Final Report of a Phase I Trial of Olaparib with Cetuximab and Radiation for Heavy Smoker Patients with Locally Advanced Head and Neck Cancer.

Purpose: Our goal was to evaluate the safety and toxicity of combining a PARP inhibitor, olaparib with cetuximab and fractionated intensity modulated radiation therapy for patients with locally advanced head and neck cancer and heavy smoking histories. Experimental Design: Patients with ≥10 pack/year history of smoking were treated with olaparib at doses ranging from 25 mg-200 mg orally twice daily (BID) beginning ~10 days prior to initiation of and with concurrent radiation (69.3 Gy in 33 fractions) using a TITE-CRM model. Cetuximab was administered starting ~5 days prior to radiation per standard of care. Results: A total of 16 patients were entered onto the study with 15 evaluable for acute toxicity. The most common treatment-related Grade 3-4 side effects were radiation dermatitis and mucositis (38% and 69%, respectively). The maximum tolerated dose was determined to be 50 mg PO BID, but the RP2D was deemed to be 25 mg PO BID. At a median follow up of 26 months, the actuarial median overall survival was 37 months but was not reached for other endpoints. Two-year overall survival, progression free survival, local control, and distant control rates were 72%, 63%, 72%, 79%, respectively. Patients who continued to smoke during therapy experienced higher recurrence rates. MYCand KMT2Awere identified as potential correlatives of response on gene amplification and mutational analysis. Conclusion: Olaparib at 25 mg oral BID with concurrent cetuximab and radiation was well tolerated with reduced dermatitis within the radiation field. Responses rates were promising for this high-risk population.

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