Best Approach in Recurrent-Ovarian-Cancer-with Cediranib-Olaparib

Study Overview
=================
Brief Summary
-----------------
This is a Phase II, randomized, multi-centre study aiming at comparing the efficacy of Olaparib and Cediranib vs. weekly Paclitaxel in terms of progression free survival (PFS) in platinum refractory or resistant recurrent ovarian cancer. Patients will be randomised in a 1:1:1 ratio to three treatment arms: Arm A: Paclitaxel 80 mg/mq every week Arm B: Cediranib 20 mg/day + Olaparib 600 mg / day (i.e. 300 mg BD) given every day Arm C: Cediranib 20 mg/day given 5 days per weeks + Olaparib 600 mg / day (i.e. 300 mg BD) given 7 days per weeks

Official Title
-----------------
The BAROCCO Study (Best Approach in Recurrent-Ovarian-Cancer-with Cediranib-Olaparib): an Italian Multicenter Randomized Phase II Study of Weekly Paclitaxel vs. Cediranib-Olaparib With Continuous Schedule vs. Cediranib-Olaparib With Intermittent Schedule in Patients With Platinum Resistant High Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer.

Conditions
-----------------
Ovarian Neoplasms

Intervention / Treatment
-----------------
* Drug: Paclitaxel
* Drug: Cediranib
* Drug: Olaparib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients affected by pathologically confirmed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. Relapsed/progressive disease within 6 months from last platinum-based chemotherapy (platinum resistant/refractory disease). Any line of treatment (after the first). Any last chemotherapy line, including Paclitaxel, that should have been administered at least 6 months before the study beginning. Patients must be women > 18 years of age. Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below: Haemoglobin ≥ 10.0 g/dL and no blood transfusions in the 28 days prior to entry/randomization - Absolute neutrophil count (ANC) ≥ 1.5 x 109/L White blood cells (WBC) > 3x109/L Platelet count ≥ 100 x 109/L Total bilirubin ≤ 1.5 x institutional Upper Limit of Normal (ULN) AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional Upper Limit of Normal, unless liver metastases are present in which case it must be ≤ 5x ULN Creatinine clearance estimated using the Cockcroft-Gault equation ≥51 mL/min,. ECOG performance status 0-1. Patients must have a life expectancy ≥ 16 weeks. Evidence of non-childbearing status for women of childbearing potential (negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on day 1 or postmenopausal women. Postmenopausal status is defined as: Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments LH and FSH levels in the post-menopausal range for women under 50 Radiation-induced oophorectomy with last menses >1 year ago, Chemotherapy-induced menopause with >1 year interval since last menses Surgical sterilization (bilateral oophorectomy or hysterectomy) Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment, scheduled visits and examinations including follow up. At least one lesion (measurable as defined by RECIST 1.1) that can be accurately assessed by CT scan or MRI with Chest X-ray at baseline and follow up visits. BRCA1-2 mutation status known. In case of BRCA status unknown, the BRCA test must be performed before the randomization or, if not feasible, within the end-of the study treatment. Provision of informed consent prior to any study specific procedures. In case of patients unable to give written informed consent, is necessary to have the subject or legal representative sign, but in any case a witness must be present and sign and date with the person providing informed consent. Exclusion Criteria: Any previous treatment with a PARP inhibitor, including Olaparib. Prior treatment with Cediranib (previous bevacizumab or other antiangiogenic drugs are allowed) Previous progression to weekly Paclitaxel Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≥ 5 years Patients receiving any systemic chemotherapy, radiotherapy (except for palliative reasons), within 2 weeks from the last dose prior to study treatment (or a longer period depending on the defined characteristics of the agents used). The patient can receive bisphosphonates for bone metastases, before and during the study as long as these were started at least 4 weeks prior to treatment with study drug. Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting Olaparib is 2 weeks. Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort ) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting Olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents. Persistent toxicities (>=CTCAE grade 2) with the exception of alopecia, caused by previous cancer therapy. Resting ECG with QTc > 470msec on 2 or more time points within a 24 hour period or family history of long QT syndrome. Greater than +1 proteinuria on two consecutive dipsticks taken no less than 1 week apart unless urinary protein < 1.5g in a 24 hr period or urine protein/creatinine ratio < 1.5. A history of poorly controlled hypertension or resting blood pressure >150/100 mmHg in the presence or absence of a stable regimen of anti-hypertensive therapy (measurements will be made after the patient has been resting supine for a minimum of 5 minutes. Two or more readings should be taken at 2-minute intervals and averaged. If the first two diastolic readings differ by more than 5 mmHg, then an additional reading should be obtained and averaged). Blood transfusions within 28 days prior to study start. Features suggestive of Myelodysplastic syndrome or Acute myeloid leukemia (MDS/AML) on peripheral blood smear. Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 28 days prior to treatment. Major surgery within 4 weeks of starting study treatment and patients must have recovered from any effects of any major surgery. Patients considered at poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, unstable spinal cord compression (untreated and unstable for at least 28 days prior to study entry), superior vena cava syndrome, extensive bilateral lung disease on HRCT scan or any psychiatric disorder that prohibits obtaining informed consent. Patients unable to swallow medications and patients with gastrointestinal disorders likely to interfere with absorption of the study medication. Breast feeding women. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving antiviral therapy. Patients with known active hepatic disease (i.e., Hepatitis B or C). Patients with a known hypersensitivity to Olaparib, Cediranib or any of the excipients of the products. Patients with a known hypersensitivity to Paclitaxel. Patients with uncontrolled seizures. History of abdominal fistula or gastrointestinal perforation. Prior gastrectomy.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A<br>Intravenous administration of weekly Paclitaxel (dosage: 80 mg/mq) for a maximum of 6 cycles. Cycle is defined as 4 weeks. | Drug: Paclitaxel<br>* Comparator active compound<br>|
| Experimental: Arm B<br>Oral administration of two experimental drugs: Cediranib 20 mg/day given 7 days per week Olaparib 600 mg / day (i.e. 300 mg twice a day) 7 days per week until progression, unacceptable toxicity, patient or physician decision to discontinue or death. | Drug: Cediranib<br>* Experimental compound<br>Drug: Olaparib<br>* Experimental compound<br>|
| Experimental: Arm C<br>Oral administration of two experimental drugs: Cediranib 20 mg/day given 5 days per week Olaparib 600 mg / day (i.e. 300 mg twice a day) 7 days per week until progression, unacceptable toxicity, patient or physician decision to discontinue or death. | Drug: Cediranib<br>* Experimental compound<br>Drug: Olaparib<br>* Experimental compound<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: Progression Free Survival (PFS) | PFS is defined as time from randomization to the date of first progression or death for any cause, whichever comes first. | Up to one year after the last patient enrolled | 
| Safety: Number of evacuations per day | Number of evacuations per day used as an index of gastro-intestinal toxicity profile of experimental drugs | Up to the fourth week of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: Objective Response Rate (ORR) | Percentage of patients with an objective response as determined by RECIST 1.1 | Up to one year after the last patient enrolled | 
| Efficacy: PFS2 | PFS2 is defined as time from first progression to the date of second progression or death for any cause, whichever comes first. | Up to one year after the last patient enrolled | 
| Efficacy: Overall Survival (OS) | OS is defined as time from randomization to the date of death for any cause | Up to one year after the last patient enrolled | 
| Efficacy: Quality of Life | Quality of Life evaluated by the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) questionnaire | Up to sixth month of study treatment | 
| Safety: Maximum toxicity grade | Maximum toxicity grade experienced by each patient, for each toxicity, according to NCI-CTCAE v. 4.03 | Up to 30 days after the end of treatment (up to one year after the last patient enrolled) | 
| Safety: Number of patients experiencing grade 3-4 toxicity for each toxicity | Number of patients experiencing grade 3-4 toxicity for each toxicity according to NCI-CTCAE v. 4.03 | Up to 30 days after the end of treatment (up to one year after the last patient enrolled) | 
| Safety: Type, frequency and nature of SAEs | Type, frequency and nature of SAEs, according to NCI-CTCAE v. 4.03 | Up to 30 days after the end of treatment (up to one year after the last patient enrolled) | 
| Safety: Number of patients with at least a SAE; patients with at least a SADR | Number of patients with at least a SAE; patients with at least a SADR, according to NCI-CTCAE v. 4.03 | Up to 30 days after the end of treatment (up to one year after the last patient enrolled) | 
| Safety: Number of patients with at least a SUSAR | Number of patients with at least a SUSAR, according to NCI-CTCAE v. 4.03 | Up to 30 days after the end of treatment (up to one year after the last patient enrolled) | 
| Compliance: Number of administered cycles | Number of administered cycles | Up to one year after the last patient enrolled | 
| Compliance: Reasons for discontinuation and treatment modification | Reasons for discontinuation and treatment modification | Up to one year after the last patient enrolled | 
| Compliance: Dose intensity | Entire dose administered during treatment | Up to one year after the last patient enrolled |