Induction and Maintenance Treatment With PARP Inhibitor and Immunotherapy in HPV-negative HNSCC

NCT04681469 | Recruiting Phase 2

• 1 other identifier: PRIME H&N
• Study Type: interventional
• Target: 49
• Locations: 1 country
• Sites: 1

Brief Summary

We propose a window of opportunity trial to evaluate safety and efficacy of a short course of the study combination, composed by an Anti-PD-1 monoclonal antibody (Dostarlimab (TSR-042)) and a PARPi (Niraparib). The study population will be surgically resectable, HPV-negative (defined by p16 negative status) locally advanced HNSCC. Maintenance treatment will be then delivered, so to better integrate the therapeutic benefits of this drug combination. Response to neoadjuvant treatment will be evaluated by the rate of major pathologic response, morphologic, and functional imaging (MRI with functional evaluation -DWI). We anticipate that neoadjuvant and maintenance PARPi plus immunotherapy treatment could lead to a reduction of loco-regional recurrence (LRR) and distant metastasis (DM) rates in such a high-risk population. Furthermore, the window of opportunity portion of this trial will allow in vivo acquisition of valuable knowledge on mechanisms of action and primary resistance to Anti-PD-1 monoclonal antibody and PARPi in HNSCC. In this phase of the study, biological specimens will be collected (pre-treatment tumor biopsy, tissues from the surgical specimen, liquid biopsy, blood and saliva samples) as well as functional imaging (MRI).

Conditions

Head and Neck Squamous Cell Carcinoma

Outcome Measures

Primary Outcomes (2)

• Rate of Major Pathological Response (Treatment Activity)

  Rate of Major Pathological Response (MPR, i.e. less than 10% viable tumor cells identified on routine hematoxylin and eosin staining in pathological surgical specimen) in patients with locally advanced HNSCC treated with Niraparib + Dostarlimab (TSR-042) in the WoO setting

  Day 0, at surgery

• Incidence of grade 3-5 toxicities (Treatment Safety)

  Safety stopping rule: the first 6 patients will be evaluated for surgical toxicities graded according to Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 and documented over the 4 weeks period following surgery in order to determine if preoperative study protocol is safe. Once the safety is established total planned enrolment will be completed. Surgical safety in the whole population will be evaluated up to 4 weeks after surgery considering the following: 1. postoperative bleeding requiring surgical revision 2. delayed wound healing or wound dehiscence 3. wound infection 4. fistula 5. need for secondary surgical interventions (not considered part of institutional standard of care) 6. skin loss/flap necrosis including partial or total flap as applicable. Then, the safety of the entire treatment in terms of rate of grade \>3 adverse events, or hospitalization, or extension of the hospitalization due to complications will be assessed.

  12 months

Secondary Outcomes (4)

• Radiological Response

  6 weeks of treatment

• Progression free survival

  At the end of the treatment phase every 3 months for the first year and every 4 months for the second year

• Radiological and pathological response

  At the end of the treatment phase every 3 months for the first year and every 4 months for the second year

• Genomic expression

  At baseline and at surgery on day 0

Study Arms (1)

Single Arm Treatment

EXPERIMENTAL

For all patient's population: * Niraparib 200 mg/day: day -49 to day -21; * Dostarlimab 500 mg iv: day -49 and day -28; At day -21, clinical evaluation will be performed and the patient will be directed to surgery with exclusion from the study in case of progressive disease. Radiological assessment will be performed according to the physician's judgement. If no clinical evidence of disease progression: * Niraparib 200 mg/day: day -21 to day -7 * Dostarlimab 500 mg iv: day -7 * Radiological assessment (day -1, ± 3 days), * Surgery (original margin) at day 0 (±3 days) * Standard postoperative (chemo)radiotherapy according to pathologic report; * Maintenance Niraparib, 200 mg/day for 6 months * Maintenance Dostarlimab, 500 mg iv q3W for the first four cycles and 1000 mg iv Q6W thereafter for 3 months.

Drug: Niraparib

Interventions

Niraparib DRUG

For all patient's population: * Niraparib 200 mg/day: day -49 to day -21; * Dostarlimab 500 mg iv: day -49 and day -28; At day -21, clinical evaluation will be performed and the patient will be directed to surgery with exclusion from the study in case of progressive disease. Radiological assessment will be performed according to the physician's judgement. If no clinical evidence of disease progression: * Niraparib 200 mg/day: day -21 to day -7 * Dostarlimab 500 mg iv: day -7 * Radiological assessment (day -1, ± 3 days), * Surgery (original margin) at day 0 (±3 days) * Standard postoperative (chemo)radiotherapy according to pathologic report; * Maintenance Niraparib, 200 mg/day for 6 months * Maintenance Dostarlimab, 500 mg iv q3W for the first four cycles and 1000 mg iv Q6W thereafter for 3 months.

Also known as: Dostarlimab

Single Arm Treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients of both genders, aged ≥18 years;
• Signed written informed consent;
• Primary histologically proven p16 negative squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx amenable to surgery with curative intent. p16 status will be assessed as surrogate marker for HPV infection only for oropharyngeal cancers. p16 status will be assessed using the CINtec p16 Histology assay (Ventana Medical Systems, Tucson, AZ, USA) with strong and diffuse nuclear and cytoplasmic staining in at least 70% of cells used as the cutpoint for positivity.
• Clinical stage III-IV(M0) according to the VIII edition of AJCC staging system; recurrent/metastatic HNSCC, or previously treated HNSCC with local or systemic therapies, are not eligible for this study.
• Performance status ECOG 0-1;
• Availability of fresh tumor tissue via biopsy and provided for study purposes;
• Willing to provide blood and saliva samples for study purposes;
• Absence of a second malignancy (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, oesophageal, colon, endometrial, cervical/dysplasia, melanoma, or breast) unless a complete remission was achieved at least 2 years prior to study entry AND no additional therapy is required during the study period;
• Patient has adequate organ and marrow function (absolute neutrophil count ≥ 1500, hemoglobin ≥ 9.0 gram/deciliter (g/dL), platelet count ≥ 100,000, total bilirubin ≤1.5 times institution's upper limit of normal, AST/SGOT and ALT/SPGT ≤ 2.5 times institutional upper limit of normal, albumin ≥ 2.0 g/dL, serum creatinine ≤ 1.5 times institutional upper limit of normal or creatinine clearance ≥ 60 milliliters per minute (mL/min) according to Cockroft-Gault formula, or local institutional standard method);
• Patient must be able to swallow study drug;
• Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment;
• Female participant has a negative serum pregnancy test within 72 hours prior to taking study treatment if of childbearing potential and agrees to use an adequate method of contraception from screening through 180 days after the last dose of study treatment, or is of nonchildbearing potential. Nonchildbearing potential is defined as follows (by other than medical reasons):
• ≥45 years of age and has not had menses for \>1 year
• Patients who have been amenorrhoeic for \<2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation
• Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure, otherwise the patient must be willing to use an adequate barrier method throughout the study, starting with the screening visit through 180 days after the last dose of study treatment. See Section 3.3 for a list of acceptable birth control methods. Information must be captured appropriately within the site's source documents. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient.

You may not qualify if:

• Patient has recurrent/metastatic disease;
• Patient with locally advanced disease not amenable of surgery with curative intent;
• Patient has received prior local or systemic treatment for HNSCC;
• Patient with p16/HPV positive HNSCC;
• Patient with sinonasal, nasal cavity or nasopharyngeal cancer;
• Patient with SCC on neck disease with unknown primary tumor site;
• Patient must not be simultaneously enrolled in an interventional clinical trial;
• Patient must not have had major surgery ≤3 weeks prior to initiating protocol therapy and patient must have recovered from any surgical effects;
• Participant must not have received investigational therapy ≤ 4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is shorter, prior initiating protocol therapy;
• Participant has had radiation therapy encompassing \>20% of the bone marrow within 2 weeks; or any radiation therapy within 1 week prior to Day 1 of protocol therapy;
• Participant must not have a known hypersensitivity to niraparib and TSR-042 components or excipients;
• Participant must not have received a transfusion (platelets or red blood cells) ≤ 4 weeks prior to initiating protocol therapy;
• Participant must not have received colony stimulating factors (eg, granulocyte colony-stimulating factor, granulocyte macrophage colony stimulating factor, or recombinant erythropoietin) within 4 weeks prior initiating protocol therapy;
• Participant has had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy that persisted \> 4 weeks and was related to the most recent treatment;
• Participant must not have any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML);

Sponsors & Collaborators

• Gruppo Oncologico del Nord-Ovest: lead

Study Sites (1)

Asst Degli Spedali Civili Di Brescia

Brescia, 25123, Italy

RECRUITING

MeSH Terms

Conditions

Squamous Cell Carcinoma of Head and Neck

Interventions

niraparib; dostarlimab

Condition Hierarchy (Ancestors)

Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Head and Neck Neoplasms; Neoplasms by Site

Study Officials

• Paolo Bossi

  ASST Spedali Civili di Brescia

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Paolo Bossi

CONTACT

+390303998969; paolo.bossi@unibs.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 21, 2020
• First Posted: December 23, 2020
• Study Start: February 8, 2021
• Primary Completion: June 1, 2023
• Study Completion (Estimated): June 1, 2028
• Last Updated: August 4, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: since the end of the study for at least 5 years
• Access Criteria: direct request to PI

Locations

IT (1)