Olaparib Monotherapy in HRRm or HRD Positive Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Sharp & Dohme LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Dec 2018 → 11 Dec 2025

Decision date (initial)

2023-02-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Merck Sharp & Dohme LLC

External identifiers

EU CT number

2022-500797-34-00

EudraCT number

2018-003007-19

WHO UTN

U1111-1278-1505

ClinicalTrials.gov

NCT03742895

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenetic, Efficacy, Therapy, Pharmacogenomic, Pharmacokinetic, Others, Pharmacodynamic, Safety

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.

Secondary objectives 8

1. To evaluate the duration of response (DOR) as assessed by BICR according to modified RECIST 1.1 or PCWG-modified RECIST 1.1, following olaparib administration in Cohort 1, Cohort 2, and Cohort 3.
2. To evaluate overall survival (OS), following administration of olaparib in Cohort 1, Cohort 2, and Cohort 3.
3. To evaluate progression-free survival (PFS) as assessed by BICR according to modified RECIST 1.1 or PCWG-modified RECIST 1.1, following olaparib administration in Cohort 1, Cohort 2, and Cohort 3.
4. To evaluate the safety and tolerability of olaparib in Cohort 1, Cohort 2, and Cohort 3.
5. To evaluate 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 Cohort 1 and Cohort 2.
6. To assess time to earliest progression by CA-125 following olaparib administration in participants with BRCA1/2 non-mutated ovarian cancer.
7. To evaluate the PSA response rate to olaparib administration in participants with prostate cancer.
8. To evaluate progression-free survival after next-line treatment (PFS2), as assessed by the investigator, in participants with sBRCAm breast cancer.

Conditions and MedDRA coding

Treatment of participants with positive cancer for HRRm or HRD.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. (For all participants) 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.
2. (For all participants) 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.
3. (For all participants) Has a life expectancy of at least 3 months.
4. (For all participants) Has an Eastern Cooperative Oncology Group (ECOG) performance status of either 0 or 1, as assessed within 7 days of treatment initiation.
5. (For all participants) Male participants must agree to use contraception during the treatment period and for at least 95 days (3 months and 5 days) after the last dose of study treatment and refrain from donating sperm during this period.
6. (For all participants) A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: 1. Is not a woman of childbearing potential (WOCBP). 2. Is a WOCBP and using a contraceptive method that is highly effective 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 180 days 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. Abstains from breastfeeding during the study intervention period and for at least 30 days after the last dose of study intervention.
7. (For all participants) Has adequate organ function.
8. (For participants who have non-breast or -ovarian cancers that are breast cancer susceptibility gene 1/2 (BRCA1/2) mutated (BRCAm), or who have cancers that are BRCA1/2 non-mutated and homologous recombination repair mutated, or homologous recombination deficient without a mutation in HRR pathway) 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 mutation) 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.
9. (For participants who have non-breast or -ovarian cancers that are breast cancer susceptibility gene 1/2 (BRCA1/2) mutated (BRCAm), or who have cancers that are BRCA1/2 non-mutated and homologous recombination repair nonmutated) Has either centrally-confirmed known or suspected deleterious mutations in at least 1 of the genes involved in HRR or centrally-confirmed HRD.
10. (For participants who have non-breast or -ovarian cancers that are breast cancer susceptibility gene 1/2 (BRCA1/2) mutated (BRCAm), or who have cancers that are BRCA1/2 non-mutated and homologous recombination repair nonmutated) For participants receiving prior platinum (cisplatin, carboplatin, or oxaliplatin either as monotherapy or in combination) for advanced (metastatic and/or unresectable) solid tumor, have no evidence of disease progression during the platinum chemotherapy or ≤4 weeks of completing the platinum-containing regimen.
11. (For participants who have somatic BRCAm breast cancer) Has histologically- or cytologically-confirmed breast cancer with evidence of metastatic disease.
12. (For participants who have somatic BRCAm breast cancer) Has a known or suspected deleterious mutation in breast cancer susceptibility gene (BRCA) 1 or BRCA2 and does not harbor a germline BRCA1 or BRCA2 mutation - testing can be done centrally or locally. Blood and tissue samples must be provided by all participants.
13. (For participants who have somatic BRCAm breast cancer) Has received treatment with an anthracycline unless contraindicated and a taxane in either the neoadjuvant/adjuvant or metastatic setting.
14. (For participants who have somatic BRCAm breast cancer) Participants 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.

Exclusion criteria 14

1. Has a known additional malignancy that is progressing or has required active treatment in the last 5 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, ductal carcinoma in situ, or cervical carcinoma in situ that has undergone potentially curative therapy are not excluded
2. Has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML.
3. Has known central nervous system (CNS) metastases and/or carcinomatous meningitis. Note: Participants with previously treated brain metastases may participate if radiologically stable, clinically stable, and without requirement for steroid treatment for at least 14 days prior to the first dose of study treatment.
4. Has received colony-stimulating factors (e.g., 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 treatment.
5. Has a known history of human immunodeficiency virus (HIV) infection.
6. Has known active hepatitis infection (i.e., Hepatitis B or C).
7. Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (e.g., gastrectomy, partial bowel obstruction, malabsorption).
8. Has received prior therapy with olaparib or with any other polyadenosine 5' diphosphoribose (poly[ADP ribose]) polymerization (PARP) inhibitor.
9. Has a known hypersensitivity to the components or excipients in olaparib.
10. Has received previous allogenic bone-marrow transplant or double umbilical cord transplantation (dUCBT).
11. 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 treatment.
12. 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.
13. Has a primary cancer of unknown origin.
14. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Objective Response Rate (ORR)

Secondary endpoints 9

1. Duration of Response (DOR)
2. Overall Survival (OS)
3. Progression Free Survival (PFS)
4. Number of Participants Experiencing an Adverse Event (AE)
5. Number of Participants Discontinuing Study Treatment due to an Adverse Event (AE)
6. Objective Response Rate (ORR) in Participants with HRRm or HRD Positive Cancer
7. Time to Earliest Progression by Cancer Antigen-125 (CA-125)
8. Prostate-specific Antigen (PSA) Response Rate in Participants with Prostate Cancer
9. Progression-Free Survival After Next-Line Treatment in Participants with sBRCAm Breast Cancer

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Sharp & Dohme LLC

Sponsor organisation

Merck Sharp & Dohme LLC

Address

126 East Lincoln Avenue

City

Rahway

Postcode

07065-4607

Country

United States

Scientific contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Rachel Salisbury

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Rachel Salisbury

Third parties 7

Locations

6 EU/EEA countries · 21 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 23 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications