Trial Title:
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
NCT ID:
NCT05879484
Condition:
Sinonasal Cancer
Squamous Non-small Cell Lung Cancer
Lung Cancer
Head and Neck Squamous Cell Carcinoma
Head and Neck Carcnimona
Head and Neck Cancer
Conditions: Official terms:
Carcinoma
Lung Neoplasms
Carcinoma, Squamous Cell
Squamous Cell Carcinoma of Head and Neck
Pembrolizumab
Conditions: Keywords:
Pd-L1 Inhibitor
Valemetostat + pembrolizumab
Pembrolizumab
Valemetostat
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
pembrolizumab
Description:
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 group label:
Arm 1
Arm group label:
Arm 2
Intervention type:
Drug
Intervention name:
valemetostat
Description:
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 group label:
Arm 1
Arm group label:
Arm 2
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.
Criteria for eligibility:
Criteria:
-INCLUSION CRITERIA:
1. 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.
OR
-Histologically or cytologically confirmed R/M sinonasal carcinomas of the head and
neck.
OR
-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.
2. PD-L1 combined positive score (CPS) >= 1, confirmed by Food and Drug Administration
(FDA) approved 22C3 PharmDx test.
3. 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.
4. 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.
5. Age >=18 years.
6. Eastern Cooperative Oncology Group (ECOG) performance status <=2 (Phase Ib) or <= 1
(Phase II).
7. Participants must have adequate organ and marrow function as defined below:
7.1 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <=3.0 X
upper limit of normal (ULN)
7.2 Total bilirubin <=1.5 X ULN. Note: Participants with Gilbert's syndrome may have
total bilirubin <3.0 mg/dL
7.3 Absolute neutrophil count (ANC) >=1.5 X 10^9/L
7.4 Hemoglobin (Hgb) >=8.5 g/dL
7.5 Platelet count >=75 X 10^9/L
7.6 Creatinine clearance >=60 mL/min (calculated by the Cockcroft-Gault equation).
8. Acute non-hematologic toxic effects (as evaluated by NCI Common Terminology Criteria
for Adverse Events (CTCAE), version 5.0 of any prior therapy (except alopecia)
resolved as shown below:
8.1 Peripheral motor neuropathy, Peripheral sensory neuropathy: Grade <=2
8.2 Fatigue: Grade <=2
8.3 All others: Grade <=1
9. Participants with treated brain metastases are eligible if follow-up brain imaging
after central nervous system (CNS)-directed therapy shows no evidence of progression
within 4 weeks before study treatment initiation.
10. Participants with new or progressive brain metastases (active brain metastases) or
leptomeningeal disease are eligible if the treating physician determines that
immediate CNS specific treatment is not required per Standard of Care.
11. Participants must have measurable disease by RECIST 1.1.
12. Human immunodeficiency virus (HIV)-infected participants on effective
anti-retroviral therapy with undetectable viral load are eligible for this trial.
13. For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV
viral load must be undetectable on suppressive therapy, if indicated. Participants
with a history of current HCV infection who are currently on treatment must have an
undetectable HCV viral load to be eligible.
14. Women of child-bearing potential (WOCBP) must agree to use a highly effective method
of contraception (hormonal, intrauterine device (IUD), surgical sterilization,
abstinence) for the duration of the study treatment and up to 4 months after the
last dose of the study drug(s).
A female is considered of childbearing potential following menarche and until
becoming postmenopausal (no menstrual period for a minimum of 12 months) unless
permanently sterile (undergone a hysterectomy, bilateral salpingectomy, or bilateral
oophorectomy) with surgery at least 1 month before the first dose of study drug(s)
or confirmed by follicle-stimulating hormone (FSH) test >40 mIU/mL and estradiol <40
pg/mL (<140 pmol/L).
Men must agree to use an effective method of contraception (barrier, surgical
sterilization, abstinence) for the duration of the study treatment and up to 4
months after the last dose of the study drug(s). We also will recommend men with
female partners of childbearing potential to ask female partners to be on highly
effective birth control (hormonal, intrauterine device (IUD), surgical
sterilization).
15. Female participants must not donate, or retrieve for their own use, ova from the
time of study treatment initiation and throughout the study treatment period, and
for at least 4 months after the final study drug(s) administration. Male
participants must not freeze or donate sperm within the same period.
16. Breastfeeding participants must be willing to discontinue breastfeeding from study
treatment initiation through 4 months after the last dose of the study drug(s).
17. Participants must have disease amenable for biopsies (not used for evaluation of
disease per RECIST 1.1) and be willing to undergo these biopsies (Phase II only).
18. The ability of a participant to understand and the willingness to sign a written
informed consent document.
EXCLUSION CRITERIA:
1. History of allergic reactions attributed to compounds of similar chemical or
biologic composition to valemetostat or pembrolizumab used in the study.
2. 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).
3. 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).
4. History of previous treatment with EZH2 inhibition.
5. Participants currently receiving any medications or substances that are moderate or
strong inducers or moderate or strong inhibitors of cytochrome P450 (CYP3A).
6. Participants currently receiving any medications or substances that are P-gp
inhibitors (e.g., amiodarone, clarithromycin, diltiazem, erythromycin, ketoconazole,
itraconazole, propafenone, quinidine, and verapamil).
7. 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).
8. 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.
9. Cardiovascular diseases with the following criteria:
9.1 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
9.2 Diagnosed or suspected long QT syndrome, or known family history of long QT
syndrome
9.3 History of clinically relevant ventricular arrhythmias, such as ventricular
tachycardia, ventricular fibrillation, or Torsade de pointes
9.4 Uncontrolled arrhythmia (participants with asymptomatic, controllable atrial
fibrillation may be enrolled), or asymptomatic persistent ventricular tachycardia at
screening
9.5 Participant has clinically relevant bradycardia of less than 50 bpm at screening
unless the participant has a pacemaker
9.6 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
9.7 Myocardial infarction within 6 months prior to treatment initiation
9.8 Angioplasty or stent graft implantation within 6 months prior to treatment
initiation
9.9 Uncontrolled angina pectoris within 6 months prior to treatment initiation
9.10 History of New York Heart Association (NYHA),
https://www.merckmanuals.com/professional/multimedia/table/new-york-heart-
association-nyha-classification-of-heart-failure) Class 3 or 4 congestive heart
failure
9.11 Coronary/peripheral artery bypass graft within 6 months prior to treatment
initiation
9.12 Uncontrolled hypertension (resting systolic blood pressure >180 mmHg or
diastolic blood pressure >110 mmHg) at screening
9.13 Complete left bundle branch block at screening
10. History of autoimmune disease with the exception of controlled thyroid disease,
psoriasis not requiring medications, vitiligo, and alopecia.
11. Prior malignancy active within the previous 2 years except for locally curable
cancer that is currently considered as cured and does not require additional
Standard of Care treatment, such as cutaneous basal or squamous cell carcinoma,
superficial bladder cancer, or cervical carcinoma in situ, or an incidental
histological finding of prostate cancer.
12. Ongoing uncontrolled systemic bacterial, fungal, or viral infection currently
requiring treatment with intravenous antibiotics, antivirals, or antifungals.
13. Pregnancy (confirmed with beta-human chorionic gonadotropin (beta-HCG) serum or
urine pregnancy test performed in females of childbearing potential at screening).
14. Uncontrolled intercurrent illness or situations that would limit compliance with
study requirements.
Gender:
All
Minimum age:
18 Years
Maximum age:
120 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
National Institutes of Health Clinical Center
Address:
City:
Bethesda
Zip:
20892
Country:
United States
Contact:
Last name:
National Cancer Institute Referral Office
Phone:
888-624-1937
Start date:
November 17, 2024
Completion date:
July 1, 2027
Lead sponsor:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
National Institutes of Health Clinical Center (CC)
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05879484
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_001545-C.html
