Maintenance Immune Check-point Inhibitor Following Post-operative Chemo-radiation in Subjects With HPV-negative HNSCC

NCT03673735 | Withdrawn Phase 3

• 2 other identifiers: EORTC 1735-HNCG2018-002730-21
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This is a phase III randomized blind placebo-controlled study, designed to show the superiority of the experimental arm to the control arm. After surgery and checking eligibility criteria, patients will be randomized between the control and the experimental arms with a 1:1 ratio (randomization will take place at a maximum 4 weeks after surgery):

• Experimental Arm: Durvalumab (one dose) before chemoradiotherapy (CRT) and for 6 months every 4 weeks (Q4W) after CRT
• Control Arm: placebo (one dose) before CRT and for 6 months Q4W after CRT Radiotherapy planning will take place after randomization. The primary endpoint of this trial is disease free survival (DFS), measured from the date of randomization to the date of first occurrence of any loco-regional recurrence, metastatic progression, or death due to any cause.

Conditions

Squamous Cell Head and Neck Carcinoma

Outcome Measures

Primary Outcomes (1)

• disease free survival

  The main study objective is to test whether treatment with Durvalumab, given before and after completion of standard adjuvant chemoradiation, significantly prolongs disease free survival in macroscopically completely resected HPV negative advanced head and neck cancer at high risk of recurrence.

  3 years and half after last pateint in

Secondary Outcomes (6)

• overall survival

  5 years after last patients in

• Cumulative incidence of distant metastases

  5 years after last patients in

• Cumulative incidence of loco-regional recurrence

  5 years after last patients in

• Cumulative incidence of second cancers (all sites)

  5 years after last patients in

• Rate of toxicity assessed by clinicians

  5 years after last patients in

Study Arms (2)

Experimental Arm

EXPERIMENTAL

Patients will receive 1 infusion of 1500 mg Durvalumab within 1 week prior to concurrent chemoradiotherapy. Chemoradiation should start within 6 weeks after surgery and within 1 week maximum of the induction phase. Radiation will consist of 33 fractions over 6 weeks for a total of 66 Gy. Chemotherapy will consist of cisplatin 100 mg/m2 given on days 1, 22 and 43 of radiotherapy. Maintenance phase with Durvalumab will begin within 1 to 28 days maximum after the end of radiotherapy and will consist of 6 doses administered every 4 weeks.

Drug: Durvalumab; Radiation: radiotherapy; Drug: Cisplatin

Control arm

PLACEBO COMPARATOR

Patients will receive 1 infusion of placebo within 1 week prior to concurrent chemoradiotherapy. Chemoradiation should start within 6 weeks after surgery and within 1 week maximum of the induction phase. Radiation will consist of 33 fractions over 6 weeks for a total of 66 Gy. Chemotherapy will consist of cisplatin 100 mg/m2 given on days 1, 22 and 43 of radiotherapy. Maintenance phase with placebo will begin within 1 to 28 days maximum after the end of radiotherapy and will consist of 6 doses administered every 4 weeks.

Radiation: radiotherapy; Drug: Placebo; Drug: Cisplatin

Interventions

Durvalumab DRUG

Durvalumab (one dose) before CRT and for 6 months Q4W after CRT

Also known as: MEDI4736

Experimental Arm

radiotherapy RADIATION

radiotherapy is administered in 33 fractions over 6.5 weeks fro a total of 66 Gy

Control arm; Experimental Arm

Placebo DRUG

placebo (one dose) before CRT and for 6 months Q4W after CRT

Also known as: saline solution

Control arm

Cisplatin DRUG

Cisplatin (100mg/m2) is administered at day 1, 22, 43 of radiotherapy

Also known as: chemotherapy

Control arm; Experimental Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with squamous cell carcinoma of the oral cavity (excluding lip), larynx, hypopharynx or p16-negative oropharynx (p16 determined locally)
• Surgical treatment no more than 4 weeks prior randomization (which may include revisions, secondary flaps etc., VACs) with completed wound healing no later than 4 weeks after the initial procedure
• At high risk of locoregional recurrence based on extranodal extension (ENE) and/or R1 resection margin \< 1 mm, as documented in the pathology report of surgery.
• With postoperative pathology stage III or IV or stage II but with positive margins (based on AJCC 8th edition)
• Availability of FFPE tumor tissue block from the resection specimen
• Availability of operative and pathology report and preoperative diagnostic images for retrospective review
• ECOG Performance status 0-1
• Age ≥ 18 years
• Adequate bone marrow, liver and renal functions within 7 days from randomization
• Audiogram must be within normal range
• Chemoradiation planned to start within maximum of 2 weeks from randomization. Whenever indicated, dental extraction should be carried out at least 10 days before the start of CRT.
• Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients within 72 hours prior to randomization.
• Patients of childbearing / reproductive potential must agree to use highly effective methods of contraception based on the Clinical trials Facilitation Group (CFTG) guidance from randomization up to 90 days after the last dose of Durvalumab/placebo (Appendix I) or 6 months after the last CRT, whichever is longer.
• Female subjects who are breast feeding should discontinue nursing prior to randomization to 90 days after the last dose of Durvalumab.
• Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

You may not qualify if:

• Evidence of distant metastases before and after surgery
• Any evidence of early locoregional recurrence after surgery
• Any prior treatment with chemotherapy, radiotherapy or cetuximab
• Any previous treatment with a PD1 or PD-L1 inhibitor, including Durvalumab, a CTLA-4 inhibitor including tremelimumab or other checkpoint inhibitors or other immunotherapy during the last 12 months
• Any contraindication to cisplatin and radiotherapy
• Body weight \</=30 kg
• Any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
• Current or prior use of immunosuppressive medication within 14 days prior to enrollment, 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, or steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)
• History of allogenic organ transplantation
• Receipt of live attenuated vaccination within 30 days prior to enrollment Note: Patients, if enrolled, should not receive live vaccine whilst receiving Durvalumab and up to 30 days after the last dose of Durvalumab.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.). Following disorders are acceptable:
• Vitiligo or alopecia
• Hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement
• Any chronic skin condition that does not require systemic therapy
• Active disease in the last 5 years may be included but only after consultation with the treating physician

Sponsors & Collaborators

• European Organisation for Research and Treatment of Cancer - EORTC: lead

MeSH Terms

Conditions

Squamous Cell Carcinoma of Head and Neck

Interventions

durvalumab; Radiotherapy; Saline Solution; Cisplatin; Drug Therapy

Condition Hierarchy (Ancestors)

Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Head and Neck Neoplasms; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Therapeutics; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 3, 2018
• First Posted: September 17, 2018
• Study Start: June 1, 2021
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): December 1, 2027
• Last Updated: May 10, 2021

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will not share