Recruiting
Phase 1

Venetoclax

Sponsor:

Andrew E. Place, MD

Code:

NCT05292664

Conditions

Myelodysplastic Syndromes, de Novo

Myelodysplastic Syndromes, Secondary

Myelodysplastic Syndromes, Previously Treated

Treatment-Related Acute Myeloid Leukemia

Therapy-Related Myelodysplastic Syndrome

Eligibility Criteria

Sex: All

Age: 1 - 40

Healthy Volunteers: Not accepted

Interventions

Venetoclax

Azacitidine

Cytarabine

Methotrexate

Hydrocortisone

Study Details

Brief summary:

This trial is evaluating the safety and tolerability of venetoclax with chemotherapy in pediatric and young adult patients with hematologic malignancies, including myelodysplastic syndrome (MDS), acute myeloid leukemia derived from myelodysplastic syndrome (MDS/AML), and acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL).

The names of the study drugs involved in this study are below. Please note this is a list for the study as a whole, participants will receive drugs according to disease cohort.

  • Venetoclax
  • Azacitidine
  • Cytarabine
  • Methotrexate
  • Hydrocortisone
  • Leucovorin
  • Dexamethasone
  • Vincristine
  • Doxorubicin
  • Dexrazoxane
  • Calaspargase pegol
  • Hydrocortisone

Conditions

Myelodysplastic Syndromes, de Novo

Myelodysplastic Syndromes, Secondary

Myelodysplastic Syndromes, Previously Treated

Treatment-Related Acute Myeloid Leukemia

Therapy-Related Myelodysplastic Syndrome

Study ID

NCT05292664

Start date

Mar 29, 2023

Status verified date

Mar, 2026

Completion date

Jul 2, 2030

Anticipated

Primary completion date

Jul 2, 2028

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 1 - 40

Healthy Volunteers: Not accepted

Inclusion Criteria

Cohort A Inclusion Criteria:

  • MDS, AML arising from MDS (MDS/AML), therapy related myeloid neoplasm (tMDS/AML) meeting at least one of the following criteria:

  • MDS with excess blasts (>10%)
  • MDS with blasts <10% with high-risk features
  • MDS refractory to initial treatment
  • Relapsed MDS
  • MDS/AML: May be newly diagnosed or relapsed/refractory disease.
  • Therapy related myeloid neoplasm (tMDS/AML): May be initial or relapsed/refractory disease.

  • Note: MDS or MDS/AML may be derived from a germline predisposition to myeloid malignancy as long as that condition does not confer increased toxicity to treatment.
  • Age ≤ 40 years of age, except the following subjects that must be <18 years to enroll

  • Subjects with MDS/AML that have not received prior therapy
  • Subjects enrolled onto Dose level -2.
  • Lansky/Karnofsky performance status ≥ 50%
  • Participants must have fully recovered from the acute toxic effects of all and meet all of the following criteria:

  • Myelosuppressive chemotherapy: 14 days, or 5 half-lifes (whichever is shorter) must have elapsed since the completion of myelosuppressive therapy. Individuals may have received any of the following medications without a "wash-out" period

  • Standard maintenance therapy: dexamethasone/prednisone, vincristine, 6MP, low dose methotrexate)
  • Hydroxyurea
  • Intrathecal chemotherapy with methotrexate, hydrocortisone and/or cytarabine.
  • Radiation therapy (XRT):

  • Total Body Irradiation (TBI) or cranial radiation therapy: Must have been completed more than 90 days prior to study entry
  • XRT for chloroma does not require a washout period.
  • Palliative XRT does not require a washout
  • Small molecule inhibitors (BCR-ABL or FLT3 inhibitors, for example): 7 days, or 5 half-lifes, whichever is shorter) must have elapsed since the completion of therapy. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur.
  • Immunotherapy: At least 30 days after the administration of any type of immunotherapy, including, but not limited to, tumor vaccines, chimeric antigen receptor (CAR) therapy, other immune effector cell therapy and checkpoint inhibitors.
  • Monoclonal antibodies: At least 3 half-lives of the antibody
  • Prior hematopoietic stem cell transplant (HSCT):

  • Allogeneic HSCT > 90 days of study entry
  • No evidence of graft-versus-host-disease (GVHD)
  • Adequate organ function, as defined by

  • Serum alanine aminotransferase (ALT) ≤5X upper limit of normal (ULN)
  • Direct bilirubin ≤ 3X
  • Ejection fraction ≥ 50% or shortening fraction of ≥ 24% on screening echocardiogram.
  • Female participants of childbearing potential must have a negative urine or serum HCG prior to study entry and at the start of therapy. All females of childbearing potential must refrain from breastfeeding during study participation, and all male and females of childbearing potential must agree to use an effective form of contraception (abstinence, hormonal, or barrier) prior to study entry, for duration of participation, and for a minimum of 30 days following the last dose of treatment.

Cohort B Inclusion Criteria

  • MDS, MDS/AML, therapy related myeloid neoplasm (tMDS/AML) that is derived from the following germline disorders:

  • Dyskeratosis Congenita or associated telomeropathies
  • Fanconi Anemia
  • Nijmegen Breakage
  • Other related disorders with high risk of toxicity may be eligible for this cohort after discussion with the Sponsor-Investigator.
  • And meets at least one the following disease characteristics:

  • MDS with excess blasts (>10%)
  • MDS with blasts <10% with high-risk features
  • MDS refractory to initial treatment
  • Relapsed MDS
  • MDS/AML: May be newly diagnosed or relapsed/refractory disease.
  • Therapy related myeloid neoplasm (tMDS/AML): May be initial or relapsed/refractory disease.
  • Age ≤ 40 years of age
  • Lansky/Karnofsky performance status ≥ 50%
  • Participants must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study and meet all of the following criteria:

  • Myelosuppressive chemotherapy: 14 days, or 5 half-lifes (which ever is shorter) must have elapsed since the completion of myelosuppressive therapy. Individuals may have received any of the following medications without a "wash-out" period

  • Standard maintenance therapy: dexamethasone/prednisone, vincristine, 6MP, low dose methotrexate
  • Hydroxyurea
  • Intrathecal chemotherapy with methotrexate, hydrocortisone and/or cytarabine.
  • Radiation therapy (XRT):

  • Total Body Irradiation (TBI) or cranial radiation therapy: Must have been completed more than 90 days prior to study entry
  • XRT for chloroma does not require a washout period.
  • Palliative XRT does not require a washout
  • Small molecule inhibitors (BCR-ABL or FLT3 inhibitors, for example): 7 days, or 5 half-lifes, whichever is shorter) must have elapsed since the completion of therapy. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur.
  • Immunotherapy: At least 30 days after the administration of any type of immunotherapy, including, but not limited to, tumor vaccines, chimeric antigen receptor (CAR) therapy, other immune effector cell therapy and checkpoint inhibitors.
  • Monoclonal antibodies: At least 3 half-lives of the antibody
  • Prior hematopoietic stem cell transplant (HSCT): Must meet all of the following conditions:

  • Allogeneic HSCT > 90 days of study entry
  • No evidence of graft-versus-host-disease (GVHD)
  • Adequate organ function, as defined by

  • Serum alanine aminotransferase (ALT) ≤5X upper limit of normal (ULN)
  • Direct bilirubin ≤ 3X upper limit of normal for age and institution.
  • Ejection fraction ≥ 50% or shortening fraction of ≥ 24% on screening echocardiogram.
  • Because of the teratogenic effects of venetoclax on developing fetuses, female participants of childbearing potential must have a negative urine or serum HCG prior to study entry and at the start of therapy. All females of childbearing potential must refrain from breastfeeding during study participation, and all male and females of childbearing potential must agree to use an effective form of contraception (abstinence, hormonal, or barrier) prior to study entry, for duration of participation, and for a minimum of 30 days following the last dose of treatment.

Cohort C Inclusion Criteria

  • Part I: B-cell or T-cell acute lymphoblastic leukemia (ALL), mixed phenotype acute lymphoblastic leukemia (MPAL) or lymphoblastic lymphoma (LBL) in first or greater relapse or refractory to at least 1 prior remission induction attempt.

  • For ALL/MPAL: Bone marrow involvement ≥ 5% by aspirate morphology or ≥ 1% assessable by flow cytometry or validated molecular minimal residual disease (MRD) testing
  • For LBL: Radiographically detectable mass or lymph node involvement
  • Part II: Histologically confirmed diagnosis of one of the following:

  • T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL) in first or greater relapse or refractory to at least 1 prior remission induction attempt.

  • For T-ALL: Bone marrow involvement ≥ 5% by aspirate morphology or ≥ 1% assessable by morphology, flow cytometry or validated MRD testing
  • For T-LBL (biopsy proven at current or prior relapse): Radiographically detectable mass or lymph node involvement OR
  • Relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) with bone marrow involvement ≥1% (assessable by morphology, flow cytometry or validated MRD testing) and at least one of the following characteristics:

  • First relapse with adverse biologic determinants as described below:

  • KMT2A rearrangement
  • Low hypodiploidy, defined as ≤ 40 chromosomes
  • t(17;19)
  • IKZF1 deletion (without targetable ABL1 fusion)
  • Ph-like ALL (without targetable ABL1 fusion)
  • Other biologic determinants with adverse prognosis in discussion with the Sponsor-Investigator
  • Early first bone marrow relapse occurring <36 months from initial diagnosis
  • Primary refractory ALL that has failed 1 prior induction attempt
  • Age: ≥ 1 and ≤ 21 years of age
  • Lansky/Karnofsky performance status ≥ 50%
  • Participants must have fully recovered from the acute toxic effects of all prior and meet all of the following criteria:

  • Myelosuppressive chemotherapy: 14 days, or 5 half-lives, whichever is shorter, must have elapsed since the completion of myelosuppressive therapy. Individuals may have received any of the following medications without a "wash-out" period:

  • Standard maintenance therapy: dexamethasone/prednisone, vincristine, 6MP, low dose methotrexate
  • Hydroxyurea
  • Intrathecal chemotherapy with methotrexate, hydrocortisone and/or cytarabine.
  • Radiation therapy (XRT):

  • Total Body Irradiation (TBI) or cranial radiation therapy: Must have been completed more than 90 days prior to study entry
  • XRT for chloroma does not require a washout period.
  • Palliative XRT does not require a washout
  • Small molecule inhibitors (BCR-ABL or FLT3 inhibitors, for example): 7 days, or 5 half-lifes, whichever is shorter) must have elapsed since the completion of therapy. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur.
  • Immunotherapy: At least 30 days after the administration of any type of immunotherapy, including, but not limited to, tumor vaccines, chimeric antigen receptor (CAR) therapy, other immune effector cell therapy and checkpoint inhibitors.
  • Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose of a monoclonal antibody
  • Prior hematopoietic stem cell transplant (HSCT): Patients who have received HSCT are eligible, but must meet all of the following conditions:

  • Allogeneic HSCT > 90 days of study entry
  • No evidence of graft-versus-host-disease (GVHD)
  • Adequate organ function, as defined by the following laboratory values:

  • Serum alanine aminotransferase (ALT) ≤5X upper limit of normal (ULN), unless deemed secondary to leukemic involvement in discussion with site PI.)
  • Direct bilirubin ≤ 3X upper limit of normal for age and institution.
  • Serum amylase ≤ 3X institutional ULN .
  • Cardiac function as defined as below:

  • Ejection fraction ≥ 50% or shortening fraction of ≥ 24% on screening echocardiogram.
  • Maximum prior cumulative doxorubicin dose ≤ 360 mg/m2 or equivalent
  • Because of the teratogenic effects of venetoclax on developing fetuses, female participants of childbearing potential must have a negative urine or serum HCG prior to study entry and at the start of therapy. All females of childbearing potential must refrain from breastfeeding during study participation, and all male and females of childbearing potential must agree to use an effective non-hormonal form of contraception (abstinence, barrier) prior to study entry, for duration of participation, and for a minimum of 3 months following the last dose of treatment (as calaspargase pegol can render hormonal contraceptives ineffective).

Exclusion Criteria

Cohort A Exclusion Criteria

  • Use of strong or moderate CYP3A inhibitors/inducers within 3 days of study entry
  • Individuals who have had a stem cell transplant and are still receiving treatment for GVHD or GVHD prophylaxis, or who have evidence of acute GVHD
  • Individuals with known active hepatitis; baseline testing not required.
  • Patients with systemic infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment.
  • Patients known to have human immunodeficiency virus (HIV) infection; baseline testing for HIV is not required.
  • Pregnant or nursing women are excluded.
  • Individuals with significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.

Cohort B Exclusion Criteria

  • Use of strong or moderate CYP3A inhibitors/inducers within 3 days of study entry
  • Individuals who have had a stem cell transplant and are still receiving treatment for GVHD or GVHD prophylaxis, or who have evidence of acute GVHD
  • Individuals with known active hepatitis; baseline testing not required.
  • Patients with systemic infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment.
  • Patients known to have human immunodeficiency virus (HIV) infection; baseline testing for HIV is not required.
  • Pregnant or nursing women are excluded.
  • Individuals with significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.

Cohort C Exclusion Criteria

  • Use of strong or moderate CYP3A inhibitors/inducers within 3 days of study entry
  • Individuals who have had a stem cell transplant and are still receiving treatment for GVHD or GVHD prophylaxis, or who have evidence of acute GVHD, or who are less than 90 days from stem cell infusion
  • Individuals with known active hepatitis; baseline testing not required.
  • Patients with systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment.
  • Patients known to have human immunodeficiency virus (HIV) infection; baseline testing for HIV is not required.
  • Pregnant or nursing women are excluded
  • Individuals with significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.
  • Individuals with a history of allergic reactions to any of the agents being used in this trial, with the exception of pegaspargase or calaspargase pegol. Participants with a history of allergy to pegylated formulation of asparasginase are allowed on study but should receive commercial supply of asparaginase Erwinia chrysanthemi (Erwinaze), crisantaspase (Erwinase), or asparaginase erwinia chrysanthemi (recombinant)-rywn (Rylaze) instead of calaspargase pegol (see Sections 6.2.6 and 6.2.7). Individuals with a history of allergy to Erwinaze, Erwinase or Rylaze are excluded from the study.
  • History of asparaginase-associated pancreatitis.
  • Known, active and propagating deep venous thrombus (DVT).
  • Individuals with isolated CNS or testicular relapse.
  • Presence of surface immunoglobulin by flow cytometry and/or known t(8;14), t(2;8), or t(8;22).
  • Individuals with a history of a different malignancy are ineligible except for the following circumstances:

  • Individuals are eligible if they have been disease-free for at least 1 year and are deemed by the investigator to be at low risk for recurrence of that malignancy.
  • Individuals with the following cancers are eligible if diagnosed and treated within the past year: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.

Study Design

Enrollment

30 participants

Anticipated

Allocation

Non randomized

Intervention Model

Parallel Assignment

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: Cohort A

For Part 1, participants will receive:

  • Patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 14-20 people will participate in Part 2 (Dose Expansion) of this cohort Treatment cycle is approximately 28 days for up to 4 cycles

  • Venetoclax-once daily on predetermined days per protocol
  • Azacitidine-once daily on predetermined days per protocol

  • Cytarabine, Methotrexate, Hydrocortisone and Leucovorin will be given only if MDS/leukemia cells are detected in spinal fluid per determination of treating physician

experimental: Cohort B

Patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) with an underlying genetic condition that increases their risk for developing treatment-related toxicities. It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 6 people will participate in Part 2 (Dose Expansion) of this cohort.

  • Venetoclax-once daily on predetermined days per protocol
  • Azacitidine-once daily on predetermined days per protocol
  • Cytarabine, Methotrexate, Hydrocortisone and Leucovorin will be given only if MDS/leukemia cells are detected in spinal fluid per determination of treating physician

experimental: Cohort C

Patients with relapsed/refractory acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LBL) or acute leuekmai of ambiguous lineage. It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 12 people will participate in Part 2 (Dose Expansion) of this cohort.

Cohort C: Treatment cycle is approximately 32 days for one cycle and will be a single treatment cycle:

Dosage, duration and timings as outlined in protocol.

  • Venetoclax
  • Dexamethasone
  • Vincristine
  • Doxorubicin
  • Dexrazoxane
  • Calaspargase pegol

---Short acting Erwinia preparations (recombinant or native Erwinia asparaginase) may be used for participants with known pegaspargase or calaspargase pegol allergy
  • Cytarabine
  • Methotrexate
  • Hydrocortisone
  • Leucovorin- \*Cytarabine, Methotrexate, Hydrocortisone and Leucovorin may be given more frequently if leukemia/lymphoma cells are detected in spinal fluid),

Interventions

Venetoclax

Tablet taken orally

Azacitidine

Taken intravenously

Cytarabine

Lumbar Puncture

Methotrexate

Lumbar Puncture

Hydrocortisone

Lumbar Puncture

Leucovorin

Taken Orally or intravenously

Dexamethasone

Taken Orally or intravenously

Vincristine

Taken intravenously

Doxorubicin

Taken intravenously

Dexrazoxane

Taken intravenously

Calaspargase Pegol

Taken intravenously

Erwinia asparaginase

Given as intramuscular injection

Primary outcome measure

  • Maximum tolerated dose (MTD) [ Time Frame: MTD determined during first cycle of treatment (Cohorts A&B: max. 35 Days; Cohort C: 32 days) ]
  • Recommended Phase II Dose [ Time Frame: RP2D is determined during first cycle of treatment (Cohorts A&B: max. 35 Days; Cohort C: 32 days) ]
  • Incidence of Grade 2 or Higher Treatment-Related Toxicity [ Time Frame: Up to 30 days after last dose of study treatment ]
  • Incidence of calaspargase pegol related toxicities [ Time Frame: Cohort C only: Up to 30 days after last dose of study treatment ]

Central Contacts and Locations

Central contacts

Andrew E Place, MD, PhD

617-632-2313andrew_place@dfci.harvard.edu

Jessica A Pollard, MD, PhD

617-632-4321Jessica_Pollard@dfci.harvard.edu

Locations

University of California San Francisco-Benioff Children's Hospital

Recruiting

San Francisco, California, United States, 94158

Contacts

Elliot Stieglitz, MD

Elliot.Stieglitz@ucsf.edu

Children's Hospital Colorado

Recruiting

Aurora, Colorado, United States, 80045

Contacts

Kelly Faulk, MD

720-777-6503Kelly.Faulk@childrenscolorado.org

Children's Healthcare of Atlanta at Arthur M. Blank Hospital

Recruiting

Atlanta, Georgia, United States, 30329

Contacts

Himalee Sabnis, MD

404-785-7986hsabnis@emory.edu

Ann & Robert H Lurie Children's Hospital of Chicago

Recruiting

Chicago, Illinois, United States, 60611

Contacts

Loretta Li, MD

312-227-8859LLi@luriechildrens.org

Dana-Farber Cancer Institute

Recruiting

Boston, Massachusetts, United States, 02215

Contacts

Andrew E Place, MD, PhD

617-632-2313andrew_place@dfci.harvard.edu

Principal Investigator:

Andrew E Place, MD, PhD

More Information

Sponsor

Andrew E. Place, MD

Last update posted

Mar 12, 2026

Last verified

Mar, 2026

Keywords

  • Myelodysplastic Syndrome (MDS)
  • Treatment-related Acute Myelogenous Leukemia
  • AML arising from MDS
  • Relapsed or Refractory Acute Lymphoblastic Leukemia
  • Relapsed or Refractory Acute Lymphoblastic Lymphoma
  • Relapsed or Refractory MDS
  • Treatment-related MDS
  • Relapsed or Refractory Acute leukemia of ambiguous lineage

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-08. This information was provided to ClinicalTrials.gov by Andrew E. Place, MD on 2026-03-12.