Clinical Trials Register

Summary
EudraCT Number:	2011-004250-26
Sponsor's Protocol Code Number:	CO-338-010
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-09-05
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2011-004250-26

A.3

Full title of the trial

A Phase I/II, Open-Label, Safety, Pharmacokinetic, and Preliminary Efficacy Study of Oral Rucaparib in Patients with gBRCA Mutation Breast or Ovarian Cancer, or Other Solid Tumor

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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

A.4.1

Sponsor's protocol code number

CO-338-010

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Clovis Oncology Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Clovis Oncology Inc., 2525 28th Street Suite 100, Boulder, CO 80301
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Clovis Oncology UK Ltd
B.5.2	Functional name of contact point	Dr Lindsey Rolfe
B.5.3	Address:
B.5.3.1	Street Address	Sheraton House, Castle Park
B.5.3.2	Town/ city	Cambridge
B.5.3.3	Post code	CB3 0AX
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+4401223370037
B.5.6	E-mail	lrolfe@clovisoncology.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Rucaparib
D.3.2	Product code	CO-338 (previously known as PF-01367338)
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Rucaparib
D.3.9.2	Current sponsor code	CO-338
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Rucaparib
D.3.2	Product code	CO-338 (previously known as PF-01367338)
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Rucaparib
D.3.9.2	Current sponsor code	CO-338
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	60
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

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.

E.1.1.1

Medical condition in easily understood language

Patients with solid tumors and patients with breast cancer or ovarian cancer associated with gBRCA mutations

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.0
E.1.2	Level	LLT
E.1.2	Classification code	10049280
E.1.2	Term	Solid tumour
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.0
E.1.2	Level	LLT
E.1.2	Classification code	10033130
E.1.2	Term	Ovarian cancer NOS
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.0
E.1.2	Level	LLT
E.1.2	Classification code	10006192
E.1.2	Term	Breast cancer NOS
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.0
E.1.2	Level	LLT
E.1.2	Classification code	10025315
E.1.2	Term	Lymphoma malignant
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the safety profile of escalating doses of continuous daily oral rucaparib in patients with advanced solid tumors, and to determine the maximum tolerated dose and recommended Phase II Dose (Part 1 only)
To characterize the pharmacokinetic profile of oral rucaparib when administered as a continuous daily dose (Part 1 only)
To evaluate overall response rate in patients with locally advanced or metastatic breast cancer associated with gBRCA mutation and in patients with relapsed platinum-sensitive ovarian cancer associated with a gBRCA mutation (Part 2 only)

E.2.2

Secondary objectives of the trial

To characterize the single-dose pharmacokinetic profile of oral rucaparib after a high-fat breakfast compared to that in the fasted state
(Part 1 only)
To evaluate the effects of oral rucaparib on the QT/QTc interval measured by electrocardiogram (Part 1 only)
To evaluate the safety and tolerability of oral rucaparib (Part 1 and Part 2)
To evaluate duration of response in patients with locally advanced or metastatic breast cancer associated with gBRCA mutation and in patients with relapsed platinum-sensitive ovarian cancer associated with a gBRCA mutation (Part 2 only)
To evaluate antitumor activity of oral rucaparib in various solid tumors (Part 1 only)

E.2.3

Trial contains a sub-study

E.3

Principal 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

E.4

Principal 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

E.5 End points

E.5.1

Primary end point(s)

1.The incidence of Grade 3 or 4 adverse events (AEs) and clinical laboratory abnormalities defined as DLTs (Part 1 only)
2.PK parameters: area under the curve from time zero to time t (AUC0-t), AUC from time zero to infinity (AUC0-∞), Cmax, time to maximum concentration (Tmax), elimination half-life (t1/2), elimination rate constant (kel), volume of distribution at steady state after non-iv administration (Vss/F), and total plasma clearance (Cl/F)(Part 1 only)
3.ORR per RECIST Version 1.1 (Part 2 only)

E.5.1.1

Timepoint(s) of evaluation of this end point

Not Applicable

E.5.2

Secondary end point(s)

1.PK parameters Cmax and AUC (fasted and fed)(Part 1 only)
2.Change from baseline in QT/QTc interval (Part 1 only)
3.The incidence of AEs, clinical laboratory abnormalities, and ECG abnormalities (Parts 1 and 2)
4.Duration of response per RECIST Version 1.1 (Part 2 only)
5.Response per RECIST Version 1.1 (Part 1 only)

E.5.2.1

Timepoint(s) of evaluation of this end point

Not Applicable

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Canada

Israel

United States

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The trial will be completed when all enrolled patients have experienced Progressive Disease, or have discontinued the study due to another reason.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

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:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

122

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Not applicable. After the end of the study, patients will receive subsequent anticancer therapy at the investigator's discretion.

No aplicable, tras la finalizacion del estudio , los pacientes recibiran tratamiento oncologico a discreción del invetigador

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-12-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-12-06

P. End of Trial
P.	End of Trial Status	Completed

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