OPHELIA (OPHELIA (OlaParib and durvalumab in 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 durvalumab and olaparib, cisplatin and olaparib, monotherapy with olaparib or no treatment, before starting standard treatment.
OPHELIA is a window-of-opportunity phase II study randomized between combination with durvalumab and olaparib, cisplatin and olaparib, monotherapy with olaparib or no treatment, before starting standard treatment. Although patients will be randomized between the 4 arms, no formal comparison between the 4 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. The primary endpoint will be the change in the tumour Ki-67 before and after treatment with the combination of olaparib + durvalumab or olaparib + cisplatin or olaparib monotherapy. 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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
41
50/25 mg BD split x 5 days
60 mg/m\^2 d1-d5
300 mg BD x 21-28 days.
1500 mg d1
Euromedica General Clinic of Thessaloniki
Thessaloniki, Thessaloniki, Greece
University Hospital "Attikon", 2nd Department of Internal Medicine, Division of Oncology
Athens, Greece
Investigation of the change in the tumour Ki-67 before and after treatment with the combination of olaparib + durvalumab or olaparib + cisplatin or olaparib monotherapy.
Time frame: At baseline and at the day of the surgery or 2nd biopsy (at days 23-29 days)
Objective response rate according to RECIST 1.1 criteria
Time frame: Imaging studies will be performed at baseline and on week 4
Pathologic complete response rate
Time frame: On week 4 only for operable patients
Metabolic response rate assessed by FDG-PET/CT scan (optional)
Time frame: At baseline, on week 4
Number of participants with tolerability to the treatment.
Time frame: From the 1st day of therapy and every week for 4 weeks maximum and 90 days after last therapy administration
Surgical complication rate
Time frame: Up to 30 days after surgery or the day of initiation of the next anticancer therapy
Mutations in genes associated with DNA repair
Time frame: At baseline, on day of surgery or the 2nd biopsy (at days 23-29)
Expression of tissue biomarker: PARP1
Time frame: At baseline, on day of surgery or the 2nd biopsy (at days 23-29)
Expression of tissue biomarker: BRACA1,2
Time frame: At baseline, on day of surgery or the 2nd biopsy (at days 23-29)
Expression of tissue biomarker: ERCC1
Time frame: At baseline, on day of surgery or the 2nd biopsy (at days 23-29)
Expression of tissue biomarker: PDL-1
Time frame: At baseline, on day of surgery or the 2nd biopsy (at days 23-29)
Expression of tissue biomarker: TILs
Time frame: At baseline, on day of surgery or the 2nd biopsy (at days 23-29)
Plasma methylation biomarker: PARP1 methylation in plasma cell-free DNA
Time frame: At baseline, a day before surgery and 90 days after surgery
Plasma methylation biomarker: BRCA1,2 methylation in plasma cell-free DNA
Time frame: At baseline, a day before surgery and 90 days after surgery
Plasma methylation biomarker: ERCC1 methylation in plasma cell-free DNA
Time frame: At baseline, a day before surgery and 90 days after surgery
Plasma methylation biomarker: RAD51C methylation in plasma cell-free DNA
Time frame: At baseline, a day before surgery and 90 days after surgery
Single-nucleotide polymorphisms: PARP-1 Val762Ala
Time frame: Sample will be collected once at baseline
Single-nucleotide polymorphisms: ERCC1 Asn118Asn (C/T)
Time frame: Sample will be collected once at baseline
Single-nucleotide polymorphisms:ERCC2 Lys751Gln (T/G)
Time frame: Sample will be collected once at baseline
Single-nucleotide polymorphisms: GSTP1 Ile105Val (A/G)
Time frame: Sample will be collected once at baseline
Single-nucleotide polymorphisms: XPD Lys751Gln (A/C, C/C)
Time frame: Sample will be collected once at baseline
Single-nucleotide polymorphisms: XRCC1 Arg399Gln (G/A)
Time frame: Sample will be collected once at baseline
Circulating tumor cells (CTCs) evaluated for DNA repair biomarkers
Time frame: At baseline, a day before surgery and 90 days after surgery
Circulating tumor cells (CTCs) evaluated for PD-L1
Time frame: At baseline, a day before surgery and 90 days after surgery
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