IMGN632 as Monotherapy or With Venetoclax and/or Azacitidine for Patients With CD123-Positive Acute Myeloid Leukemia

Overview

This is an open-label, multicenter, Phase 1b/2 study to determine the safety and tolerability of IMGN632 and assess the antileukemia activity of IMGN632 when administered in combination with azacitidine and/or venetoclax in patients with relapsed and frontline CD123-positive AML, and antileukemia activity of IMGN632 when administered as monotherapy in patients with MRD+ AML after frontline treatment.

Full Title of Study: “A Phase 1b/2 Study of IMGN632 as Monotherapy or Combination With Venetoclax and/or Azacitidine for Patients With CD123-Positive Acute Myeloid Leukemia”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: June 16, 2022

Detailed Description

This is an open-label, multicenter, Phase 1b/2 study to determine the safety and tolerability of IMGN632 and assess the antileukemia activity of IMGN632 when administered in combination with azacitidine and/or venetoclax in patients with relapsed and frontline CD123-positive AML, and antileukemia activity of IMGN632 when administered as monotherapy in patients with MRD+ AML after frontline treatment.

This study explores multiple IMGN632 doses in combination and monotherapy Regimens, including (A) azacitidine, (B) venetoclax, (C) azacitidine+venetoclax, and (D) monotherapy in MRD+ AML. For combination Regimens A-C, a Phase 1b Dose Escalation Cohort will determine the recommended Phase 2 dose (RP2D) of IMGN632 in that specific combination Regimen, followed by a Phase 2 Dose Expansion Cohort for each combination Regimen to further characterize the safety profile and assess the antileukemia activity of the different combination Regimens. Regimen D will open with a Dose Expansion Cohort using the IMGN632 monotherapy dose and schedule based on safety data from the initial Phase 2 study (IMGN632-0801) and will not have a Dose Escalation Phase.

Interventions

  • Drug: Azacitidine
    • IMGN632 in combination with azacitidine
  • Drug: IMGN632
    • IMGN632 in combination with azacitidine
  • Drug: Venetoclax
    • IMGN632 in combination with venetoclax

Arms, Groups and Cohorts

  • Experimental: Regimen A
    • IMGN632, administered intravenously on the first day of a 21 day cycle at 0.015 mg/kg, 0.045 mg/kg, or 0.09 mg/kg, in combination with azacitidine, administered subcutaneously or intravenously daily at 75 mg/m2 given for 7 days over a 28 day cycle
  • Experimental: Regimen B
    • IMGN632, administered intravenously on the first day of a 21 day cycle at 0.015 mg/kg, 0.045 mg/kg, or 0.09 mg/kg, in combination with venetoclax, administered orally daily at 100 mg on the first day, 200mg on the second day, and 400 mg on the third day through the 21st day of a 21 day cycle
  • Experimental: Regimen C
    • IMGN632, administered intravenously on the first day of a 21 day cycle at 0.015 mg/kg, 0.045 mg/kg, or 0.09 mg/kg, in combination with azacitidine, administered subcutaneously or intravenously daily at 75 mg/m2 given for 7 days over a 28 day cycle and venetoclax, administered orally daily at 100 mg on the first day, 200mg on the second day, and 400 mg on the third day through the 28th day of a 28 day cycle
  • Experimental: Regimen D
    • IMGN632, administered intravenously on the first day of a 21 day cycle at 0.045 mg/kg, as a monotherapy for MRD+ patients

Clinical Trial Outcome Measures

Primary Measures

  • Safety and Tolerability
    • Time Frame: approximately 7 months
    • Evaluate the safety and tolerability and identify an RP2D of IMGN632 when administered in combination with azacitidine, with venetoclax, and with azacitidine and venetoclax, in patients with relapsed AML through review of Treatment Emergent Adverse Events and abnormal laboratory values that result in a failure to meet the criteria for re-treatment
  • Preliminary antileukeumia activity
    • Time Frame: approximately 20 months
    • Assess preliminary antileukemia activity of IMGN632 when administered as a monotherapy and in combination with azacitidine, with venetoclax, and with azacitidine and venetoclax in patients with relapsed or untreated AML as assessed by complete response, complete remission with partial hematologic recovery, complete remission with incomplete recovery, morphologic leukemia-free state, partial response, and duration of response
  • Minimal Residual Disease Levels
    • Time Frame: approximately 18 months
    • Assess Minimal Residual Disease Levels using central flow cytometry-based testing

Participating in This Clinical Trial

Patient Inclusion Criteria

1. Patient must be ≥ 18 years of age.

2. Patients must have confirmed diagnosis of AML (excluding acute promyelocytic leukemia) based on World Health Organization classification (Arber 2016).

3. Disease characteristics and allowable prior therapy:

1. Patients must be evaluated for any available standard of care therapies and, in the opinion of the treating physician, be deemed appropriate for this experimental therapy.

2. Treatment-naïve (untreated) patients will be allowed in the Expansion Phase for Regimens A (IMGN632 + azacitidine) and C (IMGN632 + azacitidine + venetoclax). No prior treatments with HMAs for MDS are allowed.

3. Patients must have CD123-positive AML as confirmed by local flow cytometry (or immunohistochemistry [IHC]).

4. Patients may have received prior CD123-targeted therapies, except IMGN632, as long as CD123 remains detectable during screening.

5. Relapsed AML patients will be allowed to enroll in the Escalation Phase of Regimens A, B, and C (IMGN632 + azacitidine, venetoclax, or azacitidine + venetoclax, respectively) and the Expansion Phase of Regimens A and B and may have received up to 2 prior lines of therapy, eg, frontline treatment (induction, consolidation [including transplant], and maintenance) and 1 salvage regimen.

6. Patients enrolling in Regimen D must be in CR (CR/CRi) for no more than 6 months and be MRD+, confirmed by central laboratory testing, after intensive induction/consolidation therapy.

4. Patients enrolling on Regimen D (MRD+ AML), must first have an evaluable screening bone marrow sample confirmed as MRD+ by central flow testing of MRD.

5. Eastern Cooperative Oncology Group performance status ≤ 1. If nonambulatory due to a chronic disability, must be Karnofsky performance status > 70.

6. Previous treatment-related toxicities must have resolved to Grade 1 or baseline (excluding alopecia).

7. Total white blood cell count must be less than 25 x 10^9 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 1.

8. Liver enzymes (AST and ALT) ≤ 3 × the upper limit of normal (ULN).

9. Total bilirubin ≤ 1.5 × the ULN within 14 days of enrollment.

10. Serum creatinine ≤ 1.5 mg/dL within 14 days of enrollment.

11. Echocardiogram or multigated acquisition scan (MUGA) demonstrating an ejection fraction ≥ 45%.

12. Patients with prior autologous and 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, and the patient must be off all systemic immunosuppression for at least 2 weeks before dosing.

13. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care.

14. Women of childbearing potential (WCBP), defined as sexually mature women who have not undergone surgical sterilization or who have not been naturally postmenopausal for at least 12 consecutive months (ie, who have had menses any time in the preceding 12 consecutive months), must agree to use highly effective contraceptive methods (examples include oral, parenteral, or implantable hormonal contraceptive, intrauterine device, barrier contraceptive with spermicide, partner's latex condom or vasectomy) while on study drug and for at least 12 weeks after the last dose of study drug.

15. WCBP must have a negative pregnancy test within 3 days before the first dose of study drug.

16. A male patient must agree to use a latex condom even if he has had a successful vasectomy and must continue to follow these requirements for at least 12 weeks after the last dose of study drug.

17. Patients with prior malignancy are eligible; however, the patient must be in remission from the prior malignancy and have completed all chemotherapy and radiotherapy for the prior malignancy at least 6 months before enrollment, and all treatment-related toxicities must have resolved to Grade 1 or less.

Patient Exclusion Criteria

1. 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.

2. Patients who have been previously treated with IMGN632.

3. Patients with myeloproliferative neoplasm-related secondary AML are excluded from the Dose Expansion Phase of the study.

4. 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.

5. Patients with a history of sinusoidal obstruction syndrome/venous occlusive disease of the liver.

6. 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.

7. 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).

8. Patients who have undergone a major surgery within 4 weeks (or longer if not fully recovered) before study enrollment.

9. 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.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 120 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • ImmunoGen, Inc.
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Patrick Zweidler-McKay, PhD MD, Study Director, ImmunoGen, Inc.
  • Overall Contact(s)
    • Patrick Zweidler-McKay, PhD MD, 781-895-0600, IMGN0802@immunogen.com

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