Advanced Head and Neck Squamous Cell CarcinomaPhase 1NCT04533750
Testing the Addition of M3814 (Peposertib) to Radiation Therapy for Patients With Advanced Head and Neck Cancer Who Cannot Take Cisplatin
A Phase 1 study testing Intensity-Modulated Radiation Therapy and Peposertib in people with Advanced Head and Neck Squamous Cell Carcinoma and Advanced Hypopharyngeal Squamous Cell Carcinoma, run by National Cancer Institute (NCI) at 27 sites in United States.
Trial summary
This phase I trial investigates the side effects and best dose of peposertib when given together with radiation therapy in treating patients with head and neck cancer that has spread to other places in the body (advanced) who cannot take cisplatin. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Advanced Head and Neck Squamous Cell Carcinoma, Advanced Hypopharyngeal Squamous Cell Carcinoma, Advanced Laryngeal Squamous Cell Carcinoma
- What is being tested?
- Intensity-Modulated Radiation Therapy and Peposertib
- Type of treatment
- Pill or oral medicine, Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 21 participants
- Where
- 27 sitesUnited States
- Study dates
- 20 Dec 2021to 15 Dec 2026
- Phase
- Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Pathologically (histologically) proven diagnosis of HNSCC of the oral cavity, oropharynx, larynx, or hypopharynx prior to registration;
- Patients with oropharynx cancer need p16 determination by immunohistochemistry (where positive is defined as greater than 70% strong nuclear or nuclear and cytoplasmic staining of tumor cells), Note: Institutions must screen patients using a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. A rigorous laboratory accreditation process similar to the United States (U.S.) CLIA certification, such as the provincial accreditation status offered by the Ontario Laboratory Accreditation (OLA) Program in Canada, the College of American Pathologists (CAP), or an equivalent accreditation in other countries, is acceptable. The p16 results must be reported on the pathology report being submitted;
- Oral cavity, larynx, hypopharynx, or p16-negative oropharynx cancer must be stages T1-2N2-3 or T3N1-3 or T4N0-3 (American Joint Committee on Cancer [AJCC] version 8);
- p16-positive oropharynx cancer patients, stages T4N0-3 or T1-3N2-3 (AJCC version 8);
- The patient has measurable disease as defined by the presence of at least one measurable lesion per RECIST 1.1;
- Please note: A histological or pathological specimen from cervical lymph nodes with well-defined primary site documented clinically or radiologically is acceptable
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- Clinical stage noted above should be based upon following diagnostic workup:
- History/physical examination within 30 days prior to registration;
- Examination by radiation oncologist or medical oncologist or otolaryngology (ENT) or head \& neck surgeon 30 days prior to registration, including fiber optic exam with laryngopharyngoscopy;
- Diagnostic quality computed tomography (CT) or magnetic resonance imaging (MRI) of neck, with contrast, within 30 days prior to registration. Fludeoxyglucose F-18 (18F-FDG) whole body positron emission tomography (PET)-CT scan within 42 days of registration is strongly recommended but does not replace the CT or MRI study. Note: If CT component of the PET/CT is of diagnostic quality then PET/CT can be used for eligibility, however the PET/CT scan must be done within 30 days prior to registration
- Diagnostic quality, cross sectional imaging of the thorax within 42 days prior to registration; 18-F-FDG-PET/CT or conventional CT are acceptable
- Age >= 18 years
- Patients must have a contraindication to cisplatin as defined in the following bullet points. Sites must complete the online tool at comogram.org prior to registration to determine if the patient is eligible. The scores must be recorded on a case report form (CRF). (Refer to data submission table on the NRG-HN008 protocol page on the NRG website);
- Age >= 70 with moderate to severe comorbidity, defined as having one or more of the following conditions within 30 days prior to registration;
- Modified Charlson Comorbidity Index >= 1
- Adult Comorbidity Evaluation (ACE)-27 Index >= 1
- Omega score < 0.80
- G-8 score =< 14
- Cancer and Aging Research Group (CARG) Toxicity Score >= 30%
- Cumulative Illness Rating Scale for Geriatrics (CIRS-G) Score >= 4 OR
- Age < 70 with severe comorbidity, defined as having two or more of the following conditions within 30 days prior to registration;
- Modified Charlson Comorbidity Index >= 1
- ACE-27 Index >= 1
- Omega score < 0.80
- G-8 score =< 14
- CARG Toxicity Score >= 30%
- CIRS-G Score >= 4 OR
- Age >= 18 with an absolute or relative contraindication to cisplatin, defined as one or more of the following criterion within 30 days prior to registration:
- Pre-existing peripheral neuropathy grade >= 1;
- Creatinine clearance (CrCl) must be > 30 and < 60 mL/min
- For this calculation, use the Cockcroft-Gault formula
- History of hearing loss, defined as either:
- Existing need of a hearing aid OR
- >= 25 decibel shift over 2 contiguous frequencies on a pretreatment hearing test as clinically indicated
- Zubrod Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 within 30 days prior to registration
- Whole blood cell (WBC) >= 2000 cells/mm^3 (within 30 days prior to registration)
- Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (within 30 days prior to registration)
- Platelets >= 100,000 cells/mm^3 (within 30 days prior to registration)
- Hemoglobin >= 9.0 g/dL (within 30 days prior to registration); Note: The use of transfusion is acceptable
- Creatinine clearance (CrCl) > 30 mL/min (within 30 days prior to registration)
- Total bilirubin =< 1.5 x upper limit of normal (ULN) (except patients with Gilbert syndrome who can have total bilirubin < 3.0 mg/dL) (within 30 days prior to registration)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (within 30 days prior to registration)
- For women of child bearing potential (e.g. uterus present and menstruating), a negative serum pregnancy test within 14 days prior to registration. Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL
- The patient must provide study-specific informed consent prior to study entry
- Known human immunodeficiency virus (HIV) infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months and CD4 T cell count >= 200 are eligible for this trial. Testing is not required for entry into protocol
- Patients with a history of hepatitis B or C infection are eligible if they have an undetectable viral load
- Willing to use highly effective contraceptives for males and females of childbearing potential during therapy and for 12 weeks after the last dose of M3814 (peposertib); this inclusion is necessary because the treatment in this study may be significantly teratogenic
- Patients must be able to swallow whole tablets
Who cannot join
- Definitive clinical or radiologic evidence of distant (beyond cervical lymph node and neck tissue) metastatic disease
- Carcinoma of the neck of unknown primary site origin
- Patients with oral cavity cancer are excluded from participation if the patient is medically operable and the resection of the primary tumor is considered technically feasible by an oral or head and neck cancer surgical subspecialist
- Gross total excision of both primary and nodal disease; this includes tonsillectomy, local excision of primary site, and nodal excision that removes all clinically and radiographically evident disease
- Note: Patients with RECIST, version (v.) 1.1 evaluable remaining cancer either in the neck or primary site remain eligible
- Prior invasive malignancy (except non-melanomatous skin cancer carcinoma, in situ of the breast, oral cavity, or cervix, low or very low-risk prostate cancer) unless disease free for a minimum of 3 years
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- Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable if not within =< 3 years
- Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
- Severe, active co-morbidity defined as follows:
- History of bone marrow transplant and organ transplant, including allogenic stem cell transplantation;
- Unstable angina requiring hospitalization in the last 6 months;
- New York Heart Association Functional classification III/IV (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.);
- Myocardial infarction within the last 6 months;
- Persistent grade 3-4 (Common Terminology Criteria for Adverse Events [CTCAE] version 5.0) electrolyte abnormalities that cannot be reversed despite as indicated by repeat testing;
- Ongoing active infection that is associated with symptoms and/or requires antibiotic therapy at the time of registration (excluding asymptomatic bacteriuria, genital herpes, oral herpes, thrush, bacterial vaginosis, vaginal candidiasis, topical antifungals)
- Pregnancy and nursing females, if applicable
- Concomitant use of proton pump inhibitors (or unable to stop 5 days prior to treatment)
- Receipt of live vaccinations within 28 days prior to registration
- Patients unable to discontinue medications or substances that are:
- Strong inhibitors, inducers or sensitive substrates of CYP3A4/5, CYP2C19, or CYP2C9 prior to study treatment;
- Substrates of CYP1A2, CYP2B6, or CYP3A4/5 with a narrow therapeutic prior to study treatment;
- Note: Opioids are allowed, with the exception of methadone
- Fridericia's correction formula (QTcF) > 450 ms for males and > 470 ms for females
Trial locations and contacts
27 sites in 1 country.
27 sites in 1 country
United States27 sites
Emory University Hospital Midtown
Atlanta, Georgia, 30308
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, 30322
Medical University of South Carolina
Charleston, South Carolina, 29425
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
Carle at The Riverfront
Danville, Illinois, 61832
Carle Physician Group-Effingham
Effingham, Illinois, 62401
Inova Schar Cancer Institute
Fairfax, Virginia, 22031
Banner MD Anderson Cancer Center
Gilbert, Arizona, 85234
UT MD Anderson Cancer Center
Houston, Texas, 77030
UC San Diego Moores Cancer Center
La Jolla, California, 92093
The James Graham Brown Cancer Center at University of Louisville
Louisville, Kentucky, 40202
Carle Physician Group-Mattoon/Charleston
Mattoon, Illinois, 61938
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, 33136
NYU Langone Hospital - Long Island
Mineola, New York, 11501
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York, New York, 10016
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104
Stanford Cancer Institute Palo Alto
Palo Alto, California, 94304
Mayo Clinic Hospital in Arizona
Phoenix, Arizona, 85054
Providence Portland Medical Center
Portland, Oregon, 97213
Highland Hospital
Rochester, New York, 14620
University of Rochester
Rochester, New York, 14642
Sanford Cancer Center Oncology Clinic
Sioux Falls, South Dakota, 57104
Sanford USD Medical Center - Sioux Falls
Sioux Falls, South Dakota, 57117-5134
Moffitt Cancer Center
Tampa, Florida, 33612
Banner University Medical Center - Tucson
Tucson, Arizona, 85719
University of Arizona Cancer Center-North Campus
Tucson, Arizona, 85719
Carle Cancer Center
Urbana, Illinois, 61801
About this study
Official title: Phase I Trial With Expansion Cohort of DNA-PK Inhibition and IMRT in Cisplatin-Ineligible Patients With Stage 3-4 Local-Regionally Advanced Head and Neck Squamous Cell Carcinoma (HNSCC)
This phase I trial investigates the side effects and best dose of peposertib when given together with radiation therapy in treating patients with head and neck cancer that has spread to other places in the body (advanced) who cannot take cisplatin. Peposertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. This trial aims to see whether adding peposertib to radiation therapy is safe and works well in treating patients with head and neck cancer.
Read the detailed description
PRIMARY OBJECTIVE:
- To determine the recommended phase 2 dose (RP2D) of M3814 (peposertib) when given in combination with intensity-modulated radiation therapy (IMRT).
SECONDARY OBJECTIVES:
- To evaluate the safety and tolerability of the combination of M3814 (peposertib) with radiotherapy.
II. To estimate the rates of grade 3 or greater acute toxicities of the regimen.
III. To estimate late toxicities of the regimen. IV. To evaluate the clinical response rate, based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, at 3 months post completion of radiotherapy.
- To estimate 6 and 12-month progression-free survival (PFS) in the dose expansion cohort (DEC).
VI. To estimate 6 and 12-month overall survival (OS) in the DEC.
EXPLORATORY OBJECTIVE:
- To estimate the pharmacokinetic (PK) parameter of M3814 (peposertib) using population PK approaches.
OUTLINE: This is a dose-escalation study of peposertib.
Dose Level -1:
Beginning 60-90 minutes before each radiation treatment, patients receive oral peposertib 50 mg once daily and undergo IMRT 70 Gy in 35 fractions over 7 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT), magnetic resonance imaging (MRI), or receive fludeoxyglucose F-18 (18F-FDG) intravenously (IV) and undergo positron emission tomography (PET)/CT during screening and follow-up.
Dose Level 1:
Beginning 60-90 minutes before each radiation treatment, patients receive oral peposertib 100 mg once daily and undergo IMRT 70 Gy in 35 fractions over 7 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, or receive 18F-FDG IV and undergo PET/CT during screening and follow-up.
Dose Level 2:
Beginning 60-90 minutes before each radiation treatment, patients receive oral peposertib 150 mg once daily and undergo IMRT 70 Gy in 35 fractions over 7 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, or receive 18F-FDG IV and undergo PET/CT during screening and follow-up.
Dose Level 3:
Beginning 60-90 minutes before each radiation treatment, patients receive oral peposertib 200 mg once daily and undergo IMRT 70 Gy in 35 fractions over 7 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, or receive 18F-FDG IV and undergo PET/CT during screening and follow-up.
Dose Level 4:
Beginning 60-90 minutes before each radiation treatment, patients receive oral peposertib 250 mg once daily and undergo IMRT 70 Gy in 35 fractions over 7 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, or receive 18F-FDG IV and undergo PET/CT during screening and follow-up.
After completion of treatment, patients are followed up every 3 months for 2 years.
- Conditions
- Advanced Head and Neck Squamous Cell Carcinoma, Advanced Hypopharyngeal Squamous Cell Carcinoma, Advanced Laryngeal Squamous Cell Carcinoma, Advanced Oral Cavity Squamous Cell Carcinoma, Advanced Oropharyngeal Squamous Cell Carcinoma, Clinical Stage III HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8
- Being tested
- Intensity-Modulated Radiation Therapy, Peposertib
- Medical subject headings
- Oropharyngeal Neoplasms, Hypopharyngeal Neoplasms, Laryngeal Neoplasms, Mouth Neoplasms, Carcinoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Intensity-Modulated Radiation TherapyRadiation
Also called IMRT, Intensity modulated radiation therapy (procedure), Intensity Modulated RT, Intensity-Modulated Radiotherapy
Undergo IMRT
PeposertibDrug
Also called 3-Pyridazinemethanol, alpha-(2-Chloro-4-fluoro-5-(7-(4-morpholinyl)-4-quinazolinyl)phenyl)-6-methoxy-, (alphaS)-, M 3814, M-3814, M3814
Given PO
| Study group | Role | What they receive |
|---|---|---|
| Peposertib 100 mg + IMRT (DL1) | Experimental | Beginning 60-90 minutes before each radiation treatment, patients receive oral peposertib 100 mg once daily and undergo IMRT 70 Gy in 35 fractions over 7 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, or receive 18F-FDG IV and undergo PET/CT during screening and follow-up. Receives: Radiation: Intensity-Modulated Radiation Therapy; Drug: Peposertib |
| Peposertib 150 mg + IMRT (DL2) | Experimental | Beginning 60-90 minutes before each radiation treatment, patients receive oral peposertib 150 mg once daily and undergo IMRT 70 Gy in 35 fractions over 7 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, or receive 18F-FDG IV and undergo PET/CT during screening and follow-up. Receives: Radiation: Intensity-Modulated Radiation Therapy; Drug: Peposertib |
| Peposertib 200 mg + IMRT (DL3) | Experimental | Beginning 60-90 minutes before each radiation treatment, patients receive oral peposertib 200 mg once daily and undergo IMRT 70 Gy in 35 fractions over 7 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, or receive 18F-FDG IV and undergo PET/CT during screening and follow-up. Receives: Radiation: Intensity-Modulated Radiation Therapy; Drug: Peposertib |
| Peposertib 250 mg + IMRT (DL4) | Experimental | Beginning 60-90 minutes before each radiation treatment, patients receive oral peposertib 250 mg once daily and undergo IMRT 70 Gy in 35 fractions over 7 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, or receive 18F-FDG IV and undergo PET/CT during screening and follow-up. Receives: Radiation: Intensity-Modulated Radiation Therapy; Drug: Peposertib |
| Peposertib 50mg + IMRT (DL -1) | Experimental | Beginning 60-90 minutes before each radiation treatment, patients receive oral peposertib 50 mg once daily and undergo IMRT 70 Gy in 35 fractions over 7 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, or receive 18F-FDG IV and undergo PET/CT during screening and follow-up. Receives: Radiation: Intensity-Modulated Radiation Therapy; Drug: Peposertib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of participants who experienced Dose-limiting toxicities (DLTs)
DLT was defined as any Grade 3 or higher adverse event definitely or probably related to peposertib or radiotherapy, excluding Grade 3 mucositis, Grade 3 radiation dermatitis, isolated Grade 3-4 asymptomatic lymphocytopenia, Grade 3 nausea or vomiting of <3 days duration with adequate therapy, Grade 3 fatigue, Grade 3 dysphagia, Grade 3 pain within the radiation field, Grade 3 asymptomatic amylase elevation, and other clinically insignificant laboratory abnormalities, or inability to complete at least 80% of the planned radiotherapy dose or radiotherapy delay >1 week due to adverse events definitely or probably related to peposertib.
Measured: From start of treatment through 4 weeks after completion of radiotherapy (approximately 11 weeks)
Maximum tolerable dose (MTD)
MTD was determined using a Bayesian Optimal Interval (BOIN) dose-escalation design based on the occurrence of dose-limiting toxicities (DLTs).
Measured: From start of treatment through 4 weeks after completion of radiotherapy (approximately 11 weeks)
Secondary outcomes (5)
Number of Participants by Highest Grade Acute Adverse Event Reported
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grades adverse event severity as follows: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death related to adverse event. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.
Measured: From start of treatment through 90 days after completion of radiotherapy (approximately 11 weeks)
Number of Participants by Highest Grade Late Adverse Event Reported
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grades adverse event severity as follows: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death related to adverse event. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.
Measured: From 91 days through 2 years after completion of radiotherapy (approximately 11 weeks)
Clinical response rate
Clinical response rate is defined as the proportion of participants achieving a complete or partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
Measured: 3 months after completion of IMRT (approximately 11 weeks)
6-Month and 1-Year Progression-free survival (PFS) rates at 6 months and one year
A PFS event was defined as locoregional failure, distant metastasis, or death due to any cause. Progressive disease was defined according to RECIST v1.1 criteria. PFS rates were estimated using the Kaplan-Meier method. Participants without a PFS event were censored at the date last known progression-free. Confidence intervals were calculated using a log-log transformation.
Measured: 6 months and 1 year after completion of IMRT
6-Month and 1-Year Overall survival (OS) rates
Survival rates were estimated using the Kaplan-Meier method. Participants alive at last known follow-up were censored. Confidence intervals were calculated using a log-log transformation.
Measured: 6 months and 1 year after completion of IMRT (approximately 11 weeks)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Sep 2020
- Study start20 Dec 2021
- Primary completion7 Dec 2025
- Study completion15 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Advanced Head and Neck Squamous Cell CarcinomaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 21 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Collaborators
- NRG Oncology
- Responsible party
- Sponsor
- Investigators
- Maura L Gillison, Principal investigator, NRG Oncology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04533750
- Sponsor's protocol ID
- NCI-2020-06481
- Other IDs
- NCI-2020-06481, NRG-HN008, NRG-HN008, U10CA180868
- Status last verified
- Jun 2026
- First submitted
- 29 Aug 2020
- Last updated
- 13 Oct 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.