Testing the Addition of M3814 (Peposertib) to Radiation Therapy for Patients With Advanced Head and Neck Cancer Who Cannot Take Cisplatin

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Clinical Stage III HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8; Stage III Hypopharyngeal Carcinoma AJCC v8; Stage III Laryngeal Cancer AJCC v8; Stage III Lip and Oral Cavity Cancer AJCC v8; Stage III Oropharyngeal (p16-Negative) Carcinoma AJCC v8; Stage IVA Lip and Oral Cavity Cancer AJCC v8; Advanced Head and Neck Squamous Cell Carcinoma; Stage IVA Hypopharyngeal Carcinoma AJCC v8; Stage IVA Laryngeal Cancer AJCC v8; Stage IVA Oropharyngeal (p16-Negative) Carcinoma AJCC v8; Stage IVB Hypopharyngeal Carcinoma AJCC v8; Stage IVB Laryngeal Cancer AJCC v8; Stage IVB Oropharyngeal (p16-Negative) Carcinoma AJCC v8; Stage IVB Lip and Oral Cavity Cancer AJCC v8; Advanced Hypopharyngeal Squamous Cell Carcinoma; Advanced Laryngeal Squamous Cell Carcinoma; Advanced Oral Cavity Squamous Cell Carcinoma; Advanced Oropharyngeal Squamous Cell Carcinoma
• Intervention / Treatment: Procedure: Magnetic Resonance Imaging; Radiation: Intensity-Modulated Radiation Therapy; Procedure: Positron Emission Tomography; Drug: Peposertib; Other: Fludeoxyglucose F-18; Procedure: Computed Tomography

Detailed Description

PRIMARY OBJECTIVE:

I. To determine the recommended phase 2 dose (RP2D) of M3814 (peposertib) when given in combination with intensity-modulated radiation therapy (IMRT).

SECONDARY OBJECTIVES:

I. 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.

V. 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:

I. To estimate the pharmacokinetic (PK) parameter of M3814 (peposertib) using population PK approaches.

OUTLINE: This is a dose-escalation study of peposertib.

Beginning 60-90 minutes before each radiation treatment, patients receive peposertib orally (PO) once daily (QD) and undergo IMRT daily Monday-Friday for 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.

After completion of treatment, patients are followed up every 3 months for 2 years.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Banner MD Anderson Cancer Center
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Hospital in Arizona
    • Tucson, Arizona, United States, 85719
      • Banner University Medical Center - Tucson
    • Tucson, Arizona, United States, 85719
      • University of Arizona Cancer Center-North Campus
  • California
    • La Jolla, California, United States, 92093
      • UC San Diego Moores Cancer Center
    • Palo Alto, California, United States, 94304
      • Stanford Cancer Institute Palo Alto
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine-Sylvester Cancer Center
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Emory University Hospital Midtown
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital/Winship Cancer Institute
  • Illinois
    • Danville, Illinois, United States, 61832
      • Carle at The Riverfront
    • Effingham, Illinois, United States, 62401
      • Carle Physician Group-Effingham
    • Mattoon, Illinois, United States, 61938
      • Carle Physician Group-Mattoon/Charleston
    • Urbana, Illinois, United States, 61801
      • Carle Cancer Center
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • The James Graham Brown Cancer Center at University of Louisville
  • New York
    • Mineola, New York, United States, 11501
      • NYU Langone Hospital - Long Island
    • New York, New York, United States, 10016
      • Laura and Isaac Perlmutter Cancer Center at NYU Langone
    • Rochester, New York, United States, 14642
      • University of Rochester
    • Rochester, New York, United States, 14620
      • Highland Hospital
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Portland Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57117-5134
      • Sanford USD Medical Center - Sioux Falls
    • Sioux Falls, South Dakota, United States, 57104
      • Sanford Cancer Center Oncology Clinic
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Inova Schar Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

• 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

Exclusion Criteria:

• 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
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (peposertib, IMRT); Beginning 60-90 minutes before each radiation treatment, patients receive peposertib PO QD and undergo IMRT daily Monday-Friday for 7 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, or 18F-FDG PET/CT during screening and follow-up.

Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Radiation: Intensity-Modulated Radiation Therapy; Undergo IMRT; Other Names: IMRT; Intensity Modulated RT; Intensity-Modulated Radiotherapy; Radiation, Intensity-Modulated Radiotherapy; Intensity modulated radiation therapy (procedure); Procedure: Positron Emission Tomography; Undergo PET/CT; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; PT; Positron emission tomography (procedure); Drug: Peposertib; Given PO; Other Names: MSC2490484A; 3-Pyridazinemethanol, alpha-(2-Chloro-4-fluoro-5-(7-(4-morpholinyl)-4-quinazolinyl)phenyl)-6-methoxy-, (alphaS)-; M 3814; M-3814; M3814; MSC 2490484A; MSC-2490484A; Nedisertib; Other: Fludeoxyglucose F-18; Given IV; Other Names: 18FDG; FDG; fludeoxyglucose F 18; Fludeoxyglucose (18F); Fludeoxyglucose F18; Fluorine-18 2-Fluoro-2-deoxy-D-Glucose; Fluorodeoxyglucose F18; Procedure: Computed Tomography; Undergo CT or PET/CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Dose-limiting toxicity	Up to 28 days after the end of intensity-modulated radiation therapy (IMRT)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of acute toxicity	Will be as measured by Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0	Up to 3 months from IMRT completion
Incidence of late toxicity	Will be as measured by CTCAE v5.0.	More than 3 months from IMRT completion for up to 2 years
Clinical response rate	Will be assessed by Response Evaluation Criteria in Solid Tumors 1.1.	At 3 months post completion of IMRT
Progression-free survival (PFS) rates	Will be estimated using the Kaplan-Meier (K-M) method (Kaplan and Meier 1958). Point estimates of the PFS at 6 months and 1 year post-IMRT along with their 95% confidence intervals after using a log-log transformation will be calculated using the K-M curves.	At 6 months and 1 year
Overall survival (OS) rates	Will be estimated using the Kaplan-Meier (K-M) method (Kaplan and Meier 1958). Point estimates of the OS at 6 months and 1 year post-IMRT along with their 95% confidence intervals after using a log-log transformation will be calculated using the K-M curves.	At 6 months and 1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic (PK) parameter of M3814 (peposertib)	Plasma PK values will be estimated in the context of the Merck popPK model at the end of the trial and reported as such. PK-outcome relationships may be assessed in an exploratory fashion.	Within 30 minutes before administration, 2 hours and 4 hours after administration on day 1 of weeks 1 and 2

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Collaborators: NRG Oncology
• Investigators: Principal Investigator: Maura L Gillison, NRG Oncology

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2021
• Primary Completion (Actual): December 7, 2025
• Study Completion (Estimated): December 15, 2026

Study Registration Dates

• First Submitted: August 29, 2020
• First Submitted That Met QC Criteria: August 29, 2020
• First Posted (Actual): September 1, 2020

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 9, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mouth Diseases; Stomatognathic Diseases; Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Otorhinolaryngologic Diseases; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Pharyngeal Diseases; Laryngeal Diseases; Carcinoma; Laryngeal Neoplasms; Mouth Neoplasms; Oropharyngeal Neoplasms; Hypopharyngeal Neoplasms; Investigative Techniques; Therapeutics; Carbohydrates; Chemistry Techniques, Analytical; Spectrum Analysis; Radiotherapy; Deoxyglucose; Deoxy Sugars; Radiotherapy, Conformal; Radiotherapy, Computer-Assisted; Fluorodeoxyglucose F18; Magnetic Resonance Spectroscopy; Radiotherapy, Intensity-Modulated; peposertib
• Other Study ID Numbers: NCI-2020-06481 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA180868 (U.S. NIH Grant/Contract); NRG-HN008 (Other Identifier: CTEP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No