Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

All Conditions

Immune System Diseases

Rare Diseases

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Hypersensitivity

Carcinoma

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endocrine System Diseases

Gonadal Disorders

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Ovarian Cancer

Ovarian Epithelial Cancer

Antineoplastic Agents

All Drugs and Chemicals

Gemcitabine

Carboplatin

Antimetabolites

Phase II Arm A will randomize patients to treatment regimen of carboplatin and gemcitabine without BNC105P

Phase II Arm B will randomize patients to treatment regimen of carboplatin and gemcitabine and will include BNC105P

Carboplatin AUC4 on day 1 of 21-day cycle, for a maximum of 6 cycles.

Gemcitabine escalations 800 and 1000 mg/m2 (as determined in phase I) on days 1 and 8 of a 21 day cycle, for a maximum of 6 cycles.

Carboplatin AUC 4 on day 1 of a 21 day cycle, for a maximum of 6 cycles.

Gemcitabine 800 or 1000 mg/m2 (as determined in phase I) on days 1 and day 8 of 21-day cycle, for a maximum of 6 cycles.

BNC105P as determined in phase I, on days 2 and 9 of a 21 day cycle for a maximum of 6 cycles, followed by single agent maintenance BNC105P 16 mg/m2 for a maximum of 6 additional cycles.

BNC105P

Danny Rischin, Professor

Daniela Matei, M.D.

This phase I/II trial will determine the recommended dose and activity of BNC105P for patients with partially platinum sensitive ovarian cancer in first or second relapse.

OUTLINE: This is a multi-center study.

BNC105P is a novel vascular disrupting agent (VDA) with promising preclinical activity combined with platinum or gemcitabine. The results of standard chemotherapy with carboplatin and gemcitabine for ovarian cancer relapsing within 12 months of an initial platinum-based regimen require improvement. This trial will determine the recommended dose and activity of BNC105P administered with carboplatin and gemcitabine.

PHASE I:

This trial uses a standard 3+3 design for allocating participants to a starting dose level in Phase I.

If dose level 1 is deemed to have acceptable toxicity then dose levels 2a and 2b can be opened at the same time. Dose level 3 will only open if both dose levels 2a and 2b are deemed to have acceptable toxicity.

The underlying assumptions for determining the recommended doses for the triple combination of carboplatin, gemcitabine and BNC105P are that the likely minimum doses required of each agent are carboplatin AUC 4, gemcitabine 800 mg/m2 and BNC105P 12 mg/m2. This corresponds to dose level 1.

PHASE II 1:1 RANDOMIZATION:

Carboplatin AUC 4 on day 1, gemcitabine 800 or 1000 mg/m2 on days 1 and 8 of a 21 day cycle for a maximum of 6 cycles.

OR

Carboplatin AUC 4 on day 1, gemcitabine 800 or 1000 mg/m2 on days 1 and day 8 with dose of BNC105P as determined in phase I, on days 2 and 9 of a 21 day cycle for a maximum of 6 cycles, followed by single agent maintenance BNC105P 16 mg/m2 for a maximum of 6 additional cycles

Minimum follow up for 12 months

ECOG Performance Status for Phase I: 0-1; ECOG Performance Status for Phase II: 0-2

Life Expectancy: Less than 12 weeks

Hematopoietic (both phases):

* Platelet count ≥ 100 x 109/L
* ANC ≥ 1.5 x 109/L
* Haemoglobin \> 9g/dl (can be post transfusion)
* INR ≤ 1.5 x ULN

Hepatic (both phases):

* Total Bilirubin ≤ 1.5 x the upper limit of normal (ULN)
* ALT ≤ 2.5 x ULN

Renal (both phases):

* Creatinine clearance ≥ 55 mL/min according to Cockcroft Gault formula
* If Calculated GFR is 50 - 54 mL/min an isotopic GFR may be performed. If the isotopic GFR is \> 55ml/min, the patient will be eligible for the study but the calculated GFR will be used for dose calculation.

Cardiovascular (both phases):

* Normal left ventricular ejection fraction (LVEF), i.e. ≥ 50% on Gated Heart Pool Scan, or fractional shortening on echocardiogram ≥ institutional LLN performed within 2 months prior to randomisation
* Corrected QTc \< 470 msec on ECG performed within 4 weeks prior to randomisation.

BNC105P Combination Study in Partially Platinum Sensitive Ovarian Cancer Patients

Phase I/II BNC105P Combination Study in Partially Platinum Sensitive Ovarian Cancer Patients in First or Second Relapse

To determine the recommended dose of BNC105P given with gemcitabine and carboplatin (maximum dose of BNC105P with no more than 1 DLT in 6 phase I participants)

To determine the objective response rate (ORR) in those with evaluable disease (ORR = CR, PR according to RECIST 1.1 and/or GCIG CA125 criteria) (percentage of those with measurable disease achieving CR or PR according to RECIST 1.1 and/or GCIG CA125 criteria)

To determine the progression free and overall survival distribution rates in this patient population

To determine the adverse event rates (Numbers (%) with G2-5 AE (NCI CTCAE v4.0)

To determine the effects on aspects of health related quality of life (HRQL measured with FOSI and MOST), including symptom benefit (Numbers (%) with significant symptom benefit)

Plasma will be collected to assess BNC105P pharmacokinetics on days 2 and 9 of cycle 1 only. Results will be compared with data from previous trials of BNC105P to determine their consistency and to establish if there is any major interaction with carboplatin and gemcitabine.

To determine the associations between baseline biomarkers, ORR, PFS, OS and AE

University of Sydney

Australia New Zealand Gynaecological Oncology Group

Bionomics Limited

Hoosier Cancer Research Network

Symptoms and General Pathology

Digestive System Diseases

Cicatrix

Fallopian Tube Neoplasms

Peritoneal Neoplasms

Fallopian Tube Diseases

Abdominal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Peritoneal Diseases

Fallopian Tube Cancer

Paclitaxel

Albumin-Bound Paclitaxel

Cisplatin

Poly(ADP-ribose) Polymerase Inhibitors

Rucaparib

Tubulin Modulators

Antimitotic Agents

Enzyme Inhibitors

Drug: Oral rucaparib

600 mg BID (twice a day)

Other Names:

* CO-338
* PF 01367338
* AG 14699
* Rubraca

Monotherapy platinum (cisplatin or carboplatin) or platinum-based doublet chemotherapy (carboplatin/paclitaxel, carboplatin/gemcitabine, or cisplatin/gemcitabine administered per local standard of care and regulations. Specific comparator will depend on platinum status and investigator decision.

Single agent paclitaxel will be administered per local standard of care and regulations. Specific comparator will depend on platinum status and investigator decision.

Chemotherapy will be administered per local standard of care and regulations. Specific comparator will depend on platinum status and investigator decision.

Chemotherapy

Tablets of rucaparib, at a dose of 600 mg, will be taken orally twice a day

The purpose of this study is to determine how patients with ovarian, fallopian tube, and primary peritoneal cancer will best respond to treatment with rucaparib versus chemotherapy.

Rucaparib is an orally available, small molecule inhibitor of poly-adenosine diphosphate \[ADP\] ribose polymerase (PARP) being developed for treatment of ovarian cancer associated with homologous recombination (HR) DNA repair deficiency (HRD). The safety and efficacy of rucaparib has been evaluated in several Phase 1 and Phase 2 studies. An oral formulation is the focus of current development efforts. Rucaparib is currently being investigated as monotherapy in patients with cancer associated with breast cancer susceptibility gene 1 (BRCA1) or BRCA2 mutations.

While PARP inhibitors have demonstrated consistent robust clinical activity in patients with relapsed ovarian cancer associated with HRD, prospective studies evaluating efficacy and safety of PARPi versus standard of care chemotherapy have been limited. The primary purpose of this Phase 3 study is to compare the efficacy and safety of rucaparib versus chemotherapy as treatment for relapsed ovarian cancer in patients with a deleterious BRCA1/2 mutation in their tumor.

ARIEL4: A Study of Rucaparib Versus Chemotherapy BRCA Mutant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Patients

ARIEL4 (Assessment of Rucaparib In Ovarian CancEr TriaL): A Phase 3 Multicenter, Randomized Study of Rucaparib Versus Chemotherapy in Patients With Relapsed, BRCA Mutant, High Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

The primary efficacy endpoint is invPFS for the Treatment Part of the study. The time to invPFS is calculated in months as the time from randomization to disease progression +1 day, as determined by RECIST v1.1 (Response Evaluation Criteria in Solid Tumors) criteria or death due to any cause, whichever occurs first. Progression is defined using RECIST v1.1, as at least a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

A secondary endpoint is the ORR for the Treatment Part of the study. ORR is defined as the percentage of patients with a confirmed CR (complete response) or PR (partial response) by RECIST v1.1. The confirmed response is defined as a CR or PR on subsequent tumor assessment at least 28 days after first response documentation. CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter.

A secondary endpoint is the DOR for the Treatment Part of the study. The DOR as assessed by investigator is analyzed in the subgroup of patients who had a confirmed response by RECIST v1.1. DOR for any confirmed RECIST CR or PR will be measured from the date of the first response until the first date that progressive disease (PD) is documented. DOR is calculated in months as the time from the first date of the scan showing a response to the first scan with disease progression +1 day. Any patients with an ongoing response are censored at the date of the last post-baseline scan. Only tumor scans up to and within 6 weeks of start of any subsequent anti-cancer treatment are included. Progressive disease (PD) is defined using RECIST v1.1, as at least a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

A secondary endpoint is ORR for the Treatment Part of the study defined as the percentage of patients with best response of CR or PR using RECIST v1.1 or response per Gynecologic Cancer InterGroup Cancer Antigen 125 (GCIG CA-125) criteria. Complete response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Response to CA-125 has occurred if there is at least a 50% decrease from baseline: 1. in a sample collected after initiation of study treatment AND 2. that is confirmed in a subsequent sample collected ≥21 days after the prior sample. The absolute value of this confirmatory sample must be ≤110% of the prior sample. The date when the first sample with a 50% decrease from baseline is observed is the date of the CA-125 response.

EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer patients. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Global scores are converted to a score of 0 to 100, with a higher score indicating improved health status. Mean changes from baseline global score over the first 6 cycles in the Treatment Part of the study were analyzed.

Overall survival (OS) is defined as the number of days from the date of randomization to the date of death (due to any cause). Patients who are still alive were censored on the date of their last available visit or last date known to be alive.

Foundation Medicine

pharmaand GmbH

Adverse events are reported for the Safety Population, defined as patients who received at least one dose of protocol-specified treatment.

Patients randomized to the rucaparib arm in the Treatment Part of the study.

Rucaparib (Treatment Part)

Patients randomized to the chemotherapy arm in the Treatment Part of the study.

Chemotherapy (Treatment Part)

Patients randomized to chemotherapy who then crossed over upon disease progression and were treated with rucaparib.

Rucaparib (Crossover Part)

Patients randomized to the rucaparib arm.

Patients randomized to the chemotherapy arm.

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Eastern Cooperative Oncology Group (ECOG) Performance Status Scale. ECOG 0 = Fully active, able to carry on all pre-disease performance without restriction. ECOG 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (eg, light house work or office work).

ECOG at Baseline

Number of Prior Chemotherapy Regimens

Number of Prior Platinum Regimens

* Platinum resistant: patients who progressed ≥ 1 to \< 6 months after the last dose of platinum-based chemotherapy;
* Partially platinum-sensitive: patients who progressed ≥ 6 to \< 12 months after last dose of platinum-based chemotherapy; and
* Platinum sensitive: patients who progressed ≥ 12 months after last dose of platinum-based chemotherapy

Randomization Stratification: Platinum Status

* BRCA1: patients with a deleterious breast cancer susceptibility gene 1 (BRCA1) mutation in their tumor
* BRCA2: patients with a deleterious breast cancer susceptibility gene 2 (BRCA2) mutation in their tumor
* Non-BRCA: patients without a BRCA mutation in their tumor

Combined Local and Central Lab BRCA Mutation Results

Mutation Type

Patients with a BRCA Reversion Mutation

Medical Information Department

Efficacy Population - All randomized patients in the treatment part of study with a deleterious BRCA mutation, excluding those identified to have a BRCA reversion mutation. As noted in the Baseline Characteristics Module, 1 patient in the Chemotherapy Arm did not have a BRCA mutation (Non-BRCA) and is therefore excluded from the overall number of patients analyzed.

Investigator Assessed Progression-Free Survival (invPFS) by RECIST Version 1.1 for Rucaparib Versus Chemotherapy (Efficacy Population)

Intent-to-treat (ITT) Population - All randomized patients in the treatment part of study.

Investigator Assessed Progression-Free Survival (invPFS) by RECIST Version 1.1 for Rucaparib Versus Chemotherapy (ITT Population)

Efficacy population with measurable disease at baseline. Efficacy population defined as all randomized patients with a deleterious BRCA mutation, excluding those identified to have a BRCA reversion mutation.

Investigator Assessed Overall Response Rate (ORR) by RECIST v1.1 (Efficacy Population)

Intent-to-treat (ITT) population with measurable disease at baseline. ITT population defined as all randomized patients.

Investigator Assessed Overall Response Rate (ORR) by RECIST v1.1 (ITT Population)

Efficacy population with measurable disease at baseline and a confirmed response. Efficacy population defined as all randomized patients with a deleterious BRCA mutation, excluding those identified to have a BRCA reversion mutation. As noted in the Baseline Characteristics Module, 1 patient in the Chemotherapy Arm did not have a BRCA mutation (Non-BRCA) and is therefore excluded from the overall number of patients analyzed.

Investigator Assessed Duration of Response (DOR) by RECIST v1.1 (Efficacy Population)

Intent-to-treat (ITT) population with measurable disease at baseline and a confirmed response. ITT population defined as all randomized patients.

Investigator Assessed Duration of Response (DOR) by RECIST v1.1 (ITT Population)

Efficacy population with measurable disease at baseline and/or CA-125 response evaluable. Efficacy population defined as all randomized patients with a deleterious BRCA mutation, excluding those identified to have a BRCA reversion mutation.

Investigator Assessed Overall Response Rate (ORR) by RECIST v1.1 and/or CA-125 Response (Efficacy Population)

Intent-to-treat (ITT) population with measurable disease at baseline and/or CA-125 response evaluable. ITT population defined as all randomized patients.

Investigator Assessed Overall Response Rate (ORR) by RECIST v1.1 and/or CA-125 Response (ITT Population)

Efficacy population - All randomized patients with a deleterious BRCA mutation, excluding those identified to have a BRCA reversion mutation, and with a baseline value and at least one post-baseline value for the EORTC QLQ-C30 Global Health Status score during the first 6 cycles.

Least Squares Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status Score for the First 6 Cycles (Efficacy Population)

Intent-to-treat (ITT) population - All randomized patients with a baseline value and at least one post-baseline value for the EORTC QLQ-C30 Global Health Status score during the first 6 cycles.

Least Squares Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status Score for the First 6 Cycles (ITT Population)

Overall Survival (Efficacy Population)

Intent-to-Treat (ITT) Population - All randomized patients in the treatment part of the study.

Overall Survival (ITT Population)

Patients randomized to the rucaparib arm received oral rucaparib 600 mg twice a day (BID) in continuous 28-day cycles.

Patients randomized to the chemotherapy arm received either weekly intravenous (IV) paclitaxel or IV platinum-based chemotherapy per investigator choice and per standard of care. The starting dose of weekly paclitaxel was 60 to 80 mg/m2 administered via IV infusion (ie, on Days 1, 8, and 15) in each 28-day cycle (with a week break from dosing on Day 22 in each cycle). The dosage and administration of single-agent cisplatin or carboplatin or doublet carboplatin/paclitaxel, carboplatin/gemcitabine, or cisplatin/gemcitabine IV infusion followed institutional guidelines for each agent. Upon progression of disease, patients had the option to cross over to rucaparib and receive oral rucaparib 600 mg BID in continuous 28-day cycles.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
BNC105P Combination Study in Partially Platinum Sensitive Ovarian Cancer Patients	NCT01624493	Ovarian Cancer	Carboplatin Gemcitabine Carboplatin Gemcitabine BNC105P	18 Years -	Hoosier Cancer Research Network
BNC105P Combination Study in Partially Platinum Sensitive Ovarian Cancer Patients	NCT01624493	Ovarian Cancer	Carboplatin Gemcitabine Carboplatin Gemcitabine BNC105P	18 Years -	Hoosier Cancer Research Network
ARIEL4: A Study of Rucaparib Versus Chemotherapy BRCA Mutant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Patients	NCT02855944	Ovarian Cancer Epithelial Ovar... Fallopian Tube ... Peritoneal Canc...	Chemotherapy Rucaparib	18 Years -	pharmaand GmbH
ARIEL4: A Study of Rucaparib Versus Chemotherapy BRCA Mutant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Patients	NCT02855944	Ovarian Cancer Epithelial Ovar... Fallopian Tube ... Peritoneal Canc...	Chemotherapy Rucaparib	18 Years -	pharmaand GmbH

Spots Global Cancer Trial Database for partially platinum sensitive