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

NCT ID: NCT04533750

Last Updated: 2026-02-02

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 21 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-12-20
• Study Completion Date: 2026-12-15

Brief 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. 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.

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.

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; 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 Hypopharyngeal Carcinoma AJCC v8; Stage IVA Laryngeal Cancer AJCC v8; Stage IVA Lip and Oral Cavity 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 Lip and Oral Cavity Cancer AJCC v8; Stage IVB Oropharyngeal (p16-Negative) Carcinoma AJCC v8

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Computed Tomography

Intervention Type: PROCEDURE

Undergo CT or PET/CT

Fludeoxyglucose F-18

Intervention Type: OTHER

Given IV

Intensity-Modulated Radiation Therapy

Intervention Type: RADIATION

Undergo IMRT

Magnetic Resonance Imaging

Intervention Type: PROCEDURE

Undergo MRI

Peposertib

Intervention Type: DRUG

Given PO

Positron Emission Tomography

Intervention Type: PROCEDURE

Undergo PET/CT

Interventions

Computed Tomography

Undergo CT or PET/CT

Intervention Type: PROCEDURE

Fludeoxyglucose F-18

Given IV

Intervention Type: OTHER

Intensity-Modulated Radiation Therapy

Undergo IMRT

Intervention Type: RADIATION

Magnetic Resonance Imaging

Undergo MRI

Intervention Type: PROCEDURE

Peposertib

Given PO

Intervention Type: DRUG

Positron Emission Tomography

Undergo PET/CT

Intervention Type: PROCEDURE

Other Intervention Names

CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized axial tomography (procedure); Computerized Tomography; Computerized Tomography (CT) scan; CT; CT Scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; tomography; 18FDG; FDG; Fludeoxyglucose (18F); fludeoxyglucose F 18; Fludeoxyglucose F18; Fluorine-18 2-Fluoro-2-deoxy-D-Glucose; Fluorodeoxyglucose F18; IMRT; Intensity modulated radiation therapy (procedure); Intensity Modulated RT; Intensity-Modulated Radiotherapy; Radiation, Intensity-Modulated Radiotherapy; Magnetic Resonance; Magnetic Resonance Imaging (MRI); Magnetic resonance imaging (procedure); Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI; MRI Scan; MRIs; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; sMRI; Structural MRI; 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; MSC2490484A; Nedisertib; Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron emission tomography (procedure); Positron Emission Tomography Scan; Positron-Emission Tomography; PT

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

NRG Oncology

OTHER

Sponsor Role: collaborator

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Maura L Gillison

Role: PRINCIPAL_INVESTIGATOR

NRG Oncology

Locations

Banner MD Anderson Cancer Center

Gilbert, Arizona, United States

Mayo Clinic Hospital in Arizona

Phoenix, Arizona, United States

Banner University Medical Center - Tucson

Tucson, Arizona, United States

University of Arizona Cancer Center-North Campus

Tucson, Arizona, United States

UC San Diego Moores Cancer Center

La Jolla, California, United States

Stanford Cancer Institute Palo Alto

Palo Alto, California, United States

University of Miami Miller School of Medicine-Sylvester Cancer Center

Miami, Florida, United States

Moffitt Cancer Center

Tampa, Florida, United States

Emory University Hospital Midtown

Atlanta, Georgia, United States

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, United States

Carle at The Riverfront

Danville, Illinois, United States

Carle Physician Group-Effingham

Effingham, Illinois, United States

Carle Physician Group-Mattoon/Charleston

Mattoon, Illinois, United States

Carle Cancer Center

Urbana, Illinois, United States

The James Graham Brown Cancer Center at University of Louisville

Louisville, Kentucky, United States

NYU Langone Hospital - Long Island

Mineola, New York, United States

Laura and Isaac Perlmutter Cancer Center at NYU Langone

New York, New York, United States

Highland Hospital

Rochester, New York, United States

University of Rochester

Rochester, New York, United States

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, United States

Providence Portland Medical Center

Portland, Oregon, United States

Medical University of South Carolina

Charleston, South Carolina, United States

Sanford Cancer Center Oncology Clinic

Sioux Falls, South Dakota, United States

Sanford USD Medical Center - Sioux Falls

Sioux Falls, South Dakota, United States

M D Anderson Cancer Center

Houston, Texas, United States

Inova Schar Cancer Institute

Fairfax, Virginia, United States

Countries

United States

Provided Documents

Document Type: Informed Consent Form

View Document

Other Identifiers

NCI-2020-06481

Identifier Type: REGISTRY

Identifier Source: secondary_id

NRG-HN008

Identifier Type: OTHER

Identifier Source: secondary_id

NRG-HN008

Identifier Type: OTHER

Identifier Source: secondary_id

U10CA180868

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2020-06481

Identifier Type: -

Identifier Source: org_study_id