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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AbbVie Deutschland GmbH & Co. KG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Jan 2020 → ongoing

Decision date (initial)

2024-09-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

ImmunoGen, Inc.

External identifiers

EU CT number

2024-514197-50-00

EudraCT number

2019-002477-56

ClinicalTrials.gov

NCT04086264

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Pharmacogenomic, Pharmacokinetic, Safety, Dose response

IMGN632 in Combination with Azacitidine and/or Venetoclax (Regimens A-C)
1. Dose Escalation Cohorts:
Evaluate the safety and tolerability and identify a recommended Phase 2 dose (RP2D) of IMGN632 when administered in combination with azacitidine (Regimen A) or venetoclax (Regimen B) or azacitidine + venetoclax (Regimen C) in patients with relapsed or refractory CD123-positive AML.

2. Dose Expansion Cohorts:
- Assess preliminary antileukemia activity of IMGN632 when administered in combination with azacitidine (Regimen A) or venetoclax (Regimen B), azacitidine+venetoclax (Regimen C) in patients with eitherrelapsed or untreated AML
- Assess MRD levels.

IMGN632 Monotherapy in MRD+ Fit and Unfit AML (Regimen D Cohorts D1 and D2)
- Regimen D (Cohorts D1 and D2): Assess preliminary antileukemia activity of IMGN632 as monotherapy in MRD+ Fit (Cohort D1) and MRD+ Unfit AML (Cohort D2) patient populations
- Assess MRD levels.

Secondary objectives 4

1. Evaluate the safety and tolerability of IMGN632 when administered in combination with azacitidine (Regimen A) or venetoclax (Regimen B) or azacitidine + venetoclax Regimen C) in patients with AML (Dose Expansion Phase) [All Dose Escalation and Dose Expansion Cohorts (Regimens A-C)]
2. Characterize the pharmacokinetics (PK) of IMGN632 when used in combination with azacitidine and/or venetoclax [All Dose Escalation and Dose Expansion Cohorts (Regimens A-C)]
3. Evaluate the safety and tolerability of IMGN632 as monotherapy in MRD+ Fit (Cohort D1) and MRD+ Unfit (Cohort D2) AML patients [Regimen D (Cohorts D1 and D2)]
4. Evaluate other potential predictive and/or prognostic biomarkers including protein analysis, gene expression profiling, and genomic analysis of relevant genes involved in the mechanism of action of study drugs, or in hematologic malignancies (Regimens A-C only) for the complete list of the Secondary [Exploratory: Dose Escalation, Dose Expansion, and Monotherapy Cohorts (Regimens A-D)]

Conditions and MedDRA coding

CD123 positive Acute Myeloid Leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

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 C (Triplet) (IMGN632 + azacitidine + venetoclax). No prior treatments with hypomethylating agents (HMAs) for MDS are allowed. 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. f. 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.
4. Eastern Cooperative Oncology Group performance status ≤ 1. If non ambulatory 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 WBC 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; patients with Gilbert syndrome must have total bilirubin ≤ 3.0 × ULN with direct bilirubin < 1.0 × ULN at the time of enrollment. Note: Subjects who are < 75 years of age may have a bilirubin of ≤ 3.0 x ULN
9. An estimated glomerular filtration rate (eGFR) of > 30 mL/min/1.73m2 or creatinine clearance of > 30 mL/min.
10. Left ventricular ejection fraction (LVEF) ≥ 45% based on locally available assessment, eg, echocardiogram or other modality. Note: This inclusion criterion does not apply to patients enrolling in cohorts C1 and/or C2 as unfit.
11. 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.
12. Patients with prior malignancy are eligible; however, 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.
13. Patients in expansion Cohorts C1 and C2 must be considered ineligible for intensive induction therapy defined by the following: a. ≥ 75 years of age OR b. < 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
14. 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.

Exclusion criteria 13

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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 8

1. Dose Escalation (Regimens A-C): RP2D of IMGN632 when administered in combination with azacitidine (Regimen A) or venetoclax (Regimen B) or azacitidine + venetoclax (Regimen C).
2. Dose Escalation (Regimens A-C): Treatment-emergent adverse events (TEAEs), laboratory test results, physical examination, and vital signs.
3. Dose Expansion Cohorts (Regimens A-C): Composite CR rate (CRMRD-, CR, CRh, CRp, CRi).
4. Dose Expansion Cohorts (Regimens A-C): Overall response rate (ORR) (CRMRD-, CR, CRh, CRp, CRi, MLFS, PR).
5. Dose Expansion Cohorts (Regimens A-C): Duration of remission (DOR).
6. Dose Expansion Cohorts (Regimens A-C): MRD levels using central flow cytometry–based testing.
7. Dose Expansion Cohorts (Regimen D): MRD+ to MRD- conversion rate and relapse-free survival (RFS) in MRD+ Fit (Cohort D1) and MRD+ Unfit (Cohort D2) AML patients.
8. Dose Expansion Cohorts (Regimen D): MRD levels using central flow cytometry–based testing.

Secondary endpoints 8

1. Regimens A-C : Treatment-emergent adverse events (TEAEs) (Expansion Cohort).
2. Regimens A-C: IMGN632 PK parameters for intact antibody-drug conjugate (ADC), total antibody, and free payload (FGN849) include, but are not limited to,Cycle 1 and Cycle 3 maximum plasma concentration (Cmax), area under the time concentration curve (AUC), terminal half-life (t½), clearance (CL), volume of distribution at steady state (Vss), and time that Cmax occurs (tmax).
3. Regimens A-C: Blood concentration of azacitidine, venetoclax, and azacitidine + venetoclax measured before and after their administration.
4. Regimens A-C: ADA response
5. Regimens A-C: MRD levels using central flow cytometry–based testing (Dose Escalation Phase).
6. Regimen D: Treatment-emergent adverse events (TEAEs).
7. Regimen D: IMGN632 PK parameters for intact ADC, total antibody, and free payload (FGN849) include, but are not limited to, Cycle 1 and Cycle 3 maximum plasma concentration (Cmax), area under the time concentration curve (AUC), terminal half-life (t½), clearance (CL), volume of distribution at steady state (Vss), and time that Cmax occurs (tmax).
8. Regimen D: ADA response.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AbbVie Deutschland GmbH & Co. KG

Sponsor organisation

AbbVie Deutschland GmbH & Co. KG

Address

Knollstrasse

City

Ludwigshafen Am Rhein

Postcode

67061

Country

Germany

Scientific contact point

Organisation

AbbVie Deutschland GmbH & Co. KG

Contact name

Global Clinial Trial Helpdesk

Public contact point

Organisation

AbbVie Deutschland GmbH & Co. KG

Contact name

Global Clinial Trial Helpdesk

Third parties 10

Locations

4 EU/EEA countries · 10 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 23 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications