OPHELIA (OlaParib in patients with HEad and neck squamous-celL carcInomA) trial : Preoperative Administration of Olaparib With or Without Cisplatin in Patients Who Are Candidates for Surgery of Carcinoma of Head and Neck

Preoperative Administration of Olaparib With or Without Cisplatin in Patients Who Are Candidates for Surgery of Carcinoma of Head and Neck: Condition:   Squamous Cell Carcinoma of the Head and Neck

Interventions:   Drug: Olaparib;   Drug: Cisplatin;   Drug: Olaparib

Sponsors:   Hellenic Cooperative Oncology Group;   AstraZeneca;   Pfizer

OPHELIA (OlaParib in patients with HEad and neck squamous-celL carcInomA) trial is a Greek, investigator-initiated, randomized open-label window-of-opportunity phase II study. Patients with operable histologically documented squamous-cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx will be randomized between combination with cisplatin and olaparib, monotherapy with olaparib or no treatment, before standard treatment.

Condition	Intervention	Phase
Squamous Cell Carcinoma of the Head and Neck	Drug: Olaparib Drug: Cisplatin	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Factorial Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Phase ΙΙ (Window) Preoperative Study of Olaparib With or Without Cisplatin or no Treatment in Patients With Histologically Proven Squamous Cell Carcinoma of the Head and Neck Who Are Candidates for Surgery

Resource links provided by NLM:

Genetics Home Reference related topics: head and neck squamous cell carcinoma

MedlinePlus related topics: Cancer

Drug Information available for: Cisplatin Olaparib

U.S. FDA Resources 

Further study details as provided by Hellenic Cooperative Oncology Group:

Primary Outcome Measures:

• Investigation of the change between initial and post-treatment Ki67 measured on Formalin- Fixed Parafin-Embedded collected tumour biopsy or surgical sample, before and after treatment with the combination of olaparib + cisplatin or olaparib monotherapy. [ Time Frame: At baseline and at the day of the surgery or 2nd biopsy (at days 23-29 days) ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

• Objective response rate according to RECIST 1.1 criteria [ Time Frame: Imaging studies will be performed at baseline and on week 4 ] [ Designated as safety issue: No ]
• Pathologic complete response rate [ Time Frame: On week 4 only for operable patients ] [ Designated as safety issue: No ]
• Metabolic response rate assessed by FDG-PET/CT scan (optional) [ Time Frame: At baseline, on week 4 ] [ Designated as safety issue: No ]
• Number of participants with tolerability to the treatment. [ Time Frame: From the 1st day of therapy and every week for 4 weeks maximum and 30 days after last therapy administration ] [ Designated as safety issue: No ]
• Surgical complication rate [ Time Frame: Up to 30 days after surgery or the day of initiation of the next anticancer therapy ] [ Designated as safety issue: No ]
• Mutations in genes associated with DNA repair [ Time Frame: At baseline, on day of surgery or the 2nd biopsy (at days 23-29) ] [ Designated as safety issue: No ]
• Expression of tissue biomarker: PARP1 [ Time Frame: At baseline, on day of surgery or the 2nd biopsy (at days 23-29) ] [ Designated as safety issue: No ]
• Expression of tissue biomarker: BRACA1,2 [ Time Frame: At baseline, on day of surgery or the 2nd biopsy (at days 23-29) ] [ Designated as safety issue: No ]
• Expression of tissue biomarker: ERCC1 [ Time Frame: At baseline, on day of surgery or the 2nd biopsy (at days 23-29) ] [ Designated as safety issue: No ]
• Plasma methylation biomarker: PARP1 methylation in plasma cell-free DNA [ Time Frame: At baseline, a day before surgery and 30 days after surgery ] [ Designated as safety issue: No ]
• Plasma methylation biomarker: BRCA1,2 methylation in plasma cell-free DNA [ Time Frame: At baseline, a day before surgery and 30 days after surgery ] [ Designated as safety issue: No ]
• Plasma methylation biomarker: ERCC1 methylation in plasma cell-free DNA [ Time Frame: At baseline, a day before surgery and 30 days after surgery ] [ Designated as safety issue: No ]
• Plasma methylation biomarker: RAD51C methylation in plasma cell-free DNA [ Time Frame: At baseline, a day before surgery and 30 days after surgery ] [ Designated as safety issue: No ]
• Single-nucleotide polymorphisms: PARP-1 Val762Ala [ Time Frame: Sample will be collected once at baseline ] [ Designated as safety issue: No ]
• Single-nucleotide polymorphisms: ERCC1 Asn118Asn (C/T), ERCC2 Lys751Gln (T/G), GSTP1 Ile105Val (A/G), XPD Lys751Gln (A/C, C/C), XRCC1 Arg399Gln (G/A) [ Time Frame: Sample will be collected once at baseline ] [ Designated as safety issue: No ]
• Circulating tumor cells (CTCs) evaluated for DNA repair biomarkers [ Time Frame: At baseline, a day before surgery and 30 days after surgery ] [ Designated as safety issue: No ]
• Circulating tumor cells (CTCs) evaluated for PD-L1 [ Time Frame: At baseline, a day before surgery and 30 days after surgery ] [ Designated as safety issue: No ]

Estimated Enrollment:	39
Study Start Date:	September 2016
Estimated Study Completion Date:	June 2018
Estimated Primary Completion Date:	December 2017 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Monotherapy with olaparib Patients in the monotherapy arm will be treated with olaparib until the 21st -28th day depending on the day of surgery, will be reassessed by imaging (tumour objective response by RECIST) on the 22nd -28th day and then have a second biopsy or be operated on the 23rd - 29th day. If surgery is delayed, olaparib will be continued until the day before surgery.	Drug: Olaparib 300 mg BD x 21-28 days. Other Name: Lynparza
Experimental: Combination of cisplatin and olaparib Patients in the combination arm will receive treatment until the 5th day, will be reassessed by imaging (tumour objective response by RECIST) on the 22nd -28th day and then will have a second biopsy or be operated on the 23rd - 29th day.	Drug: Olaparib 50/25 mg BD split x 5 days Other Name: Lynparza Drug: Cisplatin 60 mg/m^2 d1-d5 Other Name: Platamine
No Intervention: No treatment arm Patients in the "no treatment" arm will wait to be operated or have a second biopsy on the 23rd - 29th day.Optionally, patients who have a baseline FDG-PET/CT scan may be re-examined on the 22nd -28th day by the same modality to assess metabolic response.

Detailed Description:

OPHELIA is a window-of-opportunity phase II study randomized between combination with cisplatin and olaparib, monotherapy with olaparib or no treatment, before standard treatment.

Although patients will be randomized between the 3 arms, no formal comparison between the 3 arms will be performed. Patients allocated to the olaparib monotherapy arm will serve as a proof-of-concept to interpret the mechanism of action of olaparib. Patients allocated in the "no treatment" group will be used as control.

Primary endpoint will be the change in tumour Ki67 (ΔKi67) that is caused by the investigational treatment. Secondary endpoints will be early tumour response by RECIST criteria, pathologic complete response rate, tolerability to treatment and surgical complications rate, and optionally, metabolic response assessed by FDG-PET/CT scan. Translational correlates will be tested in tumour tissue, plasma and germline DNA.

All the endpoints will be analyzed by an "as treated analysis" since the trial does not include a formal comparison of the treatment arms.

Administration of olaparib monotherapy has been associated with reports of the following laboratory findings and/or clinical diagnoses, generally of mild or moderate severity (CTCAE Grade 1 or 2) and generally not requiring treatment discontinuation.



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