Clinical Trial 20287

• Overview

  Study 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

  Summary:

  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.

  Objective:

  2.1.1. Dose Escalation Cohorts- Regimen A (IMGN632 + azacitidine)Evaluate the safety and tolerability and identify an RP2D of IMGN632 when administered in combination with azacitidine in patients with relapsed AML Regimen B (IMGN632 + venetoclax) Evaluate the safety and tolerability and identify an RP2D of IMGN632 when administered in combination with venetoclax in patients with relapsed AML Regimen C (IMGN632 + azacitidine + venetoclax) Evaluate the safety and tolerability and identify an RP2D of IMGN632 when administered in combination with azacitidine and venetoclax in patients with relapsed AML 2.1.2. Dose Expansion Cohorts Regimen A (IMGN632 + azacitidine) Assess preliminary antileukemia activity of IMGN632 when administered in combination with azacitidine in patients with either relapsed or untreated AML Assess MRD levels Regimen B (IMGN632 + venetoclax) Assess preliminary antileukemia activity of IMGN632 when administered in combination with venetoclax in patients with relapsed AML Assess MRD levels Regimen C (IMGN632 + azacitidine + venetoclax) Assess preliminary antileukemia activity of IMGN632 when administered in combination with azacitidine and venetoclax in patients with untreated AML Assess MRD levels Regimen D (IMGN632 monotherapy in MRD+ maintenance) Assess preliminary antileukemia activity of IMGN632 when administered as monotherapy in patients with MRD+ AML after frontline therapy

• Treatments

  Therapies:

  Chemotherapy (NOS); Immunotherapy; Therapy (NOS)

  Medications:

  GDC-0199 (Venetoclax); IMGN632 (); Venetoclax (); azacitidine (5-azacitidine)

• Inclusion Criteria

  • Patient must be 18 years of age or older
  • Patients must have confirmed diagnosis of AML (excluding acute promyelocytic leukemia) based on WHO 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 transplat) 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 Regimen C (Triplet) (IMGN632 + azacitidine + venetoclax) in separate cohorts. No prior treatments with HMAs for MDS are allowed. (c) Patients may have received prior CD123-targeted therapies, except IMGN632, as long as CD123 remains detectable during screening. (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 patinets will be allowed to enroll 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. (f) Patients enrolling in Regimen D must be in CR (CR/CRi) and be MRD+, confirmed by central laboratory testing.
  • 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.
  • Eastern Cooperative Oncology Group performance status 70.
  • Previous treatment-related toxicities must have resolved to Grade 1 or baseline (excluding alopecia).
  • Lab values outlined per protocol.
  • Echocardiogram or multigated acquisition scan (MUGA) demonstrating an ejection fraction ≥ 45%.
  • 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.
  • Voluntary written informed consent before performance of any study-related procedure not part of normal medical care.
  • 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.
  • WCBP must have a negative pregnancy test within 3 days before the first dose of study drug.
  • 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.
  • Patients with prior malignancy are eligible; however, the patient must be in remission from 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

• Exclusion Criteria

  • 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.
  • Patients who have been previously treated with IMGN632.
  • 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/venous 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.
  • Women who are pregnant or breastfeeding
  • Prior known hypersensitivity reactions to monoclonal antibodies (>/= Grade 3)
  • Prior known hypersensitivity reactions to study drugs and/or their excipients.
  • Patients who have a history of allergy to IMGN632 (or any of its excipients), azacitidine, or venetoclax.
  • Other exclusions may apply

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