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Radiation Therapy With Durvalumab or Cetuximab in Treating Patients With Stage III-IVB Head and Neck Cancer Who Cannot Take Cisplatin

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ClinicalTrials.gov Identifier: NCT03258554
Recruitment Status : Suspended (Scheduled Interim Monitoring)
First Posted : August 23, 2017
Last Update Posted : December 5, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This randomized phase II/III trial studies how well radiation therapy works with durvalumab or cetuximab in treating patients with stage III-IVB head and neck cancer who cannot take cisplatin. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Monoclonal antibodies, such as durvalumab and cetuximab, may interfere with the ability of tumor cells to grow and spread. It is not known if radiation therapy with durvalumab will work better than the usual therapy of radiation therapy with cetuximab in treating patients with head and neck cancer.

Condition or disease Intervention/treatment Phase
Head and Neck Squamous Cell Carcinoma Squamous Cell Carcinoma of Unknown Primary Origin Stage III Hypopharyngeal Squamous Cell Carcinoma AJCC v7 Stage III Laryngeal Squamous Cell Carcinoma AJCC v6 and v7 Stage III Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7 Stage III Oropharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVA Hypopharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVA Laryngeal Squamous Cell Carcinoma AJCC v7 Stage IVA Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7 Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVB Hypopharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVB Laryngeal Squamous Cell Carcinoma AJCC v7 Stage IVB Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7 Stage IVB Oropharyngeal Squamous Cell Carcinoma AJCC v7 Biological: Cetuximab Biological: Durvalumab Radiation: Intensity-Modulated Radiation Therapy Other: Laboratory Biomarker Analysis Other: Quality-of-Life Assessment Other: Questionnaire Administration Phase 2 Phase 3

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 523 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomized Phase II/III Trial of Radiotherapy With Concurrent MEDI4736 (Durvalumab) vs. Radiotherapy With Concurrent Cetuximab in Patients With Stage III-IVB Head and Neck Cancer With a Contraindication to Cisplatin
Actual Study Start Date : December 12, 2017
Estimated Primary Completion Date : December 31, 2025
Estimated Study Completion Date : December 31, 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Arm I (cetuximab, radiation therapy)
Patients receive cetuximab IV weekly over 60-120 minutes. Treatment repeats every week for up to 8 courses in the absence of disease progression or unacceptable toxicity. Beginning 5-7 days after first cetuximab dose, patients undergo IMRT 5 fractions per week for up to 7 weeks.
Biological: Cetuximab
Given IV
Other Names:
  • Cetuximab Biosimilar CMAB009
  • Chimeric Anti-EGFR Monoclonal Antibody
  • Chimeric MoAb C225
  • Chimeric Monoclonal Antibody C225
  • Erbitux
  • IMC-C225

Radiation: Intensity-Modulated Radiation Therapy
Undergo IMRT
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Experimental: Arm II (durvalumab, radiation therapy)
Patients receive durvalumab IV over 60 minutes every 4 weeks. Treatment repeats every 4 weeks for up to 7 courses in the absence of disease progression or unacceptable toxicity. Beginning week 2, patients undergo IMRT 5 fractions per week for up to 7 weeks.
Biological: Durvalumab
Given IV
Other Names:
  • Imfinzi
  • Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer
  • MEDI-4736
  • MEDI4736

Radiation: Intensity-Modulated Radiation Therapy
Undergo IMRT
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies




Primary Outcome Measures :
  1. Dose-limiting toxicity (DLT) defined as the occurrence of an adverse event (AE) during the specified observation window (Lead -in) [ Time Frame: Up to 4 weeks after radiation therapy (RT) ]
    AEs will be graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

  2. Progression-free survival (PFS) (Phase II) [ Time Frame: From randomization until first evidence of local, regional, or distant disease progression or recurrence, or death from any cause, assessed up to 3 years ]
    PFS will be estimated using the Kaplan-Meier method. The difference in PFS between the two arms will be tested using a log-rank test.

  3. Overall survival (OS) (Phase III) [ Time Frame: From randomization until death from any cause, assessed up to 3 years ]
    OS will be estimated using the Kaplan-Meier method. The difference in OS between the two arms will be tested using a log-rank test. Exploratory analysis adjusting for important factors such as age, site, Zubrod performance status, and clinical stages will be conducted using Cox models.


Secondary Outcome Measures :
  1. Locoregional failure (LRF) [ Time Frame: From randomization until first evidence of local, regional disease progression or recurrence, or death from study cancer or unknown causes, assessed up to 3 years ]
    LRF will be estimated by cumulative incidence methods and compared using a cause-specific log-rank test. All failure times will be measured from the date of study randomization to the date of failure or last follow up.

  2. Distant metastasis (DM) [ Time Frame: From randomization until first evidence of distant metastasis, assessed up to 3 years ]
    DM will be estimated by cumulative incidence methods and compared using a cause-specific log-rank test. All failure times will be measured from the date of study randomization to the date of failure or last follow up.

  3. Competing mortality [ Time Frame: Up to 3 years ]
    Will be estimated by cumulative incidence methods and the effects of other covariates will be assessed using the Generalized Competing Event Model for Cancer Risk model.

  4. Response on 4-month fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/computed tomography (CT), measured by Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Up to 4 months ]
    Response rates between the two arms will be compared using Fisher's exact test.

  5. Acute toxicity [ Time Frame: Up to 180 days after the end of radiation therapy ]
    The rates of adverse events will be estimated using a binomial distribution along with their associated 95% confidence intervals and will be compared using Fisher's exact test.

  6. Late toxicity [ Time Frame: Up to 3 years ]
    Late toxicities > 180 days after the end of radiation therapy. The rates of adverse events will be estimated using a binomial distribution along with their associated 95% confidence intervals and will be compared using Fisher's exact test.

  7. Change in quality of life (QOL) analysis [ Time Frame: Baseline up to 12 months ]
    Assessed using European Organization for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ)/Head-and-Neck module (H&N35), EuroQol- 5 Dimension (EQ5D), M. D. Anderson Dysphagia Inventory (MDADI), patient reported outcomes (PRO)-CTCAE, geriatric screening (G8). The mean summary score of the EORTC QLQ/H&N35, EQ5D, MDADI, PRO-CTCAE, G8, CCI, and the subscales will be determined. The mean change from baseline at each time point will be summarized using mean and standard deviations for each arm. Mean change from baseline will be compared between the arms using a two sample t test. If data normality assumptions are not met, the Wilcoxon rank sum test will be used to test the hypothesis. Mean change from baseline will be tested using an omnibus F test followed by individual comparisons of change scores at different time points within each treatment group. The same analysis will be conducted for between group comparisons at each time point.

  8. Change in swallowing QOL using total composite M. D. Anderson Dysphagia Inventory (MDADI) score [ Time Frame: Baseline up to 1 year ]
    The mean change from baseline at each time point will be summarized using mean and standard deviations for each arm. Mean change from baseline will be compared between the arms using a two sample t test. If data normality assumptions are not met, the Wilcoxon rank sum test will be used to test the hypothesis.

  9. Translational research, including PD-L1 and p16 [ Time Frame: Up to 3 years ]
    Analyses of interaction between treatment arm and marker status will be done. Additionally toxicity for the two arms by marker status will be compared. Univariable and multivariable analysis will be performed using the Cox proportional hazards model for OS. Potential covariates evaluated for the multivariate models would be assigned treatment, age, Zubrod performance status, T-stage, N-stage, primary site, smoking history, other risk factors, as well as p16 and/PD-L1.


Other Outcome Measures:
  1. Secondary biomarker analysis [ Time Frame: Baseline up to 1 month after last systemic dose ]
    Will perform multiparametric flow cytometry on peripheral mononuclear cells (PBMC) from patient-derived blood samples to quantify changes in immune cell frequency and activation status before, during and after radiation combined with cetuximab or radiation combined with durvalumab. To assess the statistical significance of pre- to post-treatment changes in levels of immunoglobulin (Ig)Gs as well as other markers, normalized signal intensities (log2) will be tested using a paired t test within an arm and two sample t test between the two arms. If the distribution assumption is violated for the t tests, nonparametric tests, such as the Wilcoxon signed-rank test will be considered. Lastly, the association between PFS and OS and post-treatment changes in frequency and activation state of T-cells, clonality and diversity of T cell receptor (TCR), and IgG levels will be evaluated using a two-sided Wald test at 0.05 level on the basis of Cox models.

  2. Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) [ Time Frame: Up to 3 years ]
    PRO-CTCAE is not intended for expedited reporting, real time review or safety reporting. PRO-CTCAE data are exploratory and not currently intended for use in data safety monitoring or adverse event stopping rules.

  3. QOL endpoints using other items in EORTC QLQ/HN35, EQ5D and MDADI subscales [ Time Frame: Up to 12-24 months from end of RT ]
    The mean change from baseline at each time point will be summarized using mean and standard deviations for each arm. Mean change from baseline will be compared between the arms using a two sample t test. If data normality assumptions are not met, the Wilcoxon rank sum test will be used to test the hypothesis. Mean change from baseline will be tested using an omnibus F test followed by individual comparisons of change scores at different time points within each treatment group. The same analysis will be conducted for between group comparisons at each time point.



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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:

  • PRIOR TO STEP 1 REGISTRATION INCLUSION CRITERIA
  • Patients must have pathologically confirmed, previously untreated, unresected squamous cell carcinoma of the larynx, hypopharynx, oropharynx, oral cavity, or carcinoma of unknown head/neck primary within 60 days prior to step 1 registration; submission of hematoxylin and eosin (H&E) stained slides and formalin-fixed and paraffin-embedded (FFPE) tissue block (or punch biopsy of FFPE block) to the biospecimen bank at University of California, San Francisco (UCSF) for central review for oropharyngeal and unknown primaries and for p16 analysis for all other non- oropharyngeal primaries is mandatory for all patients; investigators should check with their pathology department regarding release of biospecimens before approaching patients about participation in the trial; for oropharyngeal and unknown primaries, submission of H&E and p16 stained slides to the biospecimen bank at UCSF for central review is also required prior to step 2 registration

    • Note: fine needle aspirates (FNA) samples are not acceptable since they do not provide enough material for PD-L1 and p16 testing
  • Patients must have stage III-IVB head and neck squamous cell carcinoma (HNSCC) (American Joint Committee on Cancer [AJCC] seventh [7th] edition) based on the following minimum diagnostic workup within 60 days prior to step 1 registration:

    • General history and physical examination by a radiation oncologist, medical oncologist, and/or ear, nose and throat (ENT) or head & neck surgeon
    • For larynx, hypopharynx, and base of tongue primaries, a laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) is required, unless the patient cannot tolerate or refuses
    • Imaging of the head and neck with a neck CT or magnetic resonance imaging (MRI) (with contrast, unless contraindicated) or PET/CT (with contrast, unless contraindicated)
    • Chest imaging: chest CT with and without contrast (unless contraindicated) or PET/CT
  • 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 step 1 registration to determine if the patient is eligible; the scores must be recorded on a case report form (CRF)

    • Age >= 70 with moderate to severe comorbidity or vulnerability to cisplatin, defined as having any one of the following conditions within 30 days prior to step 1 registration:

      • Modified Charlson Comorbidity Index >= 1
      • Adult Comorbidity Evaluation (ACE)-27 Index >= 1
      • Generalized Competing Event Model for Cancer Risk (GCE) omega PFS score < 0.60
      • Geriatric screening (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 or vulnerability to cisplatin, defined as having two or more of the following conditions within 30 days prior to step 1 registration

      • Modified Charlson Comorbidity Index >= 1
      • ACE-27 Index >= 1
      • GCE omega PFS-score < 0.60
      • 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 within 30 days prior to Step 1 registration:

      • Creatinine clearance (CC) > 30 and < 60 cc/min; for this calculation, use the Cockroft-Gault formula
      • Zubrod performance status 2 prior to step 1 registration
      • Pre-existing peripheral neuropathy grade >= 1
      • 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
  • Within 14 days prior to step 1 registration: Absolute neutrophil count (ANC) >= 1,000 cells/mm^3
  • Within 14 days prior to step 1 registration: Platelets >= 100,000 cells/mm^3
  • Within 14 days prior to step 1 registration: Hemoglobin >= 9.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 9.0 g/dl is acceptable)
  • Within 14 days prior to step 1 registration: Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 times institutional upper limit of normal
  • Within 14 days prior to step 1 registration: Serum bilirubin =< 1.5 x institutional upper limit of normal
  • Within 14 days prior to step 1 registration: Measured creatinine clearance (CL) > 30 mL/min or calculated creatinine CL > 30 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
  • For women of childbearing potential, a negative serum or urine pregnancy test within 14 days prior to step 1 registration; Note: women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause; the following age-specific requirements apply:

    • Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy)
    • Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
  • The patient or a legally authorized representative must provide study-specific informed consent prior to step 1 registration
  • PRIOR TO STEP 2 REGISTRATION INCLUSION CRITERIA
  • For patients with oropharyngeal or unknown primaries: p16 determination by immunohistochemistry (defined as greater than 70% strong nuclear or nuclear and cytoplasmic staining of tumor cells), confirmed by central pathology review

    • Note: for patients with oral cavity, laryngeal, and hypopharyngeal primaries, analysis of p16 status prior to step 2 registration/randomization is not required (p16 status will be analyzed centrally post-hoc); step 2 registration for these patients can be completed after step 1 registration

Exclusion Criteria:

  • PRIOR TO STEP 1 REGISTRATION EXCLUSION CRITERIA
  • Prior invasive malignancy within the past 3 years (except for non-melanomatous skin cancer, and early stage treated prostate cancer)
  • Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
  • Prior immunotherapy
  • Prior systemic therapy, including cytotoxic chemotherapy, biologic/targeted therapy, or immune therapy for the study cancer
  • Distant metastases
  • If both of the following conditions are present, the patient is ineligible:

    • < 10 pack-year smoking history
    • p16-positive carcinoma of the oropharynx or unknown primary that are T0-3, N0-2b (AJCC 7th Edition)

      • Note: in the event that a registered patient has a p16-positive result on central review with the tumor and nodal stage T0-3, N0-2b (AJCC 7th Edition), then the site will be notified that the patient is ineligible
  • Zubrod performance status >= 3
  • Body weight =< 30 kg
  • Patients with oral cavity cancer are excluded from participation if the patient is medically operable and resection of the primary tumor is considered technically feasible by an oral or head and neck cancers surgical subspecialist;(please consult the surgical oncology co-principal investigator [PI], Steven Chang, Doctor of Medicine [MD], if clarification is needed on an individual case)
  • Within 14 days of step 1 registration, unless corrected prior to step 1 registration: Sodium < 130 mmol/L or > 155 mmol/L
  • Within 14 days of step 1 registration, unless corrected prior to step 1 registration: Potassium < 3.5 mmol/L or > 6 mmol/L
  • Within 14 days of step 1 registration, unless corrected prior to step 1 registration: Fasting glucose < 40 mg/dl or > 400 mg/dl
  • Within 14 days of step 1 registration, unless corrected prior to step 1 registration: Serum calcium (ionized or adjusted for albumin) < 7 mg/dl or > 12.5 mg/dl
  • Within 14 days of step 1 registration, unless corrected prior to step 1 registration: Magnesium < 0.9 mg/dl or > 3 mg/dl
  • Unstable angina and/or congestive heart failure requiring hospitalization within 3 months prior to step 1 registration
  • Transmural myocardial infarction within 3 months prior to step 1 registration
  • Respiratory illness requiring hospitalization at the time of step 1 registration

    • Note: if the respiratory illness is resolved and the patient meets the eligibility status above, then the patient can be considered for the trial
  • Idiopathic pulmonary fibrosis or other severe interstitial lung disease that requires oxygen therapy or is thought to require oxygen therapy within 1 year prior to step 1 registration
  • Clinically apparent jaundice and/or known coagulation defects
  • Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.])

    • The following are exceptions to this criterion:

      • Patients with vitiligo or alopecia;
      • Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement;
      • Any chronic skin condition that does not require systemic therapy;
      • Patients without active disease in the last 5 years may be included but only after consultation with the medical oncology study chair;
      • Patients with celiac disease controlled by diet alone
  • History of active primary immunodeficiency including, but not limited to acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; Note: human immunodeficiency virus (HIV) testing is not required for entry into this protocol; the need to exclude patients with AIDS from this protocol is necessary because the treatment involved in this protocol may be immunosuppressive; patients with known HIV, CD4 counts >= 200/uL, and undetectable viral loads who are stable on an antiretroviral regimen may be included
  • Current or prior use of immunosuppressive medication within 14 days before step 1 registration, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
  • Receipt of live attenuated vaccination within 30 days prior to step 1 registration
  • Medical or psychiatric illness which would compromise the patient's ability to tolerate treatment or limit compliance with study requirements
  • Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception during treatment and for 6 months after the last dose of cetuximab or MEDI14736 (durvalumab); this exclusion is necessary because the treatment involved in this study may be significantly teratogenic; women who are breastfeeding are also excluded
  • Prior allergic reaction or hypersensitivity to cetuximab or MEDI4736 (durvalumab) or any of study drug excipients
  • History of (non-infectious) pneumonitis that required steroids or current pneumonitis
  • History of allogenic organ transplantation
  • Uncontrolled hypertension
  • Uncontrolled cardiac arrhythmia
  • Uncontrolled serious chronic gastrointestinal condition associated with diarrhea
  • Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis [TB] testing in line with local practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] result), hepatitis C; patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible; patients positive for hepatitis C (hepatitis C virus [HCV]) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)

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): NCT03258554


  Show 54 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Loren Mell NRG Oncology

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03258554     History of Changes
Other Study ID Numbers: NCI-2017-01522
NCI-2017-01522 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-HN004 ( Other Identifier: NRG Oncology )
NRG-HN004 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
First Posted: August 23, 2017    Key Record Dates
Last Update Posted: December 5, 2018
Last Verified: August 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Squamous Cell
Head and Neck Neoplasms
Neoplasms, Unknown Primary
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Neoplasms by Site
Neoplasm Metastasis
Neoplastic Processes
Pathologic Processes
Cisplatin
Cetuximab
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunoglobulin G
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs