Venetoclax Basket Trial for High Risk Hematologic Malignancies

NCT05292664 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 21-757
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 5

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; Acute Lymphoblastic Leukemia, in Relapse; Acute Lymphoblastic Leukemia With Failed Remission; Lymphoblastic Lymphoma, in Relapse; Lymphoblastic Lymphoma, Refractory; Acute Leukemia of Ambiguous Lineage in Relapse; Acute Leukemia of Ambiguous Lineage

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

Outcome Measures

Primary Outcomes (4)

• Maximum tolerated dose (MTD)

  To determine the maximum tolerated dose (MTD of venetoclax given in combination with regimen-prescribed chemotherapy. The MTD is defined as the dose level associated with observed DLTs in \<33% of enrolled subjects

  MTD determined during first cycle of treatment (Cohorts A&B: max. 35 Days; Cohort C: 32 days)

• Recommended Phase II Dose

  To determine the Recommended Phase 2 Dose (RP2D) of venetoclax given in combination with regimen-prescribed chemotherapy. The RP2D is defined either as the MTD or maximum dose tested should MTD not be reached.

  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

  All grade 2 or higher adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAE v5 criteria. Incidence is the number of patients experiencing at least one treatment-related grade 2 or higher AE of any type during the time of observation.

  Up to 30 days after last dose of study treatment

• Incidence of calaspargase pegol related toxicities

  Describe the incidence and severity of calaspargase pegol-related toxicities in subjects with relapsed/refractory ALL/LBL per collected Adverse Events using CTCAE v5 criteria.

  Cohort C only: Up to 30 days after last dose of study treatment

Secondary Outcomes (6)

• Overall Response Rate (ORR)

  Cohorts A&B: Best response during up to 4 cycles (each cycle is max 35 days). Cohort C: Response to treatment after 32 days

• Complete Remission (CR) Rate

  Cohorts A&B: Best response during up to 4 cycles (each cycle is max 35 days). Cohort C: Response to treatment after 32 days

• Complete Remission with Inadequate Count Recovery (CRi) Rate

  Cohort C: Response to treatment

• Complete Remission with Inadequate Platelet Recovery (CRp) Rate

  Cohorts A&B: Best response during up to 4 cycles (each cycle is max 35 days). Cohort C: Response to treatment after 32 days

• 2-year Overall Survival (OS)

  Up to 2 years

Other Outcomes (2)

• Proportion of patients to receive all doses of venetoclax

  Determined during first cycle of treatment (Cohorts A&B: max. 35 Days, Cohort C: 32 days)

• Percentage of patients to proceed to Hematopoietic Stem Cell Transplant (HSCT)

  Up to 2 years

Study Arms (3)

Cohort A

EXPERIMENTAL

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

Drug: Venetoclax; Drug: Azacitidine; Drug: Cytarabine; Drug: Methotrexate; Drug: Hydrocortisone; Drug: Leucovorin

Cohort B

EXPERIMENTAL

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

Drug: Venetoclax; Drug: Azacitidine; Drug: Cytarabine; Drug: Methotrexate; Drug: Hydrocortisone; Drug: Leucovorin

Cohort C

EXPERIMENTAL

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),

Drug: Venetoclax; Drug: Cytarabine; Drug: Methotrexate; Drug: Hydrocortisone; Drug: Leucovorin; Drug: Dexamethasone; Drug: Vincristine; Drug: Doxorubicin; Drug: Dexrazoxane; Drug: Calaspargase Pegol; Drug: Erwinia asparaginase

Interventions

Hydrocortisone DRUG

Lumbar Puncture

Also known as: Cortisone, Hydrocortisone Sodium Succinate, Hydrocortisone Sodium Phosphate

Cohort A; Cohort B; Cohort C

Leucovorin DRUG

Taken Orally or intravenously

Also known as: Calcium Leucovorin,, Citrovorum Factor, Folinic Acid

Cohort A; Cohort B; Cohort C

Dexamethasone DRUG

Taken Orally or intravenously

Also known as: dexamethasone sodium phosphate, dexamethasone acetate

Cohort C

Vincristine DRUG

Taken intravenously

Also known as: Vincristine Sulfate, LCR, VCR

Cohort C

Doxorubicin DRUG

Taken intravenously

Also known as: Adriamycin, Rubex

Cohort C

Dexrazoxane DRUG

Taken intravenously

Also known as: Zinecard

Cohort C

Calaspargase Pegol DRUG

Taken intravenously

Also known as: Asparlas

Cohort C

Erwinia asparaginase DRUG

Given as intramuscular injection

Also known as: Rylze or native Erwinia asparaginase

Cohort C

Venetoclax DRUG

Tablet taken orally

Also known as: Venclexta

Cohort A; Cohort B; Cohort C

Azacitidine DRUG

Taken intravenously

Also known as: Vidaza

Cohort A; Cohort B

Cytarabine DRUG

Lumbar Puncture

Also known as: Ara-C, Arabinosylcytosine

Cohort A; Cohort B; Cohort C

Methotrexate DRUG

Lumbar Puncture

Also known as: Amethopterin, Methotrexate Sodium, MTX

Cohort A; Cohort B; Cohort C

Eligibility Criteria

• Age: 1 Year - 40 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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.
• 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.
• Use of strong or moderate CYP3A inhibitors/inducers within 3 days of study entry

Sponsors & Collaborators

• Andrew E. Place, MD: lead
• AbbVie: collaborator
• Servier: collaborator
• Children's Cancer Research Fund: collaborator
• University of Colorado, Denver: collaborator
• Boston Children's Hospital: collaborator
• Gateway for Cancer Research: collaborator

Study Sites (5)

University of California San Francisco-Benioff Children's Hospital

San Francisco, California, 94158, United States

RECRUITING

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

RECRUITING

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

Atlanta, Georgia, 30329, United States

RECRUITING

Ann & Robert H Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

RECRUITING

MeSH Terms

Conditions

Myelodysplastic Syndromes; Neoplasm Metastasis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Biphenotypic, Acute; Recurrence

Interventions

venetoclax; Azacitidine; Cytarabine; Methotrexate; Hydrocortisone; Cortisone; hydrocortisone sodium phosphate; Leucovorin; Dexamethasone; dexamethasone 21-phosphate; dexamethasone acetate; Vincristine; Doxorubicin; Dexrazoxane; calaspargase pegol; asparaginase erwinia chrysanthemi recombinant

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Arabinonucleosides; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Coenzymes; Enzymes and Coenzymes; Pregnadienetriols; Pregnadienes; Steroids, Fluorinated; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Indolizidines; Indolizines; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Aminoglycosides; Glycosides; Carbohydrates; Razoxane; Diketopiperazines; Piperazines

Study Officials

• Andrew E Place, MD, PhD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Andrew E Place, MD, PhD

CONTACT

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

Jessica A Pollard, MD, PhD

CONTACT

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor-Investigator

Study Record Dates

• First Submitted: March 5, 2022
• First Posted: March 23, 2022
• Study Start: March 29, 2023
• Primary Completion (Estimated): July 2, 2028
• Study Completion (Estimated): July 2, 2030
• Last Updated: March 12, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (5)