An Open-label, Phase 1a/1b, Dose Escalation and Dose Expansion Study Investigating the Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of PHST001 in Adult Patients With Advanced Relapsed and/or Refractory Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 272
- 试验地点
- 24
- 主要终点
- AE
研究概览
简要总结
This is a multi-center, first-in-human (FIH), open-label, Phase 1a/1b dose escalation and dose expansion study to assess the safety, PK, pharmacodynamics, and antitumor activity of PHST001 monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b) in adult participants with advanced relapsed and/or refractory solid tumors (including but not limited to CNS tumors in Phase 1a only). In Phase 1b cohort expansions, the study will focus on participants with advanced relapsed and/or refractory ovarian cancer, endometrial cancer, and cholangiocarcinoma. The study's primary objective is to evaluate the safety and tolerability of PHST001 and determine the RP2D (Recommended Phase 2 dose) of PHST001 monotherapy and in combination with chemotherapy as well as assess the anti-tumor activity of PHST001 and chemotherapy in Phase 1b.
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
- •Histologically or cytologically confirmed advanced solid tumor which has relapsed from or been refractory to all locally available standard therapies.
- •Adequate organ function per laboratory testing
- •Pregnancy prevention requirements
- •Measurable disease per RECIST v1.1 (or RANO) as assessed by the local site Investigator/radiology
- •Performance status of 0 or 1 on Eastern Cooperative Oncology Group (ECOG) scale
排除标准
- •Diagnosis of immunodeficiency
- •History of a previous additional malignancy, unless potentially curative treatment has been completed, with no evidence of malignancy for 5 years. Participants with basal cell carcinoma of the skin, Stage I melanoma, melanoma in situ, squamous cell carcinoma of the skin, early-stage prostate cancer, or carcinoma in situ, excluding carcinoma in situ of the bladder, who have undergone potentially curative therapy are not excluded and can be enrolled regardless of disease-free period following completion of potentially curative therapy. Participants with early-stage breast cancer who have undergone curative intent treatment and with no disease recurrence for 2 years after treatment are not excluded.
- •Active known CNS metastases and/or carcinomatous meningitis. Participants with previously treated CNS metastases may participate provided they are radiologically stable (i.e., without evidence of progression for at least 2 weeks by repeat imaging [note that the repeat imaging should be performed during study screening]), clinically stable, and without requirement of steroid treatment for at least 14 days prior to the first dose of study treatment.
- •Received prior systemic anticancer therapy including investigational agents within 21 days or, if shorter, within 5 half-lives prior to the first dose of study treatment. Participants must have recovered from all AEs due to previous therapies to Grade ≤1 or baseline. Participants with Grade ≤2 neuropathy may be eligible. Participants with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may be eligible.
- •Prior autologous or allogeneic hematopoietic stem cell transplant or solid organ transplant.
- •Received previous treatment with another agent targeting CD24.
研究组 & 干预措施
Dose Escalation (Phase 1a)
Nine dose levels will be sequentially tested in PHST001 monotherapy dose escalation: 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 4.0 mg/kg, 6.0 mg/kg, 9.0 mg/kg, 18.0 mg/kg, and 36.0 mg/kg.
干预措施: PHST001 (Biological)
Dose Expansion (Phase 1b)
PHST001 will be administered in combination with chemotherapy for three indicated tumor types: ovarian cancer, endometrial cancer, and cholangiocarcinoma.
The first portion of Phase 1b will consist of safety run-in groups based on the chemotherapy combination. There will be six groups: 1) combination with paclitaxel, 2) combination with topotecan, 3) combination with doxorubicin, 4) combination with 5-fluorouracil, folinic acid, and irinotecan [FOLFIRI], 5) combination with 5-fluorouracil, folinic acid, and oxaliplatin [FOLFOX], and 6) combination with gemcitabine.
The second portion of Phase 1b will begin following clearance of a safety run-in group, and subsequent participants will enroll into tumor-specific expansion cohorts at a fixed dose of PHST001 in combination with chemotherapy.
干预措施: PHST001 (Biological)
Dose Expansion (Phase 1b)
PHST001 will be administered in combination with chemotherapy for three indicated tumor types: ovarian cancer, endometrial cancer, and cholangiocarcinoma.
The first portion of Phase 1b will consist of safety run-in groups based on the chemotherapy combination. There will be six groups: 1) combination with paclitaxel, 2) combination with topotecan, 3) combination with doxorubicin, 4) combination with 5-fluorouracil, folinic acid, and irinotecan [FOLFIRI], 5) combination with 5-fluorouracil, folinic acid, and oxaliplatin [FOLFOX], and 6) combination with gemcitabine.
The second portion of Phase 1b will begin following clearance of a safety run-in group, and subsequent participants will enroll into tumor-specific expansion cohorts at a fixed dose of PHST001 in combination with chemotherapy.
干预措施: Chemotherapy per Standard of Care (Drug)
结局指标
主要结局
AE
时间窗: 90 days after the last dose of PHST001
Evaluate the safety and tolerability of PHST001
DLT
时间窗: 21 days after the first dose of PHST001
Evaluate the safety and tolerability of PHST001
Frequency of Dose-Limiting Toxicities (DLTs) to assess the safety and tolerability of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b)
时间窗: From first dose of PHST001 through 21 days after the first dose of PHST001
Based on toxicities observed
Frequency of Serious Adverse Events (SAEs) to assess the safety and tolerability of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b)
时间窗: From signed consent up to 90 days after the last dose of PHST001
Based on toxicities observed
Frequency of Treatment Emergent Adverse Events (TEAEs) to assess the safety and tolerability of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b)
时间窗: From first dose up to 90 days after the last dose of PHST001
Based on toxicities observed
Frequency of Treatment Related Adverse Events (TRAEs) to assess the safety and tolerability of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b)
时间窗: From first dose up to 90 days after the last dose of PHST001
Based on toxicities observed
Frequency of Adverse Events of Special Interest (AESIs) to assess the safety and tolerability of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b)
时间窗: From first dose up to 90 days after the last dose of PHST001
Based on toxicities observed
Frequency of AEs Leading to Dose Interruption or Treatment Discontinuation and AEs Leading to Death to assess the safety and tolerability of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b)
时间窗: From first dose up to 90 days after the last dose of PHST001
Based on toxicities observed
Overall Response Rate (ORR) based on RECIST v1.1 to assess the preliminary antitumor activity of PHST001 in combination with chemotherapy (Phase 1b)
时间窗: From screening and during treatment up to 2 years
Defined as the proportion of subjects with confirmed complete response (CR) or partial response (PR); a confirmed response is a response that persists on repeat-imaging ≥ 4 weeks after initial documentation of response.
Duration of Response (DOR) based on RECIST v1.1 to assess the preliminary antitumor activity of PHST001 in combination with chemotherapy (Phase 1b)
时间窗: From screening and during treatment up to 2 years
Defined as time from date of first objective response (either CR or PR) to first documentation of radiographic disease progression.
Best Overall Response (BOR) based on RECIST v1.1 to assess the preliminary antitumor activity of PHST001 in combination with chemotherapy (Phase 1b)
时间窗: From screening and during treatment up to 2 years
Defined as the best response recorded for a participant across all time-point assessments from the start of treatment until disease progression or end of treatment.
Progression-Free Survival (PFS) based on RECIST v1.1 to assess the preliminary antitumor activity of PHST001 in combination with chemotherapy (Phase 1b)
时间窗: From screening and during treatment up to 2 years
Defined as the time from first dose of PHST001 to first documentation of radiographic disease progression or death, whichever occurs first.
Overall Survival (OS) based on RECIST v1.1 to assess the preliminary antitumor activity of PHST001 in combination with chemotherapy (Phase 1b)
时间窗: From screening and during treatment up to 2 years
Defined as the time from first dose of PHST001 to the date of death.
次要结局
- RECIST v1.1(From screening and during treatment up to 2 years)
- PK(From treatment until 90 days after last dose of PHST001)
- PD(From treatment until end of treatment of up to 2 years of PHST001)
- Overall Response Rate (ORR) based on RECIST v1.1 (or RANO for primary CNS Tumors) to assess the preliminary antitumor activity of PHST001 as monotherapy (Phase 1a)(From screening and during treatment up to 2 years)
- Duration of Response (DOR) based on RECIST v1.1 (or RANO for primary CNS Tumors) to assess the preliminary antitumor activity of PHST001 as monotherapy (Phase 1a)(From screening and during treatment up to 2 years)
- Best Overall Response (BOR) based on RECIST v1.1 (or RANO for primary CNS Tumors) to assess the preliminary antitumor activity of PHST001 as monotherapy (Phase 1a)(From screening and during treatment up to 2 years)
- Maximum Observed Concentration (Cmax) to characterize the serum PK of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b).(From treatment until 90 days after last dose of PHST001)
- Time to Maximum Concentration (tmax) to characterize the serum PK of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b)(From treatment until 90 days after last dose of PHST001)
- Concentration at the End of a Dosing Interval (Ctrough) to characterize the serum PK of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b)(From treatment until 90 days after last dose of PHST001)
- Area Under the Concentration-time Curve (AUC) to characterize the serum PK of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b)(From treatment until 90 days after last dose of PHST001)
- Volume of Distribution at Steady-state (Vss) to characterize the serum PK of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b)(From treatment until 90 days after last dose of PHST001)
- Clearance (CL) to characterize the serum PK of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b)(From treatment until 90 days after last dose of PHST001)
- Terminal Elimination Half-life (t½) to characterize the serum PK of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b)(From treatment until 90 days after last dose of PHST001)
- Progression-Free Survival (PFS) based on RECIST v1.1 (or RANO for primary CNS Tumors) to assess the preliminary antitumor activity of PHST001 as monotherapy (Phase 1a).(From screening and during treatment up to 2 years)
- Overall Survival (OS) based on RECIST v1.1 (or RANO for primary CNS Tumors) to assess the preliminary antitumor activity of PHST001 as monotherapy (Phase 1a).(From screening and during treatment up to 2 years)