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Squamous Cell Head and Neck CarcinomaPhase 3ADHERENCT03673735

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

A Phase 3 study testing Durvalumab, radiotherapy and Cisplatin in people with Squamous Cell Head and Neck Carcinoma, run by European Organisation for Research and Treatment of Cancer - EORTC.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Squamous Cell Head and Neck Carcinoma
What is being tested?
Durvalumab, radiotherapy and Cisplatin
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
0 participants
Where
No sites listed yet
Study dates
Jun 2021to Dec 2027
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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.
  • Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with CRT or Durvalumab may be included only after consultation with the clinical research physician
  • Before patient randomization, written informed consent must be given according to ICH/GCP, and national/local regulations

Who cannot join

  • 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
  • Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
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  • 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
  • Celiac disease controlled by diet alone
  • Diverticulosis
  • Known allergy or hypersensitivity to cisplatin and Durvalumab or any of its excipients
  • Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension (defined as blood pressure above 160/90 mm Hg despite medication), unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, active peptic ulcer disease or gastritis, liver cirrhosis CHILD B+, C, active bleeding diatheses
  • History of active primary immunodeficiency
  • 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, or human immunodeficiency virus (positive HIV 1/2 antibodies). 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.
  • History of another primary malignancy with the exception of:
  • Malignancy treated with curative intent and with no known active disease ≥5 years before enrollment and of low potential risk for recurrence
  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  • Adequately treated carcinoma in situ without evidence of disease
  • History of symptomatic brain metastases and leptomeningeal carcinomatosis
  • Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
  • Female subjects who are pregnant or male or female subjects of reproductive potential who are not willing to employ effective birth control from randomisation to 90 days after the last dose of Durvalumab
  • Any psychological, familial, sociological or geographical condition that could increase risk of incurring AEs or compromise the ability of the patient to give written informed consent, or hamper compliance with the study protocol and follow-up schedule; these conditions should be discussed with the patient before registration in the trial

About this study

Official title: A Randomized Phase III Study on Maintenance Durvalumab vs Placebo Following Post-operative Concomitant Chemoradiation in Subjects With HPV-negative Squamous Cell Head and Neck Carcinoma (HNSCC) With High Risk of Recurrence

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.
Being tested
Durvalumab, radiotherapy, Placebo, Cisplatin
Medical subject headings
Squamous Cell Carcinoma of Head and Neck

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DurvalumabDrug

    Also called MEDI4736

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

  • radiotherapyRadiation

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

  • PlaceboDrug

    Also called saline solution

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

  • CisplatinDrug

    Also called chemotherapy

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

Study groups in NCT03673735
Study groupRoleWhat they receive
Experimental ArmExperimentalPatients 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.
Receives: Drug: Durvalumab; Radiation: radiotherapy; Drug: Cisplatin
Control armPlacebo comparatorPatients 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.
Receives: Radiation: radiotherapy; Drug: Placebo; Drug: Cisplatin

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: 3 years and half after last pateint in

Secondary outcomes (6)

  1. overall survival

    To assess the impact of postoperative Durvalumab on the overall survival

    Measured: 5 years after last patients in

  2. Cumulative incidence of distant metastases

    Time to distant metastases is defined as the time interval between the date of randomization and the first date when distant disease is detected. Cumulative incidence of distant metastases is estimated considering death or diagnosis of loco-regional recurrence in absence of distant disease is considered as a competing risk event. If a recurrence is detected at the same time at both loco-regional and distant sites, this is considered as a competing risk for this endpoint.

    Measured: 5 years after last patients in

  3. Cumulative incidence of loco-regional recurrence

    Time to loco-regional recurrence is the time interval between the date of randomization and the date where local or regional recurrence is first detected. Cumulative incidence of loco-regional recurrence is estimated considering death or diagnosis of distant metastases in absence of loca l or regional recurrence is considered as a competing risk event. If a recurrence is detected at the same time at both loco-regional and distant sites, this is considered as an event of interest for this endpoint.

    Measured: 5 years after last patients in

  4. Cumulative incidence of second cancers (all sites)

    first diagnosis of any second cancer in the head and neck region or outside the head and neck region. Cumulative incidence of second cancer is estimated considering death without a second cancer is considered as a competing risk.

    Measured: 5 years after last patients in

  5. Rate of toxicity assessed by clinicians

    All adverse events will be recorded; the investigator will assess whether those events are drug related (reasonable possibility, no reasonable possibility) and this assessment will be recorded in the database for all adverse events. Adverse events will be recorded according to NCI-CTCAE

    Measured: 5 years after last patients in

  6. Health-related quality of Life questionnaires: QLQ-C30

    To compare the addition of immunotherapy to chemo-radiation therapy on health-related quality of life. Quality of life will be assessed with the EORTC Quality of Life Questionnaire (QLQ-C30) version 3.

    The EORTC Quality of Life Questionnaire (QLQ-C30) version 3 is patient questionnaire composed of 30 single questions which form 15 multi-item and single-item scales. These include five functional scales (physical, role, emotional, social, and cognitive), three multi-item symptom scales (fatigue, nausea and vomiting and pain), six single item symptom scales (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties) and a global health status/QoL scale. The scoring algorithm for the scales results in a score from 0 to 100 where a high score for a functional scale represents a healthy level of functioning, but a high score for a symptom scale represents a high level of problems.

    Measured: 5 years after last patients in

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Sep 2018
  2. Study startJun 2021 (estimated)
  3. Primary completionJul 2026 (estimated)
  4. Study completionDec 2027 (estimated)

Why it stopped: Company withdrew interest

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03673735
Sponsor's protocol ID
EORTC 1735-HNCG
Other IDs
2018-002730-21, 2018
Acronym
ADHERE
Status last verified
May 2021
First submitted
3 Aug 2018
Last updated
10 May 2021
Results posted
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Durvalumab, radiotherapy and Cisplatin in people with Squamous Cell Head and Neck Carcinoma, run by European Organisation for Research and Treatment of Cancer - EORTC.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 10 May 2021. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

disease free survival (time frame: 3 years and half after last pateint in). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03673735.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 May 2021.

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