A study of IMGN632 alone or in combination with Venetoclax and/or Azacitidine for Patients with CD123-Positive Acute Myeloid Leukemia

Phase 1

Conditions: CD123 positive Acute Myeloid Leukemia
MedDRA version: 20.0Level: SOCClassification code 10029104Term: Neoplasms benign, malignant and unspecified (incl cysts and polyps)System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2019-002477-56-GB

Lead Sponsor: ImmunoGen, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 274

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.
3. 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 A (IMGN632 + azacitidine) and C (Triplet) (IMGN632 + azacitidine + venetoclax) in separate cohorts. No prior treatments with hypomethylating agents (HMAs) for MDS are allowed.
Note: Patients who are MRD+ following frontline treatment are eligible for the Regimen D Cohorts D1 and D2 (Expansion Phase).
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.
Note: Patients may also 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/CRh/CRp/CRi) for no more than 6 months and be MRD+ at the time of screening, confirmed
by central laboratory testing, after induction/consolidation therapy (which may include stem cell transplant).
Note: Fit patients who previously received intensive treatment (eg 3+7, HiDAC, etc.) are eligible for Regimen D Cohort D1. Unfit patients who previously received nonintensive treatment (eg, HMA, low dose cytarabine, etc.) are eligible for Regimen D Cohort D2.
4. Eastern Cooperative Oncology Group performance status = 1. If nonambulatory due to a chronic disability, must be Karnofsky
performance status > 70.
5. Previous treatment-related toxicities must have resolved to Grade 1 or baseline (excluding alopecia).
6. Total white blood cell 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 1.
7. Liver enzymes (AST and ALT) = 3 × the upper limit of normal (ULN).
8. Total bilirubin = 1.5 × the ULN within 14 days of enrollment.
9. Serum creatinine = 1.5 mg/dL within 14 days of enrollment.
10. Left ventricular ejection fraction (LVEF) = 45% based on locally available assessment, eg, ECHO or other modality.
11. 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 potent systemic immunosuppression for at least 2 weeks
before dosing.
12. Voluntary written informed consent before performan

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.
10. Women who are pregnant or breastfeeding.
11. Prior known hypersensitivity reactions to monoclonal antibodies (=Grade 3).
12. Prior known hypersensitivity reactions to study drugs and/or any of their excipients.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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