A Phase 1b/2 Study of IMGN632 as Monotherapy or Combination with Venetoclax and/or Azacitidine for Patients with CD123-Positive Acute Myeloid Leukemia

ENROLLING
Protocol # :
19-606
Conditions
Acute Myeloid Leukemia
Phase
I/II
Disease Sites
Myeloid and Monocytic Leukemia
Principal Investigator
DeAngelo, Daniel, J
Site Investigator
McMasters, Malgorzata
Mendez, Lourdes
Site Research Nurses
Tichon, Jennifer

Trial 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 participants with relapsed and frontline CD123-positive
AML.

Eligibility Requirements

Patient Inclusion Criteria

- Patient must be ≥ 18 years of age.

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

- Disease characteristics and allowable prior therapy:

- 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.

- Treatment-naïve (untreated) patients will be allowed in the Expansion Phase for
Regimen C (Triplet) (IMGN632 + azacitidine + venetoclax). No prior treatments
with hypomethylating agents (HMAs) for MDS are allowed.

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

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

- 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.

- 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. Note: Fit patients who received intensive treatment
(eg 3+7, HiDAC) are eligible for Regimen D Cohort D1. Unfit patients who received
non-intensive treatment (eg, HMA, low dose cytarabine) are eligible for Regimen D
Cohort D2.

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

- For patients enrolling in Regimens A-D, total WBC count must < 25 × 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.

- 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.

- An estimated glomerular filtration rate (eGFR) of > 30 mL/min/1.73 m2 or creatinine
clearance of > 30 mL/min.

- Left ventricular ejection fraction (LVEF) ≥ 45% for patients enrolling in Regimens A-D
based on locally available assessment, eg, echocardiogram or other modality.

- 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 IMGN632.

- 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 acceptable contraceptive methods while on study
drug and for at least 7 months after the last dose of IMGN632.

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

- Male patients who are able to father children must agree to use acceptable methods of
contraception throughout the study and for at least 4 months after the last dose of
study drug(s).

- Patients with prior malignancy are eligible; however, the 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. Note: patients with tumors with a negligible risk for
metastasis or death (eg, adequately controlled basal cell carcinoma or squamous cell
carcinoma of the skin, or carcinoma in situ of the cervix or breast) are eligible.

- Patients in expansion Cohorts C1 and C2 must be considered ineligible for intensive
induction therapy defined by the following:

- ≥ 75 years of age OR

- < 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.

Patient 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 any of their excipients.

- Patients who have a history of allergy to IMGN632 (or any of its excipients),
azacitidine, or venetoclax.

19-606