A Phase 3 study of Dostarlimab as Sequential Therapy after Chemoradiation compared to placebo in adult participants with Locally Advanced Unresected Head and Neck Squamous Cell Carcinoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Glaxosmithkline Research & Development Limited, Glaxosmithkline Research & Development Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

29 May 2024 → ongoing

Decision date (initial)

2024-04-29

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Pharma R&D

External identifiers

EU CT number

2023-508613-17-00

ClinicalTrials.gov

NCT06256588

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate the efficacy of dostarlimab as sequential therapy following CRT as compared to placebo in participants with PD-L1 positive LA unresected HNSCC as per BICR.

Secondary objectives 5

1. To estimate the difference in overall survival (OS) for participants treated with dostarlimab as sequential therapy following CRT as compared to placebo in participants with LA unresected HNSCC.
2. To evaluate the efficacy of dostarlimab as sequential therapy following CRT as compared to placebo in participants with PD-L1 positive LA unresected HNSCC as per investigator assessment.
3. Evaluate the safety and tolerability of dostarlimab compared to placebo.
4. To describe the pharmacokinetics of dostarlimab administered after CRT in participants with LA unresected HNSCC, that has not been previously treated.
5. To determine the immunogenicity of dostarlimab administered after CRT in participants with LA unresected HNSCC, that has not been previously treated.

Conditions and MedDRA coding

Neoplasms, Head and Neck

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Plan to share IPD

Yes

IPD plan description

IPD plan description: Study Sponsor will assess requests from qualified researchers for anonymized individual patient-level data (IPD) and related study documents. Data sharing is subject to certain criteria, conditions, and exceptions. For further information, refer to https://www.gsk-studyregister.com/About_GSK_Patient_Level_Data_Sharing_Final_13July2023.pdf IPD Sharing Access Criteria: Anonymized IPD is shared with researchers whose proposals are approved by an Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension may be granted, when justified, for up to 6 months. IPD Sharing Time Frame:Anonymized IPD will be made available within 6 months of publication of primary, key secondary and safety results for studies in product with approved indication(s) or terminated asset(s) across all indications.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Is at least 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of signing the informed consent form (ICF).
2. Has newly diagnosed unresected LA histologically confirmed HNSCC of the oral cavity, oropharynx, hypopharynx or larynx and completed cisplatin plus radiotherapy (termed “CRT” in this protocol) with curative intent and has no evidence of distant metastatic disease.
3. 3. Disease defined as: a) Oropharyngeal p16 positive: T4 (N0-N3), M0; N3 (T1-T4), M0 b) Oropharyngeal p16 negative: Any T3-T4 (N0-N3), M0; Any N2a-N3 (T1-T4), M0 c) Larynx/hypopharynx/oral cavity (independent of p16): Any T3-T4 (N0-N3), M0; Any N2a-N3 (T1-T4), M0. NOTE: Tumors to be staged according to the 8th edition of the American Joint Committee on Cancer (AJCC) staging manual (Amin, 2017). NOTE: Participants with distant metastases (defined as new tumor identified at a site distant from the head and neck anatomic region or draining lymph nodes), including central nervous system (CNS) metastases and/or carcinomatosis, are not eligible, either pre-CRT, or in the screening period post-CRT. NOTE: For eligibility assessment: TNM stage for oropharyngeal HNSCC must be based on p16 status as determined by CINtec assay.
4. 4. Participants must have met the following minimum requirements for CRT delivered as part of local SoC: a. For Cisplatin: Minimum cumulative exposure of 200 mg/m2 as part of CRT, delivered as either Q3W (e.g., 100 mg/m2 cycles), or Q1W (e.g., 40 mg/m2) cycles. Dose delays and dose modification are permitted per local practice providing all other requirements are met. It is recommended that concurrent cisplatin and RT be started and completed as close to each other as possible. b. Total Radiation dose of 65 Gy to 72 Gy over 6 – 7 weeks (up to +7 days if required) to the high-risk disease site.
5. 5. Has provided acceptable core or excisional biopsy obtained prior to CRT (see Laboratory Manual for detail) demonstrating: a. PD-L1 positive tumor status as defined by CPS ≥ 1 using the Agilent 22C3 assay performed at central laboratory. b. If the primary tumor site is oropharyngeal carcinoma, the participant must have HPV results defined as p16 IHC testing using the CINtec p16 histology assay and a ≥70% cutoff point (p16 IHC positive is ≥70% of carcinoma TC(s) with nuclear and cytoplasmic moderate to strong staining; see Section 8.1.5 for details). If HPV status was previously tested locally using the CINtec assay (compliant to applicable local regulation), no additional central lab testing will be required.
6. 6. Participants with known HIV infection are allowed with the following requirements: a) Documented evidence of plasma HIV-1 RNA levels persistently <50 c/mL confirmed ≤3 months prior to AND at screening; Plasma HIV-1 RNA consistently <50 c/ml required; if single increase >50 c/ml occurred, they cannot have been persistent nor associated with antiretroviral resistance per investigator assessment unless undetectable viral load is defined differently by local guidelines and agreed with the sponsor’s Central Study Team. In the 3 to 12 months prior to screening, plasma HIV-1 RNA levels consistently <50 c/mL are required; if single/isolated increases ≥50 c/mL occurred and are thought to be neither persistent nor associated with antiretroviral resistance per investigator assessment, the participant would be eligible if entry criteria are otherwise met. AND b) CD4 cell count ≥350 cells/mm3 over the 12 months prior to AND at screening (and no measurement <350cells/mm3 during that time period) AND c) Is on an uninterrupted combination antiretroviral therapy (ART) regimen for at least 3 months prior to screening, with a combination ART regimen consistent with locally recommended guidelines. NOTE: Participants who test as HIV positive during Screening will not be eligible for the study by default, owing to insufficient time to meet the safety requirements described in inclusion criteria 6, a, b, and c (above).
7. No history of HIV-associated non-Hodgkin lymphoma ≤5 years prior to study entry and no history of HIV- associated invasive cervical cancer.
8. No treatment with an HIV-1 immunotherapeutic vaccine within 90 days of screening.

Exclusion criteria 10

1. 1. Has received prior radiation therapy, systemic therapy, targeted therapy, or surgery for management of head and neck cancer not considered part of CRT. Participants receiving induction chemotherapy are excluded. CRT combinations with components other than cisplatin and RT (e.g., experimental agents, including radiosensitizers/radioprotectants, cetuximab) are not eligible.
2. 2. Has cancer outside of the oropharynx, larynx, hypopharynx or oral cavity, such as nasopharyngeal, sinus, other para-nasal, or other unknown primary head and neck cancer. Has more than one primary HNSCC tumor
3. Any unresolved toxicity CTCAE >Grade 2 from the prior CRT.
4. Has a known additional malignancy that progressed or required active treatment within the past 2 years.
5. Has Grade 3-4 bleeding due to underlying malignancy or has high risk of bleeding (examples include but not limited to tumors encasing or infiltrating a major vessel (i.e., carotid artery, jugular vein) and/or other high-risk features such as an arteriovenous fistula.
6. Is immunocompromised in the opinion of the investigator.
7. Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
8. 11. Has any history of interstitial lung disease or pneumonitis (past or current).
9. 8. Has experienced any of the following with prior immunotherapy: any imAE of Grade ≥3, immune-mediated severe neurologic events of any grade (e.g., myasthenic syndrome/myasthenia gravis, encephalitis, Guillain-Barré Syndrome, or transverse myelitis), exfoliative dermatitis of any grade (Stevens-Johnson Syndrome, toxic epidermal necrolysis, or DRESS syndrome), or myocarditis of any grade. Non-clinically significant laboratory abnormalities are not exclusionary.
10. 23. Has documented presence of HBsAg at Screening or within 3 months prior to randomization. Participants with a negative HBsAg and positive HBcAb result are eligible only if HBV DNA is negative.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Event Free Survival (EFS) where an event is defined as: • First record of locoregional progression or recurrence, or distant metastasis per RECIST 1.1 as per BICR, • Salvage surgery at the primary tumor site when invasive cancer is present, • Neck dissection or surgery performed >20 weeks after completion of CRT when invasive cancer is present, • Death from any cause.

Secondary endpoints 5

1. OS, defined as time from randomization to death from any cause
2. Event Free Survival (EFS) where an event is defined as: • First record of locoregional progression or recurrence, or distant metastasis per RECIST 1.1 as per investigator assessment. • Salvage surgery at the primary tumor site when invasive cancer is present. • Neck dissection or surgery performed >20 weeks after completion of CRT when invasive cancer is present. • Death from any cause.
3. Frequency and severity of TEAEs, immune-mediated TEAEs, SAEs TEAE/SAEs leading to dose delays, withdrawal or death. Clinically significant changes in laboratory, vital signs, and safety assessment parameters
4. Serum concentrations and relevant PK parameters (C-EoI and C trough) for dostarlimab
5. Incidence of ADA against dostarlimab

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Glaxosmithkline Research & Development Limited

Sponsor organisation

Glaxosmithkline Research & Development Limited

Address

G S K House, 980 Great West Road 980 Great West Road

City

Brentford

Postcode

TW8 9GS

Country

United Kingdom

Scientific contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Public contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Third parties 28

Glaxosmithkline Research & Development Limited

Sponsor organisation

Glaxosmithkline Research & Development Limited

Address

79 New Oxford Street

City

London

Postcode

WC1A 1DG

Country

United Kingdom

Sponsor responsibilities

Article 77 compliance

Glaxosmithkline Research & Development Limited

Contact point sponsor

Glaxosmithkline Research & Development Limited

Article 77 implementation

Glaxosmithkline Research & Development Limited

Locations

13 EU/EEA countries · 94 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 421 files

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

Application history

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