Adjuvant immunotherapy after salvage surgery in head and neck squamous cell carcinoma: phase 2 trial evaluating the efficacy and the toxicity of nivolumab alone, and of the combination nivolumab and ipilimumab

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Gustave Roussy

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

13 Feb 2018 → ongoing

Decision date (initial)

2024-10-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-516810-39-00

EudraCT number

2017-001277-17

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Pharmacokinetic, Efficacy, Safety

To evaluate two years disease-free survival (DFS) after salvage surgery followed by nivolumab (first cohort of patients), or followed by nivolumab-ipilimumab combination (NIC; second cohort of patients).

Secondary objectives 4

1. To evaluate toxicity, overall survival, quality of life.
2. To correlate these endpoints with HPV status.
3. To evaluate DFS in high and low risk subgroups determined by immunoscore, a prognostic test based on type and location of tumor infiltrating lymphocytes; to evaluate DFS in subgroups determined by immunohistochemical expression of PDL1. DFS will be analyzed in subgroups treated by nivolumab alone (first cohort), and in subgroups treated by NIC (second cohort).
4. To characterize Pharmacokinetic of the agents and explore Pharmacodynamic

Conditions and MedDRA coding

Adjuvant therapy after salvage surgery of high risk recurrent head and neck squamous cell carcinoma (HNSCC)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. These criteria will be similar to the criteria of the previous trials of reirradiation after salvage surgery, and manuscript of the second randomized trial:
2. Absence of grade III or IV sequelae related to the first irradiation (except for salivary sequelae).
3. Recurrence or second primary of HNSCC in a previously irradiated area at a dose ≥ 50 Gys
4. HNSCC of oral cavity, oro and hypopharynx, larynx only if extralaryngeal spread (rT4), isolated nodal recurrence
5. Patient who has received salvage surgery with curative intent and macroscopic complete resection : - for cohorts 1 and 2: similarly, to inclusion criteria of previous reirradiation trials, more than 6 months between radiotherapy and salvage surgery - for cohorts 1bis and 2bis: less than 6 months between radiotherapy and salvage surgery
6. Recurrence of bad prognosis justifying an adjuvant treatment: - clinically infiltrative recurrence or second primary; or nodal recurrence upper or equal to 3 cm, or association of local and nodal recurrence; - superficial recurrence, but histologic gravity signs on surgical specimen indicating a high risk of recurrence after salvage surgery (histologic involvement of surgical margins or margins less than 3mm, perineural spread or vascular emboli, one, or more invaded nodes). Nodal recurrence without tumor recurrence and inferior to 3cm, but with capsular rupture at histologic examination.
7. No distant metastases, confirmed by CT scan
8. Sufficient healing for beginning adjuvant treatment within 8 weeks (+/- 2 weeks) of salvage surgery
9. Male and female between 18 and 75 years (included)
10. ECOG 0 or 1
11. Immunosuppressive doses of systemic medication, such as steroids or absorbed topical steroids (doses > 10 mg/day prednisone or equivalent) must be discontinued at least 2 weeks before study drug administration
12. Screening laboratory values must meet the following criteria (using CTCAE v4) and should be obtained within 14 days to the administration of the first study treatment.: WBC > 2000/μL. Polynuclear neutrophils >1.5 x 109/L. Platelets > 75 x 109/L. Hemoglobin > 8.0 g/dL. ALAT/ASAT< 3.0 x ULN. Bilirubin < 1.5 x ULN (except Gilbert Syndrome: < 3.0 mg/dL). Creatinine clearance > 40 mL/min (measured or calculated by Cockroft and Gault formula) or serum creatinine < 2.0 x ULN
13. Women of childbearing potential must have a negative serum β-HCG pregnancy test within 24 hours prior to the administration of the first study treatment.Sexually active women of childbearing potential must agree to use a highly effective method of contraception or to abstain from sexual activity during the study and for at least 5 months after the last study treatment administration. Sexually active males patients must agree to use condom during the study and for at least 7 months after the last study treatment administration. Also, it is recommended their women of childbearing potential partner use a highly effective method of contraception.
14. Women who are breastfeeding should discontinue nursing prior to the first dose of study drug and until 5 months after the last dose.
15. Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedures as per protocol.
16. Patients must be affiliated to a social security system or beneficiary of the same

Exclusion criteria 23

1. Recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma that originated from the skin and salivary gland, or non- squamous histologies (eg, mucosal melanoma).
2. Patients with positive tests for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating active or chronic infection
3. Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
4. Patients having received prior therapy with anti-PD-1, anti-PD-L1, anti- PDL2, anti-CD137, or anti-CTLA-4 antibody (or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
5. Patients receiving anti-cancer therapies must be discontinued at least 4 weeks prior to administration of study drug. Palliative, focal radiation therapy, and immunosuppressive doses of systemic corticosteroids, except replacement organotherapy (hydrocortisone and fludrocortisone), must be discontinued at least 2 weeks before administration of study drug. All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have resolved to grade 1 (NCI CTCAE version 4) or to baseline or stabilized before administration of study drug. Subjects with toxicities attributed to systemic prior anticancer therapy which are not expected to resolve and result in long lasting sequelae, such as neuropathy after platinum based therapy, are permitted to enroll.
6. Use of non-oncology vaccines containing live virus for prevention of infectious diseases within 4 weeks prior to study drug. The use of the inactivated seasonal influenza vaccine (Fluzone®) is allowed. Known or underlying medical condition (e.g., a condition associated with diarrhea or acute diverticulitis) that, in the investigator’s opinion, would make the administration of study drug hazardous to the patient or obscure the interpretation of toxicity determination or adverse events.
7. Patients with positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
8. Recurrence or second primary of HNSCC in a non previously irradiated area, or at a dose < 50 Gys
9. Macroscopic incomplete surgery (no debulking allowed)
10. Superficial recurrence without nodal recurrence, and without histologic gravity signs (histologic involvement of surgical margins, perineural spread)
11. Nodal recurrence less than 3 cm, without local recurrence and without capsular rupture at histologic examination
12. Serious medical adverse conditions, such as severe cardiac and/or pneumologic and/or liver dysfunction. Non exhaustive list, to be appreciated in each center
13. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to V5.0 du 28/11//2023 Confidential Page 8 of 68 autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
14. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
15. Patients requiring concomitant treatment with therapeutic doses of anticoagulants will not be eligible for this clinical trial. Patients treated with low dose of anticoagulants for thrombo-embolic events prophylaxis are allowed.
16. History of auto immune, immune mediated inflammatory disease including but not limited to colitis, pneumonitis, hepatitis, nephritis, inflammatory of skin, SNC, eyes, glands producing hormons
17. Active serious infections in particular if requiring systemic antibiotic or antimicrobial therapy
18. History of severe hypersensitivity reaction to any monoclonal antibody
19. History of allergy to study drugs components
20. Treatment with other investigational drugs or treatment in another clinical trial within the past 4 weeks before start of therapy or concomitantly with the trial
21. Pregnancy or breastfeeding
22. Psychological, familial or social factor incompatible with informed consent, and regular follow-up.
23. Previous allogenic stem cell transplant or patients recipient of solid organ transplant

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Two-years DFS, defined as the time from the beginning of the immunotherapy and the first locoregional or distant recurrence, or death from any cause, in cohorts 1 and 2

Secondary endpoints 4

1. Two-years DFS in cohorts 1bis and 2 bis
2. Grade 3, 4, 5 toxicity, quality of life, 1-year and 2-year overall survival
3. DFS in subgroups determined by HPV analysis, immunoscore, PDL1 immunohistochemistry (all cohorts)
4. PK, PD assessments

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Gustave Roussy

Sponsor organisation

Institut Gustave Roussy

Address

114 Rue Edouard Vaillant

City

Villejuif

Postcode

94800

Country

France

Scientific contact point

Organisation

Institut Gustave Roussy

Contact name

Bureau projet Promotion- DRC

Public contact point

Organisation

Institut Gustave Roussy

Contact name

Bureau projet Promotion- DRC

Locations

1 EU/EEA country · 13 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications