View Cancer Clinical Trials

Details

Title Randomized Phase II/III Trial of Radiotherapy with Concurrent MEDI4736 (Durvalumab) vs. Radiotherapy with Concurrent Cetuximab in Patients with Locoregionally Advanced Head and Neck Cancer with a Contraindication to Cisplatin

IRB NRG-HN004

CC 19-1319

Hospital Main Campus, Mansfield, North Coast Cancer, Wooster

Stage Locoregionally Advanced

Phase Phase 2, Phase 3

Disease Head and Neck, Squamous Cell Carcinoma of Head and Neck

Drug Tisagenlecleucel (CTL019)

Description

• Lead-In: To determine the safety of radiotherapy (RT) with concurrent and adjuvant anti-PD-L1 therapy [MEDI4736 (durvalumab)] is safe in patients with locoregionally advanced head and neck cancer (HNC) who have a contraindication to cisplatin.
• Phase II: To test the hypothesis that concurrent RT and anti-PD-L1 therapy improves PFS compared to standard therapy (RT with concurrent cetuximab) in patients with locoregionally advanced HNC who have a contraindication to cisplatin.
• Phase III: To test the hypothesis that concurrent RT and anti-PD-L1 therapy improves overall survival compared to standard therapy (RT with concurrent cetuximab) in patients with locoregionally advanced HNC who have a contraindication to cisplatin.

• To compare toxicity using CTCAE and PRO-CTCAE between patients treated with RT + anti-PD-L1 therapy versus RT/cetuximab.
• To test the effect of anti-PD-L1 therapy in the subpopulation of patients with tumors that overexpress PD-L1.
• To compare overall survival, response (at 4-month FDG-PET-CT), locoregional failure, distant metastasis, and competing mortality in the two arms by known risk factors, including p16 status and w score.
• To test the hypothesis that MEDI4736 (durvalumab) therapy arm will have less decline in the physical function domain of European Organization for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30 Version 3.0) based on the change in score from baseline to 12 months from end of RT, compared to the cetuximab-RT arm in patients with locoregionally advanced HNC who have a contraindication to cisplatin.
• To test the hypothesis that MEDI4736 (durvalumab) therapy arm at 1 year (from end of RT) will have less decline in swallowing related QOL using the MDADI total composite score, based on the change in score from baseline to 12 months from end of RT, compared to the cetuximab-RT arm in patients who are medically unfit for cisplatin.
• To compare swallowing related performance and function short and long term using the PSS-HN.
• To evaluate gastrostomy tube retention rates between arms.

Inclusion Criteria

Prior to Step 1 Registration

1. 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 H&E stained slides and formalin-fixed and paraffin-embedded (FFPE) tissue block (or punch biopsy of FFPE block) to the Biospecimen Bank at UCSF for central review for oropharyngeal and unknown primaries and for p16 analysis for all other nonoropharyngeal primaries is mandatory for all patients. 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 (See Section 10 for further criteria for central pathology review). Note: Fine needle aspirates (FNA) samples are not acceptable since they do not provide enough material for PD-L1 and p16 testing.
2. Patients must have locoregionally advanced HNSCC (see table in protocol)
   • for p16-positive oropharyngeal/unknown primaries, AJCC 8th edition stage III andselected stage I-II based on smoking status in pack-years
   • for laryngeal, hypopharyngeal, and oral cavity primaries and p16-negative oropharyngeal/unknown primaries, AJCC 8th edition stage III-IVBBased on the following minimum diagnostic workup within 60 days prior to Step 1 registration:
     • General history and physical examination by a Radiation Oncologist or Medical Oncologist or ENT Physician or Head & Neck Surgeon
     • For larynx, hypopharynx, and base of tongue primaries, a laryngopharyngoscopy (mirror or fiberoptic or direct procedure) is required, unless the patient cannot tolerate or refuses
     • Imaging of the head and neck with a neck CT or MRI (with contrast, unless contraindicated) or PET/CT. Note that the CT portion of the PET/CT must be of diagnostic quality, including contrast administration unless contraindicated. If the CT portion of the PET/CT study is low-dose (non-diagnostic), then an additional CT or MRI study with contrast (unless contraindicated) is required.
     • Chest imaging: Chest CT with or without contrast (unless contraindicated) or PET/CT
3. 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 CRF. (Refer to data submission table on the NRG-HN004 protocol page on the CTSU website).
   • Age ≥ 70 with moderate to severe comorbidity or vulnerability to cisplatin, defined as having one or more of the following conditions within 30 days prior to Step 1 registration:
     • Modified Charlson Comorbidity Index ≥ 1
     • ACE-27 Index ≥ 1
     • GCE wPFS score < 0.60
     • G-8 score ≤ 14
     • CARG Toxicity Score ≥ 30%
     • 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 wPFS 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, Patient must be greater than 18 years old
     • 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 as clinically indicated
4. Adequate hematologic function within 14 days prior to Step 1 registration defined as follows:
   • Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3
   • Platelets ≥ 100,000 cells/mm3
   • Hemoglobin ≥ 9.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 9.0 g/dl is acceptable).
5. Adequate hepatic and renal function within 14 days prior to Step 1 registration defined as follows:
   • AST or ALT ≤ 2.5 times institutional upper limit of normal
   • Serum bilirubin ≤ 1.5 x institutional upper limit of normal
   • 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 Cockcroft-Gault formula
6. 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).
7. The patient or a legally authorized representative must provide study-specific informed consent prior to Step 1 registration.

Prior to Step 2 Registration (for patients with oropharyngeal and unknown primaries)

8. 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; (see Section 10.1 for details). 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

1. Prior invasive malignancy within the past 3 years (except for non-melanomatous skin cancer, and early stage treated prostate cancer)
2. Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
3. Prior immunotherapy
4. Prior systemic therapy, including cytotoxic chemotherapy, biologic/targeted therapy, or immune therapy for the study cancer
5. Major surgery within 28 days prior to Step 1 registration
6. Proven evidence of distant metastases
7. 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, N0-1 (AJCC 8th Edition) Note: In the event that a registered patient with ≤ 10 pack-years has a p16-positive result on central review with the tumor and nodal stage T0-3, N0-1 (AJCC 8th Edition), then the site will be notified that the patient is ineligible.
8. Age < 18 years
9. Zubrod performance status ≥ 3
10. Body weight ≤ 30 kg
11. 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-PI, Steven Chang, MD, if clarification is needed on an individual case.)
12. Any of the following severe laboratory abnormalities within 14 days of Step 1 registration, unless corrected prior to Step 1 registration:
    • Sodium < 130 mmol/L or > 155 mmol/L
    • Potassium < 3.5 mmol/L or > 6 mmol/L
    • Fasting glucose < 40 mg/dl or > 400 mg/dl
    • Serum calcium (ionized or adjusted for albumin) < 7 mg/dl or > 12.5 mg/dl
    • Magnesium < 0.9 mg/dl or > 3 mg/dl
13. Unstable angina and/or congestive heart failure requiring hospitalization within 3 months prior to Step 1 registration
14. Transmural myocardial infarction within 3 months prior to Step 1 registration
15. 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.
16. 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
17. History of (non-infectious) pneumonitis that required steroids or current pneumonitis
18. Clinically apparent jaundice and/or known coagulation defects
19. 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.
20. History of active primary immunodeficiency including, but not limited to Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; Note: 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/μL, and undetectable viral loads who are stable on an antiretroviral regimen may be included.
21. 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
22. Receipt of live attenuated vaccination within 30 days prior to Step 1 registration
23. Medical or psychiatric illness which would compromise the patient's ability to tolerate treatment or limit compliance with study requirements
24. 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.
25. Prior allergic reaction or hypersensitivity to cetuximab or MEDI4736 (durvalumab) or any of study drug excipients.
26. History of allogenic organ transplantation
27. Uncontrolled hypertension
28. Uncontrolled cardiac arrhythmia
29. Uncontrolled serious chronic gastrointestinal condition associated with diarrhea
30. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive 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 (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.