A Phase 1 Study of SEA-CD70 in Myeloid Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 170
- 试验地点
- 152
- 主要终点
- Number of participants with adverse events (AEs)
研究概览
简要总结
This trial will look at a drug called SEA-CD70 with and without azacitidine, to find out if it is safe for participants with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). It will study SEA-CD70 to find out what its side effects are and if it works for AML and MDS. A side effect is anything the drug does besides treating cancer.
This study will have seven groups or "parts."
- Part A will find out how much SEA-CD70 should be given to participants
- Part B will use the dose found in Part A to find out how safe SEA-CD70 is and if it works to treat participants with MDS.
- Part C will use the dose found in Part A to find out how safe SEA-CD70 is and if it works to treat participants with AML.
- Part D will find out how much SEA-CD70 with azacitidine should be given to participants
- Part E will use the dose found in Part D to find out how safe SEA-CD70 with azacitidine is compared to azacitidine alone and if it works to treat participants with MDS or MDS/AML that has not been treated.
- Part F will use the dose found in Part D to find out how safe SEA-CD70 with azacitidine is and if it works to treat participants with MDS or MDS/AML.
- Part G will find out how much SEA-CD70 with azacitidine and with venetoclax should be given to participants with AML. Also, to evaluate safety and tolerability of PF-08046040 in combination with azacitidine and venetoclax in participants with previously untreated AML who are unfit for standard induction chemotherapy.
详细描述
This is a phase 1, open-label, multicenter, dose-finding, and dose expansion study designed to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of SEA-CD70 monotherapy and SEA-CD70 in combination with azacitidine in adults with myeloid malignancies. The study will be conducted in up to 6 parts.
- Part A is a dose-escalation cohort designed to identify the MTD or recommended expansion dose of SEA-CD70 monotherapy in participants with relapsed/refractory (hypomethylating agent [HMA]-failure) MDS.
- Part B is an expansion cohort designed to evaluate the safety and tolerability of SEA-CD70 monotherapy in participants with relapsed/refractory (HMA-failure) MDS.
- Part C is an expansion cohort designed to evaluate the safety and tolerability of SEA-CD70 monotherapy in participants with relapsed/refractory AML.
- Part D contains dose-finding/dose optimization cohorts designed to evaluate the safety/tolerability and identify the recommended expansion dose of SEA-CD70 in combination with azacitidine in participants with 1) relapsed/refractory (HMA-failure) MDS or MDS/AML, and 2) previously untreated higher-risk per IPSS-M (Moderate High, High or Very High) MDS or MDS/AML.
- Part E is an expansion cohort designed to evaluate the safety and tolerability of SEA-CD70 in combination with azacitidine vs azacitidine in participants with previously untreated higher-risk per IPSS-M (Moderate High, High, or Very High) MDS or MDS/AML.
- Part F is an expansion cohort designed to evaluate the safety and tolerability of SEA-CD70 in combination with azacitidine in participants with relapsed/refractory (HMA-failure) MDS or MDS/AML.
- Part G will find out how much SEA-CD70 with azacitidine and with venetoclax should be given to participants with previously untreated AML who are unfit for standard of care induction chemotherapy
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
- •Part A Inclusion Criteria
- •Participants with cytologically/histologically confirmed MDS (2016 World Health Organization (WHO) classification) with
- •Measurable disease per WHO MDS with excess blasts criteria
- •MDS that is relapsed or refractory and must not have other therapeutic options
- •Treatment failure after prior hypomethylating agent (HMA) therapy for MDS
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- •Part B Inclusion Criteria
- •Participants with cytologically/histologically confirmed MDS (WHO classification) with:
- •Measurable disease per WHO MDS with excess blasts (MDS-EB) criteria
- •MDS that is relapsed or refractory and must not have other therapeutic options
- •Treatment failure after prior HMA therapy for MDS
- •ECOG Performance Status of 0-2
- •Part C Inclusion Criteria
- •Participants with relapsed or refractory AML (ICC 2022) (except for acute promyelocytic leukemia [APL]):
- •Who have received either 2 or 3 previous regimens
- •Who have received 1 previous regimen to treat active disease and have at least one of the following:
- •Age > 60 and ≤75 years.
- •Primary resistant AML or secondary AML
- •First CR duration <6 months
- •Adverse-risk per European Leukemia Network genetic risk stratification
- •Age 18-75 years
- •ECOG performance status of 0-2
- •Parts D and F Inclusion Criteria
- •Participants with diagnosis of MDS or MDS/AML (ICC 2022 criteria)
- •Disease which has relapsed, failed to respond after minimum of 6 cycles, or progressed following an HMA in the immediately preceding line of therapy.
- •Eligible for continued therapy with azacitidine
- •ECOG Performance Status 0-2
- •Parts D and E Inclusion Criteria
- •Participants with diagnosis of MDS or MDS/AML (ICC 2022 criteria), previously untreated.
- •Participants with higher-risk per IPSS-M MDS and MDS/AML
- •ECOG Performance Status 0-2
- •Part G Inclusion Criteria
- •Participants with diagnosis of AML (ICC 2022 criteria), previously untreated and ineligible for standard induction chemotherapy.
- •Age ≥18 years.
- •ECOG Performance Status of 0-2.
排除标准
- •(All Parts)
- •Previous exposure to CD70-targeted agents
- •Prior allogeneic hematopoietic stem cell transplant, for any condition
- •Central nervous system leukemia
- •History of clinically significant sickle cell anemia, autoimmune hemolytic anemia, or idiopathic thrombocytopenic purpura
- •Parts D, F and G only: Prior oral HMA or oral HMA-combinations
- •Part G: conditions that preclude enteral route of administration; concomitant use of strong/moderate CYP3A inducers; history of myeloproliferative neoplasm
研究组 & 干预措施
Part E
SEA-CD70 + azacitidine vs azacitidine expansion cohort in previously untreated higher-risk MDS or MDS/AML
干预措施: azacitidine (Drug)
Part F
SEA-CD70 + azacitidine expansion cohort in relapsed/refractory MDS or MDS/AML
干预措施: SEA-CD70 (Drug)
Part D
SEA-CD70 + azacitidine dose-finding/dose optimization cohorts in relapsed/refractory MDS or MDS/AML, and previously untreated higher-risk MDS or MDS/AML
干预措施: azacitidine (Drug)
Part B
SEA-CD70 expansion cohort in relapsed/refractory (HMA-failure) MDS
干预措施: SEA-CD70 (Drug)
Part C
SEA-CD70 expansion cohort in relapsed/refractory AML
干预措施: SEA-CD70 (Drug)
Part D
SEA-CD70 + azacitidine dose-finding/dose optimization cohorts in relapsed/refractory MDS or MDS/AML, and previously untreated higher-risk MDS or MDS/AML
干预措施: SEA-CD70 (Drug)
Part F
SEA-CD70 + azacitidine expansion cohort in relapsed/refractory MDS or MDS/AML
干预措施: azacitidine (Drug)
Part G
SEA-CD70 + azacitidine +venetoclax dose-finding/dose optimization in previously untreated and unfit for induction therapy AML
干预措施: Venetoclax (Drug)
Part G
SEA-CD70 + azacitidine +venetoclax dose-finding/dose optimization in previously untreated and unfit for induction therapy AML
干预措施: SEA-CD70 (Drug)
Part G
SEA-CD70 + azacitidine +venetoclax dose-finding/dose optimization in previously untreated and unfit for induction therapy AML
干预措施: azacitidine (Drug)
Part A
SEA-CD70 dose escalation cohort in relapsed/refractory (HMA-failure) MDS
干预措施: SEA-CD70 (Drug)
Part E
SEA-CD70 + azacitidine vs azacitidine expansion cohort in previously untreated higher-risk MDS or MDS/AML
干预措施: SEA-CD70 (Drug)
结局指标
主要结局
Number of participants with adverse events (AEs)
时间窗: Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years
Any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment.
Number of participants with laboratory abnormalities
时间窗: Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years
To be summarized using descriptive statistics.
Number of participants with a dose-limiting toxicity (DLT) at each dose level (Parts A and D only)
时间窗: Though end of DLT evaluation period; up to approximately 4 weeks
To be summarized using descriptive statistics.
次要结局
- Rate of TI maintenance(Up to approximately 4 years)
- Complete remission with partial hematologic recovery (CRh) rate(Up to approximately 4 years)
- Overall response rate (ORR)(Up to approximately 4 years)
- AUC - Area under the plasma concentration-time curve(Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years)
- Cmax - Maximum observed plasma concentration(Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years)
- Incidence of antidrug antibodies (ADA)(Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years)
- Complete remission with limited count recovery (CRL) rate for participants with MDS or MDS/AML(Up to approximately 4 years)
- Ctrough - Minimum plasma concentration per dosing interval(Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years)
- Tmax - Time to maximum concentration attained(Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years)
- Hematologic response (HI) rate(Up to approximately 4 years)
- Overall survival (OS)(Up to approximately 4 years)
- Event-free survival (EFS)(Up to approximately 4 years)
- T1/2 - Terminal elimination half-life(Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years)
- Complete remission (CR) Rate and complete remission equivalent (CReq) rate(Up to approximately 4 years)
- Complete remission with incomplete blood count recovery (CRi) rate(Up to approximately 4 years)
- Duration of remission (DOR)(Up to approximately 4 years)
- Time to response (TTR)(Up to approximately 4 years)
- Progression-free survival (PFS)(Up to approximately 4 years)
- MRD-negative ORR(Up to approximately 4 years)
- Rate of conversion to transfusion independence (TI)(Up to approximately 4 years)