Clinical Trials /

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

NCT04533750

Description:

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.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
  • Hypopharyngeal Squamous Cell Carcinoma
  • Laryngeal Squamous Cell Carcinoma
  • Oral Cavity Squamous Cell Carcinoma
  • Oropharyngeal Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-06481
  • SECONDARY ID: NCI-2020-06481
  • SECONDARY ID: NRG-HN008
  • SECONDARY ID: NRG-HN008
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT04533750

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
  • 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

Interventions

DrugSynonymsArms
Peposertib3-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, NedisertibTreatment (peposertib, IMRT)

Purpose

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 (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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (peposertib, IMRT)ExperimentalPatients receive peposertib PO QD and undergo IMRT daily Monday-Friday for 7 weeks in the absence of disease progression or unacceptable toxicity.
  • Peposertib

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

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

Measure:Incidence of acute toxicity
Time Frame:Up to 3 months from IMRT completion
Safety Issue:
Description:Will be as measured by Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0
Measure:Incidence of late toxicity
Time Frame:More than 3 months from IMRT completion for up to 2 years
Safety Issue:
Description:Will be as measured by CTCAE v5.0.
Measure:Clinical response rate
Time Frame:At 3 months post completion of IMRT
Safety Issue:
Description:Will be assessed by Response Evaluation Criteria in Solid Tumors 1.1.
Measure:Progression-free survival (PFS) rates
Time Frame:At 6 months and 1 year
Safety Issue:
Description: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.
Measure:Overall survival (OS) rates
Time Frame:At 6 months and 1 year
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

September 8, 2020