| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Homologous recombination repair mutation (HRRm) or Homologous recombination deficiency (HRD) positive cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Male and female participants with previously treated, advanced (metastatic and/or unresectable) HRRm and/or HRD-positive solid tumors |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the objective response rate (ORR) as assessed by blinded independent central review (BICR) according to modified Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) or Prostate Cancer Working Group (PCWG)-modified RECIST 1.1, following olaparib administration in Cohort 1, Cohort 2 and Cohort 3 |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate
-DOR as assessed by BICR according to modified RECIST 1.1 or PCWG-modified RECIST 1.1, following olaparib administration in Cohorts 1, 2 and 3.
-OS, following administration of olaparib in Cohorts 1, 2, and 3.
-PFS as assessed by BICR according to modified RECIST 1.1 or PCWG- modified RECIST 1.1, following
olaparib administration in Cohorts 1, 2, and 3.
-the safety and tolerability of olaparib in Cohorts 1, 2, and 3.
-the ORR, DOR, OS, and PFS in participants who are {1) HRRm, {2) HRD positive, and {3) in all participants regardless of biomarker status following olaparib administration in Cohorts 1 and 2.
-time to earliest progression by CA-125 following olaparib administration in participants with BRCA1/2 non-mutated ovarian cancer.
-the PSA response rate to olaparib administration in participants with prostate cancer.
-progression-free survival after next-line treatment {PFS2), as assessed
by the investigator, in participants with sBRCAm breast cancer. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Cohorts 1 and 2:
1. Has a histologically- or cytologically-confirmed advanced (metastatic and/or unresectable) solid tumor (except ovarian cancer whose tumor has a germline or somatic BRCA mutation and breast
cancer whose tumor has a germline BRCA) that is not eligible for curative treatment and for which standard of care therapy has failed. Participants must have progressed on or be intolerant to standard of care therapies that are known to provide clinical benefit. There is no limit on the number of prior treatment regimens
2. Has either centrally-confirmed known or suspected deleterious mutations in at least 1 of the specified 15 genes involved in HRR (ie, BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L) or centrally-confirmed HRD based on the Lynparza HRR-HRD assay
3. If participants have received prior platinum (cisplatin, carboplatin, or oxaliplati, etc. either as monotherapy or in combination) for advanced (metastatic and/or unresectable) solid tumor, they are eligible to enter the study provided there has been no evidence of disease progression during the platinum chemotherapy or ≤ 4 weeks of completing the platinum-containing regimen.
Cohorts 1, 2 and 3
4. Participant has measurable disease per RECIST 1.1 or PCWG-modified RECIST 1.1 as assessed by the local site Investigator/radiology and confirmed by BICR. BICR must confirm the presence of radiologically measurable disease based on RECIST 1.1 or PCWG-modified RECIST 1.1 for the participant to be eligible for the study. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
5. Is able to provide a newly obtained core or excisional biopsy of a tumor lesion or either an archival formalin-fixed paraffin embedded (FFPE) tumor tissue block or slides. A newly obtained biopsy is preferred, but not required if archival tissue is available for analysis
6. Has a life expectancy of at least 3 months
7. Is Male or Female who is at least 18 years of age at the time of signing the informed consent
8. Has an Eastern Cooperative Oncology Group (ECOG) performance status of either 0 or 1, as assessed within 3 days of treatment initiation
9. A male participant must agree to use contraception during the treatment period and for at least 95 days (3 months and 5 days), corresponding to time needed to eliminate any study intervention(s) (ie, olaparib) plus a spermatogenesis cycle, after the last dose of study intervention and refrain from donating sperm during this period
10. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies:
• Not a woman of childbearing potential (WOCBP)
OR
• A WOCBP and * uses a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The length of time required to continue contraception for each study intervention is as follows:
- Olaparib: 180 days
The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
• Has a negative highly sensitive pregnancy test (urine or serum as required by local
regulations) within either 24 hours (urine) or 72 hours (serum) before the first dose of study intervention.
* Abstains from breastfeeding during the study intervention period and for at least 30 days after the last dose of study intervention
11. The participant (or legally acceptable representative if applicable) has provided documented written informed consent for the study. The participant may also provide consent for FBR. However, the participant may participate in the main study without participating in FBR
12. Has adequate organ function
Cohort 3:
13. Has histologically- or cytologically-confirmed breast cancer with evidence of metastatic disease
14. Has a known or suspected deleterious mutation in BRCA1 or BRCA2
and does not harbor a germline BRCA1 or BRCA2 mutation.
15. Must have received treatment with an anthracycline (e.g. doxorubicin, epirubicin) unless contraindicated and a taxane (e.g. paclitaxel, docetaxel) in either the neoadjuvant / adjuvant or metastatic setting.
16. With estrogen and/or progesterone receptor-positive disease must have received and
progressed on at least one endocrine therapy (adjuvant or metastatic), or have disease that the treating
physician believes to be inappropriate for endocrine therapy. |
|
| E.4 | Principal exclusion criteria |
Participant
1.has a known additional malignancy that is progressing or has required active treatment in the last 5 years
2.has MDS/AML or with features suggestive of MDS/AML
3.has persistent toxicities(>CTCAE Grade 2)caused by previous cancer therapy, excluding alopecia
4.has known central nervous system(CNS)metastases and/or carcinomatous meningitis
5.has an active infection requiring systemic therapy
6.has a history or current evidence of any condition(eg, cytopenia, transfusion-dependent anemia, or thrombocytopenia), therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s involvement for the full duration of the study, or is not in the best interest of the participant to be involved, in the opinion of the treating Investigator
7.received colony-stimulating factors(eg, granulocyte colony-stimulating factor[G-CSF], granulocyte macrophage colony-stimulating factor[GM-CSF]or recombinant erythropoietin)within 28 days prior to the first dose of study intervention
8.is considered a 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, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography(HRCT)scan or any psychiatric disorder that prohibits obtaining informed consent
9.has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study
10.has a known history of human immunodeficiency virus(HIV)infection. Testing for HIV at screening is only required if mandated by local health authority
11.has known active hepatitis(ie, Hepatitis B or C)
a)Active hepatitis B virus(HBV)is defined by a known positive HBV surface antigen(HBsAg)result. Participants with a past or resolved HBV infection(defined as the presence of hepatitis B core antibody and absence of HBsAg)are eligible
b)Participants positive for hepatitis C virus(HCV)antibody are eligible only if polymerase chain reaction is negative for HCV RNA
12.is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption(eg, gastrectomy, partial bowel obstruction, malabsorption)
13.has received prior therapy with olaparib or with any other PARP inhibitor
14.has a known hypersensitivity to the components or excipients in olaparib
15.is currently receiving either strong(eg, itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir)or moderate (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil)inhibitors of cytochrome P450 CYP)3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 2 weeks
16.is currently receiving either strong(phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort)or moderate(eg. bosentan, efavirenz, modafinil)inducers of CYP3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 5 weeks for phenobarbital and 3 weeks for other agents
17.has received previous allogenic bone-marrow transplant or double umbilical cord transplantation (dUCBT)
18.has received a whole blood transfusion in the last 120 days prior to entry to the study. Packed red blood cells and platelet transfusions are acceptable if not performed within 28 days of the first dose of study intervention
19.is currently enrolled in and receiving study therapy, was enrolled in a study of an investigational agent and received study therapy, or used an investigational device within 4 weeks(28 days)of the first dose of study intervention
20.either had major surgery within 2 weeks of starting study intervention or has not recovered from any effects of any major surgery
21.is involved in the planning and/or conduct of the study(applies to both Sponsor staff and/or staff at the study site)
22.in the judgement of the Investigator, is unlikely to comply with the study procedures, restrictions, and requirements of the study
23.has received any anti-neoplastic systemic chemotherapy or biological therapy, targeted therapy, or an anticancer hormonal therapy within 3 weeks prior to the first dose of study intervention.
24.has a primary cancer of unknown origin
|
Principal exclusion criteria continued (US English Language):
25.has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation(≤ 2 weeks of radiotherapy)to non-CNS disease |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective response rate (ORR) based on RECIST 1.1 or PCWG-modified RECIST 1.1 (participants with prostate cancer) as assessed by blinded independent central review |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary analysis will be conducted when all enrolled participants have at least 9 months follow-up |
|
| E.5.2 | Secondary end point(s) |
1) Duration of response(DOR)
2) Evaluate overall survival(OS
3) Progression free survival(PFS)
4) Progression Free Survival after next-line treatment (PFS2)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Canada |
| Colombia |
| Guatemala |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| New Zealand |
| Peru |
| United States |
| France |
| Romania |
| Spain |
| Switzerland |
| Italy |
| Denmark |
| Ireland |
| Russian Federation |
| Turkey |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Receipt of the last laboratory result or LVLS, whichever comes last |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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