A Phase 1a/1b Multicenter, Open-label Dose Escalation/Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Evidence of Antitumor Activity of PLN-101095 as Monotherapy and in Combination With Pembrolizumab in Adult Participants With Advanced or Metastatic Solid Tumors Who Have Disease Progression While on an Immune Checkpoint Inhibitor (FORTIFY)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 124
- 试验地点
- 15
- 主要终点
- Proportion of participants with treatment-emergent adverse events and serious adverse events per CTCAE Version 5.0.
研究概览
简要总结
This is a Phase 1a/1b, dose-escalation/expansion, consecutive-cohort, open-label study to evaluate the safety, tolerability, PK, PD, and preliminary evidence of antitumor activity of PLN-101095 in combination with pembrolizumab (the study treatment regimen) in adult participants with advanced or metastatic solid tumors for which pembrolizumab is indicated but have documented disease progression (refractory [primary resistance]) or relapsed [secondary resistance]) after at least 3 months from the start of treatment with pembrolizumab.
The study will consist of 2 main parts:
- Part 1: Consecutive dose-escalation cohorts using a Bayesian optimal interval (BOIN) dose escalation design with accelerated titration
- Part 2: Dose-expansion cohorts using Simon's 2-stage design
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Has histologically or cytologically confirmed advanced or metastatic solid tumor
- •Have received ≥12 weeks of continuous anti-PD-1 or anti-PD-L1 treatment administered as monotherapy or in combination with other anticancer therapies
- •Have demonstrated documented prior clinical benefit, defined as CR or PR at any time during treatment, or SD lasting ≥6 months (Part 2 only)
- •Must have subsequently developed radiographic disease progression while receiving anti-PD-1 or anti-PD-L1 treatment or within ≤12 weeks after the last dose of such treatment
- •At least 1 measurable lesion, as defined by RECIST v1.1
- •Estimated survival of ≥3 months
- •Have adequate bone marrow and organ function.
- •A female participant is eligible to participate if she is not pregnant, not breastfeeding
排除标准
- •Any immune-related medical conditions that would put participants at greater risk when receiving pembrolizumab
- •Has a known additional malignancy that is progressing or has required active treatment within the past 2 years
- •Has received prior radiotherapy within 2 weeks for palliative bone-directed therapy and 4 weeks for all other radiotherapy
- •Has undergone major surgery within 4 weeks prior to the first dose of study treatment or has not adequately recovered from surgery or related complications
- •Has a diagnosis of immunodeficiency or use of systemic steroids >10 mg/day
- •Has an active autoimmune disease that has required systemic treatment in the past 2 years
- •Has known active CNS metastases (brain and/or leptomeningeal metastases)
- •Has significant cardiac disease
- •Has an active infection requiring systemic therapy (including uncontrolled HIV, Hepatitis B and C)
- •Has received a live or live-attenuated vaccine within 30 days or a non-live vaccine within 7 days prior to the first dose of PLN-101095
研究组 & 干预措施
Part 1 Dose Escalation - 1000 mg TID
PLN-101095 1000 mg TID in combination with pembrolizumab in participants with solid tumors
干预措施: PLN-101095 (Drug)
Part 1 Dose Escalation - 1000 mg TID
PLN-101095 1000 mg TID in combination with pembrolizumab in participants with solid tumors
干预措施: Pembrolizumab (Drug)
Part 1 Dose Escalation - 2000 mg BID
PLN-101095 2000 mg BID in combination with pembrolizumab in participants with solid tumors
干预措施: Pembrolizumab (Drug)
Part 2 Dose Expansion - NSCLC
PLN-101095 given as monotherapy and in combination with pembrolizumab in participants with Non-small cell lung cancer (NSCLC)
干预措施: PLN-101095 (Drug)
Part 2 Dose Expansion - NSCLC
PLN-101095 given as monotherapy and in combination with pembrolizumab in participants with Non-small cell lung cancer (NSCLC)
干预措施: Pembrolizumab (Drug)
Part 1 Dose Escalation - 500 mg BID
PLN-101095 500 mg BID in combination with pembrolizumab in participants with solid tumors
干预措施: PLN-101095 (Drug)
Part 1 Dose Escalation - 1000 mg BID
PLN-101095 1000 mg BID in combination with pembrolizumab in participants with solid tumors
干预措施: PLN-101095 (Drug)
Part 1 Dose Escalation - 250 mg BID
Cohort 1 PLN-101095 250 mg BID in combination with pembrolizumab in participants with solid tumors
干预措施: PLN-101095 (Drug)
Part 2 Dose Expansion - TMB-high solid tumors
PLN-101095 given as monotherapy and in combination with pembrolizumab in participants with Tumor mutational burden (TMB)-high solid tumors
干预措施: Pembrolizumab (Drug)
Part 2 Dose Expansion - ccRCC
PLN-101095 given as monotherapy and in combination with pembrolizumab in participants with Clear cell renal cell carcinoma (ccRCC)
干预措施: PLN-101095 (Drug)
Part 1 Dose Escalation - 250 mg BID
Cohort 1 PLN-101095 250 mg BID in combination with pembrolizumab in participants with solid tumors
干预措施: Pembrolizumab (Drug)
Part 1 Dose Escalation - 1000 mg BID
PLN-101095 1000 mg BID in combination with pembrolizumab in participants with solid tumors
干预措施: Pembrolizumab (Drug)
Part 1 Dose Escalation - 2000 mg BID
PLN-101095 2000 mg BID in combination with pembrolizumab in participants with solid tumors
干预措施: PLN-101095 (Drug)
Part 1 Dose Escalation - 500 mg BID
PLN-101095 500 mg BID in combination with pembrolizumab in participants with solid tumors
干预措施: Pembrolizumab (Drug)
Part 2 Dose Expansion - ccRCC
PLN-101095 given as monotherapy and in combination with pembrolizumab in participants with Clear cell renal cell carcinoma (ccRCC)
干预措施: Pembrolizumab (Drug)
Part 2 Dose Expansion - TMB-high solid tumors
PLN-101095 given as monotherapy and in combination with pembrolizumab in participants with Tumor mutational burden (TMB)-high solid tumors
干预措施: PLN-101095 (Drug)
结局指标
主要结局
Proportion of participants with treatment-emergent adverse events and serious adverse events per CTCAE Version 5.0.
时间窗: Signing ICF until 16 weeks after end of study treatment regimen
Number of participants with a Dose Limiting Toxicity (DLT) defined as toxicities that meet predefined severity criteria, assess as having a suspected relationship to study drug, unrelated to disease, inter-current illness, or concomitant medications.
时间窗: First dose to 35 days
Safety and tolerability of PLN-101095 in combination with pembrolizumab in Parts 1 and 2
时间窗: Day 1 until 16 weeks after end of study treatment regimen
Proportion of participants with treatment-emergent adverse events and serious adverse events.
Anti-tumor activity of PLN-101095 in combination with pembrolizumab in Part 2
时间窗: First dose to disease progression or death from any cause, whichever occurs first.
Proportion of participants achieving confirmed iPR or iCR per iRECIST Version 1.1.
Safety and tolerability of PLN-101095 in combination with pembrolizumab in Parts 1 and 2
时间窗: First dose to 35 days
Number of participants with a Dose Limiting Toxicity (DLT) defined as toxicities that meet predefined severity criteria, assess as having a suspected relationship to study drug, unrelated to disease, inter-current illness, or concomitant medications.
次要结局
- Time to maximum observed concentration (Tmax) to characterize the plasma pharmacokinetics (PK).(First dose until 10 weeks)
- Area under the concentration-time curve over a dosing interval (AUC0-τ) to characterize the plasma pharmacokinetics (PK).(First dose until 10 weeks)
- Disease control rate (DCR) is defined by the proportion of participants who maintain disease control (iCR, iPR or iSD) per iRECIST Version 1.1.(Day 1 until end of study treatment regimen)
- Objective response rate (ORR) is defined by the proportion of participants with an iCR or iPR per iRECIST Version 1.1.(Day 1 until end of study treatment regimen)
- Maximum observed plasma concentration (Cmax) to characterize the plasma pharmacokinetics (PK).(First dose until 10 weeks)
- PK of PLN-101095 monotherapy in Parts 1 and 2(Day 14, 0 to up to 12 hours)
- Duration of anti-tumor activity of PLN-101095 in combination with pembrolizumab in Part 2(First objective response (CR or PR) to disease progression or death from any cause, whichever occurs first)
- Duration of anti-tumor activity of PLN-101095 in combination with pembrolizumab in Part 2(First dose to progression or death from any cause, whichever occurs first)