Pharmacodynamic Study to Assess the Anti-proliferative Activity of the PARP Inhibitor Olaparib in Patients With HPV Positive and HPV Negative HNSCC
- Registration Number
- NCT02686008
- Lead Sponsor
- Yale University
- Brief Summary
This is an open label pilot study evaluating the pharmacodynamics and safety of single agent olaparib administered at 300mg bid (twice a day) for 14 days orally in patients with human papillomavirus (HPV) -positive and human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC)
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- WITHDRAWN
- Sex
- All
- Target Recruitment
- Not specified
- Histologically confirmed HNSCC with surgically resectable disease
- No prior chemotherapy or radiation therapy as treatment for the observed HNSCC
- Patients must provide written informed consent
- Age >=18 years of age
- Eastern Cooperative Oncology Group (ECOG) Performance Status score of <2
- Normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
- Hemoglobin >= 10 g/dL and no blood transfusions in the 28 days prior to entry/randomization
- Absolute neutrophil count >=1.5 x 10^9/L
- No features suggesting of MDS/AML on peripheral blood smear
- White blood cells > 3 x 10^9/L
- Platelet count >= 100 x 10^9/L
- Total bilirubin <= 1.5 x institutional upper limit of normal (ULN)
- AST (SGOT)/ALT (SGPT) < 2.5 x institutional upper limit of normal unless liver metastases are present in which case it must be < 5x ULN
- Serum creatinine <= 1.5 x institutional ULN OR creatinine clearance >= 50 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
- Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of the study participation and must have negative serum or urine pregnancy test within 1 week prior to beginning treatment on this trial
- Must be abler to understand and sign a written informed consent document
- Patients with known brain metastases. Patients may have received WBRT within 14 days or focal radiation within 1 week of cycle 1, day 1. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 28 days prior to treatment
- Women must not be pregnant or breastfeeding
- Patients with known hypersensitivity to olaparib or any of the excipients of the product
- Patients receiving any other investigational agents within 4 weeks of starting the study
- Involvement in the planning and/or conduct of the study
- Any previous treatment with a PARP inhibitor, including olaparib
- Concomitant use of known CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin, and nelfinavir
- Persistent toxicities (>=CTCAE grade 2)
- Resting ECG with QTC >470msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
- Blood transfusions within 1 month prior to study start
- Patients with myelodysplastic syndrome/acute myeloid leukemia
- Major surgery within 14 days of starting study treatment and patients must have recovered from any effects of any major surgery
- Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection.
- Unable to swallow oral medication
- Immunocompromised patients, e.g., patients who are known to be serologically positive for HIV and are receiving antiviral therapy
- Known active hepatic disease
- Uncontrolled seizures
- Previous cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for 5 years
- Currently on warfarin(subcutaneous heparin is permitted)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description HPV positive tumors Olaparib 10 patients with HPV positive tumors: p16 positive and HPV positive tumors HPV negative tumors Olaparib 10 patients with HPV negative tumors: Non-oropharyngeal tumors or p16 negative and HPV negative oropharyngeal tumors
- Primary Outcome Measures
Name Time Method Change in Level of IHC-Ki-67 expression Baseline and 14 days Tissue biopsy sections will be analyzed for proliferation (IHC-Ki-67) Ki-67 is a nuclear non-histone protein that is present at low levels in quiescent cells but is increased in proliferating cells. Thus, Ki-67 reactivity, defined as percent tumor cells staining positive as measured by immunohistochemical (IHC) staining, is a specific nuclear marker for cell proliferation.
- Secondary Outcome Measures
Name Time Method Change in Tissue apoptosis Baseline and 14 days Tissue biopsy sections will be analyzed for apoptosis. For example using the IHC-cleaved caspase-3 assay.
Change in DNA repair pathways Baseline and 14 days Tissue biopsy sections will be analyzed to determine effect on DNA repair pathways (PARP activity). Specifically Poly(ADP-ribose) immunohistochemical staining of tissue biopsies will be performed and PAR intensity scored as 0 (no signal), 1 (weak), 2 (strong intensity in \>50% of tumor cells).