Phase I Trial of Olaparib (AZD2281) in Combination With C225 and Radiation Therapy in Patients With Locally Advanced, Stage IVA-B Squamous Cell Carcinomas of the Head/Neck With Heavy Smoking Histories

University of Colorado, Denver1 site in 1 country17 target enrollmentOctober 22, 2012

Overview

Brief Summary

This is a research study that plans to learn more about the safety and tolerability of an investigational drug called Olaparib, in combination with radiation therapy and cetuximab.

Hypothesis: Intensity modulated radiotherapy with concurrent C225 and Olaparib represents a feasible, biologically-based alternative to standard chemoradiation, with acceptable toxicity, for treatment of locally-advanced HNSCC in patients having a ≥ 10 pack-year smoking history.

Detailed Description

Outcomes for heavy smokers with locally-advanced head and neck squamous cell cancer (HNSCC) treated with standard chemoradiation have been traditionally poor, suggesting a critical need for translation of novel biologically-based targeted approaches into clinical practice. In clinical trials, the Poly(ADP-ribose) polymerase-1 (PARP1) inhibitor Olaparib has been combined with other systemic agents, including paclitaxel, irinotecan, carboplatin and gemcitabine, in the treatment of patients with various solid tumors. Pre-clinical models have shown cooperative effects of combining PARP inhibition with radiation. A combined modality approach utilizing RT in combination with C225 and Olaparib after induction chemotherapy represents a rational, targeted approach for investigation in locally-advanced HNSCC patients.

Registry

clinicaltrials.gov

Start Date

October 22, 2012

End Date

October 31, 2018

Last Updated

6 years ago

Study Type

Interventional

Study Design

Single Group

Sex

All

Investigators

Sponsor

University of Colorado, Denver

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Provision of fully informed consent prior to any study specific procedures.
•Patients must be \> 18 years of age.
•Histologically or cytologically confirmed (from the primary lesion and/or regional lymph nodes) squamous cell carcinoma of the oropharynx, hypopharynx, or larynx that has not been previously treated or resected
•Stage IV A or stage IV B disease prior to induction chemotherapy with no proven hematogenous metastatic disease (includes T4aN0-1M0, T1-4aN2M0, T4b, any N, M0 or any T, N3M0)
•History of ≥ 10 pack-years of smoking cigarettes.
•Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
•Hemoglobin ≥ 9.0 g/dL
•Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
•White blood cells (WBC) \> 3x109/L
•Platelet count ≥ 100 x 109/L

Exclusion Criteria

•Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
•Previous enrollment (or assignment) in the present study
•Treatment with any investigational product during the last 14 days (or a longer period depending on the defined characteristics of the agents used)
•Any previous treatment with a PARP inhibitor, including olaparib.
•Patients with second primary 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.
•Patients receiving any systemic chemotherapy or targeted agents for treatment of the current HNSCC
•Patients receiving any prior radiation therapy to the head or neck.
•Patients receiving the following classes of inhibitors of Cytochrome P450 3A4 (see Section 5.4.2 for guidelines and wash out periods).
•Azole antifungals
•Macrolide antibiotics

Arms & Interventions

Olaparib with C225 and Radiation Therapy

Patients will begin taking Olaparib at the assigned dose three days prior to their first Cetuximab infusion. Patients will receive an initial dose of Cetuximab, 400 mg/m², intravenously over 120 minutes on Day 1. The initial dose of C225 will precede the start of radiation by 5-7 days. All patients will receive RT to a total dose of 69.3 Gy in 33 fractions over 6½ weeks. Weekly C225 will be administered at 250 mg/m2 in combination with daily RT. Patients will be assigned to receive Olaparib (25, 50, 100 or 200 mg bid) in combination with RT and C225. Olaparib will be taken twice daily, beginning three days prior to first scheduled C225 infusion. A further dose level of 300mg or 400mg may be considered should the 200mg Olaparib dose be well tolerated in this C225/RT combination schedule.

Intervention: Olaparib

Olaparib with C225 and Radiation Therapy

Patients will begin taking Olaparib at the assigned dose three days prior to their first Cetuximab infusion. Patients will receive an initial dose of Cetuximab, 400 mg/m², intravenously over 120 minutes on Day 1. The initial dose of C225 will precede the start of radiation by 5-7 days. All patients will receive RT to a total dose of 69.3 Gy in 33 fractions over 6½ weeks. Weekly C225 will be administered at 250 mg/m2 in combination with daily RT. Patients will be assigned to receive Olaparib (25, 50, 100 or 200 mg bid) in combination with RT and C225. Olaparib will be taken twice daily, beginning three days prior to first scheduled C225 infusion. A further dose level of 300mg or 400mg may be considered should the 200mg Olaparib dose be well tolerated in this C225/RT combination schedule.

Intervention: Cetuximab

Olaparib with C225 and Radiation Therapy

Patients will begin taking Olaparib at the assigned dose three days prior to their first Cetuximab infusion. Patients will receive an initial dose of Cetuximab, 400 mg/m², intravenously over 120 minutes on Day 1. The initial dose of C225 will precede the start of radiation by 5-7 days. All patients will receive RT to a total dose of 69.3 Gy in 33 fractions over 6½ weeks. Weekly C225 will be administered at 250 mg/m2 in combination with daily RT. Patients will be assigned to receive Olaparib (25, 50, 100 or 200 mg bid) in combination with RT and C225. Olaparib will be taken twice daily, beginning three days prior to first scheduled C225 infusion. A further dose level of 300mg or 400mg may be considered should the 200mg Olaparib dose be well tolerated in this C225/RT combination schedule.

Intervention: Radiation Therapy