2023-509230-19-00招募中2 期
A first-in-human, Phase 1/2, open-label, multi-center, dose-escalation, dose-optimization, and dose-expansion study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and anti-tumor activity of PARP1 selective inhibitor, IMP1734, as monotherapy and in combination in participants with advanced solid tumors.
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 82
- 试验地点
- 16
- 主要终点
- Part 1 and 2: • TEAEs • DLTs • Laboratory parameters • Vital signs • ECGs • MTD (or MAD) and RDE of IMP1734 as monotherapy and in combination with anti-cancer agents
研究概览
简要总结
Part 1 and 2: To evaluate the safety and tolerability of IMP1734 as monotherapy and in combination with anti-cancer agents To determine the MTD (or MAD) and RDE as monotherapy and in combination with anti-cancer agents Part 3: To estimate the anti-tumor activity of IMP1734
研究设计
- 分配方式
- Non-randomized
- 主要目的
- Part 3 (dose expansion)
- 盲法
- None
入排标准
- 年龄范围
- 18 years 至 65+ years（65+ Years, 18-64 Years）
- 接受健康志愿者
- 是
入选标准
- •Participants must voluntarily participate and comply with study procedures
- •Female Participants should meet ≥ 1 of the following criteria: a. Lack of childbearing potential b. Post-menopausal c. For those with childbearing potential, have a negative pregnancy test at screening, not be in lactation, and willing to take highly effective contraceptive
- •Male participants had a vasectomy or use highly effective methods of (from day-0 to 6 months after last dose of IMP)
- •Both PARPi-treated and PARPi-naïve participants are eligible. For PARPi-treated participants, up to 1 prior PARPi containing treatment is allowed (Pt 1 only)
- •Participants with EOC, fallopian tube, or primary peritoneal cancer must have received 1 and only 1 prior PARPi containing treatment (Pt2 only)
- •Participants with EOC, fallopian tube, or primary peritoneal cancer should be platinum sensitive (Pt3 only)
- •Breast cancer participants are eligible provided no evidence of progression. Participants who previously received platinum-based chemotherapy as neo-adjuvant/adjuvant are eligible provided at least 12 months, between this treatment, and 1st dose of IMP (Pt3 only)
- •No prior therapy with a PARPi (Pt3 Cohort 3A only)
- •Received 1 and only 1 prior PARPi (Pt3 Cohort 3B only)
- •Participants must be ≥ 18 years of age
- •Participants must have 1 of the following: a. Confirmed advanced/recurrent/metastatic, endometrioid EOC, fallopian tube or primary peritoneal cancer (Cohorts-1A/C, Pt2/3), and: i. Must received ≥ 1 prior chemotherapy for advanced disease ii. Must be platinum resistant (Cohort-1C only) iii. Should have evaluable disease as defined: a. ≥ 1 measurable lesion per RECIST v1.1 and/or b. CA125 evaluable b. Confirmed advanced/recurrent/metastatic HER2-neg adenocarcinoma of the breast and (Cohort-1A/C and Pt3): i. Must have received ≥ 1 prior chemotherapy ii. Participants with HR+ must have received hormonal therapy iii. Should have evaluable disease defined as ≥ 1 measurable lesion c. Confirmed adenocarcinoma mPC (Cohort-1A/1B and Pt3): i. mCRPC: With ongoing ADT within 28 days before study start. Participants receiving ADT should continue treatment during the study ii. mCSPC (Cohort-1B only) Candidates for ADT and/or started ADT but no longer than 12 weeks before study start or with bilateral orchiectomy iii. Prior therapies: a. Must have received a novel hormonal agent (Cohort-1A and Pt3:mCRPC) b. Must have received up to 1 prior taxane based chemotherapy/ineligible for chemotherapy (Cohort1A, Pt3; mCRPC) c. May have received up to one prior therapy with an NHA and/or PARPi or taxane treatment (Cohort1B; mCRPC) iv. Should have evaluable disease defined as (Cohort1A/1B and Pt3): a) ≥ 1 measurable lesion per RECIST v1.1, AND/OR b) ≥ 1 evaluable lesion documented by positive bone scan c) PSA evaluable defined as a serum PSA ≥ 1 ng/mL during screening d) Histologically/cytologically confirmed advanced/recurrent/ mPDAC (Cohort-1A) i. Must have received an appropriate prior regimen per Investigator ii. Should have evaluable disease defined as ≥ 1 measurable lesion per RECIST v1.1
- •Participants are required to have deleterious or suspected deleterious germline or somatic mutations (Cohort-1A/1B and Pt3)
- •Participants with RECIST v1.1-evaluable disease must have documented radiological progressive cancer before study entry. Prostate cancer participants whose is limited to regional pelvic lymph nodes/local recurrence, not eligible
- •For prostate cancer, PSA progression per PCWG3 is acceptable (Cohort-1A/1B and Pt3)
- •ECOG Performance Status of 0 to 1
- •Life expectancy must be ≥ 12 weeks
- •Have adequate organ function
排除标准
- •Any participants treated with anti-cancer therapies
- •Any major illness that will substantially increase the risk associated with the patient’s participation in this study
- •Participants with a diagnosis of MDS or AML or have received transplantation
- •Participants with any known predisposition to bleeding
- •Live/attenuated vaccine within 28 days prior to the 1st dose of IMP
- •COVID-19 vaccine within 72 hours prior to 1st dose of IMP
- •Participants with administration of any strong inhibitors/inducers of CYP3A4 or P-gp inhibitors within 28 days or 5 half-lives (whichever is shorter) prior to the 1st dose of the IMP
- •Participants who may need continuous treatment with PPIs or P-CABs or H2-blockers during the study period
- •Receiving continuous prednisone or equivalent
- •Participants with a known history of hypersensitivity to the IMP or its ingredients.
- •Participants unable to swallow oral medications OR have malabsorption syndrome/uncontrolled GI condition
- •Participants that received prior PARP1-selective inhibitors
- •Female Participants who are pregnant or lactating/breastfeeding
- •Participants with known history of alcoholism/drug abuse
- •Participants who have participated in another clinical study with an IMP administered in the last 28 days or five half-lives (whichever is shorter)
- •Have used an investigational device within 28 days prior to the first dose of IMP
- •Cohort 1B only (mCSPC): Must not received prior treatment with 2nd generation or investigational AR, or CYP17 enzyme inhibitors
- •Cohort 1C only: Participants with ≥ Grade 2 peripheral neuropathy at time of screening
- •Participants who have undergone: major surgery, extensive field radiotherapy, palliative radiotherapy OR used a radioactive drug
- •Participants with other malignancies requiring treatment within 2 years before 1st dose of IMP
- •Participants previous treatment-related toxicities that have not recovered, i.e., to ≤ Grade 1, as evaluated by NCI-CTCAE or baseline (Grade 2 and other non clinically significant toxicities can be enrolled)
- •Participants with active CNS metastases and/or carcinomatous meningitis.
- •Participants with any of the following cardiac criteria: a. mean resting QTcF > 470 ms or QTcF < 340 ms; b. any factors that increase the risk of QT prolongation, or use of concomitant drugs that may prolong/shorten QT and at risk of Torsades de Pointes; c. any clinically important abnormalities of resting ECG
- •Participants with other cardiovascular diseases as defined by any of the following: a. symptomatic heart failure b. uncontrolled hypertension c. hypertensive heart disease d. acute coronary syndrome/acute myocardial infarction, unstable angina pectoris, coronary intervention procedure e. cardiomyopathy f. presence of clinically significant valvular heart disease g. history of arrhythmia requiring treatment; Participants with atrial fibrillation and optimally controlled ventricular rate are permitted h. stroke within 6 months prior to screening i. Participants with symptomatic hypotension at screening
- •Participants with infections, including: a. An uncontrolled acute infection, an active infection requiring systemic treatment, prophylactic use of systemic antibiotics is allowed b. HIV-infected participants must have well-controlled HIV and be on ART defined as: i. must have a CD4+ T-cell count ≥ 350 cells/mm3 at screening, ii. must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 copies/mL or the LLOQ iii. must not have had any AIDS-defining opportunistic infections within the past 12 months, iv. must have been on a stable regimen for at least 4 weeks before study entry and agree to continue ART throughout the study, v. The combination ART regimen must not contain any antiretroviral medications that interact with CYP3A4 inhibitors/inducers/substrates c. A known active Hep B/C infection d. Active tuberculosis
结局指标
主要结局
Part 1 and 2: • TEAEs • DLTs • Laboratory parameters • Vital signs • ECGs • MTD (or MAD) and RDE of IMP1734 as monotherapy and in combination with anti-cancer agents
Part 1 and 2: • TEAEs • DLTs • Laboratory parameters • Vital signs • ECGs • MTD (or MAD) and RDE of IMP1734 as monotherapy and in combination with anti-cancer agents
Part 3: • Overall response rate, which is defined as the percentage of participants who have CR/PR per RECIST v1.1 by Investigator, and/or CA125 response per GCIG criteria (ovarian cancer), and/or PSA response per PCWG3 criteria.
Part 3: • Overall response rate, which is defined as the percentage of participants who have CR/PR per RECIST v1.1 by Investigator, and/or CA125 response per GCIG criteria (ovarian cancer), and/or PSA response per PCWG3 criteria.
次要结局
- PK parameters derived from plasma concentration data of IMP1734 and/or metabolites (if applicable) following single oral dose: • Cmax, Tmax, AUC0-t, AUC0-tau, Cmax(dn), and AUC0-tau(dn) • If data permit, AUC0-inf, CL/F, Vd/F, and t1/2
- PK parameters derived from plasma concentration data of IMP1734 and/ormetabolites (if applicable) following multiple oral doses: • Cmax,ss, Ctrough, Tmax,ss, AUC0-t,ss, AUC0-tau,ss, Cmax,ss(dn), AUC0-tau(dn), Rac-Cmax,ss and Rac-AUC0-tau,ss
- • If data permit, CL/F, Vd/F, and t1/2 • Overall response rate, which is defined as the percentage of participants who have CR/PR per RECIST v1.1, by Investigator and/or CA125 response per GCIG criteria (ovarian cancer), and/or PSA response per PCWG3 criteria.
- • Efficacy evaluated per RECIST v1.1 by Investigator: o ORR, which is defined as the percentage of participants who have CR/PR o DCR o DOR o TTR o Percentage change in sum of target lesions o CBR, which is defined as the proportion of participants with BOR of CR, PR or lasting ≥ 18 weeks of SD after the start of the study drug
- • PFS • OS • For prostate cancer only: o PSA response per PCWG3 criteria o PSA progression o PSA complete response rate
- Part 3: • Efficacy evaluated per RECIST v1.1 by Investigator: o ORR, which is defined as the percentage of patients who have CR/PR o DCR o DOR o TTR o Percentage change in sum of target lesions o CBR, which is defined as the proportion of participants with BOR of CR, PR or lasting ≥ 18 weeks of SD after the start of the study drug
- Part 3:• PFS • OS • For prostate cancer only: o PSA response per PCWG3 criteria o Time to PSA progression
- • TEAEs • Laboratory parameters • Vital signs • ECGs
研究者
Viola Chen
Scientific
Eikon Therapeutics Inc.
研究点 (16)
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