| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with locally advanced or metastatic solid tumors including lymphoma and germline BRCA (gBRCA) ovarian cancer |
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| E.1.1.1 | Medical condition in easily understood language |
Patients with solid tumors and patients with ovarian cancer associated with gBRCA mutations
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| 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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049280 |
| E.1.2 | Term | Solid tumour |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033130 |
| E.1.2 | Term | Ovarian cancer NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025315 |
| E.1.2 | Term | Lymphoma malignant |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1. 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)
2. To characterize the pharmacokinetic profile of oral rucaparib when administered as a continuous daily dose (Part 1 and Part 3 only)
3. To evaluate overall response rate in patients with platinum-sensitive, relapsed, high-grade serous or endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer associated with a BRCA mutation[henceforth abbreviated to platinum- sensitive OC population] |
|
| E.2.2 | Secondary objectives of the trial |
1. To characterize the single-dose pharmacokinetic profile of oral rucaparib after a high-fat breakfast compared to that in the fasted state (Part 1 and Part 3 only)
2. To evaluate the effects of oral rucaparib on the QT/QTc interval measured by electrocardiogram (Part 1 only)
3. To evaluate the safety and tolerability of oral rucaparib (Part 1, 2 and 3)
4. To evaluate duration of response in the OC population(Part 2 only)
5. To evaluate antitumor activity of oral rucaparib in various solid tumors (Part 1 and Part 3 only)
6. To assess progression-free survival in the OC population (Part 2 only)
7. To evaluate survival (Part 2B only) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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 (<2 × ULN if hyperbilirubinemia is due to Gilbert's syndrome)
-Serum albumin ≥30 g/L (3.0 g/dL) (Part 2B only)
-Renal Function
-Serum creatinine ≤1.5 × ULN
Patients enrolling into Part 1 (Phase I portion) must also meet the following inclusion criteria:
1.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
2.Have left ventricular ejection fraction > lower level of normal as determined by echocardiogram or multigated acquisition scan evaluation using local institutional standard
3.Be willing and able to eat a high-fat breakfast on Day 1 of the study
4.Have a deleterious gBRCA mutation
All patients enrolling into Part 2 (Phase II portion in OC patients) must also meet the following inclusion criteria:
1.Have a known deleterious BRCA mutation (germline or somatic), as determined by a local laboratory that has received an international or country-specific quality standards certification
2.Have evidence of measurable disease as defined by RECIST Version 1.1
3.Have sufficient archival formalin-fixed paraffin-embedded (FFPE)
tumor tissue available for planned analyses; cytospin blocks from ascites are not acceptable
-Archival tissue from the most recently collected biopsy or debulking surgery should be provided, if available.
Additional inclusion criteria for patients into Part 2A (Phase II portion in OC) include:
1. (b) Have a histologically confirmed diagnosis of high-grade serous or endometrioid
• For mixed histology, >50% of the primary tumor must be confirmed to be high-grade serous or endometrioid upon re-review by local pathology epithelial ovarian, fallopian tube, or primary peritoneal cancer
2. (b) Have received at least two, but no more than four, prior chemotherapy regimens and have relapsed as confirmed by radiologic assessment
a. Last treatment received must have been platinum-based regimen to which patient must have been sensitive (i.e., disease progression occurred at least 6 months after last dose of platinum was administered)
b.A maximum of one non-platinum regimen may have been administered. For patients who received four prior regimens, one regimen must have been a non-platinum
c. Prior continuous or switch maintenance treatment is permitted
(hormonal treatment may be permitted following the last platinum
regimen with advance approval from the sponsor)
Additional inclusion criteria for patients into Part 2B (Phase II portion in OC) include:
1. (d) Have a histologically confirmed diagnosis of high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer.
2.(d)Have received at least three, but no more than four, prior chemotherapy
• Hormonal agents (eg. tamoxifen, letrozole, etc), anti-angiogenic agents (eg. bevacizumab, pazopanib, cediranib, nintedanib, trebananib, etc), and other non-chemotherapy agents administered as single agent treatment will not be counted as a chemotherapy regimen for the purpose of determining patient eligibility regimens and have relapsed disease confirmed by radiologic assessment
-Agents administered in the maintenance setting will not be counted as a separate regimen
3. (d) Have a documented treatment-free interval (TFI) of ≥6 months following the first chemotherapy regimen received.
Patients enrolling into Part 3 (Phase II PK portion in patients with any advanced solid tumor) must meet the following inclusion criteria:
1.Have an advanced solid tumor (inclusive of lymphoma)
2.Have a known deleterious BRCA mutation (gBRCA or somatic BRCA[sBRCA])
3.Have evidence of measurable disease as defined by RECIST Version 1.1
4.Be willing and able to fast, and to eat a high-fat breakfast on Day -7 or Day 1 of the study
5.Have sufficient archival FFPE tumor tissue available for planned analyses; cytospin blocks from ascites are not acceptable
6.Archival tissue from the most recently collected biopsy or debulking surgery should be provided, if available. Otherwise, the next oldest tissue collected should be reviewed until a suitable sample can be
provided (at least 20% tumor content with a minimum of 80% nucleated cellular content) |
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| E.4 | Principal exclusion criteria |
1.Active second malignancy, i.e., patient known to have potentially fatal cancer present for which she may be (but not necessarily) currently receiving treatment
2. Patients with a history of malignancy that has been completely treated, with no evidence of that cancer currently, are permitted to enroll in the trial provided all chemotherapy was completed >6 months prior and/or bone marrow transplant (BMT) >2 years prior to first dose of rucaparib
3.Prior treatment with any PARP inhibitor (Part 1, Part 2). Part 3 patients are permitted to have had previous PARPi, if the following conditions are met:
• PARPi was not the most recent treatment, and
• PARPi was discontinued >6 months before first planned dose of rucaparib
4. In all study parts, patients who previously received iniparib are eligible
5.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
6.Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, or history of chronic hepatitis B or C.
7.Received treatment with chemotherapy, radiation,antibody therapy or other immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors,or experimental drugs ≤14 days prior to first dose of rucaparib and/or ongoing adverse effects from such treatment > NCI CTCAE Grade 1. (ongoing Grade 2 non-hematologic toxicity related to most recent treatment regimen may be permitted with prior advanced approval from Sponsor)
8.Pre-existing duodenal stent and/or any gastrointestinal disorder or defect that would, in the opinion of the Investigator, interfere with absorption of rucaparib
9.Administration of strong CYP1A2 or CYP3A4 inhibitors ≤7 days prior to first scheduled dose of rucaparib
10.Non-study related minor surgical procedure ≤5 days, or major surgical procedure ≤21 days, prior to first dose of rucaparib; iIn all cases, the patient must be sufficiently recovered and stable before treatment administration.
11.Females who are pregnant or breastfeeding.
12.For fertile patients (female able to become pregnant or male able to father a child), refusal to use effective contraception during the period of the trial and for 6 months after the last dose of rucaparib.
13.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)
14.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.
15.Patients enrolling into Part 1 (Phase I portion) will also be excluded from participation if any of the following criteria apply:
• Family history of long QT syndrome
• Implantable pacemaker or implantable cardioverter defibrillator
• Requires treatment with any medication known to produce QT prolongation, with the exception of antiemetics deemed necessary to control nausea
Patients enrolling into Part 2B (Phase II OC portion) will also be excluded from participation if any of the following criteria apply:
Hospitalization for bowel obstruction within 3 months prior to enrollment |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. To evaluate the safety profile of escalating doses of continuous daily oral rucaparib in patients with advanced solid tumors, and to determine the MTD and RP2D (Part 1 only).The incidence of Grade 3 or 4 adverse events (AEs) and clinical laboratory abnormalities defined as dose-limiting toxicities (DLTs)
2.To characterize the pharmacokinetic (PK) profile of oral rucaparib when administered as a continuous daily dose (Part 1 and Part 3 only). PK parameters: area under the curve from time zero to the time twith the last measurable concentration (AUC0-t), AUC from time zero to infinity (AUC0-∞), maximum concentration (Cmax), time to maximum concentration (Tmax), elimination half-life (t1/2), elimination rate constant (kel), apparent volume of distribution at steady state after nonintravenous administration (Vss/F), and apparent total plasma clearance (Cl/F3.
3.To evaluate overall response rate (ORR) in patients with relapsed, high-grade serous or endometrioid epithelial ovarian,fallopian tube, or primary peritoneal cancer associated with a BRCA mutation (Part 2
only) [henceforth abbreviated to ovarian cancer (OC) population] ORR per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1; secondary analysis including Gynecologic Cancer InterGroup (GCIG) cancer antigen-125 (CA-125) criteria
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1.To characterize the single-dose PK profile of oral rucaparib after a highfat breakfast compared to that in the fasted state (Part 1 and Part 3 only). PK parameters Cmax and AUC (fasted and fed)
2.To evaluate the effects of oral rucaparib on the QT/QTc interval measured by electrocardiogram (ECG) (Part 1 only). Change from baseline in QT/QTc interval
3.To evaluate the safety and tolerability of oral rucaparib (Parts 1, 2, and 3). The incidence of AEs, clinical laboratory abnormalities, and ECG abnormalities
4.To evaluate antitumor activity of oral rucaparib in various solid tumors (Part 1 and Part 3 only).Response per RECIST v1.1; additional analyses including applicable tumor markers
5.To assess progression-free survival (PFS) in the OC population (Part 2 only). PFS defined as the time to first occurrence of disease progression per RECIST v1.1 or death
6.To evaluate duration of response in the OC population (Part 2 only). Duration of response per RECIST v1.1
7.To evaulate survival (Part 2B only) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase II PK Portion in Patients with any Advanced Solid Tumor - Part 3 |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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 | No |
| 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 |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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
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| The trial will be completed when all enrolled patients have experienced Progressive Disease, or have discontinued the study due to another reason. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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