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Includes participants with AML and MDS. Participants receive chemotherapy based on diagnosis followed by infusion of donor HPC-A.

Participants with CNS disease receive weekly age-adjusted intrathecal triples therapy until the cerebrospinal fluid becomes free of leukemia (minimum of 4 doses).

Interventions:

* Cycle 1: cytarabine, HPC-A donor infusion
* Cycle 2: Participants who have at least a partial response to Cycle 1 are eligible to receive Cycle 2: cytarabine, HPC-A infusion

Given by either intrathecal (IT) or intravenous (IV) route.

Intrathecal Triples

HPC-A

Jeffrey E. Rubnitz, MD, PhD

Allogeneic transplant can sometimes be an effective treatment for leukemia. In a traditional allogeneic transplant, patients receive very high doses of chemotherapy and/or radiation therapy, followed by an infusion of their donor's bone marrow or blood stem cells. The high-dose chemotherapy drugs and radiation are given to remove the leukemia cells in the body. The infusion of the donor's bone marrow or blood stem cells is given to replace the diseased bone marrow destroyed by the chemotherapy and/or radiation therapy. However, there are risks associated with allogeneic transplant. Many people have life-threatening or even fatal complications, like severe infections and a condition called graft-versus-host disease, which is caused when cells from the donor attack the normal tissue of the transplant patient.

Recently, several hospitals around the world have been using a different type of allogeneic transplant called a microtransplant. In this type of transplant, the donor is usually a family member who is not an exact match. In a microtransplant, leukemia patients get lower doses of chemotherapy than are used in traditional allogeneic transplants. The chemotherapy is followed by an infusion of their donor's peripheral blood stem cells. The objective of the microtransplant is to suppress the bone marrow by giving just enough chemotherapy to allow the donor cells to temporarily engraft (implant), but only at very low levels. The hope is that the donor cells will cause the body to mount an immunologic attack against the leukemia, generating a response called the "graft-versus-leukemia" effect or "graft-versus-cancer" effect, without causing the potentially serious complication of graft-versus-host disease.

With this research study, the investigators hope to find out whether or not microtransplantation will be a safe and effective treatment for children, adolescents and young adults with relapsed or refractory hematologic malignancies

PRIMARY OBJECTIVES:

* To assess the safety and feasibility of standard chemotherapy plus GCSF-mobilized Hematopoietic Progenitor Cell, Apheresis (HPC-A) in pediatric patients with relapsed or refractory hematologic malignancies.
* To estimate the response rates to standard chemotherapy plus GCSF-mobilized HPC-A in pediatric patients with relapsed or refractory hematologic malignancies.

SECONDARY OBJECTIVES:

* To describe the event-free and overall survival of patients treated with standard chemotherapy plus GCSF-mobilized HPC-A.
* To estimate the time to neutrophil and platelet recovery after treatment with standard chemotherapy plus GCSF-mobilized HPC-A.
* To determine the cumulative incidence of acute and chronic graft-versus-host disease (GVHD).

OTHER PRESPECIFIED OBJECTIVES:

* To characterize donor chimerism and microchimerism.

Patients will receive standard chemotherapy followed by infusion of donor peripheral blood mononuclear cells 2 days after the completion of chemotherapy. Patients who have at least a partial response are eligible to receive a second cycle.

Diagnostic lumbar puncture and intrathecal (IT) chemotherapy will be given prior to cycle 1. Patients without evidence of central nervous system (CNS) leukemia will receive no further IT therapy during cycle 1. Patients with CNS disease will receive weekly IT therapy (age-adjusted methotrexate, hydrocortisone, and cytarabine) until the cerebrospinal fluid (CSF) becomes free of leukemia (minimum of 4 doses).

Bone marrow aspiration (BMA) and biopsy to assess response will be performed on approximately day 29 of therapy.

For hematopoietic stem cell mobilization, donors will receive G-CSF (Filgrastim) (Neupogen®) each day for 5 days given subcutaneously (SQ) prior to HPC-A collected by leukapheresis on day 6.

Microtransplantation to Treat Refractory or Relapsed Hematologic Malignancies in Younger Patients

A Phase II Study of Microtransplantation in Patients With Refractory or Relapsed Hematologic Malignancies

Percent donor chimerism in blood and bone marrow.

If two or more patients die from causes other than leukemia progression or experience ≥ Grade 3 GVHD that is associated with detectable donor chimerism due to this protocol, or demonstrate persistent engraftment defined as \>5% donor chimerism at the time of count recovery (ANC \> 0.3 x 10\^9/L and platelet count \> 30 x 10\^/L), then the cohort will close due to intolerability. Any subject who transfers to transplant prior to completion of two courses without experiencing an unacceptable toxicity is considered inevaluable for purposes of evaluating tolerability. Accrual will be halted for intolerability if there are two or more failures in tolerability among the first six subjects who are evaluable for tolerability.

All patients will be counted towards this two-stage design. Therapeutic success for patients at time of enrollment is defined as:

* Patients with fewer than 5% blasts, a ≥ 10-fold decrease in level of minimal residual disease after completion of 1 or 2 cycles of therapy.
* Patients with greater than 5% in leukemic blasts in the marrow, achieving CR or CRi after completion of 1 or 2 cycles of therapy.

In terms of efficacy, patients who die before achieving therapeutic success will be counted as a failure, and all patients who receive ≥ 1 dose of protocol chemotherapy will be counted as a failure or success. Only subjects who withdraw or die prior to receiving the first dose of protocol chemotherapy will be considered inevaluable and replaced. The evaluation of tolerability and this phase II design will be performed concurrently, i.e., the first enrollees will be counted for both tolerability and efficacy.

We will use the Kaplan-Meier method to describe event-free survival. EFS will be defined as the time from enrollment to death, relapse, or refractory disease with event-free subjects' time censored at the date of last follow-up.

We will use the Kaplan-Meier method to describe overall survival. Overall survival will be defined as the time from enrollment to death, with living subjects' time censored at the date of last follow-up

The time to neutrophil recovery will be summarized using descriptive statistics. If there are no deaths prior to recovery of neutrophils, nonparametric confidence intervals for the median time to recovery will be computed by inverting the sign test. Otherwise, we will compute cumulative incidence curves to describe the time to platelet and neutrophil recovery while adjusting for competing events.

The time to platelet recovery will be summarized using descriptive statistics. If there are no deaths prior to recovery of platelets, nonparametric confidence intervals for the median time to recovery will be computed by inverting the sign test. Otherwise, we will compute cumulative incidence curves to describe the time to platelet and neutrophil recovery while adjusting for competing events.

Due to the small number of patients enrolled, the data is presented by patient.

Children's Oncology Group (COG) Stem Cell Committee Consensus Guidelines for Establishing Organ Stage and Overall Grade of Acute Graft Versus Host Disease (GVHD) were used. Overall clinical grade was based on the highest stage obtained:

* Grade 0: no stage 1-4 of any organ
* Grade I: stage 1-2 skin and no liver or gut involvement
* Grade II: stage 3 skin, or stage 1 liver involvement, or stage 1 GI
* Grade III: stage 0-3 skin, with stage 2-3 liver, or stage 2-3 GI
* Grade IV: stage 4 skin, liver or GI involvement

Cookies for Kids' Cancer

St. Jude Children's Research Hospital

Includes participants with AML and MDS. Participants receive chemotherapy based on diagnosis followed by infusion of donor HPC-A.

Participants with CNS disease receive weekly age-adjusted intrathecal triples therapy until the cerebrospinal fluid becomes free of leukemia (minimum of 4 doses).

Interventions:

* Cycle 1: cytarabine, HPC-A donor infusion
* Cycle 2: Participants who have at least a partial response to Cycle 1 are eligible to receive Cycle 2: cytarabine, HPC-A infusion

Cytarabine: Given by either intrathecal (IT) or intravenous (IV) route.

Intrathecal Triples: given IT.

HPC-A: Given IV.

Myeloid Malignancies

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

This study was terminated in May 2017 due to poor accrual and because of competing protocols.

Includes participants with AML and MDS. Participants receive chemotherapy based on diagnosis followed by infusion of donor HPC-A.

Number of Participants by Stratum Who Complete 2 Cycles of Therapy

Proportion of Participants Who Experience Therapeutic Success

3-year Event Free Survival (EFS)

3-year Overall Survival (OS)

Median Time to Neutrophil Recovery

Platelet recovery for Patient #1 could not be determined due to transfusions.

Time to Platelet Recovery

Stage 0

Stage I

Stage II

Stage III

Stage IV

1-year Cumulative Incidence of Acute Graft Versus Host Disease (GVHD)

Week 1

Week 2

Week 3

Week 4

Percent Donor Chimerism

No patient survived long enough to evaluate chronic GVHD.

1-year Cumulative Incidence of Chronic Graft Versus Host Disease (GVHD)

Overall Study

Immune System Diseases

Recurrence

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Lymphoma

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

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Antiemetics

Gastrointestinal Agents

Amino Acids

Etoposide

Venetoclax

Cyclophosphamide

Dexamethasone

Leucovorin

Levoleucovorin

Vincristine

Dexamethasone acetate

BB 1101

Pegaspargase

Etoposide phosphate

Blinatumomab

Dasatinib

Mercaptopurine

Asparaginase

Navitoclax

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Alkylating Agents

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Antineoplastic Agents, Hormonal

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Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Tyrosine

All eligible patients receive intervention according to the Detailed Description section with the following:

Venetoclax, Navitoclax, Dexamethasone, Vincristine, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Dasatinib, Leucovorin, Intrathecal (IT) MHA (methotrexate/hydrocortisone/cytarabine)

Block 2a Therapy:

Patients receive intervention according to the Detailed Description section with the following:

Venetoclax, Navitoclax, Dexamethasone, Cytarabine, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Dasatinib, IT MHA, Radiation

Block 2b Therapy:

Patients receive intervention according to the Detailed Description section with the following:

Venetoclax, Blinatumomab, Dexamethasone, Dasatinib, IT MHA

Following Block 2 of therapy, late (≥36 months from diagnosis) first relapse B-ALL who are MRD negative after Block 1 will continue chemotherapy using adapted R3 intensification, interim, and continuation therapies.

Patients receive intervention according to the Detailed Description section with the following:

Methotrexate, Mercaptopurine, IT MHA, Leucovorin, Dexamethasone, Vincristine, Cyclophosphamide, Etoposide, Cytarabine, Dasatinib, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Radiation

Calaspargase Pegol

Given intravenously (IV) or Intrathecal (IT).

Given intravenously (IV), oral (PO), or Intrathecal (IT).

May be used in place of Calaspargase Pegol where available. Given intravenously (IV) or intramuscularly (IM).

To be used in case of hypersensitivity or intolerance to Calaspargase Pegol or Pegaspargase. Given intravenously (IV) or intramuscularly (IM).

Erwinia asparaginase

Radiation

Seth E. Karol, MD

This is a phase I/II clinical trial evaluating the activity of combination chemotherapy with venetoclax and navitoclax in children with relapsed or refractory acute lymphoblastic leukemia or lymphoma (rALL) and assessing the combination dose of venetoclax combinations with either blinatumomab for CD19-postive patients or navitoclax and high-dose cytarabine for CD19-negative patients.

Primary Objectives

* To compare Minimal Residual Disease (MRD)-negative CR/CRi rate in children with relapsed or refractory acute lymphoblastic leukemia or lymphoma (rALL) following Block 1 therapy with venetoclax and navitoclax based reinduction to historical controls.
* To identify the recommended phase 2 combination dose (RP2D) of venetoclax based consolidation in novel combinations with a) high-dose cytarabine and navitoclax or b) blinatumomab.

Secondary Objectives

* To estimate the tolerability and activity of venetoclax based consolidation in novel combinations with a) high-dose cytarabine and navitoclax or b) blinatumomab.
* To describe event-free and overall survival in patients treated with this regimen.

Exploratory Objectives

* To evaluate MRD-negative CR/CRi rates in each prespecified groups: late first relapse B-ALL; early first relapse and second or greater relapse B-ALL; and relapsed T-ALL.
* To identify drug sensitivity patterns in patient samples prior to and after receiving combination therapy and evaluate mechanisms of disease resistance/ escape.
* To explore immune subsets during and after this regimen.
* Evaluate response to therapy in rare relapse patient subsets.
* Explore breakthrough infections in children and young adults with relapsed or refractory ALL

This is a non-randomized phase I/II clinical trial. In Block I, all patients receiving common therapy evaluating the activity of combination chemotherapy with venetoclax and navitoclax in children with relapsed or refractory acute lymphoblastic leukemia or lymphoma (rALL).

In Block 2, a phase 1 rolling six design and phase 2 extension will be used to assess the combination dose of venetoclax combinations with either blinatumomab for CD19-postive patients or navitoclax and high-dose cytarabine for CD19-negative patients. One to six participants can be concurrently enrolled onto a dose level, depending on the number of participants enrolled at the current dose level, the number of participants who have experienced a dose/combination limiting toxicity (DLT) at the current dose level, and the number of participants entered but with tolerability data pending. Dose de-escalation will occur if 2 patients at a dose level experience a targeted toxicity. If 6 patients complete a therapy block and experience 0-1 DLT, that dose will be considered the recommended phase 2 dose (RP2D). New enrollment on an arm (2a/2b) will be paused if further enrollment would result in more than 6 patients being treated on that arm before the RP2D is identified.

The primary outcome assessment will be a bone marrow with MRD testing on Day 29 of Block 1 therapy. Following that assessment, patients should continue with protocol therapy including either Block 2A (which includes high-dose cytarabine with venetoclax and navitoclax) for patients with CD19 negative leukemia, those with isolated extramedullary relapse, or whose treating physician determines that blinatumomab therapy is not in the patient's best interest; or Block 2B for patients with leukemia which is CD19 positive. Following recovery from Block 2 therapy, all patients except those with late first relapse of B-ALL (≥ 36 months from diagnosis) who are MRD-negative at \<0.01% after Block 1 therapy are off therapy. Further therapy for these patients is at the treating physician's discretion. Patients with late first relapse B-ALL relapse and who are MRD negative will proceed with intensification, interim continuation, and continuation therapy. Patients with Down's Syndrome with CD19 negative leukemia will be off therapy after Block 1 as they are ineligible for Block 2A. Patients in exploratory cohorts I and N who are late first relapse B-ALL and who are MRD-negative after Block 1 therapy may continue on protocol therapy after Block 2 or receive alternative therapy at their treating physician's discretion. Patients in exploratory cohort M and O are off therapy after Block 2.

Intervention:

Block 1 Therapy:

* Venetoclax 120mg/m\^2 (max 200mg) PO, day 1; 240mg/m\^2/dose (max 400mg) PO, 21 doses, days 2-22
* Navitoclax 25mg PO (for patients 20 - \<45kg) OR 50mg PO (for patients \>=45kg), days 3-22
* Dexamethasone 5mg/m\^2/dose BID PO/IV, days 1-7 and 15-22
* Vincristine 1.5mg/m\^2/dose (max 2mg) IV, days 1, 8, 15, and 22
* Calaspargase pegol 2500units/m\^2/dose IV, day 2
* Dasatinib 80mg/m\^2/day (max 140mg) PO, days 1-28 for ABL-class fusions and non-ETP T-ALL
* IT MHA: Intrathecal (IT) MHA (methotrexate 12 mg/hydrocortisone 24mg/cytarabine 36mg), days -7 to 1. Continue intrathecal chemotherapy weekly until negative x 2.
* Leucovorin 5mg/m2 (max 5mg) PO or IV (24 and 30 hours after each LP).

Calaspargase may be replaced by alternative forms of asparaginase due to local practice or prior allergy. If pegaspargase is used, two doses (on days 2 and 15) of 2500units/ m\^2 replace the single day 2 dose of calaspargase. For patients in exploratory cohort N, asparaginase will be omitted. For patients in exploratory cohort O, the Day 15 dose of pegaspargase may be omitted and the Day 2 dose may be capped at 2000units/m2 with a maximum dose of 3750 units.

Testicular Radiation: Patients with persistent testicular involvement by leukemia at the end of Block 1 may continue on study and may receive testicular radiation during Block 2 therapy.

Block 2a - For patients with ≥ 5% of leukemic blasts which do not have detectable CD19 on their surface, those with isolated extramedullary relapse, or whose physician determines this therapy arm is in their patient's best interest. Patients with Down Syndrome are not eligible for Block 2a therapy. Patients in exploratory cohort O are not eligible for the phase I/dose de-escalation phase of the study but may enroll on block 2 therapy after the dose has been established.:

* Venetoclax 240mg/m\^2 (max 400mg) PO, days 1-7
* Navitoclax 25mg (20-\<45kg) OR 50mg (\>=45kg) PO, days 1-7
* Dexamethasone 3mg/m\^2/dose PO/IV BID, days 1-5
* Calaspargase pegol 1000units/m\^2 IV, day 3
* Dasatinib 80mg/m2/day (max 140mg) PO, days 1-28 for ABL-class fusion and non-ETP T-ALL/ALLy
* IT MHA: Methotrexate 12 mg IT, Hydrocortisone 24mg IT, Cytarabine 36mg IT, one dose with end of cycle bone marrow assessment
* Cytarabine dosing during phase I portion for Block 2a:

  * Dose level 1: 3000mg/m\^2/dose every 12hours(h) IV infusion over 3 hours, days 1-2
  * Dose level 0: 1500mg/m\^2/dose every 12h IV infusion over 3 hours, days 1-2
  * Dose level -1: 1000mg/m\^2/dose every 12h IV infusion over 3 hours, day 1

Calaspargase may be replaced by alternative forms of asparaginase. For patients in exploratory cohort N, asparaginase will be omitted.

Block 2b Therapy: For patients with \>95% of leukemic blasts with detectable CD19 on their surface. Patients with isolated extramedullary relapse are ineligible for Block 2b therapy. Patients in exploratory cohort O are not eligible for the phase I/ dose de-escalation phase of the study but may enroll on block 2 therapy after the dose has been established.

* Blinatumomab; for patients with end of Block 1 MRD \>5%, 5mcg/m\^2/day (max 9mcg/day; patients weighing ≥45kg receive 9mcg/day fixed dose) IV, days 1-7
* Blinatumomab; for patients with end of Block 1 MRD \>5%, 15mcg/m\^2/day (max 28mcg/day; patients weighing ≥45kg receive 28mcg/day fixed dose) IV, days 8-28
* Blinatumomab; for patients with end of Block 1 MRD ≤5%, 15mcg/m\^2/day (max 28mcg/day; patients weighing ≥45kg receive 28mcg/day fixed dose) IV, days 1-28,
* Dexamethasone 10mg/m\^2 (max 20mg) 30-60 minutes prior to day 1 blinatumomab, PO/IV, days 1, 8 (For patients who start blinatumomab at 5mcg/m2/day, an additional dose of dexamethasone will be given on day 8 30-60 minutes prior to dose increase. For patients whose blinatumomab is interrupted for more than 4 hours for any reason, an additional dose of dexamethasone will be given prior to restarting blinatumomab.)
* Dasatinib 80mg/m\^2/day (max 140mg) PO, days 1-28 for ABL-class fusions
* IT MHA: Methotrexate 12 mg IT, Hydrocortisone 24mg IT, Cytarabine 36mg IT, day 29 with end of cycle bone marrow
* Venetoclax dosing during phase I portion for Block 2b:

  * Dose level 1: 240mg/m\^2 (max 400 mg) PO, days 8-28
  * Dose level 0: 240mg/m\^2 (max 400 mg) PO, days 8-21
  * Dose level -1: 240mg/m\^2 (max 400 mg) PO, days 8-14

Intensification Therapy - For late first relapse B-ALL and MRD\<0.01% after Block 1 only. Patients in exploratory cohort O are excluded.:

* High Dose (HD) Methotrexate 5000mg/m\^2/dose IV: 500mg/m\^2 over 60 minutes then 4500mg/m\^2 over 23 hours; or targeted 65 microM, day 1 and 15
* Mercaptopurine 50mg/m\^2/dose PO daily, days 1-28
* IT MHA: Methotrexate 12 mg IT, Hydrocortisone 24mg IT, Cytarabine 36mg IT, D15
* Leucovorin 15mg/m2/dose PO/IV every 6 hours (start 42 hours after HD-MTX begins) D2 and 16 (at least 3 doses).

Interim Continuation Therapy 1 and 2 (8 weeks each) - For late first relapse B-ALL and MRD\<0.01% after Block 1 only:

* Dexamethasone 3mg/m\^2/dose BID PO/IV, days 1-5
* Vincristine1.5mg/m\^2(max 2mg) IV, day 1
* Mercaptopurine 75mg/m\^2/dose PO daily or 60mg/m2/day for patients with known heterozygous inactivating mutations of TPMT or NUDT15, days 1-49
* Methotrexate 20mg/m\^2/dose PO/IV, days 8, 15, 29, 36
* High Dose (HD)-Methotrexate 5000mg/m\^2/dose IV: 500mg/m2 over 60 minutes then 4500mg/m\^2 over 23 hours; or targeted 65 microM, day 22
* Leucovorin 15mg/m\^2/dose PO/IV every 6 hours: Start 42 hours after HD-MTX, days 24 and 25 (at least 3 doses)
* Cyclophosphamide 300mg/m\^2/dose IV over 15-30 minutes, days 43 and 50
* Etoposide 150mg/m\^2/dose IV over 1-2 hours, days 43 and 50
* Cytarabine 50mg/m\^2/dose IV over 1-30 minutes, days 44-47 and 51-54
* Dasatinib 80mg/m\^2/day PO (Max 140mg), days 1-56 for ABL-class fusions
* IT MHA: Methotrexate 12 mg IT, Hydrocortisone 24mg IT, Cytarabine 36mg IT, days 22 and 43

Following recovery from Interim Continuation therapy 1, patients will repeat Block 2 therapy according to their initial Block assignment (2A for CD19-negative, 2B for CD19-positive) and receive a second cycle of interim continuation. Patients will not receive venetoclax or navitoclax during this repeated Block 2 cycle. Following recovery from Interim Continuation 2, patients will proceed to Continuation therapy.

Continuation Therapy - For late first relapse B-ALL and MRD \<0.01% after Block 1 only. Continuation cycles last 8 weeks (56 days) each. Continuation therapy continues until 2 years from the start of protocol therapy.:

* Dexamethasone 6mg/m\^2/dose BID PO/IV, days 1-5, 29-33
* Vincristine 1.5mg/m\^2 (max 2mg) IV, day 1 and 29
* Mercaptopurine 75mg/m\^2/dose PO daily or 60mg/m\^2/day for patients with known heterozygous inactivating mutations of TPMT or NUDT15 days 1-56
* Methotrexate 20mg/m\^2/dose PO/IV days 8, 15, 22, 36, 43 and 50
* Dasatinib 80mg/m\^2/day PO (Max 140mg) days 1-56 for ABL-class fusions
* IT MHA: Methotrexate 12 mg IT, Hydrocortisone 24mg IT, Cytarabine 36mg IT day 1 and 29 (patients with CNS2 or traumatic lumbar puncture with blasts present at the time of relapse will receive day 1 and 29 IT MHA for the first year of continuation therapy. Following this, patients will receive IT MHA on day 1 of each cycle until the completion of therapy. Patients with CNS3 disease at relapse will receive day 1 and 29 IT MHA during cycles 1 and 2 of continuation and then proceed to chemoradiation.)

Chemoradiation for those with CNS3 disease at relapse (late first relapse \[≥36 months from diagnosis\] B-ALL and MRD\<0.01% after Block 1 only):

Patients with CNS3 disease at relapse will receive 18Gy cranial irradiation after Cycle 2 of Continuation Therapy. Patients will not receive additional intrathecal chemotherapy following irradiation. Chemoradiation lasts 21 days.

* Dexamethasone 6mg/m2/dose BID PO/IV days 1-5 and 15-19
* Vincristine 1.5mg/m\^2 (max 2mg) IV days 1, 8 and 15
* Calaspargase 2500units/m\^2/dose IV, Day 2 (Calaspargase may be replaced by alternative forms of asparaginase and will be omitted for patients in exploratory cohort N)
* Dasatinib 80mg/m\^2/day PO (Max 140mg) days 1-21 for ABL-class fusions

All eligible patients receive a common first block of therapy and therapy in the 2nd block being determined by CD19 expression on leukemic blasts.

Trial Treating Relapsed Acute Lymphoblastic Leukemia With Venetoclax and Navitoclax

RAVEN: A Phase I/II Trial Treating Relapsed Acute Lymphoblastic Leukemia With Venetoclax and Navitoclax

Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request.

The proportion of patients with end block 1 minimal residual disease \<0.01% by flow cytometry

The recommended Phase 2 dose (RP2D) of venetoclax in combination with a) high-dose cytarabine and navitoclax or b) blinatumomab will be the dose at which 0 or 1 of 6 treated patients experience a dose limiting toxicity.

Occurrence of grade 3 or higher CTCAE version 5 events in patients receiving block 2a therapy estimated as a proportion of patients receiving that therapy

Occurrence of grade 3 or higher CTCAE version 5 events in patients receiving block 2b therapy estimated as a proportion of patients receiving that therapy

EFS will be reported as estimates using the Kaplan-Meier method

OS will be reported as estimates using the Kaplan-Meier method

AbbVie

Bone Density Conservation Agents

Fludarabine

Fludarabine phosphate

Calcium

Calcium, Dietary

Panobinostat

Histone Deacetylase Inhibitors

Participants will be given panobinostat in combination with fludarabine and cytarabine. Treatment consists of one course of therapy given over 12 days. Participants will also receive intrathecal triples and leucovorin

Panobinostat will be given orally (PO) on days 1, 3, 5, 8, 10, and 12.

Fludarabine will be given intravenously (IV), 30 mg/m\^2/dose over 30 minutes, daily for 5 days (days 8-12).

Cytarabine will be given IV, 2 gram/m\^2/dose over 4 hours, daily for 5 days (days 8-12).

Leucovorin (5 mg/m\^2/dose, max 5 mg) may be given PO or IV at 24 and 30 hours after each ITMHA.

Jeffrey E. Rubnitz, MD,PhD

Cancer is the uncontrolled growth of human cells. The growth of normal human cells is controlled by multiple mechanisms. Panobinostat belongs to a class of chemotherapy drugs called "histone deacetylase (HDAC) inhibitors." HDAC inhibitors like panobinostat block enzymes known as histone deacetylases, which stops cancer cells from dividing and causes them to die. Fludarabine and cytarabine are chemotherapy drugs that are commonly used to treat pediatric patients with refractory or relapsed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

The purpose of this study is to test the safety of panobinostat and to find the highest dose of panobinostat that can be given safely when it is combined with fludarabine and cytarabine.

This pilot study will be done in two parts: The goal of Part 1 of the study is to find the highest tolerable dose of panobinostat that can be given to patients with AML or MDS, when it is combined with fludarabine and cytarabine. Once that dose is determined, participants will be enrolled on Part 2: Dose Expansion, to look at the effect of the panobinostat/fludarabine/cytarabine combination in patients with leukemia/MDS.

PRIMARY OBJECTIVE:

* Determine a tolerable dose of panobinostat when given in combination with fludarabine and cytarabine in pediatric patients with relapsed or refractory AML or MDS.

SECONDARY OBJECTIVES:

* Characterize the pharmacokinetics of panobinostat after the first dose and at steady-state.
* Estimate the overall response rate to the combination of panobinostat, fludarabine, and cytarabine.

STUDY PART 1: Dose Escalation Cohort

During the dose escalation phase (Part 1), participants will receive one course of panobinostat plus fludarabine and cytarabine. The starting dose of panobinostat will be 10 mg/m\^2/dose, with 2 additional dose levels of 15 and 20, depending on tolerability. Each course is 12 days

STUDY PART 2: Dose Expansion Cohort

The recommended phase 2 dose (RP2D) will be chosen based on the maximum tolerated dose (MTD) and the totality of data obtained from study Part 1. Additional patients will be enrolled, if needed, so that at least 6 patients are treated with the recommended RP2D to confirm the MTD of panobinostat to be given in study Part 2.

After final MTD determination, 12 additional participants will be treated at this dose level for further evaluation of tolerability and response, including more complete toxicity data and estimation of the response rate to the combination of panobinostat, fludarabine, and cytarabine.

Panobinostat With Fludarabine and Cytarabine for Treatment of Children With Acute Myeloid Leukemia or Myelodysplastic Syndrome

A Phase I and Dose Expansion Cohort Study of Panobinostat in Combination With Fludarabine and Cytarabine in Pediatric Patients With Refractory or Relapsed Acute Myeloid Leukemia or Myelodysplastic Syndrome

Any participant who experiences non-hematologic dose-limiting toxicity (DLT) during the first 28 days after taking the initial dose of panobinostat and before receiving non-protocol therapy is considered evaluable for toxicity. Non-hematologic DLT includes any Grade 5 event and any Grade 3 or 4 event that is at least possibly related to panobinostat, unless the event is clearly due to extraneous causes or disease progression. Hematologic DLT includes failure to recover counts by Day 56 in the absence of persistent leukemia.

Participants without DLTs who receive at least 5 of the 6 prescribed cycle I doses of panobinostat and can be followed for 28 days (56 days for evaluation of hematologic toxicity) after their initial dose of panobinostat are considered evaluable for toxicity. Participants who are not evaluable for toxicity will be replaced.

The MTD is defined as the highest dose level at which six participants have been treated with at most one participant experiencing a DLT.

Plasma samples will be analyzed via a validated method for plasma panobinostat concentration. Panobinostat concentration data will be analyzed in a non-linear mixed effects population pharmacokinetic (PK) model to determine the clearance.

Plasma samples will be analyzed via a validated method for plasma panobinostat concentration. Panobinostat concentration data will be analyzed in a non-linear mixed effects population pharmacokinetic (PK) model to determine the drug absorption.

Plasma samples will be analyzed via a validated method for plasma panobinostat concentration. Panobinostat concentration data will be analyzed in a non-linear mixed effects population pharmacokinetic (PK) model to determine the PK parameters. The AUC will be estimated based on the individual estimated PK.

Plasma samples will be analyzed via a validated method for plasma panobinostat concentration. Panobinostat concentration data will be analyzed in a non-linear mixed effects population pharmacokinetic (PK) model to determine the PK parameters. The Cmax will be estimated based on the individual estimated PK.

Response will be based on blast percentage by flow cytometry. Blast percentages determined by morphology will be used in cases that are not evaluable by flow cytometry.

The efficacy of the combination of panobinostat and chemotherapy, as measured by the CR rate will be assessed for patients enrolled at the MTD. The rate of CR will be presented as a point estimate with a 95% exact binomial confidence interval.

Response will be based on blast percentage by flow cytometry. Blast percentages determined by morphology will be used in cases that are not evaluable by flow cytometry.

The efficacy of the combination of panobinostat and chemotherapy, as measured by the OR (CR + incomplete blood count recovery + partial response + therapeutic success) will be assessed for the patients enrolled at the MTD. The rate of OR will be presented as a point estimate with a 95% confidence interval.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Microtransplantation to Treat Refractory or Relapsed Hematologic Malignancies in Younger Patients	NCT02433483	Acute Myeloid L... Myelodysplastic...	Cytarabine Intrathecal Tri... HPC-A	- 21 Years	St. Jude Children's Research Hospital
Trial Treating Relapsed Acute Lymphoblastic Leukemia With Venetoclax and Navitoclax	NCT05192889	Refractory Acut... Relapsed Acute ...	Venetoclax Navitoclax Dexamethasone Vincristine Calaspargase Pe... Dasatinib Cytarabine Blinatumomab Methotrexate Mercaptopurine Cyclophosphamid... Etoposide Leucovorin Intrathecal Tri... Pegaspargase Erwinia asparag... Radiation	4 Years - 30 Years	St. Jude Children's Research Hospital
Panobinostat With Fludarabine and Cytarabine for Treatment of Children With Acute Myeloid Leukemia or Myelodysplastic Syndrome	NCT02676323	Acute Myeloid L... Myelodysplastic...	Panobinostat Fludarabine Cytarabine Intrathecal Tri... Leucovorin	- 24 Years	St. Jude Children's Research Hospital
Trial Treating Relapsed Acute Lymphoblastic Leukemia With Venetoclax and Navitoclax	NCT05192889	Refractory Acut... Relapsed Acute ...	Venetoclax Navitoclax Dexamethasone Vincristine Calaspargase Pe... Dasatinib Cytarabine Blinatumomab Methotrexate Mercaptopurine Cyclophosphamid... Etoposide Leucovorin Intrathecal Tri... Pegaspargase Erwinia asparag... Radiation	4 Years - 30 Years	St. Jude Children's Research Hospital
Panobinostat With Fludarabine and Cytarabine for Treatment of Children With Acute Myeloid Leukemia or Myelodysplastic Syndrome	NCT02676323	Acute Myeloid L... Myelodysplastic...	Panobinostat Fludarabine Cytarabine Intrathecal Tri... Leucovorin	- 24 Years	St. Jude Children's Research Hospital

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