2024-514197-50-00进行中（未招募）1/2 期
A Phase 1b/2 Study of IMGN632 as Monotherapy or Combination with Venetoclax and/or Azacitidine for Patients with CD123-Positive Acute Myeloid Leukemia
试验速览
- 阶段
- 1/2 期
- 状态
- 进行中（未招募）
- 入组人数
- 68
- 试验地点
- 10
- 主要终点
- Dose Escalation (Regimens A-C): RP2D of IMGN632 when administered in combination with azacitidine (Regimen A) or venetoclax (Regimen B) or azacitidine + venetoclax (Regimen C).
研究概览
简要总结
IMGN632 in Combination with Azacitidine and/or Venetoclax (Regimens A-C)
-
Dose Escalation Cohorts: Evaluate the safety and tolerability and identify a recommended Phase 2 dose (RP2D) of IMGN632 when administered in combination with azacitidine (Regimen A) or venetoclax (Regimen B) or azacitidine + venetoclax (Regimen C) in patients with relapsed or refractory CD123-positive AML.
-
Dose Expansion Cohorts:
- Assess preliminary antileukemia activity of IMGN632 when administered in combination with azacitidine (Regimen A) or venetoclax (Regimen B), azacitidine+venetoclax (Regimen C) in patients with eitherrelapsed or untreated AML
- Assess MRD levels.
IMGN632 Monotherapy in MRD+ Fit and Unfit AML (Regimen D Cohorts D1 and D2)
- Regimen D (Cohorts D1 and D2): Assess preliminary antileukemia activity of IMGN632 as monotherapy in MRD+ Fit (Cohort D1) and MRD+ Unfit AML (Cohort D2) patient populations
- Assess MRD levels.
入排标准
- 年龄范围
- 18 years 至 65+ years（18-64 Years, 65+ Years）
- 接受健康志愿者
- 是
入选标准
- •Patient must be ≥ 18 years of age.
- •Left ventricular ejection fraction (LVEF) ≥ 45% based on locally available assessment, eg, echocardiogram or other modality. Note: This inclusion criterion does not apply to patients enrolling in cohorts C1 and/or C2 as unfit.
- •Patients with prior autologous or allogeneic bone marrow transplant are eligible. Patients with an allogeneic transplant must meet the following conditions: The transplant must have been performed more than 120 days before the date of dosing on this study, the patient must not have active ≥ Grade 2 graft versus host disease (GvHD), or extensive chronic GvHD of any severity, and must be off all immunosuppression for at least 2 weeks prior to first dose of IMGN
- •Patients with prior malignancy are eligible; however, patient's malignancy must be well-controlled or stable and have completed all systemic chemotherapy and radiotherapy for the prior malignancy at least 6 months before enrollment, and all treatment-related toxicities must have resolved to Grade 1 (excluding alopecia). Note: patients with prostate cancer or breast cancer on adjuvant hormonal therapy are eligible and may or may not be on long-term maintenance treatment that is unlikely to interfere with study therapy.
- •Patients in expansion Cohorts C1 and C2 must be considered ineligible for intensive induction therapy defined by the following: a. ≥ 75 years of age OR b. < 75 years of age with at least one of the following co-morbidities documented within 28 days of Cycle 1 Day 1: − ECOG performance status of 2 or 3 − History of congestive heart failure requirement treatment or ejection fraction ≤ 50% or chronic stable angina − Diffusing capacity of the lung for carbon monoxide ≤ 65% or forced expiratory volume in 1 second ≤ 65% − Creatinine clearance ≥ 30 mL/min to < 45 mL/min − Moderate hepatic impairment with total bilirubin > 1.5 to ≤ 3.0 × ULN
- •Patients in Cohort C1 and C2 must have an ECOG performance status of 0 to 2 for those ≥ 75 years of age OR 0 to 3 for < 75 years of age.
- •Patients must have confirmed diagnosis of AML (excluding acute promyelocytic leukemia) based on World Health Organization classification.
- •Disease characteristics and allowable prior therapy: a. Patients must be evaluated for any available standard of care therapies (including induction, consolidation chemotherapy and/or transplant) and, in the opinion of the treating physician, be deemed appropriate for this experimental therapy. b. Treatment-naïve (untreated) patients will be allowed in the Expansion Phase for Regimens C (Triplet) (IMGN632 + azacitidine + venetoclax). No prior treatments with hypomethylating agents (HMAs) for MDS are allowed. c. Patients must have CD123-positive AML as confirmed by local flow cytometry (or immunohistochemistry [IHC]). d. Patients may have received prior CD123-targeted therapies, except IMGN632, as long as CD123 remains detectable during screening. e. Relapsed or refractory CD123-positive AML patients will be allowed to enroll in the Escalation Phase of Regimens A, B, and C (Triplet) (IMGN632 + azacitidine, venetoclax, or azacitidine + venetoclax, respectively) and relapsed CD123-positive AML patients will be allowed to enroll the Expansion Phase of Regimens A-C. f. Patients enrolling in Regimen D must be in CR (CR/CRh/CRp/CRi) and be MRD+ at the time of screening, confirmed by central laboratory testing. Patients may have no more than 2 prior lines of therapy (which may include stem cell transplant), ie. frontline or first salvage.
- •Eastern Cooperative Oncology Group performance status ≤
- •If non ambulatory due to a chronic disability, must be Karnofsky performance status ≥
- •Previous treatment-related toxicities must have resolved to Grade 1 or baseline (excluding alopecia).
- •Total WBC count must be less than 25 × 10e9 cells/L. Hydroxyurea may be used to control blood counts before Cycle 1 Day 1, at the discretion of the treating physician, according to institutional practice. During the Escalation Phase in Regimens A-C, hydroxyurea may also be used during Cycle
- •Liver enzymes (AST and ALT) ≤ 3 × the upper limit of normal (ULN).
- •Total bilirubin ≤ 1.5 × the ULN; patients with Gilbert syndrome must have total bilirubin ≤ 3.0 × ULN with direct bilirubin < 1.0 × ULN at the time of enrollment. Note: Subjects who are < 75 years of age may have a bilirubin of ≤ 3.0 x ULN
- •An estimated glomerular filtration rate (eGFR) of > 30 mL/min/1.73m2 or creatinine clearance of > 30 mL/min.
排除标准
- •Patients who have received any anticancer therapy, including investigational agents, within 14 days (or within 28 days for checkpoint inhibitors) before drug administration on this study (hydroxyurea is allowed before beginning study treatment). Patients must have recovered to baseline from all acute toxicity from this prior therapy.
- •Women who are pregnant or breastfeeding.
- •Prior known hypersensitivity reactions to monoclonal antibodies (≥ Grade 3).
- •Prior known hypersensitivity reactions to study drugs and/or any of their excipients.
- •Patients who have a history of allergy to IMGN632 (or any of its excipients), azacitidine, or venetoclax.
- •Patients who have been previously treated with IMGN
- •Patients with myeloproliferative neoplasm–related secondary AML are excluded from the Dose Expansion Phase of the study.
- •Patients with active central nervous system (CNS) AML will be excluded. A lumbar puncture does not need to be performed unless there is clinical suspicion of CNS involvement per investigator judgement. Concurrent therapy for CNS prophylaxis or continuation of therapy for controlled CNS AML is allowed with the approval of the sponsor.
- •Patients with a history of sinusoidal obstruction syndrome/ven occlusive disease of the liver.
- •Myocardial infarction within 6 months before enrollment or New York Heart Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities before study entry.
- •Clinically relevant active infection including known active hepatitis B or C, HIV infection, or cytomegalovirus or any other known concurrent infectious disease that, in the judgment of the investigator, would make a patient inappropriate for enrollment into this study (testing not required).
- •Patients who have undergone a major surgery within 4 weeks (or longer if not fully recovered) before study enrollment.
- •Serious or poorly controlled medical conditions that could be exacerbated by treatment or that would seriously compromise safety assessment or compliance with the protocol, in the judgment of the investigator.
结局指标
主要结局
Dose Escalation (Regimens A-C): RP2D of IMGN632 when administered in combination with azacitidine (Regimen A) or venetoclax (Regimen B) or azacitidine + venetoclax (Regimen C).
Dose Escalation (Regimens A-C): RP2D of IMGN632 when administered in combination with azacitidine (Regimen A) or venetoclax (Regimen B) or azacitidine + venetoclax (Regimen C).
Dose Escalation (Regimens A-C): Treatment-emergent adverse events (TEAEs), laboratory test results, physical examination, and vital signs.
Dose Escalation (Regimens A-C): Treatment-emergent adverse events (TEAEs), laboratory test results, physical examination, and vital signs.
Dose Expansion Cohorts (Regimens A-C): Composite CR rate (CRMRD-, CR, CRh, CRp, CRi).
Dose Expansion Cohorts (Regimens A-C): Composite CR rate (CRMRD-, CR, CRh, CRp, CRi).
Dose Expansion Cohorts (Regimens A-C): Overall response rate (ORR) (CRMRD-, CR, CRh, CRp, CRi, MLFS, PR).
Dose Expansion Cohorts (Regimens A-C): Overall response rate (ORR) (CRMRD-, CR, CRh, CRp, CRi, MLFS, PR).
Dose Expansion Cohorts (Regimens A-C): Duration of remission (DOR).
Dose Expansion Cohorts (Regimens A-C): Duration of remission (DOR).
Dose Expansion Cohorts (Regimens A-C): MRD levels using central flow cytometry–based testing.
Dose Expansion Cohorts (Regimens A-C): MRD levels using central flow cytometry–based testing.
Dose Expansion Cohorts (Regimen D): MRD levels using central flow cytometry–based testing.
Dose Expansion Cohorts (Regimen D): MRD levels using central flow cytometry–based testing.
Dose Expansion Cohorts (Regimen D): MRD+ to MRD- conversion rate and relapse-free survival (RFS) in MRD+ Fit (Cohort D1) and MRD+ Unfit (Cohort D2) AML patients.
Dose Expansion Cohorts (Regimen D): MRD+ to MRD- conversion rate and relapse-free survival (RFS) in MRD+ Fit (Cohort D1) and MRD+ Unfit (Cohort D2) AML patients.
次要结局
- Regimen D: Treatment-emergent adverse events (TEAEs).
- Regimen D: ADA response.
- Regimens A-C: IMGN632 PK parameters for intact antibody-drug conjugate (ADC), total antibody, and free payload (FGN849) include, but are not limited to,Cycle 1 and Cycle 3 maximum plasma concentration (Cmax), area under the time concentration curve (AUC), terminal half-life (t½), clearance (CL), volume of distribution at steady state (Vss), and time that Cmax occurs (tmax).
- Regimens A-C: Blood concentration of azacitidine, venetoclax, and azacitidine + venetoclax measured before and after their administration.
- Regimens A-C : Treatment-emergent adverse events (TEAEs) (Expansion Cohort).
- Regimens A-C: ADA response
- Regimens A-C: MRD levels using central flow cytometry–based testing (Dose Escalation Phase).
- Regimen D: IMGN632 PK parameters for intact ADC, total antibody, and free payload (FGN849) include, but are not limited to, Cycle 1 and Cycle 3 maximum plasma concentration (Cmax), area under the time concentration curve (AUC), terminal half-life (t½), clearance (CL), volume of distribution at steady state (Vss), and time that Cmax occurs (tmax).
研究者
Global Clinial Trial Helpdesk
Scientific
AbbVie Deutschland GmbH & Co. KG
研究点 (10)
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