Patologia: Tumori dell’ovaio
Fase di studio: II
Richiesta mandatoria di tessuto: Sì
Linee di trattamento: Seconda linea, Terza/N linea
Criteri di inclusione:
1. Women who have histologically or cytologically verified high-grade serous ovarian, primary peritoneal or fallopian tube cancer.
2. Cohorts 1 to 3: Have platinum-resistant disease, which is defined as disease progression within 6 months of last dose of platinum-based chemotherapy.
Progression due to rising CA125 only is not considered as platinum-resistant disease.
Cohort 4: Have primary platinum-refractory disease defined as disease progression during or within 4 weeks after the last dose of initial line of platinum-based chemotherapy for ovarian cancer.
3. Cohort 1: Are BRCA negative and have received 3 or more prior lines of therapy for high-grade serous ovarian, primary peritoneal, or fallopian tube cancer (including immunotherapy, targeted therapies, or chemotherapy (systemic or intraperitoneal).
Cohort 2: Are BRCA negative have received less than 3 prior lines of therapy for high-grade serous ovarian, primary peritoneal, or fallopian tube cancer (including immunotherapy, targeted therapies, or chemotherapy (systemic or intraperitoneal).
Note for Cohorts 1 and 2: Each line of therapy is preceded by evidence of clinical or radiographic disease progression (initial therapy is considered the first line). Switch of an agent within the same drug class (for example, cisplatin to carboplatin) within a
regimen to manage toxicity does not define the start of a new line of therapy. Similarly, maintenance therapy (continuation maintenance or switch maintenance) will not be considered a new line of treatment. Hormonal therapy is not considered a
line of therapy.
Cohort 3: Are BRCA positive and have previously received a PARP inhibitor at any time following diagnosis. Note: there is no restriction on number of lines of prior therapy.
Cohort 4: Are BRCA positive or negative; no restriction on number of lines of prior therapy.
3. Have a performance status (PS) of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale (Oken et al. 1982).
4. Have discontinued all previous treatments for cancer and recovered from acute effects of therapy. Patients must be discontinued from previous treatments
5. Have at least 1 measurable lesion using standard techniques by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Eisenhauer et al. 2009).
6. Have given written informed consent prior to any study-specific procedures and agree and are able to follow the requirements of the protocol.
7. Are of an acceptable age to provide informed consent according to the local regulations and are at least 18 years of age.
8. Have adequate organ function
9. Women of child-bearing potential participating must agree to use one highly effective (less than 1% failure rate) method of contraception or use a combination of two effective methods of contraception during treatment with study drug and for at least
12 weeks following the last dose of study drug.
Note: Unless not allowed by local regulations, women of child-bearing potential who are abstinent (if this is complete abstinence, as their preferred and usual lifestyle) or in a same sex relationship (as part of their preferred and usual lifestyle) must agree to
either remain abstinent or stay in a same sex relationship without sexual relationships with males. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), declaration of abstinence just for the duration of a trial, and
withdrawal are not acceptable methods of contraception.
10. Women of child-bearing potential participating must test negative for pregnancy prior to initiation of treatment as indicated by a negative pregnancy test at the screening visit (prior to biopsy)and within 24 hours prior of drug exposure.
11. Cohorts 1-3: Have documented test results assessing alterations in the BRCA1 and BRCA2 genes by a local laboratory prior to receiving study treatment. Results from either a blood or tissue based test are acceptable.
12. Must be able and willing to undergo mandatory tumor biopsy which will be collected following determination of eligibility and before treatment (≤28 days before C1D1).
Tumor tissue obtained from a prior biopsy may be permitted for the pretreatment sample after discussion and agreement between Lilly clinical research physician (CRP) / clinical research scientist (CRS) and investigator if a patient has not received
any therapies for the disease between the time biopsy was obtained to start of prexasertib treatment. The decision to use a tumor tissue sample from a prior biopsy will be documented in writing.
Criteri di esclusione:
1. Cohorts 1-3: Have previously received all of the following agents at any time in the platinum-resistant setting: gemcitabine, pegylated liposomal doxorubicin, and paclitaxel. It is acceptable to have received 1 or 2 of these agents for platinumresistant
2. Have non-epithelial or mixed epithelial/non-epithelial tumors (including malignant mixed Müllerian tumors), ovarian tumors with low malignant potential (borderline tumors), endometrioid, clear cell, mucinous or low-grade serous carcinomas or not otherwise specified (NOS) ovarian tumors.
3. Have known central nervous system (CNS) malignancy or metastasis. Patients with treated brain metastases that have been CNS recurrence-free for 1 year prior to study treatment may be considered if approved by the Lilly CRP/CRS.
4. Have prior malignancies unless approved by the Lilly CRP/CRS. For instance, patients with carcinoma in situ of any origin and patients with prior malignancies who are in remission and whose likelihood of recurrence is very low, as judged by the Lilly CRP/CRS, may be eligible for this study.
5. Are currently enrolled in a clinical study involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study.
6. Have previously completed or withdrawn from this study or any other study investigating prexasertib or a CHK1 inhibitor or have shown hypersensitivity to any of the study drugs or excipients.
7. Have a known serious medical condition (e.g., active infection) that, in the opinion of the investigator, would compromise the patient’s ability to adhere to the protocol.
8. Have at least one of the following:
- history of abdominal fistula or gastrointestinal (GI) perforation
- intra-abdominal abscess within last 3 months prior to the first dose of study drug
- a radiographically confirmed bowel obstruction (including sub-occlusive disease) within 3 months prior to the first dose of study drug.
9. Have a symptomatic human immunodeficiency virus (HIV) infection or symptomatic activated/reactivated hepatitis A, B, or C (screening is not required).
10. Have a serious cardiac condition, such as:
- symptomatic congestive heart failure or any uncontrolled cardiac disease
- New York Heart Association Class III/IV heart disease
- unstable angina pectoris
- symptomatic or poorly controlled cardiac arrhythmia
- myocardial infarction within the last 3 months
- have a QT interval using Fridericia’s correction (QTcF) of >480 msec on more than one electrocardiogram (ECG) obtained during the baseline (screening) period
- family history of long-QT syndrome.
11. Have a history of prior radiotherapy to the whole pelvis.
12. Have chronic daily treatment with corticosteroids (dose >10 mg/day methylprednisolone equivalent), excluding inhaled steroids.
Trattamento di controllo:
Obiettivi primari dello studio:
To estimate the ORR for each cohort
Obiettivi secondari dello studio:
- To characterize the safety and toxicity profile of prexasertib
- To characterize the PK of prexasertib
- To estimate secondary efficacy measures including DCR, DoR, CA-125 response, PFS, OS
IRCCS Istituto Nazionale dei Tumori
Via Venezian 1 - 20133 Milano - MI
Riferimento: Dr.ssa Domenica Lorusso
Istituto Europeo di Oncologia
Via Ripamonti 435 - 20141 Milano - MI
Ginecologia Oncologica Medica
Riferimento: Prof.ssa Nicoletta Colombo
Fondazione Policlinico A. Gemelli
Largo Agostino Gemelli 8 - 00168 Roma - RM
Riferimento: Prof. Giovanni Scambia
Istituto Nazionale Tumori IRCCS Fondazione Pascale
Via Mariano Semmola - 80131 Napoli - NA
UOC Oncologia Medica Uro-Ginecologica
Riferimento: Dr. Sandro Pignata
Numero di iscrizione a registro: 2017-004009-42
Data di inserimento: 08.10.2018
Fondazione IRCCS, Istituto Nazionale dei Tumori, Milano
Riferimento: Dr.ssa Domenica Lorusso