Phase Ib/II non-randomized non-comparative two-cohort study of Niraparib and Dostarlimab plus (Chemo)RadIotherapy in Locally-Advanced head and Neck squamous cell carcinoma (RADIAN)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Grupo Espanol De Tratamiento De Tumores De Cabeza Y Cuello

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

8 Nov 2023 → ongoing

Decision date (initial)

2024-08-27

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-516779-33-00

EudraCT number

2023-000183-65

ClinicalTrials.gov

NCT05784012

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

1. Cohort A: To estimate the efficacy (in terms of 1-year DFS) of niraparib and dostarlimab
given in combination as neoadjuvant and adjuvant therapy in patients with LA-HNSCC
treated with definitive radiotherapy and cisplatin.
2. Cohort B: To estimate the efficacy (in terms of 1-year DFS) of neoadjuvant, concurrent
and adjuvant niraparib in combination with neoadjuvant and adjuvant dostarlimab in
patients with LA-HNSCC unfit for cisplatin treated with definitive radiotherapy and
niraparib.

Secondary objectives 1

1. 1. To evaluate the safety and tolerability of niraparib and dostarlimab given in combination with (chemo)radiotherapy in patients with newly-diagnosed LA-HNSCC. 2. To evaluate the efficacy in terms of disease control rate and locoregional and distant control rates, event-free and overall survival of the combination of niraparib and dostarlimab in patients with newly-diagnosed LA-HNSCC treated with definitive (chemo)radiotherapy. 3. To evaluate the correlation between circulating biomarker dynamics and efficacy endpoints.

Conditions and MedDRA coding

Carcinoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Signed written and voluntary informed consent.
2. Patient must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
3. Age greater than or equal to 18 years, male or female.
4. Have histologically confirmed new diagnosis of non-metastatic squamous cell carcinoma as assessed by the Investigator based on baseline imaging and clinical assessment that is either: a. Stage III HPV-related oropharyngeal carcinoma OR b. Stage III, IVA and IVB HPV-unrelated oropharyngeal, laryngeal or hypopharyngeal carcinomas. Stage IVB oral cavity squamous cell carcinomas may be eligible upon consultation with Sponsor if considered unresectable as per treating surgeon and multidisciplinary tumor board.
5. Human papillomavirus (HPV)-relatedness in oropharyngeal primaries must be determined by positive p16 immunohistochemical staining on any tumor specimens and, if positive, confirmed by HPV DNA testing by in situ hybridization (ISH) or PCR. Positive p16 expression is defined as strong and diffuse nuclear and cytoplasmic staining in 70 % or more of the tumor cells. Local testing is acceptable.
6. Patients must have positive PD-L1 expression (CPS ≥ 1) by central laboratory (using PD-L1 immunohistochemistry [IHC] 22C3 pharmDx assay) on archival tumor tissue.
7. Have an evaluable tumor burden assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI) based on RECIST 1.1 as assessed by the local site investigator/radiology.
8. Have provided newly obtained core or excisional biopsy of a tumor lesion not previously irradiated for central biomarker analysis (fine needle aspirate [FNA] is not adequate). Repeat samples may be required if adequate tissue is not provided. Formalin-fixed, paraffin embedded tissue blocks are preferred to slides.
9. ECOG performance status 0-1.
10. Patient must have adequate organ function as determined by the following: a. Hematology i. Absolute neutrophils > 1.5 x 10 9 /L ii. Platelets > 100 x 10 9 /L iii. Hemoglobin > 90 g/L b. Biochemistry i. Bilirubin < 1.5 x upper limit of normal (ULN) ii. AST and ALT < 2.5 x ULN iii. Plasmatic albumin ≥ 3.0 g/dL. Specific criteria for Cohort A: iv. Creatinine clearance ≥ 60 mL/min as per cockroft-gault formula v. Not presenting with peripheral neuropathy ≥ grade 2 (CTCAE v5.0). vi. Not presenting with clinically-significant hearing loss/tinnitus (≥ grade 3 by CTCAE v5.0). vii. 18-69 years old (Patients ≥ 70 years old only eligible for cohort B) viii. Not presenting with cardiovascular disease: NYHA class II or higher, ischemic cardiovascular/cerebrovascular event in the past 12 months prior to inclusion in the study, clinically-significant peripheral arterial vasculopathy Specific criteria for Cohort B c. Patients considered unfit for cisplatin-based chemoradiotherapy, based on the following criteria (at least one): i. Creatinine clearance ≥30 but <60 mL/min ii. Impaired hearing loss/tinnitus (≥ grade 3 by CTCAE v5.0). iii. Peripheral neuropathy ≥grade 2 (CTCAE v5.0). iv. Age ≥ 70 years old * * Patients ≥ 70 years old must be fit according to the G8 geriatric screening test (G8 > 14 points)
11. Evidence of post-menopausal status, or negative urinary or serum pregnancy test for female pre-menopausal patients. 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: a. 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, bilateral salpingectomy or hysterectomy). b. 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).
12. Female subjects of childbearing potential must use effective contraception during therapy and for up to 180 days after receiving the last dose of niraparib or for 150 days after the last dose of dostarlimab.
13. Male patients with a female partner of childbearing potential: ● Non-sterilized males who are sexually active with a female partner of childbearing potential must use a male condom plus spermicide from screening through 150 days after receipt of the last dose of dostarlimab and/or 90 days after receipt of niraparib therapy whichever occurs later. ● Not engaging in sexual activity from screening through 150 days after receipt of the last dose of dostarlimab and/or 90 days after receipt of niraparib ( whichever occurs later) is an acceptable practice; however, occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Throughout this period, male patients should refrain from sperm donation, and female patients should refrain from egg cell donation. ● Female partners (of childbearing potential) of male patients must also use a highly effective method of contraception throughout this period

Exclusion criteria 32

1. Early stages, defined as stage I-II according to UICC/AJCC 8 th Edition staging in any localization, and including HPV-related and non-related.
2. Stage III-IVA oral cavity carcinoma, and stage IVB oral cavity carcinoma considered resectable as per treating surgeon and/or multidisciplinary tumor board.
3. Has cancer outside of the oropharynx, larynx, and hypopharynx and oral cavity.
4. Current history of other head and neck malignancies.
5. Any previous treatment for current head and neck cancer including systemic therapy, radiotherapy and/or surgery (except for a diagnostic biopsy) and no major surgery within 28 days prior to study treatment initiation.
6. Any previous radiation to the head and neck region that would result in overlap of fields for the current study.
7. Patients unable to swallow Niraparib tablets.
8. Documented weight loss of >10 % during the last 4 weeks prior to study treatment initiation (unless adequate measures are undertaken for nutritional support), OR plasmatic albumin < 3.0 g/dL. No albumin transfusions are allowed within 2 weeks before study treatment initiation.
9. Active gastrointestinal bleeding, or any other uncontrolled bleeding requiring more than 2 red blood cell transfusions or 4 units of packed red blood cells within 4 weeks prior to study treatment initiation.
10. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take niraparib.
11. History of primary immunodeficiency, history of allogeneic organ transplant that requires therapeutic immunosuppression and the use of immunosuppressive agents within 28 days of study treatment initiation or a prior history of severe (grade 3 or 4) immune mediated toxicity from other immune therapy or grade ≥ 3 infusion reaction.
12. 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, celiac disease (controlled by diet alone) or other serious gastrointestinal chronic conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis), rheumatoid arthritis, hypophysitis, uveitis, etc., within the past 3 years prior to the start of treatment. The following are exceptions to this criterion: vitiligo or alopecia; Patients with Grave’s disease, vitiligo or psoriasis not requiring systemic treatment (within the last 2 years); Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement. Any chronic skin condition that does not require systemic therapy.
13. History of interstitial lung disease e.g. pneumonitis requiring steroids (any dose) or immunomodulatory treatment within 90 days before the planned start of the study therapy; or pulmonary fibrosis or evidence of pneumonitis on baseline CT scan.
14. Any concurrent chemotherapy, biologic, immunologic or hormonal therapy for cancer treatment. Concurrent use of hormones for non-cancer-related conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable.
15. Current or prior use of immunosuppressive medication within 14 days prior to starting dosing. The following are exceptions to these criteria: a. Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection). b. Adrenal replacement steroid > 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease. c. Steroids as premedication for hypersensitivity reactions (eg, computed tomography scan premedication).
16. Active or documented history of autoimmune disease within 2 years before screening, including: a. Active or prior documented inflammatory bowel disease (eg. Crohn’s disease, ulcerative colitis). b. Patients with vitiligo, resolved childhood asthma/atopy, type I diabetes mellitus, Grave’s disease, Hashimoto’s disease, or psoriasis not requiring systemic steroids and/or immunosuppressive agents within the past 2 years, are not excluded.
17. History of stroke or transient ischemic attack within the previous 6 months.
18. History of uncontrolled hypertension: systolic BP >140 mmHg or diastolic BP >90 mmHg that has not been adequately treated or controlled prior to Day 1 of protocol therapy.
19. Any of the following cardiac abnormalities: a. Unstable angina pectoris, b. Congestive heart failure ≥ NYHA Class 2, c. QTc >480 milliseconds. QTc calculation using Fridericia formula (ms) d. Known Left ventricular ejection fraction (LVEF) < 50. e. Unstable cardiac arrhythmia
20. Concomitant medication known to cause prolonged QT that cannot be discontinued or changed to a different medication prior to enrollment.
21. Patients with prior history of posterior reversible encephalopathy syndrome (PRES)
22. Known allergy or reaction to any components of niraparib and/or dostarlimab.
23. Subjects who are human immunodeficiency (HIV) positive.
24. Has a known history of or is positive for active hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (defined as HCV RNA [qualitative] is detected). a. HBV DNA must be undetectable and HBsAg negative at Screening Visit. b. Participants who have had definitive treatment for HCV are permitted if HCV RNA is undetectable at Screening Visit.
25. Female patients who are pregnant or breast-feeding. Women of childbearing potential should not become pregnant while on treatment and should not be pregnant at the beginning of treatment.
26. Uncontrolled intercurrent illness including, but not limited to, ongoing or active clinically significant infection requiring parenteral antibiotics 2 weeks before treatment start, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring adverse events from niraparib and/or dostarlimab, or compromise the ability of the subject to give written informed consent.
27. Any condition that, in the opinion of the Investigator, would interfere with evaluation of the study regimen or interpretation of patient safety or study results.
28. History of another primary malignancy, except for: a. Malignancy treated with curative intent and with no known active disease ≥3 years before the first dose of study drug and of low potential risk for recurrence, b. Adequately treated non-melanoma skin cancer without evidence of disease, c. Adequately treated carcinoma in situ without evidence of disease.
29. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of study medications. Scheduled PEG implantation and planned tracheostomy are not considered major surgery.
30. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1.
31. Any malabsorption problem that, in the investigator's opinion, would prevent adequate absorption of the study drug.
32. Known history of myelodysplastic syndrome (MDS) or a pre-treatment cytogenetic testing result at risk for a diagnosis of MDS/acute myeloid leukemia (AML).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 1-year disease free survival

Secondary endpoints 3

1. ● Treatment-related adverse events (TRAEs) as per NCI CTCAE v5.0. ● Rate of completion of niraparib during the neoadjuvant phase. ● Rate of disease progression as per clinical examination per treating physician during neoadjuvant phase. ● Rate of radiotherapy completion. ● Rate of completion of the maintenance phase of the study
2. ● Locoregional control at 12, 18 and 24 months ● Distant control at 12, 18 and 24 months ● Event-free survival ● Overall survival
3. ● Correlation between levels of circulating tumor DNA (ctDNA) clearance at post-treatment timepoints and 1-year disease-free survival in patients with positive/detectable ctDNA at baseline. ● Correlation of ctDNA dynamics (increase/decrease) across timepoints: Pre first dose dostarlimab (Day -21); Pre first dose niraparib (Day -14); Pre radiotherapy; At cycle 4 of maintenance; EOT and/or PD, and 1-year disease-free survival and secondary outcomes.

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Grupo Espanol De Tratamiento De Tumores De Cabeza Y Cuello

Sponsor organisation

Grupo Espanol De Tratamiento De Tumores De Cabeza Y Cuello

Address

Calle De Velazquez 7 Planta 3

City

Madrid

Postcode

28001

Country

Spain

Scientific contact point

Organisation

Grupo Espanol De Tratamiento De Tumores De Cabeza Y Cuello

Contact name

A person designed by the Sponsor

Public contact point

Organisation

Grupo Espanol De Tratamiento De Tumores De Cabeza Y Cuello

Contact name

A person designed by the Sponsor

Third parties 1

Locations

1 EU/EEA country · 7 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

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

Documents 8 files

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

Application history

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