Clinical trial NCT03314740: Best Approach in Recurrent-Ovarian-Cancer-with Cediranib-Olaparib
Official title: Italian Multicenter Randomized Phase II Study of Weekly Paclitaxel vs. Cediranib-Olaparib (Continuous vs. Intermittent) in Patients With Platinum Resistant High Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ovarian Neoplasms
Lead sponsor: Mario Negri Institute for Pharmacological Research
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2017-10-19
Enrollment: 123
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Detailed description: Both the experimental arms (Arm B and C) will be compared with Arm A in terms of PFS.

If both superior to the control (Arm A), they will be compared in terms of gastrointestinal safety.

Eligibility 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.

Primary outcomes:
measure: Efficacy: Progression Free Survival (PFS)
timeFrame: An average of 30 months for each participant
measure: Safety: Number of Evacuations Per Day
timeFrame: Evacuation were collected daily for the first four weeks of treatment of experimental drugs
Secondary outcomes:
measure: Efficacy: Objective Response Rate (ORR)
timeFrame: Disease assessments were scheduled every 8 weeks (+/- 1 week) from randomization for all treatment duration (an average of 3.5 months).
measure: Efficacy: PFS2
timeFrame: Up to one year after the last patient enrolled
measure: Efficacy: Overall Survival (OS)
timeFrame: Up to one year after the last patient enrolled
measure: Efficacy: Quality of Life
timeFrame: Up to sixth month of study treatment
measure: Safety: Maximum Toxicity Grade
timeFrame: Up to 30 days after the end of treatment
measure: Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity
timeFrame: Adverse events were collected at the end of each cycle for the duration of treatment for each participant (an average of 3.5 months) and following 30 days after the end of treatment.
measure: Safety: Type, Frequency and Nature of SAEs
timeFrame: Up to 30 days after the end of treatment
measure: Safety: Number of Patients With at Least a SAE; Patients With at Least a SADR
timeFrame: Up to 30 days after the end of treatment
measure: Safety: Number of Patients With at Least a SUSAR
timeFrame: Up to 30 days after the end of treatment
measure: Compliance: Number of Administered Cycles
timeFrame: Up to one year after the last patient enrolled
measure: Compliance: Reasons for Discontinuation and Treatment Modification
timeFrame: Up to one year after the last patient enrolled
measure: Compliance: Dose Intensity
timeFrame: Up to one year after the last patient enrolled
Other outcomes:
Locations:
city: Brescia
country: Italy
facility: Spedali Civili di Brescia
state: BS
city: Monza
country: Italy
facility: Ospedale San Gerardo - ASST Monza
state: MB
city: Padova
country: Italy
facility: Istituto Oncologico Veneto (IOV)
state: PD
city: Reggio Emilia
country: Italy
facility: Arcispedale Santa Maria Nuova
state: RE
city: Rome
country: Italy
facility: Policlinico Umberto I - Università La Sapienza
state: RM
city: Milano
country: Italy
facility: Istituto Eurpeo di Oncologia (IEO)
Study officials:
affiliation: Mario Negri Institute for Pharmacological Research
name: Roldano Fossati, MD
role: STUDY_DIRECTOR
affiliation: European Institute of Oncology
name: Nicoletta Colombo, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.