Induction and Maintenance Treatment With PARP Inhibitor and Immunotherapy in HPV-negative HNSCC
Trial statusRecruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorGruppo Oncologico del Nord-Ovest
About this trial
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).
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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.
Disqualifiers
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;
Trial design
Design model
Single group
Treatments tested in this trial
Niraparib
DrugFor 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.
Treatment groups
49 Participants
are divided into 1 treatment groupGroup A: Single Arm TreatmentExperimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
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
Time frame
Day 0, at surgery2
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.
Time frame
12 monthsSecondary outcomes
1
Radiological Response
Radiological response after 6 weeks of treatment evaluated at MRI prior to surgery by: 1. RECIST v1.1 using conventional MRI imaging 2. Diffusion Weighted Imaging Magnetic Resonance Imaging (DWI MRI)
Time frame
6 weeks of treatment2
Progression free survival
Progression free survival
Time frame
At the end of the treatment phase every 3 months for the first year and every 4 months for the second year3
Radiological and pathological response
Correlation between radiological and pathological response
Time frame
At the end of the treatment phase every 3 months for the first year and every 4 months for the second year4
Genomic expression
Correlation of predictive role of baseline genomic expression, immune infiltrate, PD-L1 evaluation (by CPS) and radiomic characteristics with regard to response to induction therapy and DFS
Time frame
At baseline and at surgery on day 0Sponsors and contacts
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Source ClinicalTrials.gov