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Venetoclax Basket Trial for High Risk Hematologic Malignancies

ConditionsMyelodysplastic Syndromes, de NovoMyelodysplastic Syndromes, SecondaryMyelodysplastic Syndromes, Previously TreatedTreatment-Related Acute Myeloid LeukemiaTherapy-Related Myelodysplastic SyndromeAcute Lymphoblastic Leukemia, in RelapseAcute Lymphoblastic Leukemia With Failed RemissionLymphoblastic Lymphoma, in RelapseLymphoblastic Lymphoma, RefractoryAcute Leukemia of Ambiguous Lineage in RelapseAcute Leukemia of Ambiguous Lineage
Trial statusRecruiting
Trial phasePhase 1
Trial typeInterventional
Biological sexAll
Age1-40
SponsorAndrew E. Place, MD

About this trial

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

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

MDS with excess blasts (>10%)

MDS with blasts <10% with high-risk features

MDS refractory to initial treatment

Relapsed MDS

Disqualifiers

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.

Trial design

Design model

Parallel

Treatments tested in this trial

  • Venetoclax

    Drug

    Tablet taken orally

  • Azacitidine

    Drug

    Taken intravenously

  • Cytarabine

    Drug

    Lumbar Puncture

  • Methotrexate

    Drug

    Lumbar Puncture

  • Hydrocortisone

    Drug

    Lumbar Puncture

  • Leucovorin

    Drug

    Taken Orally or intravenously

  • Dexamethasone

    Drug

    Taken Orally or intravenously

  • Vincristine

    Drug

    Taken intravenously

  • Doxorubicin

    Drug

    Taken intravenously

  • Dexrazoxane

    Drug

    Taken intravenously

  • Calaspargase Pegol

    Drug

    Taken intravenously

  • Erwinia asparaginase

    Drug

    Given as intramuscular injection

Treatment groups

30 Participants
are divided into 3 treatment groups
Group A: Cohort AExperimental treatment 6 interventions
Group B: Cohort BExperimental treatment 6 interventions
Group C: Cohort CExperimental treatment 11 interventions

Trial outcomes

Primary outcomes

1

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

Time frame
MTD determined during first cycle of treatment (Cohorts A&B: max. 35 Days; Cohort C: 32 days)
2

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.

Time frame
RP2D is determined during first cycle of treatment (Cohorts A&B: max. 35 Days; Cohort C: 32 days)
3

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.

Time frame
Up to 30 days after last dose of study treatment
4

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.

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

Secondary outcomes

1

Overall Response Rate (ORR)

ORR will be defined as the number of patient experiencing complete remission (CR), complete remission with incomplete platelet recovery (CRp), complete remission with incomplete count recovery (CRi) and partial response.

Time frame
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

Complete Remission (CR) Rate

CR Rate is defined as the percentage of participants that reach Complete Remission (CR): Cohorts A and B: * Bone marrow \< 5% myeloblasts by flow cytometry. * No evidence of circulating blasts or extramedullary disease AND * Platelet count ≥50k/uL (or to pre-treatment baseline) and transfusion independent for 7 days AND * Neutrophil count ≥500 cells/uL without G-CSF support. Cohort C (Leukemia): * Absolute phagocyte count (APC) ≥1000/μL and platelets ≥75,000/μL without transfusions and/or exogenous growth factor support AND * Bone marrow with evidence of trilineage hematopoiesis and with \<5% blasts AND * No evidence of extramedullary disease

Time frame
Cohorts A&B: Best response during up to 4 cycles (each cycle is max 35 days). Cohort C: Response to treatment after 32 days
3

Complete Remission with Inadequate Count Recovery (CRi) Rate

Cohort C only: * APC \<1000/μL and/or platelets \<75,000/μL AND * Bone marrow with \<5% blasts AND * No evidence of extramedullary disease

Time frame
Cohort C: Response to treatment
4

Complete Remission with Inadequate Platelet Recovery (CRp) Rate

CRp Rate is defined as the percentage of participant that reach to CRp: Cohorts A \&B: * A bone marrow with \<5% blasts AND * No evidence of circulating blasts or extramedullary disease AND * Recovery of absolute neutrophil counts (ANC \> 500/μL), but with insufficient recovery of platelets (PLT counts \<50,000 ul), and platelet transfusion independence (defined as no platelet transfusion x 1 week) Cohort C: * Absolute neutrophil count (APC ≥1000/μL) AND * Platelets \< 75,000/μL AND * Bone marrow with evidence of trilineage hematopoiesis and with \<5% blasts AND * No evidence of extramedullary disease

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

Other outcomes

1

Proportion of patients to receive all doses of venetoclax

Estimate the proportion of patients who are able to receive all doses of venetoclax in cycle 1 for each cohort.

Time frame
Determined during first cycle of treatment (Cohorts A&B: max. 35 Days, Cohort C: 32 days)
2

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

Define the percentage of patients in cohorts A\&B who successfully proceed to HSCT after treatment with venetoclax combination therapy

Time frame
Up to 2 years

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Andrew E. Place, MD

Lead sponsor

Dana-Farber Cancer Institute

Sponsor institution

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

Source ClinicalTrials.gov
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