Venetoclax and Azacitidine or Chemotherapy for the Treatment of Hematologic Malignancies in Pediatric and Young Adult Patients

Inclusion Criteria

• COHORT A: MDS, MDS/AML, therapy related myeloid neoplasm (tMDS)/therapy-related acute myeloid leukemia (tAML) meeting at least one of the following criteria: * MDS with excess blasts (> 10%), or rising blast count on serial bone marrow exams * MDS with blasts < 10% with high-risk features including del5q, monosomy 5, del7q, monosomy 7, complex cytogenetics (defined as 3+ structural anomalies), congenital or acquired p53 mutations * Patients with myelodysplasia lacking high-risk MDS attributes and disease blast percentage < 10% may qualify if the treating physician determines that pretreatment prior to HSCT is in the best interest of the patient (must be discussed with Sponsor-Investigator) * MDS refractory to initial treatment * Relapsed MDS * MDS/AML: May be newly diagnosed or relapsed/refractory disease. Enrollment limited to those patients not felt to be a candidate for more intensive treatment per the treating physician * Therapy related myeloid neoplasm (tMDS/AML): May be initial or relapsed/refractory disease. If disease involvement is > 20% bone marrow blasts, more intense treatment should be considered. Patients not felt to be a candidate for more intensive treatment per treating MD may be eligible ** Note: Patients with the following characteristics may not be eligible to receive intensive AML-directed therapy and are eligible for participation in this study. *** Cumulative doses of anthracycline greater than 450 mg/m^2 doxorubicin equivalents *** History of allergy to intensive AML-directed therapies including anthracyclines, etoposide, fludarabine, cytarabine, asparaginase, gemtuzumab ozogamicin, and FLT3-inhibitors *** History of intolerance to intensive AML-directed therapies. Intolerance is described as a history of either life-threatening (Common Terminology Criteria for Adverse Events [CTCAE] Version 5.0 Grade 4) or recurrent serious (Grade 3) toxicities attributable to chemotherapy including: Nervous system disorder, infection, left or right ventricular dysfunction, increased alanine aminotransferase (ALT) or aspartate aminotransferase (AST), hyperbilirubinemia, hemorrhage, or acute kidney injury *** Alternative prior Grade >= 3 toxicities or current disabilities effecting the tolerability of intensive AML-directed therapy can be discussed with the Sponsor-Investigator. *** Subjects < 18 years of age who in the opinion of the treating provider would not benefit from intensive multi-agent conventional chemotherapy may be eligible with approval of the Sponsor-Investigator * MDS, MDS/AML or tMDS/AML as defined above may be idiopathic/de novo or derived from a germline predisposition to myeloid malignancy that is not known to confer increased toxicity to treatment, including patients with known germline ANKRD26, DDX41, ELANE and other congenital neutropenia disorders, ETV6, GATA-2, Li-Fraumeni, RUNX1, SAMD9/SAMD9L, or Shwachman-Diamond Syndrome, are eligible ** In the setting of a known germline predisposition, testing (genetic or functional studies) confirming that condition should be provided to coordinating center (DFCI) at time of screening. ** At time of enrollment, if testing for a germline predisposition syndrome is pending, subjects may enroll on Cohort A if concern for Fanconi Anemia, Nijemen Breakage Disorder or Dyskeratosis congenita/ telomere biology disorder is low per the Site principal investigator (PI). If there is concern for an alternative condition that predisposed to malignancy that has increased risk for toxicity, discussion with coordinating center (DFCI) as to suitability for enrollment onto Cohort A should occur during screening.
• COHORT A: Age =< 40 years with the following exceptions: * Subjects >= 18 years of age with MDS/AML that have not received prior therapy are not eligible ** Note: Subjects 18-40 years of age who have been previously treated and subsequently relapse or progress would be eligible * Subjects >= 18 years of age with treatment related myeloid neoplasm (tMDS/AML) that have not received prior therapy for tMDS/AML are not eligible. This includes subjects with treatment-related AML that was not preceded by a diagnosis of tMDS ** Note: Subjects 18-40 years of age who have been previously treated for this condition and subsequently relapse or progress would be eligible * Subjects ≥ 18 years of age enrolled onto Dose level -2 will be eligible
• COHORT A: Participants must have a Lansky/Karnofsky performance status >= 50%
• COHORT A: 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 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 (must be discontinued prior to first dose of study treatment) ** 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 lives (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. The duration of this interval must be discussed with the Sponsor-Investigator * 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 prior to study entry ** No evidence of graft-versus-host-disease (GVHD)
• COHORT A: Serum alanine aminotransferase (ALT) =< 5X upper limit of normal (ULN), unless deemed secondary to leukemic involvement in discussion with site PI
• COHORT A: Direct bilirubin =< 3X upper limit of normal for age and institution
• COHORT A: Ejection fraction >= 50% or shortening fraction of >= 24% on screening echocardiogram
• COHORT A: Because of the teratogenic effects of venetoclax on developing fetuses, female participants of childbearing potential must have a negative urine or serum human chorionic gonadotropin (HCG) prior to study entry and at the start of therapy (if > 7 days since screening HCG). 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. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
• COHORT A: Ability to understand and/or the willingness of their parent or legally authorized representative to sign a written informed consent document
• COHORT A: All genders, races and ethnic groups are eligible for this trial
• COHORT B: MDS, MDS/AML, therapy related myeloid neoplasm (tMDS/AML) that is derived from the following germline disorders: * Dyskeratosis Congenita or associated telomeropathies as defined by telomere length < 1st percentile on 3 out of 4 lymphocyte subsets and/or corresponding pathogenic genetic mutation * Fanconi Anemia as defined by positive chromosomal breakage test to DEB/MMC and/or corresponding pathogenic genetic mutation * Nijmegen Breakage Syndrome as defined by positive chromosomal breakage test to DEB/MMC and/or corresponding pathogenic genetic mutation * Other related disorders with high risk of toxicity may be eligible for this cohort after discussion with the Sponsor-Investigator ** In the setting of a known germline predisposition that meets Cohort B criterion, testing (genetic or functional studies) confirming that condition must be provided to coordinating center (DFCI) at time of screening to ensure appropriate cohort designation ** For potential subjects where this is concern for a germline predisposition associated with an increased risk for chemotherapy-associated toxicity that is not one of the aforementioned diagnoses, subjects may not enroll onto Cohort B until testing (genetic and/or functional) has confirmed or excluded these conditions AND the treating MD has provided to Sponsor-Investigator (DFCI) rationale for inclusion in Cohort B
• COHORT B: Cohort B patients must have at least one of the following disease characteristics: * MDS with excess blasts (>10%), or rising blast count on serial bone marrow exams * MDS with blasts <10% with high-risk features including del5q, monosomy 5, del7q, monosomy 7, complex cytogenetics (defined as 3+ structural anomalies), congenital or acquired p53 mutations * Patients with myelodysplasia lacking high-risk MDS attributes and disease blast percentage <10% may qualify if the treating physician determines that pretreatment prior to hematopoietic stem cell transplantation (HSCT) is in the best interest of the patient (must be discussed with PI) * MDS refractory to initial treatment * Relapsed MDS * MDS/AML: May be newly diagnosed or relapsed/refractory disease. Enrollment limited to those patients not felt to be a candidate for more intensive treatment per the treating physician (see Note below) * Therapy related myeloid neoplasm (tMDS/AML): May be initial or relapsed/refractory disease. If disease involvement is >20% bone marrow blasts, more intense treatment should be considered. Patients not felt to be a candidate for more intensive treatment per treating MD may be eligible * Note: Patients with the following characteristics may not be eligible to receive intensive AML-directed therapy and are eligible for participation in this study ** Cumulative doses of anthracycline greater than 450 mg/m^2 doxorubicin equivalents ** History of allergy to intensive AML-directed therapies including anthracyclines, etoposide, fludarabine, cytarabine, asparaginase, gemtuzumab ozogamicin, and FLT3-inhibitors ** History of intolerance to intensive AML-directed therapies (as above). Intolerance is described as a history of either life-threatening (Common Terminology Criteria for Adverse Events [CTCAE] Version 5.0 Grade 4) or recurrent serious (Grade 3) toxicities attributable to chemotherapy including: Nervous system disorder, infection, left or right ventricular dysfunction, increased ALT or AST, hyperbilirubinemia, hemorrhage, or acute kidney injury ** Alternative prior Grade >= 3 toxicities or current disabilities effecting the tolerability of intensive AML-directed therapy can be discussed with the Sponsor-Investigator ** Should treating physician feel that protocol regimen is optimal for patient care and safety, use of this regimen instead of multi-agent conventional chemotherapy may be approved by Sponsor-Investigator. ** Subjects who in the opinion of the treating provider would not benefit from intensive multi-agent conventional chemotherapy may be eligible with approval of the Sponsor-Investigator.
• COHORT B: Age =< 40 years of age
• COHORT B: Participants must have a Lansky/Karnofsky performance status >= 50%
• COHORT B: 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 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 (must be discontinued prior to first dose of study treatment. ** 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 lives (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. The duration of this interval must be discussed with the Sponsor-Investigator. ** 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. (See table on DVL homepage listing monoclonal antibody half- lives: https://members.childrensoncologygroup). ** 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 prior to study entry *** No evidence of graft-versus-host-disease (GVHD)
• COHORT B: Serum alanine aminotransferase (ALT) =< 5X upper limit of normal (ULN), unless deemed secondary to leukemic involvement in discussion with site PI
• COHORT B: Direct bilirubin =< 3X upper limit of normal for age and institution
• COHORT B: Ejection fraction >= 50% or shortening fraction of >= 24% on screening echocardiogram
• COHORT B: 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 (if > 7 days since screening HCG). 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. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
• COHORT B: Ability to understand and/or the willingness of their parent or legally authorized representative to sign a written informed consent document
• COHORT B: All genders, races and ethnic groups are eligible for this trial
• COHORT C: For inclusion into Cohort C, participants must meet one of the following: * 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, with or without central nervous system (CNS), testicular or other extramedullary disease. *** Patients unable to have bone marrow obtained at study entry due to co-morbid conditions (e.g., large mediastinal mass) may enroll if peripheral blast percentage is greater than 20%. ** For LBL (biopsy proven at current or prior relapse): Radiographically detectable mass or lymph node involvement, with or without CNS or testicular disease. * Part II (not yet open): 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 core/aspirate morphology or >= 1% assessable by flow cytometry or validated molecular MRD testing), with or without CNS, testicular or other extramedullary disease. **** Patients unable to have bone marrow obtained at study entry due to co-morbid conditions (e.g., large mediastinal mass) may enroll if peripheral blast percentage is greater than 20%. *** For T-LBL (biopsy proven at current or prior relapse): Radiographically detectable mass or lymph node involvement, with or without CNS or testicular disease. OR * Relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) with bone marrow involvement >= 5% by core/aspirate morphology or ≥ 1% (assessable by flow cytometry or validated molecular MRD testing), with or without CNS, testicular or other extramedullary disease and at least one of the following characteristics present at current or prior relapse: ** 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. **** Patients unable to have bone marrow obtained at study entry due to co-morbid conditions (e.g., large mediastinal mass) may enroll if peripheral blast percentage is greater than 20%
• COHORT C: Age: >= 1 and =< 21 years of age
• COHORT C: Participants must have a Lansky/Karnofsky performance status >= 50%
• COHORT C: 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-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 lives (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. The duration of this interval must be discussed with the Sponsor-Investigator. * 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. (See table on DVL homepage listing monoclonal antibody half- lives: https://members.childrensoncologygroup) * 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)
• COHORT C: Serum alanine aminotransferase (ALT) =< 5X upper limit of normal (ULN), unless deemed secondary to leukemic involvement in discussion with site PI
• COHORT C: Direct bilirubin =< 3X upper limit of normal for age and institution
• COHORT C: Serum amylase =< 3X institutional ULN
• COHORT C: Ejection fraction >= 50% or shortening fraction of ≥ 24% on screening echocardiogram
• COHORT C: Maximum prior cumulative doxorubicin dose =< 360 mg/m^2 or equivalent * For purposes of conversion to doxorubicin equivalents
• COHORT C: 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 (if > 7 days since screening HCG). 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). Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
• COHORT C: Ability to understand and/or the willingness of their parent or legally authorized representative to sign a written informed consent document
• COHORT C: All genders, races and ethnic groups are eligible for this trial

Exclusion Criteria

• COHORT A: Use of strong or moderate CYP3A inhibitors/inducers within 3 days of study entry, including grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or star fruit is prohibited
• COHORT A: Individuals who have had a stem cell transplant and are still receiving treatment for graft versus host disease (GVHD) or GVHD prophylaxis, or who have evidence of acute GVHD, or who are less than 90 days from stem cell infusion
• COHORT A: Individuals with known active hepatitis; baseline testing not required
• COHORT A: 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
• COHORT A: Patients known to have human immunodeficiency virus (HIV) infection; baseline testing for HIV is not required
• COHORT A: Pregnant or nursing women are excluded
• COHORT A: 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: Use of strong or moderate CYP3A inhibitors/inducers within 3 days of study entry, including grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or star fruit which are strong or moderate CYP3A inhibitors/inducers is prohibited
• COHORT B: 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
• COHORT B: Individuals with known active hepatitis; baseline testing not required
• COHORT B: 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
• COHORT B: Patients known to have human immunodeficiency virus (HIV) infection; baseline testing for HIV is not required
• COHORT B: Pregnant or nursing women are excluded
• COHORT B: 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: Use of strong or moderate CYP3A inhibitors/inducers within 3 days of study entry, including grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or star fruit which are strong or moderate CYP3A inhibitors/inducers is prohibited
• COHORT C: 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
• COHORT C: Individuals with known active hepatitis; baseline testing not required
• COHORT C: 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
• COHORT C: Patients known to have human immunodeficiency virus (HIV) infection; baseline testing for HIV is not required
• COHORT C: Pregnant or nursing women are excluded
• COHORT C: 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: 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 asparaginase 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. Individuals with a history of allergy to Erwinaze, Erwinase or Rylaze are excluded from the study * Note: Site must have sufficient supply of Erwinase/Erwinaze (9 doses) or Rylaze (10 doses) prior to enrollment
• COHORT C: Individuals with a history of asparaginase-associated pancreatitis
• COHORT C: Individuals with known, active and propagating deep venous thrombus (DVT). Subjects who are anticoagulated and with stable DVT by imaging are eligible
• COHORT C: Individuals with isolated CNS or testicular relapse
• COHORT C: Individuals whose lymphoblasts have surface immunoglobulin by flow cytometry and/or known t(8;14), t(2;8), or t(8;22). Absence of surface immunoglobulin by flow cytometry at time of initial diagnosis or relapse is sufficient to rule out mature B-cell leukemia; karyotype or fluorescence in situ hybridization (FISH) results documenting absence of t(8;14), t(2;8), or t(8;22) are not necessary prior to enrollment if absence of surface of immunoglobulin is documented by flow cytometry
• COHORT C: 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