NUVOLA TRIAL Open-label Multicentre Study

STATUS

Recruiting
participants needed

35
sponsor

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

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Updated on 19 February 2024

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cancer

maintenance treatment

hysterectomy

blood transfusion

platelet count

white blood cell count

serum pregnancy test

measurable disease

metastasis

carboplatin

neutrophil count

paclitaxel

liver metastasis

fallopian tube

ovarian cancer

primary peritoneal carcinoma

recurrent ovarian cancer

peritoneal cancer

oophorectomy

skin cancer

non-melanoma skin cancer

luteinizing hormone

ejection fraction

estimated creatinine clearance

follicle stimulating hormone

olaparib

tumor debulking

cytoreductive surgery

parp inhibitor

skin carcinoma

debulking surgery

treatment and maintenance

sterilisation

peripheral blood smear

adp-ribose

melanoma

cervical cancer

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.

Details

Condition	High Grade Serous Ovarian Cancer
Age	18-100 years
Treatment	Carboplatin, Paclitaxel, Olaparib
Clinical Study Identifier	NCT04261465
Sponsor	Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Last Modified on	19 February 2024

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Eligibility		Yes	No	Not Sure
Inclusion Criteria
	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)
	AST (Aspartate Aminotransferase)/ALT (Alanine aminotransferase) 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 of 51 mL/min using the Cockcroft-Gault equation
	Estimated creatinine clearance =[ (140-age [years]) x weight (kg) (x F)]
	[serum creatinine (mg/dL) x 72]; where F=0.85 for females
	\. No other invasive malignancy within the past 3 years except non-melanoma
	skin cancer or in situ cervical cancer (patients with previous cancers may be
	enrolled providing that no recurrences have be reported in the last 3 years)
	\. Written Informed Consent
	\. Postmenopausal status defined as
	Amenorrheic for 1 year or more following cessation of exogenous hormonal
	treatments Luteinizing hormone (LH) and Follicle stimulating hormone (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 sterilisation (bilateral
	oophorectomy or hysterectomy) or evidence of non-childbearing status for women
	of childbearing potential: negative urine or serum pregnancy test prior to
	Myriad BRCA test during screening part 1, within 28 days of study treatment
	and confirmed prior to treatment on day 1
	\. Patient is willing and able to comply with the protocol for the duration
	of the study including undergoing treatment and scheduled visits and
	examinations
	\. For inclusion in the optional exploratory genetic and the optional
	biomarker research, patients must provide informed consent for genetic and for
	biomarker research
Exclusion Criteria
	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
	\. Major surgery within 2 weeks of starting study treatment and patients
	must have recovered from any effects of any major surgery
	\. Patients unable to swallow orally administered medication and patients
	with gastrointestinal disorders likely to interfere with absorption of the
	study medication, including gastrectomy
	\. Breast feeding women
	\. Immunocompromised patients, e.g., patients who are known to be
	serologically positive for human immunodeficiency virus (HIV)
	\. Patients with a known hypersensitivity to olaparib or any of the
	excipients of the product
	\. Patients with a known hypersensitivity to Paclitaxel or Carboplatin, or
	any of the excipients of these agents
	\. Previous allogeneic bone marrow transplant, or double umbilical cord
	blood transplantation
	\. Previous enrolment in the present study
	\. Patients receiving any systemic chemotherapy or radiotherapy (except for
	palliative reasons) within 3 weeks prior to study treatment
	\. 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 phenobarbital and 3 weeks for other agents
	\. Whole blood transfusions in the last 120 days prior to entry to the
	study

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cancer

maintenance treatment

hysterectomy

blood transfusion

platelet count

white blood cell count

primary peritoneal carcinoma

recurrent ovarian cancer

peritoneal cancer

oophorectomy

skin cancer

non-melanoma skin cancer

luteinizing hormone

ejection fraction

estimated creatinine clearance

follicle stimulating hormone

olaparib

tumor debulking

cytoreductive surgery

parp inhibitor

skin carcinoma

debulking surgery

treatment and maintenance

sterilisation

peripheral blood smear

adp-ribose

melanoma

cervical cancer

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Study Definition

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NUVOLA TRIAL Open-label Multicentre Study