An Open-label, Multicenter Phase II Study to Compare the Efficacy of Carboplatin as First-line Followed by Second-line Olaparib Versus Olaparib as First-line Followed by Second-line Carboplatin in the Treatment of Patients With Castration Resistant Prostate Cancer Containing Homologous Recombination Deficiency
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 100
- 试验地点
- 54
- 主要终点
- Progression-free survival (PFS-1L) defined as the time interval between randomization and first documented disease progression or death due to any cause reported during, or after, first-line treatment.
研究概览
简要总结
This is an unblinded, randomized clinical study comparing the efficacy of DNA damaging chemotherapy using carboplatin, to standard of care therapy for patients who have metastatic castrate resistant prostate cancer. This trial will use olaparib or carboplatin as initial therapy with crossover to the alternate or second-line drug after first progression for patients with tumors containing BARD1, BRCA1, BRCA2, BRIP1, CHEK1, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L inactivating mutations.
Participants are randomized (1:1) and receive either carboplatin (AUC 5, IV) every 21 days, first or olaparib taken orally (300 mg), twice daily in 28 day cycles, until intolerance, complete response, or progression by Prostate Cancer Working Group 3 (PCWG3) criteria.
Participants then crossover from the first-line therapy to the second-line therapy with the opposite study medication and receive treatment to intolerance or progression (whichever is first). Enrolled participants will be allowed to crossover to second line therapy if they continue to meet initial eligibility criteria, and at least three weeks have elapsed since last administration of either carboplatin or olaparib. Throughout the study, safety and tolerability will be assessed. Progression will be evaluated with bone scan, CT of the abdomen/pelvis, or MRI and PSA as per PCWG3 criteria.
详细描述
Study General Trial Over-view
This study is designed to help better understand treatment options compared to standard therapies for patients who have targeted DNA repair mutations and metastatic castrate resistant prostate cancer (mCRPC).
Cancer therapies are aimed at finding a way to kill the cancer cells while causing minimal damage to normal (non-cancer) cells. This often works because cancers cells grow faster than many normal cells, many treatments are aimed at to take advantage of that difference. One of the ways to do this is to damage the DNA of these more rapidly growing cells. However, if the cells have a way of repairing that damage then therapies may not work as well. Some research shows that when specific changes or mutations occur in the genes involved with repairing DNA damage, resulting cancers have responded well to drugs which damage DNA.
Olaparib is known as a PARP inhibitor and is standard of care therapy for men with BRCA altered mCRPC. Carboplatin is a synthetic antineoplastic agent which has been used in the treatment of solid tumors and BRCA related cancers. When mutations occur in critical DNA-repair genes, research has found that treatment with carboplatin is also effective.
This research is being done to determine the response of mCRPC in patients with DNA repair mutations to treatment with olaparib compared to carboplatin. This study will test whether giving one drug or the other a has a better response.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Health Services Research
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Signed study informed consent form (ICF) and HIPAA authorization form
- •Diagnosis of prostate cancer (pure small-cell histology or pure high-grade neuroendocrine histology are excluded; neuroendocrine differentiation is allowed)
- •Ongoing gonadal androgen deprivation therapy with gonadotropin-releasing hormone (GnRH) analogues, antagonists or orchiectomy. Patients who have not had an orchiectomy must be maintained on effective GnRH analogue/antagonist therapy
- •mCRPC as defined by serum testosterone < 50 nanograms per milliliter (ng/ml) for patients on GnRH analogues or antagonists) and at least one of the following:
- •Prostate-specific antigen (PSA) level of at least 2 nanograms per milliliter (ng/ml) that has risen on at least 2 successive occasions at least 1 week apart
- •Evaluable disease progression by modified RECIST 1.1 (Response Evaluation Criteria in Solid Tumors)
- •Progression of metastatic bone disease on bone scan, CT or MRI with > 2 new lesions
- •Prior therapy with abiraterone acetate, enzalutamide, apalutamide, or darolutamide
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of < 2 (see Appendix 3, ECOG Grading Scale)
- •Results of previous standard DNA testing, or previous research testing, which confirms RAD51B, RAD51C, RAD51D, or RAD54L mutations (see Introduction, Section 2 for study design and previous research on targeted therapy) from primary, metastatic tumor or circulating tumor DNA, or pathogenic/likely pathogenic germline variant as assessed by a CLIA certified laboratory level assay for DNA sequencing.
- •Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
- •Hemoglobin > 10.0 grams per deciliter (g/dL)
- •Absolute neutrophil count (ANC) > 1.5 x 109/liter (L)
- •Platelet count > 100 x 109/L
- •Total bilirubin < 1.5 x institutional upper limit of normal (ULN)
- •Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT) < 2.5 x institutional upper limit of normal unless liver metastases are present in which case, they must be < 5x ULN
- •Patients must have creatinine clearance estimated using the Cockcroft-Gault equation of >51 mL/min: Estimated creatinine clearance =(140-age [years]) x weight (kg)/(serum creatinine (mg/dL) x 72)
排除标准
- •Currently receiving active therapy for other neoplastic disorder(s)
- •Concurrent enrollment in another clinical investigational drug or device study
- •Histologic evidence of small cell carcinoma (morphology alone - immunohistochemical evidence of neuroendocrine differentiation without morphologic evidence is not exclusionary)
- •Prior treatment with platinum, mitoxantrone or PARP inhibitor for castration resistant prostate cancer
- •Known parenchymal brain metastasis
- •Active or symptomatic viral hepatitis or chronic liver disease AST or ALT > 2.5 x ULN or total bilirubin > ULN (unless Gilbert's syndrome is the etiology of hyperbilirubinemia)
- •Subjects with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML
- •Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks
- •Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for phenobarbital and 3 weeks for other agents
- •Subjects unable to swallow orally administered medication and subjects with gastrointestinal disorders likely to interfere with absorption of the study medication
- •Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fraction measurement of < 35 % at baseline
- •Treatment with an investigational therapeutic within 30 days of Cycle-1
- •Presence of dementia, psychiatric illness, and/or social situations limiting compliance with study requirements or understanding HIPAA authorization and/or giving of informed consent
- •Any condition(s), medical or otherwise, which, in the opinion of the Investigators, would jeopardize either the patient or the integrity of the data obtained
研究组 & 干预措施
Treatment Arm 1 - Carboplatin to Olaparib
Participants are administered carboplatin AUC 5 IV first, which is administered Cycle-1, Day-1, and then every 21 days as first line therapy. For second line (crossover), olaparib is prescribed and taken orally at home, twice daily, 300 mg in 28 day cycles.
干预措施: Olaparib (Drug)
Treatment Arm 1 - Carboplatin to Olaparib
Participants are administered carboplatin AUC 5 IV first, which is administered Cycle-1, Day-1, and then every 21 days as first line therapy. For second line (crossover), olaparib is prescribed and taken orally at home, twice daily, 300 mg in 28 day cycles.
干预措施: Carboplatin (Drug)
Treatment Arm 2 - Olaparib to Carboplatin
Participants are prescribed olaparib which is taken orally at home, twice daily, 300 mg in 28 day cycles, as first line therapy. For second line (crossover), carboplatin is administered AUC 5 IV every 21 days thereafter.
干预措施: Carboplatin (Drug)
Treatment Arm 2 - Olaparib to Carboplatin
Participants are prescribed olaparib which is taken orally at home, twice daily, 300 mg in 28 day cycles, as first line therapy. For second line (crossover), carboplatin is administered AUC 5 IV every 21 days thereafter.
干预措施: Olaparib (Drug)
结局指标
主要结局
Progression-free survival (PFS-1L) defined as the time interval between randomization and first documented disease progression or death due to any cause reported during, or after, first-line treatment.
时间窗: Through duration of the study, up to six years
Progression free survival (PFS) by bone scan or measurable disease, Response Evaluation Criteria in Solid Tumors (RECIST 1.1) to initial therapy (PFS-1L) with either study drug.
Progression-free survival (PFS-1L) defined as the time interval between randomization and first documented disease progression or death due to any cause reported during, or after, first-line treatment
时间窗: Through duration of the study, up to 100 weeks
Progression free survival (PFS) by bone scan or measurable disease, Response Evaluation Criteria in Solid Tumors (RECIST 1.1) to initial therapy (PFS-1L) with either study drug
次要结局
- PSA measurements/response(Through duration of the study, up to six years)
- Grade 3 and 4 toxicities in first and second-line setting(Through duration of the study, up to six years)
- time interval between randomization and second documented disease progression during or after second-line or death (due to any cause)(Through duration of the study, up to six years)
- Time interval between randomization and second documented disease progression during or after second-line or death (due to any cause)(Through duration of the study, up to 100 weeks)
- PSA measurements/response(Through duration of the study, up to 100 weeks)
- Grade 3 and 4 toxicities in first and second-line setting(Through duration of the study, up to 100 weeks)
- To assess cost effectiveness of carboplatin versus olaparib for the treatment of castration-resistant metastatic prostate cancer(Through duration of the study, up to 100 weeks)