A Phase 1, Open-Label, Dose Escalation and Expansion Study of Mavrostobart (PT199) Administered Alone in Adult Patients With Advanced Solid TuMORs, in CombiNation With a Checkpoint INhibitor TreatinG Wild-type Non-Small Cell Lung Cancer, or in Combination With ChemoTherapy for Metastatic or Advanced PAncreatic Ductal AdenocaRcinoma (MORNINGSTAR)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 40
- 试验地点
- 12
- 主要终点
- To determine the maximum tolerated dose (MTD), if reached.
研究概览
简要总结
This is a first-in-human, Phase 1/2, open-label, study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of Mavrostobart (PT199) alone and in combination with a PD-1 inhibitor or chemotherapy.
详细描述
Mavrostobart (PT199) is an anti-CD73 mAb with a differentiated mechanism of action and is expected to completely inhibit CD73 enzyme activity. Mavrostobart (PT199) is designed to counter the adenosine-mediated immunosuppressive tumor microenvironment, rendering anti-tumor immune cells to be more active and more responsive to checkpoint immunotherapies, such as PD-1/PD-L1 inhibitors.
CD73 is widely overexpressed in a number of different cancers, including pancreatic ductal adenocarcinoma (PDAC), gastric carcinoma, colorectal carcinoma, non-small cell lung cancer (NSCLC), sarcomas and glioblastomas. Thus, targeting CD73 may provide benefit for patients with a high CD73 expression in their tumor.
Mavrostobart (PT199) addresses the limitations of current CD73 inhibitors and is expected to increase antitumor immune activation, especially in combination with PD-1 pathway inhibition, and thus offer a new treatment option for cancer patients.
NSCLC is known to have a high expression level of CD73, and emerging clinical data has shown that targeting CD73 may provide clinical benefit, when combined with an immune checkpoint inhibitor (ICI) and/or standard of care chemotherapies to overcome treatment resistance.
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
- •At least one measurable lesion as defined by RECIST V1.1 criteria for solid tumors.
- •For Part A: a histologically or cytologically confirmed unresectable advanced or metastatic solid tumors previously treated with therapies, or for which treatment is not available or not tolerated.
- •For Part B: A histologically or cytologically confirmed diagnosis of NSCLC without actionable genomic alterations (AGAs) such as EGFR or ALK mutations and radiological documentation of disease progression on prior treatments, which may include a checkpoint inhibitor, or patients diagnosed with metastatic and/or advanced (m/a) PDAC who have disease progression after previously treated with therapies, or for which treatment is not available or not tolerated.
- •For Part C: A histologically or cytologically confirmed diagnosis of NSCLC without actionable genomic alterations such as EGFR or ALK mutations and radiological documentation of disease progression on prior treatments, which may include a checkpoint inhibitor.
- •For Part D:
- •Cohort D1: a histologically or cytologically confirmed diagnosis of pancreatic ductal adenocarcinoma (PDAC), treatment naïve for advanced or metastatic disease, and eligible to receive standard of care treatment with gemcitabine plus nab-paclitaxel.
- •Cohort D2: a histologically or cytologically confirmed diagnosis of NSCLC without actionable genomic alterations (AGAs) such as EGFR or ALK mutations and radiological documentation of disease progression on prior treatments, which may include a checkpoint inhibitor. Patients have progressed under first-line (1L) SOC chemotherapy with or without ICI or later lines of therapy, or for which standard 1L therapy has proven to be ineffective, intolerable, or is considered inappropriate.
- •Cohort D3: a histologically or cytologically confirmed diagnosis of NSCLC without actionable genomic alterations (AGAs) such as EGFR or ALK mutations. Patients are treatment naïve and have no contra indication to receive carboplatin plus pemetrexed.
- •Cohort D4: a histologically or cytologically confirmed diagnosis of NSCLC without actionable genomic alterations (AGAs) such as EGFR or ALK mutations. Patients are treatment naïve and are eligible for 1L therapy with pembrolizumab and carboplatin plus pemetrexed.
- •In all Parts, should be able to provide a tumor tissue sample (archival or newly acquired biopsy) to be assessed for CD73 and other biomarkers (PD-L1), unless deemed by the Investigator to cause risk to the patient or per Investigator's discretion.
- •ECOG performance status of 0 or
- •Adequate organ function confirmed at screening and within 72 hours of initiating treatment.
排除标准
- •Women who are pregnant or lactating.
- •Women of child-bearing potential (WOCBP) who do not use adequate birth control.
- •Autoimmune disease requiring systemic treatment within the past twelve months. Active autoimmune disease or a history of autoimmune diseases that may relapse.
- •Condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days prior to study treatment.
- •Patients who have experienced Grade ≥ 3 immune-related events, such as (non-infectious) pneumonitis, interstitial lung disease, myocarditis.
- •Patients with untreated brain or central nervous system (CNS) metastases or brain/CNS metastases that have progressed.
- •Impaired cardiac function or significant diseases.
- •Patients who have ≥ Grade 3 neuropathy.
- •Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered from adverse events of prior therapy.
- •Patients who are currently receiving (last dose within 5 days from C1D1) treatment with therapeutic doses of warfarin sodium (Coumadin®) or any other coumarin-derivative anticoagulants.
- •Additional inclusion and exclusion criteria will apply.
研究组 & 干预措施
Part B: Combination Therapy Dose Escalation
A standard 3+3 dose escalation design will be employed, and 3 patients will be enrolled initially at each dose level. Patients will be treated with Mavrostobart (PT199) in combination with a PD-1 inhibitor, tislelizumab.
干预措施: Tislelizumab (Drug)
Part A: Monotherapy Dose Escalation
A standard 3+3 dose escalation design will be employed, and 3 patients will be enrolled initially at each dose level. Mavrostobart (PT199) will be administered as a monotherapy.
干预措施: Mavrostobart (PT199) (Drug)
Part B: Combination Therapy Dose Escalation
A standard 3+3 dose escalation design will be employed, and 3 patients will be enrolled initially at each dose level. Patients will be treated with Mavrostobart (PT199) in combination with a PD-1 inhibitor, tislelizumab.
干预措施: Mavrostobart (PT199) (Drug)
Part C: Combination Therapy Dose Expansion
Two RDEs for Part C will be determined in Part B and will be further evaluated in two dose expansion cohorts. Patients will be treated with Mavrostobart (PT199) in combination with a PD-1 inhibitor, tislelizumab.
干预措施: Mavrostobart (PT199) (Drug)
Part D: Chemotherapy Combination
The Chemotherapy Combination Therapy Dose Escalation and Expansion will investigate four cohorts, one in frontline PDAC, two in frontline NSCLC and one in second-line and later NSCLC patients. Patients will receive Mavrostobart (PT199) plus chemotherapy, with one cohort also receiving pembrolizumab.
干预措施: Mavrostobart (PT199) (Drug)
Part D: Chemotherapy Combination
The Chemotherapy Combination Therapy Dose Escalation and Expansion will investigate four cohorts, one in frontline PDAC, two in frontline NSCLC and one in second-line and later NSCLC patients. Patients will receive Mavrostobart (PT199) plus chemotherapy, with one cohort also receiving pembrolizumab.
干预措施: Carboplatin + Pemetrexed (Drug)
Part D: Chemotherapy Combination
The Chemotherapy Combination Therapy Dose Escalation and Expansion will investigate four cohorts, one in frontline PDAC, two in frontline NSCLC and one in second-line and later NSCLC patients. Patients will receive Mavrostobart (PT199) plus chemotherapy, with one cohort also receiving pembrolizumab.
干预措施: Pembrolizumab + Carboplatin + Pemetrexed (Drug)
Part C: Combination Therapy Dose Expansion
Two RDEs for Part C will be determined in Part B and will be further evaluated in two dose expansion cohorts. Patients will be treated with Mavrostobart (PT199) in combination with a PD-1 inhibitor, tislelizumab.
干预措施: Tislelizumab (Drug)
Part D: Chemotherapy Combination
The Chemotherapy Combination Therapy Dose Escalation and Expansion will investigate four cohorts, one in frontline PDAC, two in frontline NSCLC and one in second-line and later NSCLC patients. Patients will receive Mavrostobart (PT199) plus chemotherapy, with one cohort also receiving pembrolizumab.
干预措施: Gemcitabine + nab-Paclitaxel (Drug)
Part D: Chemotherapy Combination
The Chemotherapy Combination Therapy Dose Escalation and Expansion will investigate four cohorts, one in frontline PDAC, two in frontline NSCLC and one in second-line and later NSCLC patients. Patients will receive Mavrostobart (PT199) plus chemotherapy, with one cohort also receiving pembrolizumab.
干预措施: Docetaxel (Drug)
Part D: Chemotherapy Combination
The Chemotherapy Combination Therapy Dose Escalation and Expansion will investigate four cohorts, one in frontline PDAC, two in frontline NSCLC and one in second-line and later NSCLC patients. Patients will receive Mavrostobart (PT199) plus chemotherapy, with one cohort also receiving pembrolizumab.
干预措施: Pemetrexed (Drug)
Part D: Chemotherapy Combination
The Chemotherapy Combination Therapy Dose Escalation and Expansion will investigate four cohorts, one in frontline PDAC, two in frontline NSCLC and one in second-line and later NSCLC patients. Patients will receive Mavrostobart (PT199) plus chemotherapy, with one cohort also receiving pembrolizumab.
干预措施: Gemcitabine (Drug)
结局指标
主要结局
To determine the maximum tolerated dose (MTD), if reached.
时间窗: Start of the study drug till 90 days after last dose.
Recommended Phase 2 Dose of Mavrostobart (PT199) as a single agent and/or in combination with a PD-1 inhibitor.
时间窗: Start of the study drug till 90 days after last dose.
Dose Limiting Toxicity (DLT).
时间窗: Time Frame: Start of the study drug till 90 days after last dose.
次要结局
- Progression free survival duration.(Time Frame: Start of the study drug till 90 days after last dose.)
- Area Under the Curve from time 0 to last (AUC0-last) of Mavrostobart (PT199)(Time Frame: Start of the study drug till 90 days after last dose.)
- Preliminary efficacy assessed by the response rate by RECIST 1.1 for overall response rate.(Start of the study drug till 90 days after last dose.)
- Half Life (T1/2) of Mavrostobart (PT199)(Time Frame: Start of the study drug till 90 days after last dose.)
- Maximum Concentration (Cmax) of Mavrostobart (PT199)(Time Frame: Start of the study drug till 90 days after last dose.)
- Preliminary efficacy assessed by the response rate by RECIST 1.1 for disease control rate.(Time Frame: Start of the study drug till 90 days after last dose.)
- 6-month overall survival.(Time Frame: Start of the study drug till 90 days after last dose.)