Status and phase
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Treatments
About
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.
Full description
This is an investigator-initiated open-label multi-institutional phase I study of venetoclax combination therapy in both myeloid and lymphoid hematologic malignancies. This study is designed as a basket trial with three separate cohorts. All cohorts include a dose finding portion (Part I) followed by a dose expansion at the Recommended Phase II dose (RP2D, Part II).
This research study is looking to learn more about how Venetoclax works and aims to determine the safest, highest possible dose that can be combined with standard of care chemotherapies. Because of this, not everyone who participates in this research study may receive the same dose of the study drug. The dose participants receive will depend on the number of participants who have been enrolled in the study previously and how well the doses have been tolerated.
Study procedures include screening for eligibility as well as study treatment visits including evaluations and follow up visits.
This research study is a Phase I clinical trial, which tests the safety of an investigational drug and also tries to define the appropriate dose of the investigational drug to use for further studies. "Investigational" means that the drug is being studied. The U.S. Food and Drug Administration (FDA) has not approved Venetoclax for use in children. However, Venetoclax is FDA-approved as a treatment for certain types of leukemia in adults. It is actively being studied in children and adults with other types of cancer. Information from these research studies has suggested that venetoclax may also be effective in treating participants with MDS or leukemia, including MDS or leukemia that did not respond to standard treatment or that has come back after standard treatment. The survival of cancer cells is controlled by proteins within the cancer cell. One of these proteins is called BCL-2. The study drug, venetoclax, blocks this protein and is thought to reduce cell survival in some cancer cells.
Enrollment
Sex
Ages
Volunteers
Inclusion and exclusion criteria
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.
Age ≤ 40 years of age, except the following subjects that must be <18 years to enroll
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
Radiation therapy (XRT):
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):
Adequate organ function, as defined by
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:
And meets at least one the following disease characteristics:
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
Radiation therapy (XRT):
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:
Adequate organ function, as defined by
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.
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.
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:
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:
Radiation therapy (XRT):
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:
Adequate organ function, as defined by the following laboratory values:
Cardiac function as defined as below:
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
Cohort B Exclusion Criteria
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:
Primary purpose
Allocation
Interventional model
Masking
13 participants in 3 patient groups
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Central trial contact
Jessica A Pollard, MD, PhD; Andrew E Place, MD, PhD
Data sourced from clinicaltrials.gov
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