A study to test IMGN632 in adults with CD123-positive Acute Myeloid Leukemia and other CD123 positive Hematologic cancers.

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

28 Feb 2019 → ongoing

Decision date (initial)

2024-07-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

ImmunoGen, Inc.

External identifiers

EU CT number

2024-514195-40-00

EudraCT number

2018-003210-40

ClinicalTrials.gov

NCT03386513

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

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

Dose Escalation and AML/ALL/Other Expansion Phase
• BPDCN Expansion phase:
• To assess the rate of CCR in frontline de novo BPDCN patients in Cohort 6: CR+clinical CR (CRc)
BPDCN Expansion phase:
• To assess the rate of CCR in frontline de novo BPDCN patients in Cohort 6: CR+clinical CR (CRc)

Secondary objectives 12

1. To characterize the safety profile and tolerability of IMGN632 when given as a single agent across dose levels and schedules [Dose Escalation and AML/ALL/Other Expansion Phase]
2. To characterize the PK of IMGN632, total antibody, and FGN849 (active catabolite) [Dose Escalation and AML/ALL/Other Expansion Phase]
3. To evaluate the potential immunogenicity of IMGN632 [Dose Escalation and AML/ALL/Other Expansion Phase]
4. To assess the antileukemia activity in AML , ALL, and other patients (tumor-specific expansion cohorts) [Dose Escalation and AML/ALL/Other Expansion Phase]
5. To assess the rate of CCR: CR+CRc [BPDCN Expansion phase]
6. To assess DOCR for patients with CR or CRc in frontline de novo BPDCN patients in Cohort 6: CR+CRc [BPDCN Expansion phase]
7. To assess the DOCR for relapsed/refractory and other frontline patients with CR or CRc in Cohorts 1 and 6 [BPDCN Expansion phase]
8. To characterize the safety profile and tolerability of IMGN632 when given as a single agent at RP2D [BPDCN Expansion phase]
9. To assess rate of CR+CRc+CRh [BPDCN Expansion phase]
10. To assess duration of CR+CRc+CRh [BPDCN Expansion phase]
11. To assess ORR: CR+CRc+CRh+CRi+PR [BPDCN Expansion phase]
12. To assess DOR [BPDCN Expansion phase]

Conditions and MedDRA coding

Acute Myeloid Leukemia and other blood cancers

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, European Medicines Agency

Plan to share IPD

Yes

IPD plan description

Access to anonymized, individual and trial-level data (analysis data sets), as well as other information as part of responsible clinical trial data sharing

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Disease Characteristics: a. Confirmation of CD123 positivity by flow cytometry or immunohistochemistry. Patients who received prior CD123-targeting agents will be allowed as long as the blasts still have detectable CD123 expression b. Dose Escalation – Relapsed or refractory AML (excluding acute promyelocytic leukemia) or BPDCN, based on World Health Organization Classification. c. Dose Expansion - Cohort 1 - Patients with relapsed or refractory BPDCN - Cohort 2 – Patients will have relapsed AML (closed to enrollment). - Cohort 3 – Patients will have relapsed or refractory ALL (including any subtypes: B-cell, T-cell, Ph+ and Ph-) (closed to enrollment). - Cohort 4 – Patients will have relapsed or refractory other hematologic malignancies not included in the cohorts above (e.g., high-risk/very high-risk MDS, MPN, CMML, BP-CML). Other CD123+ malignancies may be considered upon discussion with the Sponsor. Note: BP-CML is defined as ≥ 30% blasts in blood, marrow, or both and the demonstration of extramedullary infiltrates of leukemic cells. - Cohort 5 – Patients will have relapsed or refractory (to nonintense therapies) AML (closed to enrollment). - Cohort 6 – Patients with frontline de novo BPDCN at screening who have not received prior systemic therapy and patients with frontline BPDCN who have a PCHM and have not received prior systemic therapy. Note: Patients in Cohort 6 may have received local therapy (radiotherapy, surgical excision, photodynamic therapy). Eligible patients must have a recurrence or progression in the field of local therapy OR disease outside the field of local therapy. Patients identified as having concomitant malignancy while on trial will continue to be identified as de novo BPDCN patients.
2. Patients with a prior autologous or allogeneic bone marrow transplant are eligible for Cohorts 1 to 5. 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 acute graft versus host disease (GvHD), or extensive chronic GvHD of any severity, and must be off all immunosuppression for at least 2 weeks before first dose of IMGN632.
3. Patients or their legally authorized representative must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), before performance of any study-related procedure not part of normal medical care.
4. Women of childbearing potential WCBP patients/partners, defined as a sexually mature woman who has not undergone surgical sterilization or who has not been naturally postmenopausal for at least 12 consecutive months (ie, who has 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 study drug.
5. WCBP must have a negative pregnancy test before the first dose of study drug.
6. Male patients/partners who are able to father children must agree to use an effective method of contraception (eg, condoms), even if they have had a successful vasectomy, throughout the study and for at least 4 months after the last dose of IMGN632.
7. Patients with prior malignancy are eligible. Patient with a PCHM are eligible as long as no current therapy is required for the second malignancy (eg, MDS, CMML). Patients with a nonhematologic prior malignancy must be in remission from the prior malignancy and have completed all chemotherapy and radiotherapy for prior malignancy at least 6 months prior to enrollment and all treatment-related toxicities must have resolved to Grade 1 or less. Note: Patients with prostate cancer or breast cancer on adjuvant hormonal therapy are eligible. 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
8. Patients in the BPDCN Expansion Phase Cohort 1 may have received up to 3 prior lines of systemic therapy (regardless of tagraxofusp-erzs exposure).
9. Age ≥ 18 years of age.
10. ECOG performance status ≤ 1. If nonambulatory due to a chronic disability, must be Karnofsky performance status > 70.
11. Previous treatment related toxicities must be resolved to Grade 1 (excluding alopecia).
12. Liver enzymes (aspartate aminotransferase and alanine aminotransferase) ≤ 2.5 × the upper limit of normal (ULN). Exceptions may be made for patients with elevated liver transaminases secondary to the underlying study disease.
13. Total bilirubin ≤ 1.5 × ULN; patients with Gilbert syndrome must have total bilirubin < 3.0 × ULN with direct bilirubin < 1.0 × ULN at the time of enrollment.
14. Estimated glomerular filtration rate of > 30 mL/min/1.73m2 or creatinine clearance of > 30 mL/min.
15. Left ventricular ejection fraction ≥ 45%.
16. Patients must not be incarcerated and must be freely willing and able to provide informed consent. Examples of patients unable to freely provide informed consent may include some adults under legal protection measure (eg, under guardianship/curatorship) or unable to express their consent and select adults under psychiatric care. Investigator’s discretion should be applied.

Exclusion criteria 13

1. Patients who, in the judgment of their treating physician, have appropriate standard of care therapies will be excluded from Cohorts 1 through 5.
2. Frontline BPDCN patients with CNS disease will be excluded. A lumbar puncture must be performed during the 28-day Screening period, before drug administration. Relapsed or refractory BPDCN patients with a known history of CNS disease must have been treated locally, have at least 1 lumbar puncture with no evidence of CNS disease, and must be clinically stable before first dose. Concurrent therapy for CNS prophylaxis or continuation of therapy for controlled CNS disease is encouraged (see Section 5.2.4.1).
3. Patients with a history of veno-occlusive disease of the liver.
4. Patients with a history of Grade 4 capillary leak syndrome, or noncardiac Grade 4 edema are ineligible, e.g., related to tagraxofusperzs or other etiology.
5. Corrected QT interval (QT interval corrected using Fridericia's) > 480 msec.
6. Myocardial infarction within 6 months before enrollment or has 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. Interval from prior cancer therapy: a. For frontline BPDCN patients with prior local therapy (eg, radiotherapy), patients must not have received treatment within 14 days before drug administration on this study. b. Relapsed or refractory BPDCN patients must not have received any anticancer therapy including chemotherapy, immunotherapy, radiotherapy, hormonal, biologic, or any investigational agents within 14 days prior to drug administration on this study. Patients must have recovered to baseline from all acute toxicity from this prior therapy. Note: Patients who have received a checkpoint inhibitor must not have received that therapy within 28 days before drug administration on this study.
8. Clinically relevant active infection including known active hepatitis B or C, human immunodeficiency virus 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).
9. Patients who have undergone a major surgery within 4 weeks (or longer if not fully recovered) before study enrollment.
10. 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.
11. Patients who are pregnant or breast-feeding.
12. Patients who have a history of allergy to IMGN632 or any of its excipients.
13. Patients who received a live vaccine four weeks or fewer prior to enrollment

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Escalation Phase: MTD and RP2D
2. BPDCN: CR+clinical CR [CRc]

Secondary endpoints 7

1. Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and DLTs
2. PK parameters, including but not limited to observed maximum concentration (Cmax) and area under the concentration versus time curve (AUC)
3. To evaluate the potential immunogenecity of IMGN632 - ADA
4. Overall response rate (OOR) (CR without minimal residual disease [CRMRD- ] + CR + complete remission with partial hematologic recovery [CRh] + complete remission with incomplete recovery [CRi] + morphologic leukemia-free state [MLFS] + partial response [PR]), complete remission rate (CRMRD-, CR, CRh), composite complete remission (CCR) rate (CRMRD-, CR, CRh, CRi), and time to event outcomes (duration of overall response [DOR], event-free survival, relapse-free survival, OS).
5. BPDCN Expansion Phase (Cohorts 1 and 6): CR+CRc
6. BPDCN Expansion Phase (Cohorts 1 and 6): ADA
7. BPDCN Expansion Phase (Cohorts 1 and 6): Conversion rate to independence of red blood cell and platelet transfusion relative to baseline

Investigational products

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

Test 1

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 7

Locations

2 EU/EEA countries · 3 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 17 files

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

Application history

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