A Phase 2 Study of Olaparib Monotherapy in Participants With Previously Treated, Homologous Recombination Repair Mutation (HRRm) or Homologous Recombination Deficiency (HRD) Positive Advanced Cancer
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 329
- 试验地点
- 130
- 主要终点
- Objective Response Rate (ORR)
研究概览
简要总结
This study will evaluate the efficacy and safety of olaparib (MK-7339) monotherapy in participants with multiple types of advanced cancer (unresectable and/or metastatic) that: 1) have progressed or been intolerant to standard of care therapy; and 2) are positive for homologous recombination repair mutation (HRRm) or homologous recombination deficiency (HRD).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •For all participants:
- •Has measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) or Prostate Cancer Working Group (PCWG)-modified RECIST 1.1 as assessed by the local site Investigator/radiology and confirmed by Blinded independent central review (BICR).
- •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.
- •Has a life expectancy of at least 3 months.
- •Has an Eastern Cooperative Oncology Group (ECOG) performance status of either 0 or 1, as assessed within 7 days of treatment initiation.
- •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.
- •A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
- •Is not a woman of childbearing potential (WOCBP).
- •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.
- •Has adequate organ function.
- •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 homologous recombination repair mutated (HRRm) but BRCA1/2 non-mutated, or homologous recombination repair non-mutated but homologous recombination deficiency (HRD) positive as centrally-confirmed by the Lynparza HRR-HRD Assay:
- •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.
- •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.
- •For participants who have somatic BRCAm breast cancer:
- •Has histologically- or cytologically-confirmed breast cancer with evidence of metastatic disease.
- •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.
- •Has received treatment with an anthracycline unless contraindicated and a taxane in either the neoadjuvant/adjuvant or metastatic setting.
- •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.
排除标准
- •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.
- •Has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML.
- •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.
- •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.
- •Has a known history of human immunodeficiency virus (HIV) infection.
- •Has known active hepatitis infection (i.e., Hepatitis B or C).
- •Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (e.g., gastrectomy, partial bowel obstruction, malabsorption).
- •Has received prior therapy with olaparib or with any other polyadenosine 5' diphosphoribose (poly[ADP ribose]) polymerization (PARP) inhibitor.
- •Has a known hypersensitivity to the components or excipients in olaparib.
- •Has received previous allogenic bone-marrow transplant or double umbilical cord transplantation (dUCBT).
- •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.
- •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.
- •Has a primary cancer of unknown origin.
- •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.
研究组 & 干预措施
Cohort 3: sBRCAm Breast Cancer
Per protocol, participants with breast cancer tumors that harbor known or suspected deleterious somatic mutations in BRCA1/2 and do not harbor a germline BRCA1/2 mutation were enrolled into Cohort 3: somatic BRCA1/2 mutations (sBRCAm). Participants in Cohort3: sBRCAm Breast Cancer received oral olaparib, 300 mg BID continuously until documented disease progression or discontinuation criteria were met.
干预措施: Olaparib (Drug)
Cohort 1: BRCA1/2 Mutated
Per protocol, participants with tumors that harbor known or suspected deleterious mutations in breast cancer susceptibility gene 1 or gene 2 (BRCA1/2) based on the Lynparza homologous recombination repair-homologous recombination deficiency (HRR-HRD) Assay, excluding breast and ovarian cancers, were considered BRCA1/2 mutated and enrolled into Cohort 1: BRCA1/2. Participants with known or suspected deleterious mutations in BRCA1/BRCA2 were enrolled into Cohort 1 whether or not they were homologous recombination repair mutated (HRRm) positive for the other protocol specified genes in the Lynparza HRR-HRD Assay, or whether they had loss of heterozygosity (LOH) protocol specified score of ≥16. Participants in Cohort 1: BRCA1/2 received oral olaparib, 300 mg twice daily (BID) continuously until documented disease progression or discontinuation criteria were met.
干预措施: Olaparib (Drug)
Cohort 2: HRD+, HRR Non-mutated
Per protocol, participants with tumors that do NOT have any known or suspected deleterious mutations in BRCA1/2, or any of the other protocol specified genes in the Lynparza HRR-HRD Assay (BRCA1/2 Non-mutated/HRR Non-mutated) but had a loss of heterozygosity (LOH) score greater than or equal to the protocol specified cutoff of 16, were considered homologous recombination deficiency positive (HRD+) and enrolled into Cohort 2: HRD+(BRCA1/2 non-mutated/HRR Non-mutated). Participants in Cohort 2: HRD+ (BRCA1/2 Non-mutated/HRR Non-mutated) received oral olaparib, 300 mg BID continuously until documented disease progression or discontinuation criteria were met.
干预措施: Olaparib (Drug)
Cohort 2: HRRm, BRCA1/2 Non-mutated
Per protocol, participants with tumors that do NOT have any known or suspected deleterious mutations in BRCA1/2 but have known or suspected deleterious mutations in any of the other protocol specified genes in the Lynparza HRR-HRD Assay were considered homologous recombination repair mutated [HRRm] and were enrolled into Cohort 2: HRRm (BRCA1/2 Non-mutated). Participants in Cohort 2: HRRm (BRCA1/2 Non-mutated) received oral olaparib, 300 mg BID continuously until documented disease progression or discontinuation criteria were met.
干预措施: Olaparib (Drug)
结局指标
主要结局
Objective Response Rate (ORR)
时间窗: Up to 53 months
ORR is defined as the percentage of participants who achieve a confirmed complete response (\[CR\]; disappearance of all target lesions) or partial response (\[PR\]: ≥30% decrease in the sum of diameters of target lesions) as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors 1.1, modified to follow a maximum of 10 target lesions in total and a maximum of 5 target lesions per organ (modified RECIST 1.1). For participants with prostate cancer, ORR will be based on Prostate Cancer Working Group (PCWG)-modified RECIST 1.1 as assessed by BICR.
All Cohorts: Objective Response Rate (ORR) as Assessed by Blinded Independent Central Review (BICR) per Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or Prostate Cancer Working Group (PCWG)-modified RECIST 1.1
时间窗: Up to approximately 78 months
ORR was defined as the percentage of participants who have a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) as assessed by the BICR per modified RECIST 1.1. For participants with prostate cancer, response will be assessed based on PCWG-modified RECIST 1.1 criteria (CR: no evidence of disease \[NED\] on bone scan; PR: non-progressive disease, non-evaluable \[NE\], NED, or CR on bone scan). Per protocol, RECIST 1.1 was modified to allow ≤ 10 target lesions in total (up to 5 per organ). The percentage of participants who experienced a CR or PR as assessed by BICR is presented.
Cohorts 1, 2, 3: Objective Response Rate (ORR) as Assessed by Blinded Independent Central Review (BICR) Per Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or Prostate Cancer Working Group (PCWG)-Modified RECIST 1.1
时间窗: Up to approximately 78 months
ORR was defined as the percentage of participants who have a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) as assessed by the BICR per modified RECIST 1.1. For participants with prostate cancer, response was assessed based on PCWG-modified RECIST 1.1 criteria (CR: soft tissue CR with no evidence of disease \[NED\] on bone scan; PR: soft tissue PR with non-progressive disease, non-evaluable \[NE\], or NED on bone scan, or soft tissue CR with non-progressive disease, or NE bone scan). Per protocol, RECIST 1.1 was modified to follow a maximum of 10 target lesions in total and a maximum of 5 target lesions per organ. The percentage of participants who experienced a CR or PR as assessed by BICR is presented.
次要结局
- Duration of Response (DOR)(Up to 53 months)
- Progression Free Survival (PFS)(Up to 53 months)
- Number of Participants Discontinuing Study Treatment due to an Adverse Event (AE)(Up to 52 months)
- Overall Survival (OS)(Up to 53 months)
- Time to Earliest Progression by Cancer Antigen-125 (CA-125)(Up to 53 months)
- Number of Participants Experiencing an Adverse Event (AE)(Up to 53 months)
- Prostate-specific Antigen (PSA) Response Rate in Participants with Prostate Cancer(Up to 53 months)
- Objective Response Rate (ORR) in Participants with HRRm or HRD Positive Cancer(Up to 53 months)
- Progression-Free Survival After Next-Line Treatment in Participants with sBRCAm Breast Cancer(Up to 53 months)
- All Cohorts: Duration of Response (DOR) as Assessed by BICR According to Modified RECIST 1.1 or PCWG-Modified RECIST 1.1(Up to approximately 78 months)
- All Cohorts: Overall Survival (OS)(Up to approximately 78 months)
- All Cohorts: Progression Free Survival (PFS) as Assessed by BICR per Modified RECIST 1.1 or PCWG-Modified RECIST 1.1(Up to approximately 78 months)
- All Cohorts: Number of Participants Experiencing an Adverse Event (AE)(Up to approximately 78 months)
- All Cohorts: Number of Participants Discontinuing Study Treatment due to an AE(Up to approximately 78 months)
- Combined Cohort 1+2: ORR as Assessed by BICR per Modified RECIST 1.1 or PCWG-Modified RECIST 1.1 in Participants who are HRRm Positive(Up to approximately 78 months)
- Progression-Free Survival After Next-Line Treatment in Participants with somatic BRCA1/2 mutations (sBRCAm) Breast Cancer(Up to approximately 78 months)
- Combined Cohort 1+2: ORR as Assessed by BICR per Modified RECIST 1.1 or PCWG-Modified RECIST 1.1 In Participants who are HRD Positive (HRD+)(Up to approximately 78 months)
- Combined Cohort 1+2: ORR as Assessed by BICR per Modified RECIST 1.1 or PCWG-Modified RECIST 1.1 in All Combined Cohort 1+2 Participants Regardless of Biomarker Status(Up to approximately 78 months)
- Combined Cohort 1+2: DOR as Assessed by BICR Per Modified RECIST 1.1 or PCWG-Modified RECIST 1.1 in Participants who are HRRm Positive(Up to approximately 78 months)
- Combined Cohort 1+2: DOR as Assessed by BICR per Modified RECIST 1.1 or PCWG-Modified RECIST 1.1 In Participants Who Are HRD Positive (HRD+)(Up to approximately 78 months)
- Combined Cohort 1+2: DOR as Assessed by BICR per modified RECIST 1.1 or PCWG-modified RECIST 1.1 in All Combined Cohort 1+2 Participants Regardless of Biomarker Status(Up to approximately 78 months)
- Combined Cohort 1+2: OS in Participants who are HRRm Positive(Up to approximately 78 months)
- Combined Cohort 1+2: OS in Participants who are HRD Positive (HRD+)(Up to approximately 78 months)
- Combined Cohort 1+2: PFS as Assessed by BICR per Modified RECIST 1.1 or PCWG-Modified RECIST 1.1 in Participants who are HRRm Positive(Up to approximately 78 months)
- Combined Cohort 1+2: PFS as Assessed by BICR per Modified RECIST 1.1 or PCWG-Modified RECIST 1.1 in Participants who are HRD Positive (HRD+)(Up to approximately 78 months)
- Combined Cohort 1+2: PFS as Assessed by BICR per Modified RECIST 1.1 or PCWG-Modified RECIST 1.1 in All Combined Cohort 1+2 Participants Regardless of Biomarker Status(Up to approximately 78 months)
- Cohort 2: Time to Earliest Progression by Cancer Antigen-125 (CA-125)(Up to approximately 78 months)
- Cohort 1 & 2: Prostate-specific Antigen (PSA) Response Rate in Participants with Prostate Cancer(Up to approximately 78 months)
- Cohort 3: PFS2 as Assessed by the Investigator in Participants with sBRCAm Breast Cancer(Up to approximately 78 months)
- Combined Cohort 1+2: OS in All Combined Cohort 1+2 Participants Regardless of Biomarker Status(Up to approximately 78 months)
- Cohorts 1, 2, 3: Duration of Response (DOR) as Assessed by BICR According to Modified RECIST 1.1 or PCWG-Modified RECIST 1.1(Up to approximately 78 months)
- Cohorts 1, 2, 3: Overall Survival (OS)(Up to approximately 78 months)
- Cohorts 1, 2, 3: Progression Free Survival (PFS) as Assessed by BICR Per Modified RECIST 1.1 or PCWG-Modified RECIST 1.1(Up to approximately 78 months)
- Cohorts 1, 2, 3: Number of Participants Experiencing an Adverse Event (AE)(Up to approximately 78 months)
- Cohorts 1, 2, 3: Number of Participants Who Discontinue Study Treatment Due to an AE(Up to approximately 78 months)
- Combined Cohort 1+2: ORR as Assessed by BICR Per Modified RECIST 1.1 or PCWG-Modified RECIST 1.1 in Participants Who Are HRRm Positive(Up to approximately 78 months)
- Combined Cohort 1+2: ORR as Assessed by BICR Per Modified RECIST 1.1 or PCWG-Modified RECIST 1.1 In Participants Who Are HRD Positive (HRD+)(Up to approximately 78 months)
- Combined Cohort 1+2: ORR as Assessed by BICR Per Modified RECIST 1.1 or PCWG-Modified RECIST 1.1 in All Combined Cohort 1+2 Participants Regardless of Biomarker Status(Up to approximately 78 months)
- Combined Cohort 1+2: DOR as Assessed by BICR Per Modified RECIST 1.1 or PCWG-Modified RECIST 1.1 in Participants Who Are HRRm Positive(Up to approximately 78 months)
- Combined Cohort 1+2: DOR as Assessed by BICR Per Modified RECIST 1.1 or PCWG-Modified RECIST 1.1 In Participants Who Are HRD Positive (HRD+)(Up to approximately 78 months)
- Combined Cohort 1+2: DOR as Assessed by BICR Per Modified RECIST 1.1 or PCWG-modified RECIST 1.1 in All Combined Cohort 1+2 Participants Regardless of Biomarker Status(Up to approximately 78 months)
- Combined Cohort 1+2: OS in Participants Who Are HRRm Positive(Up to approximately 78 months)
- Combined Cohort 1+2: OS in Participants Who Are HRD Positive (HRD+)(Up to approximately 78 months)
- Combined Cohort 1+2: PFS as Assessed by BICR Per Modified RECIST 1.1 or PCWG-Modified RECIST 1.1 in Participants Who Are HRRm Positive(Up to approximately 78 months)
- Combined Cohort 1+2: PFS as Assessed by BICR Per Modified RECIST 1.1 or PCWG-Modified RECIST 1.1 in Participants Who Are HRD Positive (HRD+)(Up to approximately 78 months)
- Combined Cohort 1+2: PFS as Assessed by BICR Per Modified RECIST 1.1 or PCWG-Modified RECIST 1.1 in All Combined Cohort 1+2 Participants Regardless of Biomarker Status(Up to approximately 78 months)
- Participants With BRCA1/2 Non-Mutated Ovarian Cancer: Time to Earliest Progression by Cancer Antigen-125 (CA-125)(Up to approximately 78 months)
- Participants With Prostate Cancer: Prostate-Specific Antigen (PSA) Response Rate(Up to approximately 78 months)
- Cohort 3: PFS2 as Assessed by the Investigator in Participants With sBRCAm Breast Cancer(Up to approximately 78 months)