Best Approach in Recurrent-Ovarian-Cancer-with Cediranib-Olaparib (BAROCCO)

• ClinicalTrials.gov Identifier: NCT03314740
• Recruitment Status: Unknown
• First Posted: October 19, 2017
• Last Update Posted: May 14, 2019
• Sponsor: Mario Negri Institute for Pharmacological Research
• Collaborator: AstraZeneca
• Information provided by (Responsible Party): Mario Negri Institute for Pharmacological Research

Study Description

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

Condition or disease	Intervention/treatment	Phase
Ovarian Neoplasms	Drug: Paclitaxel; Drug: Cediranib; Drug: Olaparib	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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.
• Actual Study Start Date: June 1, 2017
• Estimated Primary Completion Date: November 30, 2019
• Estimated Study Completion Date: November 30, 2019

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Arm A; Intravenous administration of weekly Paclitaxel (dosage: 80 mg/mq) for a maximum of 6 cycles. Cycle is defined as 4 weeks.	Drug: Paclitaxel; Comparator active compound
Experimental: Arm B; 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; Experimental compound; Drug: Olaparib; Experimental compound
Experimental: Arm C; 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; Experimental compound; Drug: Olaparib; Experimental compound

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Patients affected by uro-genital neoplasm of ovary.
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Patients affected by pathologically confirmed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer.
2. Relapsed/progressive disease within 6 months from last platinum-based chemotherapy (platinum resistant/refractory disease).
3. Any line of treatment (after the first).
4. Any "last" chemotherapy line, including Paclitaxel, that should have been administered at least 6 months before the study beginning.
5. Patients must be women > 18 years of age.

6. 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,.
7. ECOG performance status 0-1.
8. Patients must have a life expectancy ≥ 16 weeks.

9. 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)
10. 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.
11. 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.
12. 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.
13. 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:

1. Any previous treatment with a PARP inhibitor, including Olaparib.
2. Prior treatment with Cediranib (previous bevacizumab or other antiangiogenic drugs are allowed)
3. Previous progression to weekly Paclitaxel
4. 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
5. 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.
6. 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.
7. 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.
8. Persistent toxicities (>=CTCAE grade 2) with the exception of alopecia, caused by previous cancer therapy.
9. Resting ECG with QTc > 470msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
10. 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.
11. 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).
12. Blood transfusions within 28 days prior to study start.
13. Features suggestive of Myelodysplastic syndrome or Acute myeloid leukemia (MDS/AML) on peripheral blood smear.
14. 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.
15. Major surgery within 4 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
16. 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.
17. Patients unable to swallow medications and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
18. Breast feeding women.
19. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving antiviral therapy.
20. Patients with known active hepatic disease (i.e., Hepatitis B or C).
21. Patients with a known hypersensitivity to Olaparib, Cediranib or any of the excipients of the products.
22. Patients with a known hypersensitivity to Paclitaxel.
23. Patients with uncontrolled seizures.
24. History of abdominal fistula or gastrointestinal perforation.
25. Prior gastrectomy.

Contacts and Locations

Locations

Italy

Spedali Civili di Brescia

Brescia, BS, Italy, 25123

Ospedale San Gerardo - ASST Monza

Monza, MB, Italy, 20900

Istituto Oncologico Veneto (IOV)

Padova, PD, Italy, 35128

Arcispedale Santa Maria Nuova

Reggio Emilia, RE, Italy, 42123

Policlinico Umberto I - Università La Sapienza

Rome, RM, Italy, 00161

Istituto Eurpeo di Oncologia (IEO)

Milano, Italy, 20141

Sponsors and Collaborators

Mario Negri Institute for Pharmacological Research

AstraZeneca

Investigators

• Study Director: Roldano Fossati, MD; Mario Negri Institute for Pharmacological Research
• Principal Investigator: Nicoletta Colombo, MD; European Institute of Oncology

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Tattersall A, Ryan N, Wiggans AJ, Rogozinska E, Morrison J. Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer. Cochrane Database Syst Rev. 2022 Feb 16;2(2):CD007929. doi: 10.1002/14651858.CD007929.pub4.

Colombo N, Tomao F, Benedetti Panici P, Nicoletto MO, Tognon G, Bologna A, Lissoni AA, DeCensi A, Lapresa M, Mancari R, Palaia I, Tasca G, Tettamanzi F, Alvisi MF, Rulli E, Poli D, Carlucci L, Torri V, Fossati R, Biagioli E; BAROCCO study group. Randomized phase II trial of weekly paclitaxel vs. cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant high-grade epithelial ovarian cancer. Gynecol Oncol. 2022 Mar;164(3):505-513. doi: 10.1016/j.ygyno.2022.01.015. Epub 2022 Jan 19.

• Responsible Party: Mario Negri Institute for Pharmacological Research
• ClinicalTrials.gov Identifier: NCT03314740
• Other Study ID Numbers: IRFMN-OVA-7289
• First Posted: October 19, 2017
• Last Update Posted: May 14, 2019
• Last Verified: May 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Ovarian Neoplasms; Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Paclitaxel; Olaparib; Cediranib; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Poly(ADP-ribose) Polymerase Inhibitors; Enzyme Inhibitors; Protein Kinase Inhibitors