A Phase I/IIa, Open-label, Multi-center Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of the DNA Polymerase Theta Inhibitor ART6043 Administered Orally as Monotherapy and in Combination to Patients With Advanced or Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 181
- 试验地点
- 25
- 主要终点
- Part A: Number of participants with Dose Limiting Toxicities (DLTs)
研究概览
简要总结
This interventional study will evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of ART6043 as monotherapy or in combination with olaparib.
详细描述
ART6043 is being developed as an oral anti-cancer agent in combination with a poly (adenosine diphosphate ribose) polymerase (PARP) inhibitor (PARPi) in patients with cancers that harbor defects in DNA repair.
The study will consist of two parts:
- Part A (Dose-escalation phase): Part A will evaluate ART6043 as monotherapy (Part A1) in patients with advanced or metastatic cancer and in combination with olaparib (Part A2), in patients with advanced or metastatic cancer with genetic lesions that cause loss of function of known DNA Damage Response (DDR) genes. Olaparib is also referred as PARPi [Enrollment Complete]
- Part B (dose-expansion phase): To further confirm the safety of ART6043 and assess its initial effectiveness in combination compared to olaparib alone (Part B2) in patients with a germline BRCA mutation who have HER2-ve advanced or metastatic breast cancer
Patients may continue to receive ART6043 and/or olaparib as long as they may be continuing to derive clinical benefit as assessed by the investigator and/or until disease progression, withdrawal of consent or until they experience unacceptable drug-related toxicity.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 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
- •Patients who have discontinued all previous chemotherapeutic agents, non-hormonal targeted therapy, or investigational drugs for at least 21 days or 5 half-lives (not including palliative radiotherapy at focal sites), whichever is shorter. Endocrine and hormonal therapies for the treatment of cancer must have been discontinued (unless for the treatment of Prostate Cancer) at least 7 days before receiving study medication. Palliative radiotherapy must have completed 14 days prior to randomization.
- •Resolution of all toxicities of prior therapy or surgical procedures.
- •Performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) scale.
- •Have adequate organ function.
- •Patients of childbearing potential and patients with partners of childbearing potential are required to use highly effective contraception.
- •Have an estimated life expectancy of ≥12 weeks, in the judgment of the investigator.
- •Inclusion Criteria specific to Part A1 (ART6043 as Monotherapy) • Advanced or metastatic cancer. Tumors with genetic lesions known to cause loss of function of known DDR genes based on available pre-existing testing are encouraged.
- •Inclusion criteria specific to Part A2 (ART6043 in combination with olaparib)
- •Advanced or metastatic cancer with genetic lesions known to cause loss of function of known DDR genes based on available, pre-existing testing.
- •Patients for whom a PARPi is an appropriate treatment option. Patients may have received prior treatment with a PARPi.
- •Inclusion criteria specific to Part B (ART6043 in combination with olaparib or olaparib alone)
- •Histologically or cytologically confirmed HER2-ve locally advanced or metastatic carcinoma of the breast.
- •Documentation of a deleterious or suspected deleterious gBRCA mutation.
- •Previously treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting unless medically contraindicated.
- •Patients must have received no or ≤1 month of prior treatment with a PARPi.
排除标准
- •Patients who are pregnant.
- •Patients with Myelodysplastic syndrome (MDS)/Acute myeloid leukemia (AML) or with features suggestive of MDS/AML.
- •Have ongoing interstitial lung disease or pneumonitis.
- •Have any major gastrointestinal issues that could impact absorption of ART6043 or olaparib.
- •Have received a live vaccine within 30 days before the first dose of study treatment.
- •Recent major surgery within 4 weeks prior to entry into the study.
- •Have a significant bleeding disorder or vasculitis or had a Grade ≥3 bleeding episode within 12 weeks prior to enrollment.
- •Have a history of allergy or hypersensitivity to study drug components.
- •Exclusion criteria specific to Part B
- •Inflammatory breast cancer.
研究组 & 干预措施
Part A2 (ART6043 in combination with olaparib)
Patients with advanced or metastatic cancer and with PARPi as an appropriate treatment option will receive ART6043 in combination with olaparib twice daily (BID) in 21-day cycles.
干预措施: Olaparib (Drug)
Part A1 (ART6043 as monotherapy)
Patients with advanced or metastatic cancer will receive ART6043 administered in 21-day cycles.
干预措施: ART6043 (Drug)
Part A2 (ART6043 in combination with olaparib)
Patients with advanced or metastatic cancer and with PARPi as an appropriate treatment option will receive ART6043 in combination with olaparib twice daily (BID) in 21-day cycles.
干预措施: ART6043 (Drug)
Part B2 (ART6043 in combination with olaparib)
Patients with gBRCA-m, HER2-ve locally advanced or metastatic breast cancer will be randomly assigned to receive ART6043 in combination with olaparib or olaparib alone.
干预措施: Olaparib (Drug)
Part B2 (ART6043 in combination with olaparib)
Patients with gBRCA-m, HER2-ve locally advanced or metastatic breast cancer will be randomly assigned to receive ART6043 in combination with olaparib or olaparib alone.
干预措施: ART6043 (Drug)
结局指标
主要结局
Part A: Number of participants with Dose Limiting Toxicities (DLTs)
时间窗: From first dose of study treatment until the end of Cycle 1 (each cycle is 21-days)
Severity of adverse events as assessed by the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
Part B2: Progression free survival (PFS)
时间窗: Until disease progression (Upto 3.7 years).
PFS is defined as the time from randomization until objective disease progression as defined by Response evaluation criteria in solid tumors (RECIST) v1.1 or death by any cause in the absence of progression, regardless of whether the patient withdraws from study medication or receives another anti-cancer therapy prior to progression.
Part A: Number of participants with Dose Limiting Toxicities (DLTs)
时间窗: From first dose of study treatment until the end of Cycle 1 (each cycle is 21-days)
Severity of adverse events as assessed by the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
Part B1: Number of participants with adverse events
时间窗: Screening (≤28 days) Until follow-up visit (90 days after discontinuation)] (up to 3.7 years)
To assess the safety and tolerability of ART6043 given orally in combination with olaparib at the Recommended Phase II dose(s) \[RP2D(s)\].
Part B2: Progression free survival (PFS)
时间窗: Until disease progression (Upto 3.7 years).
PFS is defined as the time from randomization until objective disease progression as defined by Response evaluation criteria in solid tumors (RECIST) v1.1 or death by any cause in the absence of progression, regardless of whether the patient withdraws from study medication or receives another anti-cancer therapy prior to progression.
次要结局
- Best overall response (BOR)(Screening (≤28 days) Until disease progression/recurrence (Upto 3.7 years))
- Objective Response Rate (ORR)(Screening (≤28 days) Until disease progression/recurrence (Upto 3.7 years))
- Disease control rate (DCR)(Screening (≤28 days) Until disease progression (Upto 3.7 years))
- Duration of response (DOR)(Screening (≤28 days) Until disease progression (Upto 3.7 years))
- Change in tumor size(Screening (≤28 days) Until disease progression (Upto 3.7 years))
- Change in level of cancer antigen 125 (CA-125)(Screening (≤28 days) Until follow-up visit (Upto 3.7 years))
- Overall survival (OS)(Screening (≤28 days) Until overall survival follow-up (Upto 3.7 years))
- Plasma concentration(Pre-dose Cycle 0 Days -2, -1 , Cycle 1 Days 1, 8, 15, 16, Cycle 2 Days 1, 8, 15, Cycle 3 Day 1 Upto 3.7 Years (Each Cycle is 21-Days))
- Cancer antigen 125 levels in pre-dose tumor samples(At Screening (≤28 days))
- Part B2: Number of participants with Adverse events(Screening (≤28 days) Until follow-up visit (90 days after discontinuation)] (up to 3.7 years))
- Part A: Progression free survival (PFS)(Screening (≤28 days) Until disease progression (Upto 3.7 years))
- Change in level of cancer antigen 125 (CA-125), carcinoembryonic antigen (CEA)(Screening (≤28 days) Until follow-up visit (Upto 3.7 years))
- Part B2: Number of participants with Adverse events(Screening (≤28 days) Until follow-up visit (90 days after discontinuation)] (up to 3.7 years))
- Best overall response (BOR)(Screening (≤28 days) Until disease progression/recurrence (Upto 3.7 years))
- Objective Response Rate (ORR)(Screening (≤28 days) Until disease progression/recurrence (Upto 3.7 years))
- Disease control rate (DCR)(Screening (≤28 days) Until disease progression (Upto 3.7 years))
- Duration of response (DOR)(Screening (≤28 days) Until disease progression (Upto 3.7 years))
- Change in tumor size(Screening (≤28 days) Until disease progression (Upto 3.7 years))
- Change in level of cancer antigen 125 (CA-125)(Screening (≤28 days) Until follow-up visit (Upto 3.7 years))
- Part A and B1: Progression free survival (PFS)(Screening (≤28 days) Until disease progression (Upto 3.7 years))
- Overall survival (OS)(Screening (≤28 days) Until overall survival follow-up (Upto 3.7 years))
- Plasma concentration(Pre-dose Cycle 0 Days -2, -1 , Cycle 1 Days 1, 8, 15, 16, Cycle 2 Days 1, 8, 15, Cycle 3 Day 1 Upto 3.7 Years (Each Cycle is 21-Days))
- Half life (t1/2)(Pre-dose Cycle 0 Days -2, -1 , Cycle 1 Days 1, 8, 15, 16, Cycle 2 Days 1, 8, 15, Cycle 3 Day 1 Upto 3.7 Years (Each Cycle is 21-Days))
- Area under the plasma concentration-time curve from zero to infinity (AUC0-inf)(Pre-dose Cycle 0 Days -2, -1 , Cycle 1 Days 1, 8, 15, 16, Cycle 2 Days 1, 8, 15, Cycle 3 Day 1 Upto 3.7 Years (Each Cycle is 21-Days))
- Renal clearance(Cycle 0 Days -2, -1 (Each Cycle is 21-Days))
- Percent of ART6043 excreted in urine(Cycle 0 Day -2 ((Each Cycle is 21-Days))
- Cancer antigen 125 levels in pre-dose tumor samples(At Screening (≤28 days))