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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A PedAL/EuPAL Phase 1/2 Trial of IMGN632 in Pediatric Patients With Relapsed or Refractory Leukemia

Conditions
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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

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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 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 Patient must have leukemic blasts that are CD123-positive by flow cytometry as determined either by the treating institution or through reference laboratory testing For Cohort 3 only: Patient's AML is not treatment related Central nervous system (CNS) disease - All Cohorts Patients may have status of CNS1, CNS2, CNS3 disease without clinical signs or neurologic symptoms suggestive of CNS leukemia, such as facial nerve palsy, brain/eye involvement or hypothalamic syndrome 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 NOTE: Cytoreduction with hydroxyurea or corticosteroids must be discontinued prior to the start of protocol therapy. Use of steroids for other purposes such as premedication to prevent allergic reaction or during anesthesia is allowed Intrathecal cytotoxic therapy No waiting period is required for patients having received any combination of intrathecal cytarabine, methotrexate, and/or hydrocortisone 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): 14 days have elapsed for local palliative RT (small port); >= 84 days must have elapsed if prior craniospinal RT or if >= 50% radiation of pelvis; >= 42 days must have elapsed if other substantial bone marrow (BM) radiation For combination therapy arms: Patients must have received =< 13.6 Gy prior radiation to the mediastinum Stem cell infusions: >= 84 days since allogeneic (non-autologous) bone marrow or stem cell transplant (with or without total body irradiation [TBI]) or boost infusion (any stem cell product; not including donor lymphocyte infusion [DLI]) No evidence of graft versus host disease (GVHD) Patients must be off medications to treat or prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant for at least 14 days prior to start of protocol treatment 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): 1 to < 2 years (age); 0.6 mg/dL (male) 0.6 mg/dL (female) 2 to < 6 years (age); 0.8 mg/dL (male) 0.8 mg/dL (female) 6 to < 10 years (age); 1 mg/dL (male) 1 mg/dL (female) 10 to < 13 years (age); 1.2 mg/dL (male) 1.2 mg/dL (female) 13 to < 16 years (age); 1.5 mg/dL (male) 1.4 mg/dL (female) >= 16 years (age); 1.7 mg/dL (male) 1.4 mg/dL (female) 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) If liver abnormality is due to leukemia infiltrate, the patient will remain eligible 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: 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 Sexually active patients of reproductive potential (male and female) who have not agreed to use an effective contraceptive method or abstinence for the duration of their study participation and for 12 weeks after the last dose of IMGN632 or 6 months after last dose of DAUNOrubicin and cytarabine liposome, whichever is longer Regulatory requirements All patients and/or their parents or legal guardians must sign a written informed consent All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 22 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase I non-randomized study followed by a phase II randomized study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (IMGN632)<br>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<br>* Given IV<br>|
| Experimental: Cohort 2 (IMGN632, CPX-351, ITT, fludarabine, cytarabine)<br>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<br>* Given IV<br>Procedure: Bone Marrow Aspiration and Biopsy<br>* Undergo bone marrow aspiration/biopsy<br>Drug: Cytarabine<br>* Given IT and IV<br>* Other names: WR-28453;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Drug: Hydrocortisone Sodium Succinate<br>* Given IT<br>* Other names: Solu-Glyc;Drug: Liposome-encapsulated Daunorubicin-Cytarabine<br>* Given IV<br>* Other names: Vyxeos;Drug: Methotrexate<br>* Given IT<br>* Other names: WR-19039;Drug: Prednisolone<br>* Given IT<br>* Other names: Sterane;|
| Active Comparator: Cohort 3, Arm A (CPX-351, fludarabine, cytarabine)<br>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<br>* Given IT and IV<br>* Other names: WR-28453;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Drug: Liposome-encapsulated Daunorubicin-Cytarabine<br>* Given IV<br>* Other names: Vyxeos;|
| Experimental: Cohort 3, Arm B (CPX-351, fludarabine, cytarabine, IMGN632)<br>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<br>* Given IV<br>Procedure: Bone Marrow Aspiration and Biopsy<br>* Undergo bone marrow aspiration/biopsy<br>Drug: Cytarabine<br>* Given IT and IV<br>* Other names: WR-28453;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Drug: Liposome-encapsulated Daunorubicin-Cytarabine<br>* Given IV<br>* Other names: Vyxeos;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration versus time curve (AUC) of IMGN632 | Non-compartmental methods will be used to estimate the area under the plasma concentration versus time curve (AUC) of IMGN632. | Cycles 1 & 2 | 
| Maximum serum concentration (Cmax) of IMGN632 | Non-compartmental methods will be used to estimate the maximum serum concentration (Cmax) of IMGN632. | Cycles 1 & 2 | 
| Volume of distribution at steady state (Vss) of IMGN632 | Non-compartmental methods will be used to estimate the volume of distribution at steady state (Vss) of IMGN632. | Cycles 1 & 2 | 
| Half-life (t1/2) of IMGN632 | Non-compartmental methods will be used to estimate the half-life (t1/2) of IMGN632. | Cycles 1 & 2 | 
| Clearance (CL) of IMGN632 | Non-compartmental methods will be used to estimate the clearance (CL) of IMGN632. | Cycles 1 & 2 | 
| Time to reach maximum serum concentration (Tmax) of IMGN632 | Non-compartmental methods will be used to estimate the time to reach maximum serum concentration (Tmax) of IMGN632. | Cycles 1 & 2 |