A Phase 1/2, First in Human, Dose Escalation Study of MGD006, a CD123 x CD3 DART® Bi-Specific Antibody Based Molecule, in Patients With Relapsed or Refractory AML or Intermediate-2/High Risk Myelodysplastic Syndrome (MDS)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- MacroGenics
- 入组人数
- 244
- 试验地点
- 43
- 主要终点
- Efficacy Based on CR or CRh Rate
研究概览
简要总结
Open-label, multi-dose, single-arm, multi-center, Phase 1/2 study conducted in three segments: the Single Patient Dose Escalation Segment (complete), followed by the Multi-Patient Dose Escalation Segment (complete) and the Maximum Tolerated Dose and Schedule (MTDS) Expansion Cohort Segment (closed). Having characterized safety and determined the maximum tolerated dose and schedule, the primary objective of this study now is to assess the anti-neoplastic activity of flotetuzumab in patients with PIF/ER AML, as determined by the proportion of patients who achieve CR or CRh. Starting with Cycle 2, patients who are benefiting from flotetuzumab may receive up to a maximum of 8 cycles of treatment.
Patients will receive daily increasing doses of flotetuzumab for the first week of Cycle 1 (Lead-In Dosing) followed by 3 weeks of continuous intravenous infusion at a the assigned dose. Subsequent cycles are each 4 weeks of continuous infusion at the assigned dose. Dosing may continue for up to 8 cycles. Follow up visits may continue for 6 months after treatment is discontinued.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 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
- •Confirmed diagnosis of primary or secondary AML [any subtype except acute promyelocytic leukemia (APL)] according to World Health Organization (WHO) classification
- •Patients with AML must meet one of the following criteria, a or b:
- •Primary Induction Failure (PIF) AML, defined as disease refractory to either, i or ii:
- •i. An intensive induction attempt, per institution. Induction attempts include high-dose and/or standard-dose cytarabine ± an anthracyclines/anthracenedione ± an anti-metabolite, with or without growth factor or targeted therapy containing regimens. Examples include but are not limited to: 1 cycle of high dose cytarabine (HiDAC) containing regimen, 1 cycle of liposomal cytarabine and daunorubicin, 2 cycles of standard dose cytarabine containing regimen
- •ii. For adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy; PIF is defined as AML refractory to one of the following less intensive regimens: i ≥ 2 but ≤ 4 cycles of Bcl-2 inhibitors in combination with azacitidine, decitabine, or low dose cytarabine, or ii ≥ 2 but ≤ 4 cycles of gemtuzumab ozogamicin monotherapy
- •Early relapse (ER) AML, defined as AML in first relapse with initial CR1 duration < 6 months
- •Limit of 3 prior lines of therapy (excluding focal radiation therapy for palliative purposes): up to 2 induction (induction, re-induction) or 1 induction plus/minus 1 consolidation attempt, followed by a maximum of 1 salvage/re-induction attempt.
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤2
- •Life expectancy of at least 4 weeks
- •Peripheral blast count </= 20,000/mm3 at the time of first dose
- •Acceptable laboratory parameters and adequate organ reserve
排除标准
- •History of allogeneic stem cell transplantation
- •Prior treatment with an anti-CD123-directed agent
- •Need for concurrent other cytoreductive chemotherapy
- •Any active untreated autoimmune disorders (with the exception of vitiligo, resolved childhood atopic dermatitis, prior Grave's disease now euthyroid clinically and with stable supplementation)
- •Second primary malignancy that requires active therapy. Adjuvant hormonal therapy is allowed.
- •Antitumor therapy or investigational agent within 14 days or 5 half-lives of Cycle 1 Day
- •Requirement, at the time of study entry, for concurrent steroids > 10 mg/day of oral prednisone or the equivalent, except steroid inhaler, otic preparations, nasal spray or ophthalmic solution
- •Use of immunosuppressant medications in the 2 weeks prior to Cycle 1 Day 1
- •Use of granulocyte colony stimulating or granulocyte-macrophage colony stimulating factor in the 2 weeks prior to Cycle 1 Day 1
- •Known central nervous system (CNS) leukemia
- •Active uncontrolled infection (including, but not limited to viral, bacterial, fungal, or mycobacterial infection),
- •Known human immunodeficiency virus infection, unless all of the following criteria are met: CD4+ count ≥ 350 cells/μL, undetectable viral load, and receiving highly active antiretroviral therapy.
- •Known, active, history of or current acute or chronic hepatitis B or C virus (HBV) infection (as evidenced by detectable HBV surface antigen and HBV DNA ≥ 500 IU/mL),
- •History of hepatitis C virus (HCV) infection, unless the infection has been treated and cured,
- •Active SARS-CoV-2 infection. While SARS-CoV-2 testing is not mandatory for study entry, testing for ongoing infection should follow local clinical practice guidelines/standards. Participants with a positive test result for ongoing SARS-CoV-2 infection, known asymptomatic infection, or suspected infection are excluded unless or until asymptomatic and with subsequent negative SARS-CoV-2 laboratory test.
研究组 & 干预措施
Cohort 0-a
干预措施: Flotetuzumab 3 ng/kg/day, 4 days on and 3 days off (Biological)
Cohort 0-b
干预措施: Flotetuzumab 10 ng/kg/day, 4 days on and 3 days off (Biological)
Cohort 0-c
干预措施: Flotetuzumab 30 ng/kg/day, 4 days on and 3 days off (Biological)
Cohort 0-d
干预措施: Flotetuzumab 100 ng/kg/day, 4 days on and 3 days off (Biological)
Cohort 1
干预措施: Flotetuzumab 300 ng/kg/day, 4 days on 3 days off, after one-step lead-in dose (Biological)
Cohort 2
干预措施: Flotetuzumab 500 ng/kg/day, 4 days on 3 days off, after one-step lead-in dose (Biological)
Cohort 2a
干预措施: Flotetuzumab 500 ng/kg/day, continuous infusion, after multi-step lead-in dose (Biological)
Cohort 3
干预措施: Flotetuzumab 700 ng/kg/day, 4 days on 3 days off, after multi-step lead-in dose (Biological)
Cohort 6
干预措施: Flotetuzumab 300 ng/kg/day, continuous infusion, after multi-step lead-in dose (Biological)
Cohort 7
干预措施: Flotetuzumab 500 ng/kg/day, continuous infusion, after multi-step lead-in dose (Biological)
Cohort 8
干预措施: Flotetuzumab 700 ng/kg/day, continuous infusion, after multi-step lead-in dose (Biological)
MTD Expansion
干预措施: Flotetuzumab 500 ng/kg/day, continuous infusion, after multi-step lead-in dose (Biological)
MTD expansion with Ruxolitinib
干预措施: Flotetuzumab 500 ng/kg/day, continuous infusion, after multi-step lead-in dose (Biological)
MTD expansion with Ruxolitinib
干预措施: Ruxolitinib (Drug)
结局指标
主要结局
Efficacy Based on CR or CRh Rate
时间窗: up to 14 months
Proportion of patients achieving a best response of CR (morphologic CR \[mCR\], cytogenetic CR \[CRc\], molecular CR \[CRm\], or CRh per Interworking Group AML response criteria. CR is defined as mCR, CRc, CRm or CRh. mCR is defined as: normal. neutrophil and platelet counts, less than 5% blast cells in a bone marrow (BM) smear and. no extramedullary disease. CRc is defined as: CR with no evidence of cytogenetic abnormalities in the bone marrow. CRm is defined as: CR with no evidence of molecular abnormalities in the bone marrow. CRh is defined as: CR with partial hematologic recovery.
次要结局
- CRh Rate(up to 14 months)
- Number of Patients With Infusion Related Reaction (IRR)(During study drug administration (up to 8 months))
- Maximum Serum Concentration of Flotetuzumab(Study day 1, then every 28 days and 28 days after the last dose (up to 8 months))
- Number of Patients Alive at 6 Months(6 months)
- Mortality Rate(Throughout the study, up to 3 years.)
- Overall Complete Response Rate(up to 14 months)
- CR Rate(up to 14 months)
- Overall Response Rate(up to 14 months)
- Occurrence of Adverse Events (AEs)(up to 9 months)
- Participants With Anti-drug Antibodies(Study Day 1, then every 28 days through 28-days after the last dose (up to 8 months))
- Post-baseline Transfusion Independence Rate(56 days)
- Duration of Response of Patients With CR or CRh(Up to 2 years)
- Number of Patients With Cytokine Release Syndrome (CRS)(up to 9 months)
- Event-free Survival(Up to 2 years)
- HSCT Rate(up to 8 months)
- Occurrence of Dose Limiting Toxicity(Cycle 1 of a 28 day cycle.)
- Occurrence of Serious Adverse Events (SAEs)(up to 9 months)
- Duration of Hospitalization for Patients in the Expansion Cohort(up to 8 months)
- Number of Patients Alive at 12 Months(1 year)
- Median Time to Response(up to 14 months)
- Overall Survival(Up to 2 years)
- Rate of Hospitalization for Patients in the Expansion Cohort After Initial Discharge(up to 8 months)