clinically relevant arrhythmia with pacemakers, within 6 months prior to treatment initiation

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Lung Neoplasms; Squamous Cell Carcinoma of Head and Neck; Head and Neck Neoplasms

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Study Officials

• Vassiliki Saloura, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 26, 2023
• First Posted: May 30, 2023
• Study Start: July 9, 2025
• Primary Completion: July 9, 2025
• Study Completion: July 9, 2025
• Last Updated: July 10, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. Genomic data are made available via dbGaP through requests to the data custodians.

Locations

US (1)