A Study of the Drug IMGN632 in Children With Leukemia That Has Come Back After Treatment or is Difficult to Treat

NCT05320380 | Withdrawn Phase 1 FDA Drug

• 3 other identifiers: APAL2020BNCI-2022-02157U10CA180886
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This phase I/II trial finds the highest safe dose of IMGN632 that can be given with other chemotherapy without causing severe side effects, studies what kind of side effects IMGN632 may cause, and determines whether IMGN632 is a beneficial treatment for leukemia in children that has come back after treatment or is difficult to treat. IMGN632 is a monoclonal antibody linked to a chemotherapy drug. IMGN632 is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as CD123 receptors, and delivers the chemotherapy drug to kill them. Giving IMGN632 with other chemotherapy may cause the leukemia to stop growing or to shrink for a period of time.

Conditions

Recurrent Acute Myeloid Leukemia; Recurrent B Acute Lymphoblastic Leukemia; Recurrent Mixed Phenotype Acute Leukemia; Recurrent T Acute Lymphoblastic Leukemia; Refractory Acute Myeloid Leukemia; Refractory B Acute Lymphoblastic Leukemia; Refractory Mixed Phenotype Acute Leukemia; Refractory T Acute Lymphoblastic Leukemia

Outcome Measures

Primary Outcomes (4)

• Recommended phase 2 dose (RP2D) of IMGN632 monotherapy (Cohort 1)

  Dose limiting toxicities (DLTs) during cycle 1 will be evaluated using a rolling 6 design.

  During cycle 1 (Each cycle = 42 days)

• Flow-based overall response rate (ORR) (Cohort 1)

  ORR defined as complete remission (CR)/CR with incomplete blood count recovery (CRi)/CR with partial recovery of platelet count (CRp).

  During cycle 1 (Each cycle = 42 days)

• RP2D of combination therapy (Cohort 2)

  Dose limiting toxicities (DLTs) during cycle 1 combination of DAUNOrubicin and cytarabine liposome and IMGN632 will be evaluated using a rolling 6 design.

  During cycle 1 (Each cycle = 42 days)

• Minimal residual disease (MRD) negative flow-based ORR (Cohort 3)

  Eligible patients will be assessed for MRD negative responses at the end of each cycle of therapy and compared for those receiving therapy including DAUNOrubicin and cytarabine liposome with or without IMGN632. Responders versus non-responders will be classified based on response after up to 2 cycles with a response definition of \< 0.01% abnormal blasts by central flow cytometry in a cellular bone marrow. Fisher's Exact test will be used to compare the MRD negative response rate after up to 2 cycles (DAUNOrubicin and cytarabine liposome treatment) followed by fludarabine/cytarabine in pediatric patients with first relapse of acute myeloid leukemia randomized to treatment with or without IMGN632.

  Up to two cycles of IMGN632 with chemotherapy (Each cycle = 42 days)

Secondary Outcomes (6)

• Area under the plasma concentration versus time curve (AUC) of IMGN632

  Cycles 1 & 2

• Maximum serum concentration (Cmax) of IMGN632

  Cycles 1 & 2

• Volume of distribution at steady state (Vss) of IMGN632

  Cycles 1 & 2

• Half-life (t1/2) of IMGN632

  Cycles 1 & 2

• Clearance (CL) of IMGN632

  Cycles 1 & 2

Other Outcomes (12)

• Morphologic and flow-based CR/CRp/CRi of IMGN632 monotherapy (Cohort 1)

  Up to 2 cycles (Each cycle = 42 days)

• Rates of MRD negative response of IMGN632 monotherapy (Cohort 1)

  Up to 2 cycles (Each cycle = 42 days)

• Event-free survival (EFS) of IMGN632 monotherapy (Cohort 1)

  Up to 5 years

Study Arms (4)

Cohort 1 (IMGN632)

EXPERIMENTAL

Patients receive IMGN632 IV on days 1 and 22. Treatment repeats every 42 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Drug: Anti-CD123 ADC IMGN632

Cohort 2 (IMGN632, CPX-351, ITT, fludarabine, cytarabine)

EXPERIMENTAL

CYCLE 1: Patients receive IMGN632 IV on days 1 and 22 and CPX-351 IV over 90 minutes on days 1, 3, and 5 in the absence of disease progression or unacceptable toxicity. Patients with CNS1 also receive ITT consisting of methotrexate IT, hydrocortisone or prednisolone IT, and cytarabine IT on day 0 of cycle 1 (NOTE: Patients who received IT cytarabine or ITT at time of diagnostic LP do not need to repeat ITT on day 0 if given within 7 days of starting protocol therapy). Patients with CNS2 receive ITT QW until the CSF is clear for a maximum of 6 ITT treatments in the absence of disease progression or unacceptable toxicity. CYCLE 2: Patients receive ITT on day 0, IMGN632 IV on days 1 and 22, fludarabine IV over 30 minutes QD on days 1-5, and cytarabine IV over 1-3 hours QD on days 1-5 in the absence of disease progression or unacceptable toxicity.

Drug: Anti-CD123 ADC IMGN632; Procedure: Bone Marrow Aspiration and Biopsy; Drug: Cytarabine; Drug: Fludarabine Phosphate; Drug: Hydrocortisone Sodium Succinate; Drug: Liposome-encapsulated Daunorubicin-Cytarabine; Drug: Methotrexate; Drug: Prednisolone

Cohort 3, Arm A (CPX-351, fludarabine, cytarabine)

ACTIVE COMPARATOR

Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5 of cycle 1 in the absence of disease progression or unacceptable toxicity. Patients then receive fludarabine IV over 30 minutes QD on days 1-5 of cycle 2 and cytarabine IV over 1-3 hours QD on days 1-5 of cycle 2 in the absence of disease progression or unacceptable toxicity.

Drug: Cytarabine; Drug: Fludarabine Phosphate; Drug: Liposome-encapsulated Daunorubicin-Cytarabine

Cohort 3, Arm B (CPX-351, fludarabine, cytarabine, IMGN632)

EXPERIMENTAL

Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5 of cycle 1 and IMGN632 IV on days 1 and 22 of cycle 1 in the absence of disease progression or unacceptable toxicity. Patients then receive fludarabine IV over 30 minutes QD on days 1-5 of cycle 2, cytarabine IV over 1-3 hours QD on days 1-5 of cycle 2, and IMGN632 IV on days 1 and 22 of cycle 2 in the absence of disease progression or unacceptable toxicity.

Drug: Anti-CD123 ADC IMGN632; Procedure: Bone Marrow Aspiration and Biopsy; Drug: Cytarabine; Drug: Fludarabine Phosphate; Drug: Liposome-encapsulated Daunorubicin-Cytarabine

Interventions

Anti-CD123 ADC IMGN632 DRUG

Given IV

Cohort 1 (IMGN632); Cohort 2 (IMGN632, CPX-351, ITT, fludarabine, cytarabine); Cohort 3, Arm B (CPX-351, fludarabine, cytarabine, IMGN632)

Bone Marrow Aspiration and Biopsy PROCEDURE

Undergo bone marrow aspiration/biopsy

Cohort 2 (IMGN632, CPX-351, ITT, fludarabine, cytarabine); Cohort 3, Arm B (CPX-351, fludarabine, cytarabine, IMGN632)

Cytarabine DRUG

Given IT and IV

Also known as: .beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-Cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453

Cohort 2 (IMGN632, CPX-351, ITT, fludarabine, cytarabine); Cohort 3, Arm A (CPX-351, fludarabine, cytarabine); Cohort 3, Arm B (CPX-351, fludarabine, cytarabine, IMGN632)

Fludarabine Phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586

Cohort 2 (IMGN632, CPX-351, ITT, fludarabine, cytarabine); Cohort 3, Arm A (CPX-351, fludarabine, cytarabine); Cohort 3, Arm B (CPX-351, fludarabine, cytarabine, IMGN632)

Hydrocortisone Sodium Succinate DRUG

Given IT

Also known as: (11beta)-21-(3-Carboxy-1-oxopropyl)-11,17-dihydroxypregn-4-ene-3,20-dione, Monosodium Salt, A-Hydrocort, Buccalsone, Corlan, Cortisol Sodium Succinate, Cortop, Efcortelan, Emergent-EZ, Flebocortid, Hidroc Clora, Hycorace, Hydro-Adreson, Hydrocort, Hydrocortisone 21-Sodium Succinate, Hydrocortisone Na Succinate, Kinogen, Nordicort, Nositrol, Sinsurrene, Sodium hydrocortisone succinate, Solu-Cortef, Solu-Glyc

Cohort 2 (IMGN632, CPX-351, ITT, fludarabine, cytarabine)

Liposome-encapsulated Daunorubicin-Cytarabine DRUG

Given IV

Also known as: CPX-351, Cytarabine-Daunorubicin Liposome for Injection, Daunorubicin and Cytarabine (Liposomal), Liposomal AraC-Daunorubicin CPX-351, Liposomal Cytarabine-Daunorubicin, Liposome-encapsulated Combination of Daunorubicin and Cytarabine, Vyxeos

Cohort 2 (IMGN632, CPX-351, ITT, fludarabine, cytarabine); Cohort 3, Arm A (CPX-351, fludarabine, cytarabine); Cohort 3, Arm B (CPX-351, fludarabine, cytarabine, IMGN632)

Methotrexate DRUG

Given IT

Also known as: Abitrexate, Alpha-Methopterin, Amethopterin, Brimexate, CL 14377, CL-14377, Emtexate, Emthexat, Emthexate, Farmitrexat, Fauldexato, Folex, Folex PFS, Lantarel, Ledertrexate, Lumexon, Maxtrex, Medsatrexate, Metex, Methoblastin, Methotrexate LPF, Methotrexate Methylaminopterin, Methotrexatum, Metotrexato, Metrotex, Mexate, Mexate-AQ, MTX, Novatrex, Rheumatrex, Texate, Tremetex, Trexeron, Trixilem, WR-19039

Cohort 2 (IMGN632, CPX-351, ITT, fludarabine, cytarabine)

Prednisolone DRUG

Given IT

Also known as: (11beta)-11,17,21-Trihydroxypregna-1,4-diene-3,20-dione, .delta.1-Hydrocortisone, Adnisolone, Aprednislon, Capsoid, Cortalone, Cortisolone, Dacortin H, Decaprednil, Decortin H, Delta(1)Hydrocortisone, Delta- Cortef, Delta-Cortef, Delta-Diona, Delta-F, Delta-Phoricol, Delta1-dehydro-hydrocortisone, Deltacortril, Deltahydrocortisone, Deltasolone, Deltidrosol, Dhasolone, Di-Adreson-F, Dontisolon D, Estilsona, Fisopred, Frisolona, Gupisone, Hostacortin H, Hydeltra, Hydeltrasol, Klismacort, Kuhlprednon, Lenisolone, Lepi-Cortinolo, Linola-H N, Linola-H-Fett N, Longiprednil, Metacortandralone, Meti Derm, Meticortelone, Opredsone, Panafcortelone, Precortisyl, Pred-Clysma, Predeltilone, Predni-Coelin, Predni-Helvacort, Prednicortelone, Prednisolonum, Prelone, Prenilone, Sterane

Cohort 2 (IMGN632, CPX-351, ITT, fludarabine, cytarabine)

Eligibility Criteria

• Age: 12 Months - 22 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Patients from Children's Oncology Group (COG) sites must be enrolled on APAL2020SC
• Patients must be \>= 12 months and less than 22 years of age at the time of study enrollment
• Patient's weight at time of enrollment must be \>= 10 kg
• Patients must meet the eligibility in the appropriate Cohort for their diagnosis and disease status
• Cohort 1 (Phase 1 Monotherapy):
• Patients must meet all the following criteria:
• Patient must have bone marrow sample showing \>= 5% leukemic blasts by flow cytometry
• Patient must have been diagnosed with AML, B-ALL, T-ALL, or mixed phenotype acute leukemia (MPAL) meeting one of the following disease criteria:
• Second or greater relapse OR
• Disease that is refractory to relapse therapy
• Refractory to relapse therapy is defined as persistent disease after at least one cycle of induction chemotherapy to treat the relapse disease
• Patient must have leukemic blasts that are CD123-positive by flow cytometry as determined either by the treating institution or through reference laboratory testing.
• Cohort 2 (Combination Dose Finding) and Cohort 3 (Randomized Phase 2 Combination):
• Patients must meet all the following criteria:
• Patient must have AML in first relapse with a bone marrow sample showing \>= 1% leukemic blasts by flow cytometry

You may not qualify if:

• Plans to administer any type of non-protocol prescribed anti-cancer therapy while on protocol directed therapy. For Cohort 1, additional intrathecal therapy is allowed per treating physician's discretion
• Strong inducers or inhibitors of CYP2D6 or CYP3A4 are prohibited for 7 days prior to the 1st dose of IMGN632 to the end of the treatment for both the Phase 1 Monotherapy Dose Finding and pharmacokinetic (PK) and the Combination Dose Finding components of the study. For patients not enrolled in a dose finding portion of the study, concomitant therapy with strong inducers or inhibitors of CYP2D6 or CYP3A4 is STRONGLY discouraged but not prohibited if clinically indicated
• Patients with acute promyelocytic leukemia (APL) or juvenile myelomonocytic leukemia (JMML)
• Patients with Down syndrome
• Patients with isolated extramedullary disease or those with minimal bone marrow disease not meeting the definition of relapsed or relapse refractory as defined above
• Patients with a prior history of Grade 4 VOD/SOS (veno-occlusive disease/sinusoidal obstructive syndrome) or any history of Grade 3 VOD/SOS that, at the discretion of the treating physician, places the patient at unacceptably high risk for future severe VOD/SOS
• Patients who are currently receiving another investigational drug
• Patients receiving medications for treatment of left ventricular systolic dysfunction
• Patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known congenital bone marrow failure syndrome
• Patients with known prior allergy to any of the medications used in protocol therapy
• Patients with documented active, uncontrolled infection at the time of study entry
• Patients with history of Wilson's disease or other copper-related disorder
• Pregnancy and breastfeeding:
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants

Sponsors & Collaborators

• Children's Oncology Group: lead
• ImmunoGen, Inc.: collaborator
• National Cancer Institute (NCI): collaborator

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Burkitt Lymphoma; Leukemia, Biphenotypic, Acute; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma

Interventions

Biopsy; Cytarabine; fludarabine phosphate; Hydrocortisone; hydrocortisone hemisuccinate; CPX-351; Injections; Daunorubicin; Liposomes; Methotrexate; merphos; Prednisolone; Methylprednisolone

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Epstein-Barr Virus Infections; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Lymphoid; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids; Drug Administration Routes; Drug Therapy; Therapeutics; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Aminoglycosides; Glycosides; Carbohydrates; Membranes, Artificial; Biomedical and Dental Materials; Drug Carriers; Dosage Forms; Pharmaceutical Preparations; Manufactured Materials; Technology, Industry, and Agriculture; Biomimetic Materials; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pregnadienetriols; Pregnadienes

Study Officials

• Matthew A Kutny

  Children's Oncology Group

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Model Details: Phase I non-randomized study followed by a phase II randomized study

Study Record Dates

• First Submitted: March 22, 2022
• First Posted: April 11, 2022
• Study Start: August 1, 2023
• Primary Completion: September 1, 2023
• Study Completion: September 1, 2023
• Last Updated: September 1, 2023

Record last verified: 2023-02