Overview

Multi-center, open-label, non-randomized, non-comparative two-cohort study for patients with locally-advanced squamous cell carcinoma arising from the larynx, hypopharynx, oropharynx (Stage III, IVA and IVB according to 8th TNM/AJCC ed.) and oral cavity (unresectable, stage IVB according to 8th TNM/ American Joint Committee on Cancer (AJCC) ed.) who are candidates for definitive radiotherapy plus cisplatin (Cohort A) or as single-modality (in cisplatin unfit patient population) (Cohort B) and will receive dostarlimab and niraparib in combination pre-, during and post- radiation.

Study has three parts:

1. Neoadjuvant phase (immune-conditioning phase): patients will receive 1 dose of dostarlimab + niraparib from day -14 prior to radiotherapy (up to 48h prior to radiotherapy (RT) in Cohort A and until RT in Cohort B).
2. Concurrent phase (radiosensitization): patients will receive definitive radiotherapy (70Gy in 35 fractions) with concurrent cisplatin (Cohort A) or with concurrent niraparib (Cohort B).
3. Maintenance: Following radiotherapy, patients will receive adjuvant dostarlimab plus niraparib until week 48 (37 cycles) in both cohorts.

Eligibility

Inclusion Criteria:

Informed consent

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 > 18 years, male or female.

   Disease characteristics

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:
   1. Stage III HPV-related oropharyngeal carcinoma OR
   2. 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.
      • According to UICC/AJCC 8th Edition staging
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 human papilloma virus (HPV) DNA testing by in situ hybridisation (ISH) or polymerase chain reaction (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. 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.
7. 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.

   Patient characteristics

8. Eastern cooperative oncology group (ECOG) performance status 0-1.
9. Patient must have adequate organ function as determined by the following:
   1. Hematology i. Absolute neutrophils > 1.5 x 109/L ii. Platelets > 100 x 109/L iii. Hemoglobin > 90 g/L b. Biochemistry i. Bilirubin < 1.5 x upper limit of normal (ULN) ii. aspartate aminotransferase (AST) and alanine transaminase (ALT) < 2.5 x ULN Note: Hematology test should be obtained without transfusion or receipt of colony stimulating factors within 4 weeks prior to obtaining sample.

Specific criteria for Cohort A:

             iii. Creatinine clearance > 60 mL/min as per cockcroft -gault formula iv. Not
             presenting with peripheral neuropathy > grade 2 (CTCAE v5.0). v. Not presenting with
             clinically-significant hearing loss/tinnitus ≥ grade 3 (CTCAE v5.0).
             vi. 18-70 years old vii. Not presenting with cardiovascular disease: new york health
             association (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 (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)
         10. 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:
               1. 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).
               2. 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).
        Exclusion Criteria:
          1. Early stages, defined as stage I-II according to Union for International Cancer
             Control (UICC) / American Joint Committee on Cancer (AJCC) 8th Edition staging in any
             localization, and including HPV-related and non-related.
          2. Stage III-IVA oral cavity carcinoma considered resectable as per treating surgeon
             and/or multidisciplinary tumor board.
          3. Has cancer outside of the oropharynx, larynx, and hypopharynx, nasopharyngeal, sinus,
             other para-nasal, or other unknown primary head and neck carcinoma (HNC).
          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. Any previous radiotherapy treatment encompassing > 20 % of the bone marrow within 2
             weeks or any radiotherapy within 1 week prior to Day 1 of protocol therapy.
          8. Patients unable to swallow niraparib capsules/tablets.
          9. 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.
         10. 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.
         11. History of allergic or hypersensitivity reactions to any study drug or their
             excipients.
         12. Patients with rare hereditary problems of galactose intolerance, total lactase
             deficiency or glucose-galactose malabsorption should not take niraparib.
         13. 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.
         14. 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.
         15. History of interstitial lung disease e.g. pneumonitis requiring steroids (any dose) or
             immunomodulatory treatment within 90 days of planned start of the study therapy; or
             pulmonary fibrosis or evidence of pneumonitis on baseline CT scan.
         16. 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.
         17. Current or prior use of immunosuppressive medication within 14 days prior to starting
             dosing. The following are exceptions to these criteria:
               1. Intranasal, inhaled, topical steroids, or local steroid injections (eg,
                  intra-articular injection).
               2. Adrenal replacement steroid > 10 mg daily prednisone equivalent are permitted in
                  the absence of active autoimmune disease.
               3. Steroids as premedication for hypersensitivity reactions (eg, computed tomography
                  scan premedication).
         18. Active or documented history of autoimmune disease within 2 years before screening,
             including:
               1. Active or prior documented inflammatory bowel disease (eg. Crohn's disease,
                  ulcerative colitis).
               2. 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.
         19. History of primary immune deficiency. History of stroke or transient ischemic attack
             within the previous 6 months.
         20. 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.
         21. Any of the following cardiac abnormalities:
               1. Unstable angina pectoris,
               2. Congestive heart failure ≥ NYHA Class 2,
               3. QTc >480 milliseconds,
               4. Known Left ventricular ejection fraction (LVEF) < 50.
         22. Concomitant medication known to cause prolonged QT that cannot be discontinued or
             changed to a different medication prior to enrollment.
         23. History of organ transplant that requires use of immunosuppressive medications.
         24. Patients with prior history of posterior reversible encephalopathy syndrome (PRES)
         25. Known allergy or reaction to any components of niraparib and/or dostarlimab.
         26. Subjects who are human immunodeficiency (HIV) positive.
         27. 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 hepatitis C virus (HCV)
             RNA [qualitative] is detected).
               1. hepatitis B virus (HBV) DNA must be undetectable and HBsAg negative at Screening
                  Visit.
               2. Participants who have had definitive treatment for HCV are permitted if HCV RNA
                  is undetectable at Screening Visit.
         28. Female patients who are pregnant or breast-feeding.
         29. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             clinically significant infection requiring parenteral antibiotics 2 weeks before
             treatment start, unstable cardiac arrhythmia, 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.
         30. 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.
         31. Any previous treatment with poly-ADP ribose polymerase (PARP), programmed death ligand
             (PD-L1) and/or cytotoxic T lymphocyte associated protein (CTLA-4) inhibitors.
         32. History of another primary malignancy, except for:
               1. 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,
               2. Adequately treated non-melanoma skin cancer without evidence of disease,
               3. Adequately treated carcinoma in situ without evidence of disease.
         33. Major surgical procedure (as defined by the Investigator) within 28 days prior to the
             first dose of study medications.
         34. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous
             immunotherapy agent, or any unresolved irAE >Grade 1.
         35. Any malabsorption problem that, in the investigator's opinion, would prevent adequate
             absorption of the study drug.
         36. Known history of myelodysplastic syndrome (MDS) or a pre-treatment cytogenetic testing
             result at risk for a diagnosis of MDS/acute myeloid leukemia (AML).