A Phase I/II Study of Rucaparib, a PARP Inhibitor, in Patients with gBRCA Mutation Breast or Ovarian Cancer, or Other Solid Tumor

• Conditions: Patients with locally advanced or metastatic solid tumors who have progressed on standard therapy and patients with locally advanced or metastatic breast cancer with evidence of a germline mutation of BRCA1 or BRCA2 (gBRCA), and patients with platinum-sensitive relapsed ovarian cancer with evidence of a gBRCA mutation.; MedDRA version: 15.0Level: LLTClassification code 10049280Term: Solid tumourSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 15.0Level: LLTClassification code 10033130Term: Ovarian cancer NOSSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 15.0Level: LLTClassification code 10006192Term: Breast cancer NOSSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 15.0Level: LLTClassification code 10025315Term: Lymphoma malignantSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2011-004250-26-DE
• Lead Sponsor: Clovis Oncology Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2012-09-05
• Last Update Posted: 28 October 2013

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 122

Inclusion Criteria

For all patients:
1. Understand and voluntarily sign an approved informed consent form prior to any study-specific evaluation
2.Be >=18 years of age at the time the informed consent form is signed
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
4.Have a life expectancy of at least 3 months
5.Have adequate organ function, confirmed by the following laboratory values obtained =14 days prior to the first dose of rucaparib:
-Bone Marrow Function:
-Absolute neutrophil count =1.5 × 10e9/L
-Platelets >100 × 10e9/L
-Hemoglobin =9 g/dL
-Hepatic Function
-Aspartate aminotransferase and alanine aminotransferase =3 × upper limit of normal (ULN); if liver metastases, then =5 × ULN
-Bilirubin =1.5 × ULN
-Renal Function
-Serum creatinine =1.5 × ULN
6.Have left ventricular ejection fraction > lower level of normal as determined by echocardiogram or multigated acquisition scan evaluation using local institutional standard

Patients enrolling into Part 1 (Phase I portion) must also meet the following inclusion criteria:
7.(a) Have a histologically or cytologically confirmed solid tumor (lymphoma is included in this category) that is locally recurrent or metastatic and has progressed on standard treatment
8.(a) Be willing and able to eat a high-fat breakfast on Day 1 of the study (Note: only applicable for patients being screened for enrollment into a food-effect pharmacokinetic cohort)

Patients enrolling into Part 2 (Phase II portion) must also meet the following inclusion criteria:
Breast Cancer Arm:
7.(b) Have locally advanced or metastatic breast cancer associated with known deleterious gBRCA mutation (as determined by a local laboratory that has received an international or country-specific quality standards certification) that has progressed on at least one, but no more than three, treatment regimen(s) in the advanced or metastatic setting
8.(b) Tumor must be human epidermal growth factor receptor 2 (HER2) non-overexpressing by immunohistochemistry (IHC) (0,1+) or, IHC 2+ and fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) negative; patients IHC 3+ or FISH/CISH positive are not eligible
9.(b) Have evidence of measurable disease as defined by RECIST Version 1.1

Ovarian Cancer Arm:
7.(c) Have ovarian cancer associated with known deleterious gBRCA mutation (as determined by a local laboratory that has received an international or country-specific quality standards certification)
8.(c) Have received at least two, but no more than three, prior regimens (all platinum-based) and currently have platinum-sensitive relapsed disease, i.e., disease progression that occurred at least 6 months after completion of platinum-based therapy. Prior bevacizumab administered as part of the frontline platinum-based treatment followed by maintenance is permitted. Disease progression must have been confirmed by radiologic assessment. Patient must also have been sensitive to all prior platinum regimens received.
9.(c) Have evidence of measurable disease as defined by RECIST Version 1.1
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 110
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 12

Exclusion Criteria

For all patients:
1.History of prior malignancy except:
(a) Curatively treated non-melanoma skin cancer
(b) Solid tumor treated curatively more than 5 years ago without evidence of recurrence
(c) Synchronous endometrial cancer (Stage IA) with ovarian cancer
2.Prior treatment with any PARP inhibitor, including oral or intravenous rucaparib. Patients who previously received iniparib are eligible
3.Untreated or symptomatic central nervous system (CNS) metastases. Patients with asymptomatic CNS metastases are eligible provided they have been clinically stable for at least 4 weeks
4.Impaired cardiac function or clinically significant cardiac disease, including any of the following:
(a) Unstable angina pectoris =3 months prior to first scheduled dose of rucaparib
(b) Acute myocardial infarction =3 months prior to first scheduled dose of rucaparib
5.Known human immunodeficiency virus or acquired immunodeficiency syndrome-related illness, or history of chronic hepatitis B or C
6.Treatment with chemotherapy, radiation, hormones (except corticosteroids and megestrol acetate), antibody or other immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, matrix metalloprotease inhibitors, or experimental drugs =14 days prior to first dose of oral rucaparib and/or ongoing adverse effects from such treatment > NCI CTCAE Grade 1.
7.Ongoing requirement for therapeutic anticoagulant therapy (low-dose anticoagulants or low molecular weight heparin for prevention of deep venous thrombosis or maintenance of patency of central venous devices may be allowed provided target international normalized ratio[ INR] is =1.5)
8.Administration of strong CYP1A2 or CYP3A4 inhibitors =7 days prior to first scheduled dose of rucaparib
9.Surgical procedures =5 days prior to first scheduled dose of rucaparib; in all cases, the patient must be sufficiently recovered and stable before treatment administration.
10.Females who are pregnant or breastfeeding
11.For fertile patients (male and female), refusal to use effective contraception during the period of the trial and for 6 months after the last dose of oral rucaparib
12.Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study (e.g., substance abuse; psychiatric disturbance; or uncontrolled intercurrent illness including active infection, arterial thrombosis, and symptomatic pulmonary embolism)
13.Presence of any other condition that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the opinion of the investigator, would make the patient inappropriate for entry into the study
14. History of clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia’s method (QTcF) >450 msec (males) or >470 msec (females), PR >240 msec, or QRS >110 msec

Patients enrolling into Part 1 (Phase I portion) of the study will also be excluded from participation if any of the following criteria apply:
15. Family history of long QT syndrome
16. Implantable pacemaker or implantable cardioverter defibrillator, and
17. Requires treatment with any medication known to produce QT prolongation

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified