NUVOLA TRIAL Open-label Multicentre Study

NCT04261465 | Unknown Phase 2

• 1 other identifier: 2345
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

Brief Summary

Around 15-25% of ovarian cancer (OC) patients carry germ-line mutation in BRCA1 or BRCA2 genes. Recent evidences showed that OC women with germline BRCA1/2 mutations (gBRCAmut) have an improved survival and higher platinum-sensitivity compared to BRCA1/2 naive (BRCAwt). Interestingly, disease appearance in BRCAmut women is more diffuse than in BRCAwt cases, with significantly higher peritoneal tumour load. Nonetheless, BRCAmut women additionally show a higher benefit of platinum-based neoadjuvant chemotherapy (NACT) plus interval debulking surgery compared with BRCAwt women in terms of clinical and pathological responses, suggesting that BRCA mutational status might be used as a molecular tool to personalize treatment in high-grade serous ovarian cancer (HGSOC) patients. OLAPARIB in BRCA mutation carriers Olaparib is a potent oral poly (ADP-ribose) polymerase (PARP) inhibitor that causes synthetic lethality in BRCA1/2-deficient tumour cells. In patients with platinum-sensitive relapsed serous ovarian cancer, olaparib maintenance treatment significantly improved the duration of progression-free survival compared with placebo (hazard ratio \[HR\] 0.35 \[95% CI (confidence interval) 0.25-0.49\]; p\<0.0001), with the greatest clinical benefit in patients with BRCA mutations (HR 0.18 \[95% CI 0.10-0.31\]; p\<0.0001). Preclinical data suggest that olaparib might also potentiate the efficacy of DNA-damaging chemotherapies, including platinum-containing drugs such as carboplatin. In a recent phase Ib/II study, olaparib plus weekly carboplatin and paclitaxel in relapsed ovarian cancer patients was shown to be safe, well tolerated and effective, especially in germline BRCA mutated (gBRCAmut) patients. Possibly, the addition of a PARP inhibitor (olaparib) to NACT in HGSOC patient with germline or somatic BRCA1/2 mutation is able to increase the pathological complete response rate to conventional chemotherapy. Combination of intermittent olaparib with weekly carboplatin and paclitaxel might achieve a higher pathological response rate, with an acceptable toxicity profile.

Conditions

High Grade Serous Ovarian Cancer

Outcome Measures

Primary Outcomes (1)

• Pathological complete response

  Pathological complete response after 3 cycles of NACT including Olaparib and weekly Carboplatin-Paclitaxel in BRCAmut advanced HGSOC women.

  28 months

Study Arms (1)

Paclitaxel Carboplatin Olaparib

EXPERIMENTAL

Subjects will receive weekly therapy with paclitaxel 60 mg/m2 IV and carboplatin AUC 2 IV for 3 weeks out of 4, and olaparib tablets at the dose of 150 mg bid administered orally for 3 consecutive days (D1-D3), every week for each cycle. After 3 cycles patients will be evaluated for interval debulking surgery. After surgery they will receive consolidation treatment with paclitaxel and carboplatin according to Investigator's choice

Drug: Olaparib; Drug: Paclitaxel; Drug: Carboplatin

Interventions

Olaparib DRUG

PARP INHIBITOR

Also known as: Lynparza

Paclitaxel Carboplatin Olaparib

Paclitaxel DRUG

Chemotherapy

Paclitaxel Carboplatin Olaparib

Carboplatin DRUG

Chemotherapy

Paclitaxel Carboplatin Olaparib

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Pathologically confirmed advanced high grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer;
• Female, aged at least 18 years;
• Documented mutation in BRCA1 or BRCA2 germline and/or somatic that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function);
• FIGO stages III-IV primary ovarian, primary peritoneal, or fallopian tube cancers not suitable of primary cytoreductive surgery (Criteria for Neoadjuvant Chemotherapy despite to Primary Surgery: clinical conditions; Fagotti's score \> 10, small bowel carcinosis, mesenteric retraction);
• Measurable disease according to RECIST criteria 1.1;
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1;
• Left Ventricular Ejection Fraction (LVEF) ≥ institutional lower limit of normal;
• Patients must have a life expectancy of \>16 weeks;
• 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/randomisation (choose whichever is most applicable to the study)
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• No features suggestive of MDS/AML on peripheral blood smear
• White blood cells (WBC) \> 3x109/L
• Platelets count ≥ 100 x 109/L
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)

You may not qualify if:

• History of another neoplastic disease (except basal cell carcinoma or cervical carcinoma in situ adequately treated) unless in remission for 5 years or longer
• Other serious illnesses, such as:
• Congestive heart failure or angina pectoris; myocardial infarction within 3 months before enrolment; uncontrolled arterial hypertension or arrhythmias Psychiatric disorder that prevents compliance with protocol Uncontrolled seizures Active viral hepatitis; or chronic liver disease Active infection Any other unstable medical conditions
• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
• Non defective BRCA status or BRCA 1 and/or BRCA2 mutations that are considered to be non detrimental (e.g."Variants of uncertain clinical significance" or "Variant of unknown significance"or "Variant, favor polymorphism" or "benign polymorphism" etc)
• Patients with early stage disease (FIGO Stage I, IIA, IIB or IIC)
• Patients who have previously received chemotherapy or radiotherapy for any abdominal or pelvic tumour, including treatment for prior diagnosis at an earlier stage for their ovarian, fallopian tube or primary peritoneal cancer. (Patients who have received prior adjuvant chemotherapy for localised breast cancer may be eligible, provided that it was completed more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease).
• Patients with synchronous primary endometrial cancer, or a past history of primary endometrial cancer, unless all of the following conditions are met: Stage not greater than I-A; no more than superficial myometrial invasion, without vascular or lymphatic invasion; no poorly differentiated subtypes, including papillary serous, clear cell or other FIGO Grade 3 lesions.
• Participation in another clinical study with an investigational product
• Any previous treatment with PARP inhibitor, including olaparib.
• Resting ECG with QTc (corrected QT interval) \> 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
• Concomitant use of known potent CYP3A4 (Cytochrome P450 3A4)inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir. The required washout period prior to starting olaparib is 2 weeks.
• Persistent toxicities (\>Common Terminology Criteria for Adverse Event (CTCAE) grade 2 caused by previous cancer therapy, excluding alopecia.
• Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML.
• 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 4 weeks prior to treatment. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days.

Sponsors & Collaborators

• Fondazione Policlinico Universitario Agostino Gemelli IRCCS: lead

Study Sites (1)

Fondazione Policlinico Gemelli IRCCS

Roma, 00168, Italy

RECRUITING

Related Publications (1)

• Marchetti C, Tudisco R, Salutari V, Pietragalla A, Scambia G, Fagotti A. Neoadjuvant chemoteraphy in unresectable ovarian cancer with olaparib and weekly carboplatin plus paclitaxel: a phase II, open label multicenter study (NUVOLA trial). Int J Gynecol Cancer. 2021 Aug;31(8):1175-1178. doi: 10.1136/ijgc-2021-002727. Epub 2021 Jun 15.

  PMID: 34131041 DERIVED

MeSH Terms

Interventions

olaparib; Paclitaxel; Carboplatin

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Coordination Complexes

Study Officials

• Giovanni Scambia, Prof

  Fondazione Policlinico Gemelli IRCCS

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Giovanni Scambia, Prof

CONTACT

+390630155701; giovanni.scambia@policlinicogemelli.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 31, 2020
• First Posted: February 7, 2020
• Study Start: December 1, 2019
• Primary Completion: December 1, 2020
• Study Completion: December 1, 2022
• Last Updated: February 7, 2020

Record last verified: 2019-11

Locations

IT (1)