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

Sponsor

ImmunoGen, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04086264

Collaborator

Jazz Pharmaceuticals (Industry)

274

Enrollment

Locations

Arms

31.3

Anticipated Duration (Months)

13.7

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: Azacitidine Drug: IMGN632 Drug: Venetoclax	Phase 1/Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

274 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Nov 6, 2019

Anticipated Primary Completion Date :

Jun 16, 2022

Anticipated Study Completion Date :

Jun 16, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Regimen A IMGN632, administered intravenously on Day 7 of a 28 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 on Days 1 to 7 of a 28 day cycle. Cycle 1 azaciditine dose in subsequent cohorts may be reduced.	Drug: Azacitidine IMGN632 in combination with azacitidine Other Names: Vidaza Decitabine Drug: IMGN632 IMGN632 in combination with azacitidine Other Names: CD123-targeted ADC
Experimental: Regimen B IMGN632, administered intravenously on Day 7 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 Day 1, 200mg on Day 2, and 400 mg on the day 3 up to Day 21 of a 21 day cycle. Alternate schedules with reduced venetoclax administration may be explored.	Drug: IMGN632 IMGN632 in combination with azacitidine Other Names: CD123-targeted ADC Drug: Venetoclax IMGN632 in combination with venetoclax Other Names: Venclexta Venclyxto
Experimental: Regimen C IMGN632, administered intravenously on Day 7 of a 28 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 35-75 mg/m2 given for Days 1 to 7 of a 28 day cycle and venetoclax, administered orally daily at 100 mg on Day 1, 200mg on Day 2, and 400 mg on Day 3 up to Day 28 of a 28 day cycle. Alternate schedules with reduced venetoclax administration or reduced azacitidine dose or administration may be explored.	Drug: Azacitidine IMGN632 in combination with azacitidine Other Names: Vidaza Decitabine Drug: IMGN632 IMGN632 in combination with azacitidine Other Names: CD123-targeted ADC Drug: Venetoclax IMGN632 in combination with venetoclax Other Names: Venclexta Venclyxto
Experimental: Regimen D IMGN632, administered intravenously on Day 1 of a 21 day cycle at 0.045 mg/kg, as a monotherapy for Fit and Unfit MRD+ patients	Drug: IMGN632 IMGN632 in combination with azacitidine Other Names: CD123-targeted ADC

Outcome Measures

Primary Outcome Measures

Safety and Tolerability [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 or refractory CD123-positive 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 [approximately 20 months]
Assess preliminary antileukemia activity of IMGN632 when administered as a monotherapy in MRD+ Fit and MRD+ Unfit AML patient populations, 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 platelet recovery, morphologic leukemia-free state, partial response, and duration of remission
Minimal Residual Disease Levels [approximately 18 months]
Assess Minimal Residual Disease Levels using central flow cytometry-based testing

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 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 Regimens A (IMGN632 + azacitidine) and C (IMGN632 + azacitidine + venetoclax). No prior treatments with 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).
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.
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. 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 non-intensive treatment (eg, HMA, low dose cytarabine, etc.) are eligible for Regimen D Cohort D2.
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 ≤ 1. If nonambulatory due to a chronic disability, must be Karnofsky performance status > 70.
Previous treatment-related toxicities must have resolved to Grade 1 or baseline (excluding alopecia).
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.
Liver enzymes (AST and ALT) ≤ 3 × the upper limit of normal (ULN).
Total bilirubin ≤ 1.5 × the ULN within 14 days of enrollment.
Serum creatinine ≤ 1.5 mg/dL within 14 days of enrollment.
Echocardiogram or other modality 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 7 months 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 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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010
2	UC Irvine Medical Center	Orange	California	United States	92868
3	Moffitt Cancer Center	Tampa	Florida	United States	33612
4	Robert H. Lurie Comprehensive Cancer Center of Northwestern University	Chicago	Illinois	United States	60611
5	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
6	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
7	Roswell Park Comprehensive Cancer Center	Buffalo	New York	United States	14203
8	NewYork-Presbyterian - Weill Cornell	New York	New York	United States	10021
9	Duke University Health System	Durham	North Carolina	United States	27710
10	Cleveland Clinic	Cleveland	Ohio	United States	44195
11	MD Anderson	Houston	Texas	United States	77030
12	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
13	Centre Antoine Lacassagne	Nice		France	06100
14	University Hospital Leipzig	Leipzig		Germany	04103
15	University Hospital of Ulm	Ulm		Germany	89081
16	Istituto di Ematologia "Lorenzo e A. Seragnoli" - Policlinco S. Orsola - Malpighi	Bologna		Italy	40138
17	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST)	Meldola		Italy	47014
18	Azienda Ospedaliera Universitaria Maggiore Della Carita Novara	Novara		Italy	28100
19	MD Anderson Cancer Center Madrid, Spain	Madrid		Spain
20	Hospital Universitario y Politécnico de La Fe	Valencia		Spain	46026