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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.

Computed Tomography

Fludeoxyglucose F-18

Intensity-Modulated Radiation Therapy

Magnetic Resonance Imaging

Positron Emission Tomography

Site Public Contact

Michael A. Samuels

Ricklie A. Julian

Loren K. Mell

Stuart E. Samuels

Jimmy J. Caudell

Soumon Rudra

Prem Sobti

Rebecca A. Redman

Zujun Li

Yuhchyau Chen

Minh Phan

Nitya Alluri

Daniel Almquist

John F. Deeken

Maura L Gillison

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.

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.

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)

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.

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.

Will be as measured by Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0

Will be assessed by Response Evaluation Criteria in Solid Tumors 1.1.

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.

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.

NRG Oncology

National Cancer Institute (NCI)

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NON-OPC/p16-NEGATIVE OPC: Patients undergo radiation therapy over 5 fractions a week for a total of 33-35 fractions in the absence of disease progression or unacceptable toxicity. Patients also receive high-dose cisplatin IV Q3W (on days 1, 22, and 43) during radiation therapy in the absence of disease progression or unacceptable toxicity.

NON-OPC/p16-NEGATIVE OPC: Patients undergo radiation therapy over 5 fractions a week for a total of 33-35 fractions in the absence of disease progression or unacceptable toxicity. Patients also receive low-dose cisplatin IV QW during radiation therapy in the absence of disease progression or unacceptable toxicity.

p16-POSITIVE OPC/CUP: Patients undergo radiation therapy over 5 fractions a week for a total of 33-35 fractions in the absence of disease progression or unacceptable toxicity. Patients also receive high-dose cisplatin IV Q3W (on days 1, 22, and 43) during radiation therapy in the absence of disease progression or unacceptable toxicity.

p16-POSITIVE OPC/CUP: Patients undergo radiation therapy over 5 fractions a week for a total of 33-35 fractions in the absence of disease progression or unacceptable toxicity. Patients also receive low-dose cisplatin IV QW during radiation therapy in the absence of disease progression or unacceptable toxicity.

Quality-of-Life Assessment

Questionnaire Administration

Radiation Therapy

Furhan Yunus

Aleksandar Jankov

Mausam Patel

Gary L. Buchschacher

Jennifer M. Suga

Christopher U. Jones

Zachary S. Zumsteg

Shahzad Siddique

Shyam S. Rao

Beth M. Beadle

Jason Chan

Alexander Menter

Karng S. Log

Yuan J. Rao

Coral Olazagasti

Ryan J. Burri

Christine H. Chung

Sharad A. Ghamande

Tanmay Sahai

Bryan A. Faller

Thomas E. Lad

Alec M. Block

Paul M Harari

This phase II/III trial compares the effect of the combination of high-dose cisplatin every three weeks and radiation therapy versus low-dose cisplatin weekly and radiation therapy for the treatment of patients with locoregionally advanced head and neck cancer. Chemotherapy drugs, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. This study is being done to find out if low-dose cisplatin given weekly together with radiation therapy is the same or better than high-dose cisplatin given every 3 weeks together with radiation therapy in treating patients with head and neck cancer.

PRIMARY OBJECTIVES:

I. To determine whether radiation with low-dose cisplatin weekly is superior in terms of acute toxicity, as measured by the T-scores (TAME method), to radiation with high-dose cisplatin every 3 weeks for patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). (Phase II) II. To determine whether radiation with low-dose cisplatin weekly is non-inferior to radiation with high-dose cisplatin every 3 weeks in terms of overall survival (OS) for patients with locoregionally advanced SCCHN. (Phase III) III. To determine whether radiation with low-dose cisplatin weekly is superior in terms of acute toxicity, as measured by the T-scores (TAME method), to radiation with high-dose cisplatin every 3 weeks for patients with locoregionally advanced SCCHN. (Phase III)

SECONDARY OBJECTIVES:

I. To assess and compare progression-free survival (PFS) between arms. II. To assess and compare locoregional failure and distant metastasis between arms .

III. To assess acute and late toxicity (Common Terminology Criteria for Adverse Events \[CTCAE\] version 5.0).

IV. To assess patient-reported outcomes quality of life (PRO/QOL), as measured by the Functional Assessment of Cancer Therapy-Head and Neck (FACT-H\&N) (primary PRO), between arms.

V. To assess hearing loss, as measured by audiograms and the modified TUNE grading scale between arms.

VI. To assess hearing loss, as measured by speech audiometry Consonant-Nucleus-Consonant word scores and tympanometry (subject to the modified TUNE grading scale testing results; otherwise, it will be an exploratory objective).

VII. To assess hearing-related QOL as measured by the Hearing Handicap Inventory-Screening (HHIA-S) (secondary PRO), between arms.

EXPLORATORY OBJECTIVE:

I. To collect blood and tissue specimens for future translational science studies. For instance, to examine how germline and somatic genetic variants, such as TP53, CDKN2A, PIK3CA, PTEN, NFE2L2, and KEAP1, may influence cisplatin-related efficacy and toxicity, and to assess the effect of regular nonsteroidal anti-inflammatory drugs (NSAIDs) use and genomic activation of PIK3CA (mutation or amplification) or loss of PTEN, the negative regulator of PI3K, on disease-free survival or overall survival.

OUTLINE: Patients are assigned to 1 of 2 groups.

GROUP I (NON-OROPHARYNGEAL CANCER \[OPC\]/p16-NEGATIVE OPC): Patients are randomized to 1 of 2 arms.

ARM I: Patients undergo radiation therapy over 5 fractions a week for a total of 33-35 fractions in the absence of disease progression or unacceptable toxicity. Patients also receive high-dose cisplatin intravenously (IV) once every 3 weeks (Q3W) (on days 1, 22, and 43) during radiation therapy in the absence of disease progression or unacceptable toxicity.

ARM II: Patients undergo radiation therapy over 5 fractions a week for a total of 33-35 fractions in the absence of disease progression or unacceptable toxicity. Patients also receive low-dose cisplatin IV once a week (QW) during radiation therapy in the absence of disease progression or unacceptable toxicity.

GROUP II (p16-POSITIVE OPC/CANCER OF UNKNOWN PRIMARY \[CUP\]): Patients are randomized to 1 of 2 arms.

ARM III: Patients undergo radiation therapy over 5 fractions a week for a total of 33-35 fractions in the absence of disease progression or unacceptable toxicity. Patients also receive high-dose cisplatin IV Q3W (on days 1, 22, and 43) during radiation therapy in the absence of disease progression or unacceptable toxicity.

ARM IV: Patients undergo radiation therapy over 5 fractions a week for a total of 33-35 fractions in the absence of disease progression or unacceptable toxicity. Patients also receive low-dose cisplatin IV QW during radiation therapy in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 1 month, every 3 months during year 1-2, every 6 months during year 3-5, then annually thereafter.

Comparing High-Dose Cisplatin Every Three Weeks to Low-Dose Cisplatin Weekly When Combined With Radiation for Patients With Advanced Head and Neck Cancer

Randomized Phase II/III Trial of Radiation With High-Dose Cisplatin (100 mg/m2) Every Three Weeks Versus Radiation With Low-Dose Weekly Cisplatin (40 mg/m2) for Patients With Locoregionally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN)

OS rates will be estimated using the Kaplan-Meier method.

PFS rates will be estimated using the Kaplan-Meier method and between-arm differences compared using the log-rank test with a two-sided alpha of 0.05 (Kaplan 1958).

Measured by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.

Measured by Hearing Handicap Inventory for Adults-Screening.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Testing the Addition of M3814 (Peposertib) to Radiation Therapy for Patients With Advanced Head and Neck Cancer Who Cannot Take Cisplatin	NCT04533750	Advanced Head a... Advanced Hypoph... Advanced Laryng... Advanced Oral C... Advanced Oropha... Clinical Stage ... Stage III Hypop... Stage III Laryn... Stage III Lip a... Stage III Oroph... Stage IVA Hypop... Stage IVA Laryn... Stage IVA Lip a... Stage IVA Oroph... Stage IVB Hypop... Stage IVB Laryn... Stage IVB Lip a... Stage IVB Oroph...	Computed Tomogr... Fludeoxyglucose... Intensity-Modul... Magnetic Resona... Peposertib Positron Emissi...	18 Years -	National Cancer Institute (NCI)
Testing the Addition of M3814 (Peposertib) to Radiation Therapy for Patients With Advanced Head and Neck Cancer Who Cannot Take Cisplatin	NCT04533750	Advanced Head a... Advanced Hypoph... Advanced Laryng... Advanced Oral C... Advanced Oropha... Clinical Stage ... Stage III Hypop... Stage III Laryn... Stage III Lip a... Stage III Oroph... Stage IVA Hypop... Stage IVA Laryn... Stage IVA Lip a... Stage IVA Oroph... Stage IVB Hypop... Stage IVB Laryn... Stage IVB Lip a... Stage IVB Oroph...	Computed Tomogr... Fludeoxyglucose... Intensity-Modul... Magnetic Resona... Peposertib Positron Emissi...	18 Years -	National Cancer Institute (NCI)
Comparing High-Dose Cisplatin Every Three Weeks to Low-Dose Cisplatin Weekly When Combined With Radiation for Patients With Advanced Head and Neck Cancer	NCT05050162	Advanced Head a... Advanced Hypoph... Advanced Laryng... Advanced Oropha... Squamous Cell C...	Cisplatin Cisplatin Quality-of-Life... Questionnaire A... Radiation Thera...	18 Years -	NRG Oncology

Spots Global Cancer Trial Database for advanced hypopharyngeal squamous cell carcinoma