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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04533750
Recruitment Status : Not yet recruiting
First Posted : September 1, 2020
Last Update Posted : November 6, 2020
Sponsor:
Collaborator:
NRG Oncology
Information provided by (Responsible Party):
National Cancer Institute (NCI)

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.

Condition or disease Intervention/treatment Phase
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 Pathologic 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 Radiation: Intensity-Modulated Radiation Therapy Drug: Peposertib Phase 1

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 (to 28 days post end of radiotherapy) 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 OBJECTIVES:

I. To assess whether the tumor mutational burden (TMB), EAp53 status (p53 mutational status), mutation status for genes commonly mutated in neck and head squamous cell carcinoma (HNSCC), and deoxyribonucleic acid (DNA) repair pathway alterations determined by targeted exome sequencing of pre-treatment biopsy specimens evaluated are associated with treatment response to DNA-protein kinase (PK) inhibitor, M3814 (peposertib) and progression-free survival.

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

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

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.

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Estimated Study Start Date : January 4, 2021
Estimated Primary Completion Date : July 24, 2023
Estimated Study Completion Date : July 24, 2023


Arm Intervention/treatment
Experimental: Treatment (peposertib, IMRT)
Patients receive peposertib PO QD and undergo IMRT daily Monday-Friday for 7 weeks in the absence of disease progression or unacceptable toxicity.
Radiation: Intensity-Modulated Radiation Therapy
Undergo IMRT
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy
  • Radiation, Intensity-Modulated Radiotherapy

Drug: Peposertib
Given PO
Other Names:
  • 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




Primary Outcome Measures :
  1. Dose-limiting toxicity [ Time Frame: Up to 28 days after the end of intensity-modulated radiation therapy (IMRT) ]

Secondary Outcome Measures :
  1. Incidence of acute toxicity [ Time Frame: Up to 3 months from IMRT completion ]
    Will be as measured by Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0

  2. Incidence of late toxicity [ Time Frame: More than 3 months from IMRT completion for up to 2 years ]
    Will be as measured by CTCAE v5.0.

  3. Clinical response rate [ Time Frame: At 3 months post completion of IMRT ]
    Will be assessed by Response Evaluation Criteria in Solid Tumors 1.1.

  4. Progression-free survival (PFS) rates [ Time Frame: At 6 months and 1 year ]
    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.

  5. Overall survival (OS) rates [ Time Frame: At 6 months and 1 year ]
    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.


Other Outcome Measures:
  1. Biomarker analysis [ Time Frame: 2 years ]
    Will assess tumor mutational burden (TMB), EAp53 status (p53 mutational status), mutation status for genes commonly mutated in head and neck squamous cell carcinoma, and deoxyribonucleic acid (DNA) repair pathway alterations determined by targeted exome sequencing of pre-treatment biopsy specimens and association with treatment response and PFS.

  2. Pharmacokinetic (PK) parameter of M3814 (peposertib) [ Time Frame: Within 30 minutes before administration, 2 hours and 4 hours after administration on day 1 of weeks 1 and 2 ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • 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 or a legally authorized representative 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 or CYP2C19 prior to study treatment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04533750


Sponsors and Collaborators
National Cancer Institute (NCI)
NRG Oncology
Investigators
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Principal Investigator: Maura L Gillison NRG Oncology
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04533750    
Other Study ID Numbers: NCI-2020-06481
NCI-2020-06481 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-HN008 ( Other Identifier: NRG Oncology )
NRG-HN008 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
First Posted: September 1, 2020    Key Record Dates
Last Update Posted: November 6, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Squamous Cell
Squamous Cell Carcinoma of Head and Neck
Laryngeal Neoplasms
Mouth Neoplasms
Lip Neoplasms
Oropharyngeal Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Head and Neck Neoplasms
Neoplasms by Site
Otorhinolaryngologic Neoplasms
Laryngeal Diseases
Respiratory Tract Diseases
Respiratory Tract Neoplasms
Otorhinolaryngologic Diseases
Mouth Diseases
Stomatognathic Diseases
Lip Diseases
Pharyngeal Neoplasms
Pharyngeal Diseases