NUVOLA TRIAL Open-label Multicentre Study

  • STATUS
    Recruiting
  • End date
    Dec 1, 2022
  • participants needed
    35
  • sponsor
    Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Updated on 23 January 2021

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
Treatment carboplatin, Paclitaxel, olaparib
Clinical Study IdentifierNCT04261465
SponsorFondazione Policlinico Universitario Agostino Gemelli IRCCS
Last Modified on23 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Are you female?
Do you have High Grade Serous Ovarian Cancer?
Do you have any of these conditions: Do you have High Grade Serous Ovarian Cancer??
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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