Description:
The purpose of the study is to assess the efficacy and safety of single-agent olaparib as a
maintenance treatment in patients with relapsed High Grade Serous Ovarian Cancer (including
patients with primary peritoneal and/or fallopian tube cancer) or high grade endometrioid
cancer who do not have known deleterious or suspected deleterious germline BRCA mutations
(non-gBRCAm) and who had responded following platinum based chemotherapy
Title
- Brief Title: Multicentre Study of Olaparib Maintenance Monotherapy in Platinum Sensitive Relapsed Non gBRCAm Ovarian Cancer Patients
- Official Title: A Phase IIIb, Single-arm, Open-label Multicentre Study of Olaparib Maintenance Monotherapy in Platinum Sensitive Relapsed Non-Germline BRCA Mutated Ovarian Cancer Patients Who Are in Complete or Partial Response Following Platinum Based Chemotherapy
Clinical Trial IDs
- ORG STUDY ID:
D0816C00020
- NCT ID:
NCT03402841
Conditions
- Non-Germline BRCA Mutated Ovarian Cancer
Interventions
| Drug | Synonyms | Arms |
|---|
| Olaparib | Lynparza | Olaparib |
Purpose
The purpose of the study is to assess the efficacy and safety of single-agent olaparib as a
maintenance treatment in patients with relapsed High Grade Serous Ovarian Cancer (including
patients with primary peritoneal and/or fallopian tube cancer) or high grade endometrioid
cancer who do not have known deleterious or suspected deleterious germline BRCA mutations
(non-gBRCAm) and who had responded following platinum based chemotherapy
Detailed Description
Maintenance monotherapy with the potent polyadenosine 5'diphosphoribose [Poly (ADP-ribose)]
polymerisation (PARP) inhibitor (PARPi) olaparib will significantly prolong progression-free
survival (PFS) in platinum sensitive relapsed non-germline breast cancer susceptibility gene
(BRCA) mutated ovarian cancer patients who are in complete or partial response following
platinum based chemotherapy.
Olaparib is a potent PARPi (PARP-1, -2 and -3) that is being developed as an oral therapy,
both as a monotherapy (including maintenance) and for combination with chemotherapy and other
anticancer agents. PARP inhibition is a novel approach to targeting tumours with deficiencies
in DNA repair mechanisms. PARP enzymes are essential for repairing DNA single strand breaks
(SSBs). Inhibiting PARP enzymes leads to the persistence of SSBs, which are then converted to
the more serious DNA double strand breaks (DSBs) during the process of DNA replication.
During the process of cell division, DSBs can be efficiently repaired in normal cells by
homologous recombination (HR) repair. Tumours with HR deficiencies (HRDs), such as ovarian
cancers in patients with BRCA1/2 mutations, cannot accurately repair the DNA damage, which
may become lethal to cells as it accumulates. In such tumour types, olaparib may offer a
potentially efficacious and less toxic cancer treatment compared with currently available
chemotherapy regimens.
While multiple randomized controlled trials (RCTs) have demonstrated that platinum sensitive
BRCAm patients have profound response to maintenance treatment with PARP inhibitors, PARP
inhibitors target cells with homologous recombination deficiency (HRD), of which BRCA
mutation is only one type. Consistent with the mechanism of action of PARP inhibition,
response has also been seen in multiple RCTs in patients who are platinum sensitive but whose
tumours do not harbor BRCA mutations. Presumably these responders have defects in other
components of HRR pathways, though currently available diagnostic technology is not adequate
to reliably identify the full spectrum of HRR deficiencies. Instead, these data support the
hypothesis that platinum sensitivity itself is a clinical selection factor for HRD.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Olaparib | Experimental | Olaparib will be supplied as film-coated tablets containing 150 mg or 100 mg of olaparib.
Patients will be administered olaparib orally twice daily (bid) at 300 mg. | |
Eligibility Criteria
Key Inclusion Criteria:
- Female patients with histologically diagnosed relapsed HGSOC (including primary
peritoneal and / or fallopian tube cancer) or high grade endometrioid ovarian cancer
- Documented gBRCA1/2 mutation status
- Patients must have completed at least 2 previous courses of platinum containing
therapy
- Patients must have normal organ and bone marrow function measured within 28 days of
starting study treatment
- ECOG performance status 0-1 (see Appendix E)
- Patients must have a life expectancy ≥16 weeks
- Postmenopausal or evidence of non-childbearing status for women of childbearing
potential: negative urine or serum pregnancy test within 28 days of study treatment
and confirmed prior to treatment on day 1
- At least one lesion (measurable and/or non-measurable) that can be accurately assessed
at baseline with computed tomography (CT) or magnetic resonance imaging (MRI) and is
suitable for repeated assessment OR No evidence of disease following a complete
response to chemotherapy
- An appropriately prepared tumour sample from the cancer, of sufficient quantity and
quality (as specified in the Central Laboratory Services Manual) must be available for
future central testing of tumour genetic status
Exclusion Criteria:
- Patients receiving any systemic hormonal therapy, chemotherapy or radiotherapy (except
for palliative reasons) within 3 weeks prior to start of study treatment
- Any previous treatment with PARP inhibitor, including olaparib
- Patients with a germline BRCA mutation that is predicted to be deleterious or
suspected deleterious (known or predicted to be detrimental / lead to loss of
function)
- Other malignancy unless curatively treated with no evidence of disease for ≥5 years
except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer
of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial
carcinoma.
- Concomitant use of known strong CYP3A inhibitors and strong (or moderate CYP3A
inducers
- Persistent toxicities (≥ Grade 2 Common Terminology Criteria for Adverse Event (CTCAE)
adverse event) 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
| Maximum Eligible Age: | 95 Years |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | Female |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Progression-free survival (PFS) |
| Time Frame: | Visit 1, 4 and on the first day of each 8 week visit period, relative to the date of the 1st olaparib dose, for the first 12 months on treatment, and then each 12-week visit period, until the earlier of progression, death or EOS for up to 30 months. |
| Safety Issue: | |
| Description: | Time from date of first dose of olaparib to the date of objective radiological disease progression according to investigator assessment via RECIST 1.1 or death (by any cause in the absence of progression) |
Secondary Outcome Measures
| Measure: | Time to first subsequent therapy or death (TFST) |
| Time Frame: | Visit 2, visit 3, visit 4 and then at every tumour assessment visit. TFST only: at discontinuation of study treatment visit, at 30 days post last dose and every 12 weeks during long term follow-up (for up to 30 months). |
| Safety Issue: | |
| Description: | Time from date of first dose to date of first subsequent treatment commencement or death due to any cause if this occurs before commencement of first subsequent treatment. |
| Measure: | Time to treatment discontinuation or death (TDT) |
| Time Frame: | Visit 2, visit 3, visit 4 and then at every tumour assessment visit. TFST only: at discontinuation of study treatment visit, at 30 days post last dose and every 12 weeks during long term follow-up (for up to 30 months). |
| Safety Issue: | |
| Description: | Time from date of first dose to date of study drug discontinuation or death due to any cause if this occurs before study drug discontinuation. |
| Measure: | PFS in the following subgroups: 1. Somatic BRCA mutated and HRD scar positive; 2. HRD scar positive, non-BRCA mutated; 3. HRD scar negative, non-BRCA mutated |
| Time Frame: | Visit 1, 4 and every 8 week for the first 12 months, and each 12 week until earlier progression, death or EOS for up to 30 months. |
| Safety Issue: | |
| Description: | Time from date of first dose of olaparib to the date of objective radiological disease progression according to investigator assessment via RECIST 1.1 or death (by any cause in the absence of progression) |
| Measure: | Chemotherapy-free interval (CT_FI) |
| Time Frame: | At Screening, Visit 2, 3, 4 and subsequent tumor assessment visits, Visit 5 and subsequent safety visits until 30 days after last dose and then every 12 weeks until EOS (for up to 30 months) |
| Safety Issue: | |
| Description: | Time from the date of the last dose of platinum chemotherapy prior to olaparib maintenance therapy until the date of the initiation of the next anticancer therapy . |
| Measure: | Trial outcome index (TOI) |
| Time Frame: | At baseline, visit 3, visit 4 and then at every tumor assessment visit until progression, at discontinuation of study treatment visit and at 30 days post last dose. |
| Safety Issue: | |
| Description: | Proportion of patients with any improvement from baseline in TOI score. |
| Measure: | AEs/SAEs |
| Time Frame: | Screening, Visit 2, 3, 4 and subsequent Tumor Assessment Visit, Visit 5 and subsequent Safety Visit, until 30 days after last dose of study drug. |
| Safety Issue: | |
| Description: | Will be assessed in terms of AEs, deaths and laboratory data. |
| Measure: | Overall Survival (OS) |
| Time Frame: | Visit 1, 4, first of each 8 week visit period relative to the data of first olaparib dose, for the first 12 months on threatment and then each 12 week visit period, until death or EOS for up to 30 months. |
| Safety Issue: | |
| Description: | Time from the date of first dose of olaparib to date of death from any cause |
Details
| Phase: | Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Active, not recruiting |
| Lead Sponsor: | AstraZeneca |
Trial Keywords
- Ovarian cancer
- non-gBRCA
- Platinum
- Chemotherapy
Last Updated
July 1, 2021
