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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.
Full description
PRIMARY OBJECTIVES:
I. To determine the recommended phase 2 dose (RP2D) of anti-CD123 ADC IMGN632 (IMGN632) monotherapy in pediatric patients with second or greater relapse of CD123 positive leukemia or CD123 positive leukemia refractory to relapse therapy. (Cohort 1 [Monotherapy Phase 1]) II. To assess the flow-based overall response rate (complete remission [CR]/CR with incomplete blood count recovery [CRi]/CR with partial recovery of platelet count [CRp]) in patients with acute myeloid leukemia (AML) treated with IMGN632. (Cohort 1 [Monotherapy Phase 1]) III. To determine the safety, feasibility, and RP2D of IMGN632 in combination with liposome-encapsulated daunorubicin-cytarabine (DAUNOrubicin and cytarabine liposome) in pediatric patients with first relapse of CD123 positive AML. (Cohort 2 [Combination Therapy Dose Finding]) IV. To compare the minimal residual disease (MRD) negative flow-based overall response rate (CR/CRi/CRp) in pediatric patients with first relapse of CD123 positive AML randomized to two cycles of therapy including DAUNOrubicin and cytarabine liposome followed by fludarabine phosphate (fludarabine)/cytarabine with or without IMGN632. (Cohort 3 [Randomized Phase 2])
SECONDARY OBJECTIVE:
I. To characterize the pharmacokinetics of IMGN632 in a pediatric population. (Cohort 1 [Monotherapy Phase 1])
EXPLORATORY OBJECTIVES:
I. To describe the anti-leukemic activity (morphologic and flow-based CR/CRp/CRi after up to two cycles, rates of MRD negative response after up to 2 cycles, event free survival [EFS] and overall survival [OS]) of IMGN632 in patients with multiply relapsed or refractory relapsed pediatric leukemia including AML, B-cell acute lymphoblastic leukemia [ALL], T-cell ALL and mixed phenotype acute leukemia (MPAL). (Cohort 1) II. To describe the EFS, OS, cumulative incidence of relapse, and rate of subsequent stem cell transplant for patients with first relapse of AML randomized to treatment with up to two cycles of chemotherapy with or without IMGN632. (Cohort 3) III. To determine if CD123 expression on leukemic blasts (assessed by flow cytometry) correlates with clinical response to IMGN632. (All Cohorts) IV. To determine the cumulative incidence of left ventricular systolic dysfunction (LVSD), defined as an absolute decline in EF by >= 10% to an ejection fraction (EF) value of < 50%, or an absolute decline in shortening fraction (SF) by >= 4% to an SF value of < 25%, within 1 year of initiation of DAUNOrubicin and cytarabine liposome based therapy for relapsed pediatric AML.
V. To describe safety (adverse events) in pediatric leukemia patients treated with IMGN632 including long-term safety events related to treatment for up to 5 years. (All Cohorts)
OUTLINE: This is a phase I, dose-escalation study of IMGN632 followed by a phase II study. In phase I, patients with second or greater relapse or refractory relapsed disease of AML, B-ALL, T-ALL or MPAL with CD123 expression are assigned to Cohort I, while patients with CD123 positive AML in first relapse are assigned to Cohort II. In phase II, patients with first relapse of CD123 positive AML are assigned to Cohort III.
COHORT 1: Patients receive IMGN632 intravenously (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.
COHORT 2:
CYCLE 1: Patients receive IMGN632 IV on days 1 and 22 and liposome-encapsulated daunorubicin-cytarabine (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 intrathecal triple therapy (ITT) consisting of methotrexate intrathecally (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 lumbar puncture [LP] do not need to repeat ITT on day 0 if given within 7 days of starting protocol therapy). Patients with CNS2 receive ITT once weekly (QW) until the cerebrospinal fluid (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 once daily (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.
COHORT 3: Patients are randomized to 1 of 2 arms.
ARM A: 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.
ARM B: 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.
After completion of study treatment, patients are followed every 3 months for the first year, twice a year for year two and yearly visits until five years from enrollment.
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Inclusion criteria
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
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:
Central nervous system (CNS) disease - All Cohorts
Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2 (>= 50% Lansky or Karnofsky score). Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. Please refer to the table of myelosuppressive/Anticancer Agents on the COG website: https://www.cogmembers.org/uploadedFiles/Site/Disc/DVL/Documents/TableOfMyelosuppressiveAnti-CancerAgents.pdf. For agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned Research Coordinator prior to enrollment.
Cytotoxic chemotherapy: Must not have received within 14 days of entry onto this study, except for hydroxyurea or corticosteroids
Intrathecal cytotoxic therapy
Antibodies: >= 21 days must have elapsed from infusion of last dose of an antibody-drug conjugate. For unmodified antibodies or T cell engaging antibodies, 2 half-lives must have elapsed before enrollment. Any toxicity related to prior antibody therapy must be recovered to Grade =< 1
Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g., pegfilgrastim) or 7 days for short acting growth factor
Radiation therapy (RT):
Stem cell infusions:
Cellular therapy: >= 42 days after the completion of DLI (donor lymphocyte infusion) or any type of cellular therapy (e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.)
Ejection fraction (EF) of >= 55% or if EF unavailable, shortening fraction (SF) >= 28% by echocardiogram (within 21 days prior to enrollment and start of protocol therapy [repeat if necessary]) AND
Corrected QTc interval < 500 msec (within 7 days prior to enrollment)
Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows (within 7 days prior to enrollment):
Direct bilirubin < 2 mg/dL (< 34 umol/L), (within 7 days prior to enrollment) AND
Serum glutamate pyruvate transaminase SGPT (alanine aminotransferase [ALT]) =< 135 U/L (within 7 days prior to enrollment)
Exclusion criteria
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:
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Data sourced from clinicaltrials.gov
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