Clinical Trials /

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

NCT04086264

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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: IMGN632-0802
  • NCT ID: NCT04086264

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
AzacitidineVidaza, DecitabineRegimen A
IMGN632CD123-targeted ADCRegimen A
VenetoclaxVenclexta, VenclyxtoRegimen B

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Regimen AExperimentalIMGN632, 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
  • Azacitidine
  • IMGN632
Regimen BExperimentalIMGN632, 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
  • IMGN632
  • Venetoclax
Regimen CExperimentalIMGN632, 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
  • Azacitidine
  • IMGN632
  • Venetoclax
Regimen DExperimentalIMGN632, administered intravenously on the first day of a 21 day cycle at 0.045 mg/kg, as a monotherapy for MRD+ patients
  • IMGN632

Eligibility Criteria

        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.
      
Maximum Eligible Age:120 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety and Tolerability
Time Frame:approximately 7 months
Safety Issue:
Description: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

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:ImmunoGen, Inc.

Trial Keywords

  • Acute Myeloid Leukemia
  • AML
  • Minimal detectable disease
  • MRD
  • CD123
  • Relapsed/refractory

Last Updated

November 20, 2019