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Trial Treating Relapsed Acute Lymphoblastic Leukemia With Venetoclax and Navitoclax

Primary Purpose

Refractory Acute Lymphoblastic Leukemia, Relapsed Acute Lymphoblastic Leukemia

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Venetoclax
Navitoclax
Dexamethasone
Vincristine
Calaspargase Pegol
Dasatinib
Cytarabine
Blinatumomab
Methotrexate
Mercaptopurine
Cyclophosphamide
Etoposide
Leucovorin
Intrathecal Triples
Pegaspargase
Erwinia asparaginase
Radiation
Sponsored by
St. Jude Children's Research Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Refractory Acute Lymphoblastic Leukemia focused on measuring Recurrent Acute Lymphoblastic Leukemia, Refractory Acute Lymphoblastic Leukemia, Children, Young Adults

Eligibility Criteria

4 Years - 30 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Diagnosis:

    • Relapsed or refractory acute lymphoblastic leukemia or lymphoma with ≥1% bone marrow disease as measured by flow cytometry, PCR, or next generation sequencing. However, if an adequate bone marrow sample cannot be obtained, patients may be enrolled if there is unequivocal evidence of leukemia with ≥ 5% blasts in the peripheral blood.
    • Patients with 1-4.99% bone marrow involvement must have disease confirmed in one of the following ways: an alternative minimal residual disease assay (e.g. flow cytometry and PCR or NGS), cytogenetic abnormality consistent with patient's leukemia, FISH abnormality, or a second bone marrow with MRD ≥1% separated by 1-4 weeks.
    • Patients with ≥5% bone marrow disease by a single measurement as measured by flow cytometry, PCR, or next generation sequencing do not require a second confirmatory test.
    • Refractory disease is defined as residual leukemia ≥1% after at least 2 prior lines of frontline therapy with curative intent.
    • Patients in exploratory cohort I must have measurable extramedullary disease but may have <1% bone marrow disease.
    • Patients in exploratory cohort M must have ≥1% bone marrow disease as measured by flow cytometry of mixed phenotype acute leukemia (MPAL)/ acute leukemia of ambiguous lineage (ALAL).
  • Age ≥4 to < 30 years. Patients ≥ 22 years old are only eligible for exploratory cohort O. Sites may have different (lower) maximum ages based on institutional guidelines but may not exceed 30 years.
  • Patient weighs ≥ 20 kg.
  • Patient is able to swallow pills.
  • Lansky/Karnofsky score is ≥ 60%. The Lansky performance score should be used for participants < 16 years and the Karnofsky performance score for participants ≥ 16 years.
  • Participant has adequate organ function as defined by the following:

    • Direct bilirubin ≤ 1.5x the institutional upper limit of normal (ULN). At institutions which do not obtain a direct bilirubin in patients with a normal total bilirubin, a normal total bilirubin may be used as evidence that the direct bilirubin is not > 1.5x the ULN.
    • Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0 x the ULN unless increase is attributable to leukemic involvement.
    • Normal creatinine for age or a calculated creatinine clearance ≥ 60 mL/min/1.73 m^2.
    • Left ventricular ejection fraction (LVEF) ≥ 40% or shortening fraction ≥ 25%.

      • Patients with a history of reduced LVEF which subsequently improved with medical management are eligible if they meet the criteria above.
  • Patients must have fully recovered from the acute effects of all prior therapy (defined as resolution of all such toxicities to ≤ Grade 2).
  • For patients with prior hematopoietic stem cell transplant (HSCT), at least 90 days must have elapsed since transplant, the patient cannot have evidence of active graft-versus-host disease (GVHD), and they must be off calcineurin inhibitors for ≥4 weeks, and off other immunosuppression for ≥2 weeks.
  • Patients with Down Syndrome/ germline Trisomy 21 are eligible for Block 1 and Block 2b therapies but are ineligible for Block 2a therapy. Patients with Down Syndrome and CD19-negative disease are off therapy after the response evaluation to Block 1.
  • Prior therapy

    • ≥14 days must have elapsed since the completion of cytotoxic therapy, with the exception of standard maintenance therapy (glucocorticoids, vincristine, methotrexate, 6-mercaptopurine), tyrosine kinase inhibitors, and steroids.
    • Cytoreduction with prednisone, methylprednisolone, or hydroxyurea for ≤ 120 hours (5 days) in patients with hyperleukocytosis or extramedullary disease compromising organ function can be initiated and continued until up to 24 hours prior to the start of protocol therapy.
    • At least 21 days must have elapsed since completion of therapy with a biologic agent excluding blinatumomab. For agents that have known adverse events occurring beyond 21 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur. At least 7 days must have elapsed since blinatumomab infusion and patients must have recovered from all toxicities as described above.
    • Intrathecal cytotoxic therapy: No waiting period is required for patients having received intrathecal cytarabine, methotrexate, and/or hydrocortisone. Intrathecal chemotherapy given at the time of diagnostic LP to evaluate for relapse prior to study enrollment is allowed.
    • Patient has not had prior exposure to navitoclax
  • Male or female participant of reproductive potential must agree to use appropriate methods of contraception for the duration of study treatment and for at least 30 days after last dose of protocol treatment.
  • Additional criteria for exploratory cohorts

    • Cohort I: Diagnosis of isolated extramedullary relapse as defined by bone marrow blasts of <1% AND 1) central nervous system white blood cell count (WBC) of ≥ 5WBC/mL with blasts or 2) biopsy confirmed extramedullary leukemia.
    • Cohort M: Diagnosis of relapsed or refractory mixed phenotype acute leukemia (MPAL)/ acute leukemia of ambiguous lineage (ALAL).
    • Cohort N: Patients with relapsed or refractory ALL who, in the view of the provider, are unable to tolerate further asparaginase therapy due to prior toxicities.
    • Cohort O: Patients with relapsed or refractory ALL who are ages 22-29.9 years. This cohort may not enroll patients at all sites based on institutional guidelines or capacity.

Exclusion Criteria:

  • Known HIV infection or active hepatitis B (defined as hepatitis B surface antigen-positive) or C (defined as hepatitis C antibody-positive).
  • Pregnant or lactating (female participant of childbearing potential must have negative serum or urine pregnancy test required within 7 days prior to start of treatment).
  • Concomitant medications and food:

    • Treatment with moderate or strong cytochrome P450 3A (CYP3A) inhibitors within 3 days of starting protocol therapy.
    • Treatment with moderate or strong CYP3A inducers within 7 days of starting protocol therapy.
    • Administration or consumption within 3 days prior to the first dose of study drug or grapefruit or grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit.
  • Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.

Sites / Locations

  • St. Jude Children's Research HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Block 1

Block 2

Arm Description

All eligible patients receive intervention according to the Detailed Description section with the following: Venetoclax, Navitoclax, Dexamethasone, Vincristine, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Dasatinib, Leucovorin, Intrathecal (IT) MHA (methotrexate/hydrocortisone/cytarabine)

Block 2a Therapy: Patients receive intervention according to the Detailed Description section with the following: Venetoclax, Navitoclax, Dexamethasone, Cytarabine, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Dasatinib, IT MHA, Radiation Block 2b Therapy: Patients receive intervention according to the Detailed Description section with the following: Venetoclax, Blinatumomab, Dexamethasone, Dasatinib, IT MHA Following Block 2 of therapy, late (≥36 months from diagnosis) first relapse B-ALL who are MRD negative after Block 1 will continue chemotherapy using adapted R3 intensification, interim, and continuation therapies. Patients receive intervention according to the Detailed Description section with the following: Methotrexate, Mercaptopurine, IT MHA, Leucovorin, Dexamethasone, Vincristine, Cyclophosphamide, Etoposide, Cytarabine, Dasatinib, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Radiation

Outcomes

Primary Outcome Measures

Minimal Residual Disease (MRD)-negative response
The proportion of patients with end block 1 minimal residual disease <0.01% by flow cytometry
Recommended Phase 2 dose of venetoclax in combination with a) high-dose cytarabine and navitoclax or b) blinatumomab
The recommended Phase 2 dose (RP2D) of venetoclax in combination with a) high-dose cytarabine and navitoclax or b) blinatumomab will be the dose at which 0 or 1 of 6 treated patients experience a dose limiting toxicity.

Secondary Outcome Measures

Grade 3 or higher CTCAE events in block 2a
Occurrence of grade 3 or higher CTCAE version 5 events in patients receiving block 2a therapy estimated as a proportion of patients receiving that therapy
Grade 3 or higher CTCAE events in block 2b
Occurrence of grade 3 or higher CTCAE version 5 events in patients receiving block 2b therapy estimated as a proportion of patients receiving that therapy
Event Free Survival (EFS)
EFS will be reported as estimates using the Kaplan-Meier method
Overall survival (OS)
OS will be reported as estimates using the Kaplan-Meier method

Full Information

First Posted
January 11, 2022
Last Updated
September 14, 2023
Sponsor
St. Jude Children's Research Hospital
Collaborators
AbbVie
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1. Study Identification

Unique Protocol Identification Number
NCT05192889
Brief Title
Trial Treating Relapsed Acute Lymphoblastic Leukemia With Venetoclax and Navitoclax
Official Title
RAVEN: A Phase I/II Trial Treating Relapsed Acute Lymphoblastic Leukemia With Venetoclax and Navitoclax
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 25, 2022 (Actual)
Primary Completion Date
August 2024 (Anticipated)
Study Completion Date
July 2029 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
St. Jude Children's Research Hospital
Collaborators
AbbVie

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This is a phase I/II clinical trial evaluating the activity of combination chemotherapy with venetoclax and navitoclax in children with relapsed or refractory acute lymphoblastic leukemia or lymphoma (rALL) and assessing the combination dose of venetoclax combinations with either blinatumomab for CD19-postive patients or navitoclax and high-dose cytarabine for CD19-negative patients. Primary Objectives To compare Minimal Residual Disease (MRD)-negative CR/CRi rate in children with relapsed or refractory acute lymphoblastic leukemia or lymphoma (rALL) following Block 1 therapy with venetoclax and navitoclax based reinduction to historical controls. To identify the recommended phase 2 combination dose (RP2D) of venetoclax based consolidation in novel combinations with a) high-dose cytarabine and navitoclax or b) blinatumomab. Secondary Objectives To estimate the tolerability and activity of venetoclax based consolidation in novel combinations with a) high-dose cytarabine and navitoclax or b) blinatumomab. To describe event-free and overall survival in patients treated with this regimen. Exploratory Objectives To evaluate MRD-negative CR/CRi rates in each prespecified groups: late first relapse B-ALL; early first relapse and second or greater relapse B-ALL; and relapsed T-ALL. To identify drug sensitivity patterns in patient samples prior to and after receiving combination therapy and evaluate mechanisms of disease resistance/ escape. To explore immune subsets during and after this regimen. Evaluate response to therapy in rare relapse patient subsets. Explore breakthrough infections in children and young adults with relapsed or refractory ALL
Detailed Description
This is a non-randomized phase I/II clinical trial. In Block I, all patients receiving common therapy evaluating the activity of combination chemotherapy with venetoclax and navitoclax in children with relapsed or refractory acute lymphoblastic leukemia or lymphoma (rALL). In Block 2, a phase 1 rolling six design and phase 2 extension will be used to assess the combination dose of venetoclax combinations with either blinatumomab for CD19-postive patients or navitoclax and high-dose cytarabine for CD19-negative patients. One to six participants can be concurrently enrolled onto a dose level, depending on the number of participants enrolled at the current dose level, the number of participants who have experienced a dose/combination limiting toxicity (DLT) at the current dose level, and the number of participants entered but with tolerability data pending. Dose de-escalation will occur if 2 patients at a dose level experience a targeted toxicity. If 6 patients complete a therapy block and experience 0-1 DLT, that dose will be considered the recommended phase 2 dose (RP2D). New enrollment on an arm (2a/2b) will be paused if further enrollment would result in more than 6 patients being treated on that arm before the RP2D is identified. The primary outcome assessment will be a bone marrow with MRD testing on Day 29 of Block 1 therapy. Following that assessment, patients should continue with protocol therapy including either Block 2A (which includes high-dose cytarabine with venetoclax and navitoclax) for patients with CD19 negative leukemia, those with isolated extramedullary relapse, or whose treating physician determines that blinatumomab therapy is not in the patient's best interest; or Block 2B for patients with leukemia which is CD19 positive. Following recovery from Block 2 therapy, all patients except those with late first relapse of B-ALL (≥ 36 months from diagnosis) who are MRD-negative at <0.01% after Block 1 therapy are off therapy. Further therapy for these patients is at the treating physician's discretion. Patients with late first relapse B-ALL relapse and who are MRD negative will proceed with intensification, interim continuation, and continuation therapy. Patients with Down's Syndrome with CD19 negative leukemia will be off therapy after Block 1 as they are ineligible for Block 2A. Patients in exploratory cohorts I and N who are late first relapse B-ALL and who are MRD-negative after Block 1 therapy may continue on protocol therapy after Block 2 or receive alternative therapy at their treating physician's discretion. Patients in exploratory cohort M and O are off therapy after Block 2. Intervention: Block 1 Therapy: Venetoclax 120mg/m^2 (max 200mg) PO, day 1; 240mg/m^2/dose (max 400mg) PO, 21 doses, days 2-22 Navitoclax 25mg PO (for patients 20 - <45kg) OR 50mg PO (for patients >=45kg), days 3-22 Dexamethasone 5mg/m^2/dose BID PO/IV, days 1-7 and 15-22 Vincristine 1.5mg/m^2/dose (max 2mg) IV, days 1, 8, 15, and 22 Calaspargase pegol 2500units/m^2/dose IV, day 2 Dasatinib 80mg/m^2/day (max 140mg) PO, days 1-28 for ABL-class fusions and non-ETP T-ALL IT MHA: Intrathecal (IT) MHA (methotrexate 12 mg/hydrocortisone 24mg/cytarabine 36mg), days -7 to 1. Continue intrathecal chemotherapy weekly until negative x 2. Leucovorin 5mg/m2 (max 5mg) PO or IV (24 and 30 hours after each LP). Calaspargase may be replaced by alternative forms of asparaginase due to local practice or prior allergy. If pegaspargase is used, two doses (on days 2 and 15) of 2500units/ m^2 replace the single day 2 dose of calaspargase. For patients in exploratory cohort N, asparaginase will be omitted. For patients in exploratory cohort O, the Day 15 dose of pegaspargase may be omitted and the Day 2 dose may be capped at 2000units/m2 with a maximum dose of 3750 units. Testicular Radiation: Patients with persistent testicular involvement by leukemia at the end of Block 1 may continue on study and may receive testicular radiation during Block 2 therapy. Block 2a - For patients with ≥ 5% of leukemic blasts which do not have detectable CD19 on their surface, those with isolated extramedullary relapse, or whose physician determines this therapy arm is in their patient's best interest. Patients with Down Syndrome are not eligible for Block 2a therapy. Patients in exploratory cohort O are not eligible for the phase I/dose de-escalation phase of the study but may enroll on block 2 therapy after the dose has been established.: Venetoclax 240mg/m^2 (max 400mg) PO, days 1-7 Navitoclax 25mg (20-<45kg) OR 50mg (>=45kg) PO, days 1-7 Dexamethasone 3mg/m^2/dose PO/IV BID, days 1-5 Calaspargase pegol 1000units/m^2 IV, day 3 Dasatinib 80mg/m2/day (max 140mg) PO, days 1-28 for ABL-class fusion and non-ETP T-ALL/ALLy IT MHA: Methotrexate 12 mg IT, Hydrocortisone 24mg IT, Cytarabine 36mg IT, one dose with end of cycle bone marrow assessment Cytarabine dosing during phase I portion for Block 2a: Dose level 1: 3000mg/m^2/dose every 12hours(h) IV infusion over 3 hours, days 1-2 Dose level 0: 1500mg/m^2/dose every 12h IV infusion over 3 hours, days 1-2 Dose level -1: 1000mg/m^2/dose every 12h IV infusion over 3 hours, day 1 Calaspargase may be replaced by alternative forms of asparaginase. For patients in exploratory cohort N, asparaginase will be omitted. Block 2b Therapy: For patients with >95% of leukemic blasts with detectable CD19 on their surface. Patients with isolated extramedullary relapse are ineligible for Block 2b therapy. Patients in exploratory cohort O are not eligible for the phase I/ dose de-escalation phase of the study but may enroll on block 2 therapy after the dose has been established. Blinatumomab; for patients with end of Block 1 MRD >5%, 5mcg/m^2/day (max 9mcg/day; patients weighing ≥45kg receive 9mcg/day fixed dose) IV, days 1-7 Blinatumomab; for patients with end of Block 1 MRD >5%, 15mcg/m^2/day (max 28mcg/day; patients weighing ≥45kg receive 28mcg/day fixed dose) IV, days 8-28 Blinatumomab; for patients with end of Block 1 MRD ≤5%, 15mcg/m^2/day (max 28mcg/day; patients weighing ≥45kg receive 28mcg/day fixed dose) IV, days 1-28, Dexamethasone 10mg/m^2 (max 20mg) 30-60 minutes prior to day 1 blinatumomab, PO/IV, days 1, 8 (For patients who start blinatumomab at 5mcg/m2/day, an additional dose of dexamethasone will be given on day 8 30-60 minutes prior to dose increase. For patients whose blinatumomab is interrupted for more than 4 hours for any reason, an additional dose of dexamethasone will be given prior to restarting blinatumomab.) Dasatinib 80mg/m^2/day (max 140mg) PO, days 1-28 for ABL-class fusions IT MHA: Methotrexate 12 mg IT, Hydrocortisone 24mg IT, Cytarabine 36mg IT, day 29 with end of cycle bone marrow Venetoclax dosing during phase I portion for Block 2b: Dose level 1: 240mg/m^2 (max 400 mg) PO, days 8-28 Dose level 0: 240mg/m^2 (max 400 mg) PO, days 8-21 Dose level -1: 240mg/m^2 (max 400 mg) PO, days 8-14 Intensification Therapy - For late first relapse B-ALL and MRD<0.01% after Block 1 only. Patients in exploratory cohort O are excluded.: High Dose (HD) Methotrexate 5000mg/m^2/dose IV: 500mg/m^2 over 60 minutes then 4500mg/m^2 over 23 hours; or targeted 65 microM, day 1 and 15 Mercaptopurine 50mg/m^2/dose PO daily, days 1-28 IT MHA: Methotrexate 12 mg IT, Hydrocortisone 24mg IT, Cytarabine 36mg IT, D15 Leucovorin 15mg/m2/dose PO/IV every 6 hours (start 42 hours after HD-MTX begins) D2 and 16 (at least 3 doses). Interim Continuation Therapy 1 and 2 (8 weeks each) - For late first relapse B-ALL and MRD<0.01% after Block 1 only: Dexamethasone 3mg/m^2/dose BID PO/IV, days 1-5 Vincristine1.5mg/m^2(max 2mg) IV, day 1 Mercaptopurine 75mg/m^2/dose PO daily or 60mg/m2/day for patients with known heterozygous inactivating mutations of TPMT or NUDT15, days 1-49 Methotrexate 20mg/m^2/dose PO/IV, days 8, 15, 29, 36 High Dose (HD)-Methotrexate 5000mg/m^2/dose IV: 500mg/m2 over 60 minutes then 4500mg/m^2 over 23 hours; or targeted 65 microM, day 22 Leucovorin 15mg/m^2/dose PO/IV every 6 hours: Start 42 hours after HD-MTX, days 24 and 25 (at least 3 doses) Cyclophosphamide 300mg/m^2/dose IV over 15-30 minutes, days 43 and 50 Etoposide 150mg/m^2/dose IV over 1-2 hours, days 43 and 50 Cytarabine 50mg/m^2/dose IV over 1-30 minutes, days 44-47 and 51-54 Dasatinib 80mg/m^2/day PO (Max 140mg), days 1-56 for ABL-class fusions IT MHA: Methotrexate 12 mg IT, Hydrocortisone 24mg IT, Cytarabine 36mg IT, days 22 and 43 Following recovery from Interim Continuation therapy 1, patients will repeat Block 2 therapy according to their initial Block assignment (2A for CD19-negative, 2B for CD19-positive) and receive a second cycle of interim continuation. Patients will not receive venetoclax or navitoclax during this repeated Block 2 cycle. Following recovery from Interim Continuation 2, patients will proceed to Continuation therapy. Continuation Therapy - For late first relapse B-ALL and MRD <0.01% after Block 1 only. Continuation cycles last 8 weeks (56 days) each. Continuation therapy continues until 2 years from the start of protocol therapy.: Dexamethasone 6mg/m^2/dose BID PO/IV, days 1-5, 29-33 Vincristine 1.5mg/m^2 (max 2mg) IV, day 1 and 29 Mercaptopurine 75mg/m^2/dose PO daily or 60mg/m^2/day for patients with known heterozygous inactivating mutations of TPMT or NUDT15 days 1-56 Methotrexate 20mg/m^2/dose PO/IV days 8, 15, 22, 36, 43 and 50 Dasatinib 80mg/m^2/day PO (Max 140mg) days 1-56 for ABL-class fusions IT MHA: Methotrexate 12 mg IT, Hydrocortisone 24mg IT, Cytarabine 36mg IT day 1 and 29 (patients with CNS2 or traumatic lumbar puncture with blasts present at the time of relapse will receive day 1 and 29 IT MHA for the first year of continuation therapy. Following this, patients will receive IT MHA on day 1 of each cycle until the completion of therapy. Patients with CNS3 disease at relapse will receive day 1 and 29 IT MHA during cycles 1 and 2 of continuation and then proceed to chemoradiation.) Chemoradiation for those with CNS3 disease at relapse (late first relapse [≥36 months from diagnosis] B-ALL and MRD<0.01% after Block 1 only): Patients with CNS3 disease at relapse will receive 18Gy cranial irradiation after Cycle 2 of Continuation Therapy. Patients will not receive additional intrathecal chemotherapy following irradiation. Chemoradiation lasts 21 days. Dexamethasone 6mg/m2/dose BID PO/IV days 1-5 and 15-19 Vincristine 1.5mg/m^2 (max 2mg) IV days 1, 8 and 15 Calaspargase 2500units/m^2/dose IV, Day 2 (Calaspargase may be replaced by alternative forms of asparaginase and will be omitted for patients in exploratory cohort N) Dasatinib 80mg/m^2/day PO (Max 140mg) days 1-21 for ABL-class fusions

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Refractory Acute Lymphoblastic Leukemia, Relapsed Acute Lymphoblastic Leukemia
Keywords
Recurrent Acute Lymphoblastic Leukemia, Refractory Acute Lymphoblastic Leukemia, Children, Young Adults

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Model Description
All eligible patients receive a common first block of therapy and therapy in the 2nd block being determined by CD19 expression on leukemic blasts.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
90 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Block 1
Arm Type
Experimental
Arm Description
All eligible patients receive intervention according to the Detailed Description section with the following: Venetoclax, Navitoclax, Dexamethasone, Vincristine, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Dasatinib, Leucovorin, Intrathecal (IT) MHA (methotrexate/hydrocortisone/cytarabine)
Arm Title
Block 2
Arm Type
Experimental
Arm Description
Block 2a Therapy: Patients receive intervention according to the Detailed Description section with the following: Venetoclax, Navitoclax, Dexamethasone, Cytarabine, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Dasatinib, IT MHA, Radiation Block 2b Therapy: Patients receive intervention according to the Detailed Description section with the following: Venetoclax, Blinatumomab, Dexamethasone, Dasatinib, IT MHA Following Block 2 of therapy, late (≥36 months from diagnosis) first relapse B-ALL who are MRD negative after Block 1 will continue chemotherapy using adapted R3 intensification, interim, and continuation therapies. Patients receive intervention according to the Detailed Description section with the following: Methotrexate, Mercaptopurine, IT MHA, Leucovorin, Dexamethasone, Vincristine, Cyclophosphamide, Etoposide, Cytarabine, Dasatinib, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Radiation
Intervention Type
Drug
Intervention Name(s)
Venetoclax
Other Intervention Name(s)
Venclextra®, ABT-199
Intervention Description
Given oral (PO).
Intervention Type
Drug
Intervention Name(s)
Navitoclax
Other Intervention Name(s)
ABT-263
Intervention Description
Given oral (PO).
Intervention Type
Drug
Intervention Name(s)
Dexamethasone
Other Intervention Name(s)
Decadron®, Hexadrol®, Dexameth®
Intervention Description
Given orally (PO) or intravenously (IV).
Intervention Type
Drug
Intervention Name(s)
Vincristine
Other Intervention Name(s)
Vincristine sulfate, Oncovin®
Intervention Description
Given intravenously (IV).
Intervention Type
Drug
Intervention Name(s)
Calaspargase Pegol
Other Intervention Name(s)
Asparlas
Intervention Description
Given intravenously (IV).
Intervention Type
Drug
Intervention Name(s)
Dasatinib
Other Intervention Name(s)
Sprycel®
Intervention Description
Given oral (PO).
Intervention Type
Drug
Intervention Name(s)
Cytarabine
Other Intervention Name(s)
Ara-C, Cytosar-U®
Intervention Description
Given intravenously (IV) or Intrathecal (IT).
Intervention Type
Biological
Intervention Name(s)
Blinatumomab
Other Intervention Name(s)
Blincyto®
Intervention Description
Given intravenously (IV).
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Other Intervention Name(s)
MTX, Trexall®, amethopterin
Intervention Description
Given intravenously (IV), oral (PO), or Intrathecal (IT).
Intervention Type
Drug
Intervention Name(s)
Mercaptopurine
Other Intervention Name(s)
6-MP, Purinethol®
Intervention Description
Given oral (PO).
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan®
Intervention Description
Given intravenously (IV).
Intervention Type
Drug
Intervention Name(s)
Etoposide
Other Intervention Name(s)
VP-16, Vepesid®
Intervention Description
Given intravenously (IV).
Intervention Type
Drug
Intervention Name(s)
Leucovorin
Other Intervention Name(s)
Folinic acid
Intervention Description
Given oral (PO) or intravenously (IV).
Intervention Type
Drug
Intervention Name(s)
Intrathecal Triples
Other Intervention Name(s)
ITMHA, methotrexate/hydrocortisone/cytarabine
Intervention Description
Given Intrathecal (IT).
Intervention Type
Drug
Intervention Name(s)
Pegaspargase
Other Intervention Name(s)
Oncaspar®, PEG-asparaginase, PEG-L-asparaginase
Intervention Description
May be used in place of Calaspargase Pegol where available. Given intravenously (IV) or intramuscularly (IM).
Intervention Type
Drug
Intervention Name(s)
Erwinia asparaginase
Other Intervention Name(s)
Erwinase®
Intervention Description
To be used in case of hypersensitivity or intolerance to Calaspargase Pegol or Pegaspargase. Given intravenously (IV) or intramuscularly (IM).
Intervention Type
Radiation
Intervention Name(s)
Radiation
Other Intervention Name(s)
Irradiation
Intervention Description
See detailed description section.
Primary Outcome Measure Information:
Title
Minimal Residual Disease (MRD)-negative response
Description
The proportion of patients with end block 1 minimal residual disease <0.01% by flow cytometry
Time Frame
4 weeks from start of therapy
Title
Recommended Phase 2 dose of venetoclax in combination with a) high-dose cytarabine and navitoclax or b) blinatumomab
Description
The recommended Phase 2 dose (RP2D) of venetoclax in combination with a) high-dose cytarabine and navitoclax or b) blinatumomab will be the dose at which 0 or 1 of 6 treated patients experience a dose limiting toxicity.
Time Frame
6 weeks from the start of block 2A or 4 weeks from the start of block 2B
Secondary Outcome Measure Information:
Title
Grade 3 or higher CTCAE events in block 2a
Description
Occurrence of grade 3 or higher CTCAE version 5 events in patients receiving block 2a therapy estimated as a proportion of patients receiving that therapy
Time Frame
6 weeks from start of block 2A
Title
Grade 3 or higher CTCAE events in block 2b
Description
Occurrence of grade 3 or higher CTCAE version 5 events in patients receiving block 2b therapy estimated as a proportion of patients receiving that therapy
Time Frame
4 weeks from start of block 2b
Title
Event Free Survival (EFS)
Description
EFS will be reported as estimates using the Kaplan-Meier method
Time Frame
1, 3, and 5 years from study entry
Title
Overall survival (OS)
Description
OS will be reported as estimates using the Kaplan-Meier method
Time Frame
1, 3, and 5 years from study entry

10. Eligibility

Sex
All
Minimum Age & Unit of Time
4 Years
Maximum Age & Unit of Time
30 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis: Relapsed or refractory acute lymphoblastic leukemia or lymphoma with ≥1% bone marrow disease as measured by flow cytometry, PCR, or next generation sequencing. However, if an adequate bone marrow sample cannot be obtained, patients may be enrolled if there is unequivocal evidence of leukemia with ≥ 5% blasts in the peripheral blood. Patients with 1-4.99% bone marrow involvement must have disease confirmed in one of the following ways: an alternative minimal residual disease assay (e.g. flow cytometry and PCR or NGS), cytogenetic abnormality consistent with patient's leukemia, FISH abnormality, or a second bone marrow with MRD ≥1% separated by 1-4 weeks. Patients with ≥5% bone marrow disease by a single measurement as measured by flow cytometry, PCR, or next generation sequencing do not require a second confirmatory test. Refractory disease is defined as residual leukemia ≥1% after at least 2 prior lines of frontline therapy with curative intent. Patients in exploratory cohort I must have measurable extramedullary disease but may have <1% bone marrow disease. Patients in exploratory cohort M must have ≥1% bone marrow disease as measured by flow cytometry of mixed phenotype acute leukemia (MPAL)/ acute leukemia of ambiguous lineage (ALAL). Age ≥4 to < 30 years. Patients ≥ 22 years old are only eligible for exploratory cohort O. Sites may have different (lower) maximum ages based on institutional guidelines but may not exceed 30 years. Patient weighs ≥ 20 kg. Patient is able to swallow pills. Lansky/Karnofsky score is ≥ 60%. The Lansky performance score should be used for participants < 16 years and the Karnofsky performance score for participants ≥ 16 years. Participant has adequate organ function as defined by the following: Direct bilirubin ≤ 1.5x the institutional upper limit of normal (ULN). At institutions which do not obtain a direct bilirubin in patients with a normal total bilirubin, a normal total bilirubin may be used as evidence that the direct bilirubin is not > 1.5x the ULN. Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0 x the ULN unless increase is attributable to leukemic involvement. Normal creatinine for age or a calculated creatinine clearance ≥ 60 mL/min/1.73 m^2. Left ventricular ejection fraction (LVEF) ≥ 40% or shortening fraction ≥ 25%. Patients with a history of reduced LVEF which subsequently improved with medical management are eligible if they meet the criteria above. Patients must have fully recovered from the acute effects of all prior therapy (defined as resolution of all such toxicities to ≤ Grade 2). For patients with prior hematopoietic stem cell transplant (HSCT), at least 90 days must have elapsed since transplant, the patient cannot have evidence of active graft-versus-host disease (GVHD), and they must be off calcineurin inhibitors for ≥4 weeks, and off other immunosuppression for ≥2 weeks. Patients with Down Syndrome/ germline Trisomy 21 are eligible for Block 1 and Block 2b therapies but are ineligible for Block 2a therapy. Patients with Down Syndrome and CD19-negative disease are off therapy after the response evaluation to Block 1. Prior therapy ≥14 days must have elapsed since the completion of cytotoxic therapy, with the exception of standard maintenance therapy (glucocorticoids, vincristine, methotrexate, 6-mercaptopurine), tyrosine kinase inhibitors, and steroids. Cytoreduction with prednisone, methylprednisolone, or hydroxyurea for ≤ 120 hours (5 days) in patients with hyperleukocytosis or extramedullary disease compromising organ function can be initiated and continued until up to 24 hours prior to the start of protocol therapy. At least 21 days must have elapsed since completion of therapy with a biologic agent excluding blinatumomab. For agents that have known adverse events occurring beyond 21 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur. At least 7 days must have elapsed since blinatumomab infusion and patients must have recovered from all toxicities as described above. Intrathecal cytotoxic therapy: No waiting period is required for patients having received intrathecal cytarabine, methotrexate, and/or hydrocortisone. Intrathecal chemotherapy given at the time of diagnostic LP to evaluate for relapse prior to study enrollment is allowed. Patient has not had prior exposure to navitoclax Male or female participant of reproductive potential must agree to use appropriate methods of contraception for the duration of study treatment and for at least 30 days after last dose of protocol treatment. Additional criteria for exploratory cohorts Cohort I: Diagnosis of isolated extramedullary relapse as defined by bone marrow blasts of <1% AND 1) central nervous system white blood cell count (WBC) of ≥ 5WBC/mL with blasts or 2) biopsy confirmed extramedullary leukemia. Cohort M: Diagnosis of relapsed or refractory mixed phenotype acute leukemia (MPAL)/ acute leukemia of ambiguous lineage (ALAL). Cohort N: Patients with relapsed or refractory ALL who, in the view of the provider, are unable to tolerate further asparaginase therapy due to prior toxicities. Cohort O: Patients with relapsed or refractory ALL who are ages 22-29.9 years. This cohort may not enroll patients at all sites based on institutional guidelines or capacity. Exclusion Criteria: Known HIV infection or active hepatitis B (defined as hepatitis B surface antigen-positive) or C (defined as hepatitis C antibody-positive). Pregnant or lactating (female participant of childbearing potential must have negative serum or urine pregnancy test required within 7 days prior to start of treatment). Concomitant medications and food: Treatment with moderate or strong cytochrome P450 3A (CYP3A) inhibitors within 3 days of starting protocol therapy. Treatment with moderate or strong CYP3A inducers within 7 days of starting protocol therapy. Administration or consumption within 3 days prior to the first dose of study drug or grapefruit or grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit. Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Seth E. Karol, MD
Phone
866-278-5833
Email
referralinfo@stjude.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Seth E. Karol, MD
Organizational Affiliation
St. Jude Children's Research Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
St. Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Seth E. Karol, MD
Phone
866-278-5833
Email
referralinfo@stjude.org
First Name & Middle Initial & Last Name & Degree
Seth E. Karol, MD

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request.
IPD Sharing Time Frame
Data will be made available at the time of article publication.
IPD Sharing Access Criteria
Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.
Links:
URL
http://www.stjude.org
Description
St. Jude Children's Research Hospital
URL
http://www.stjude.org/protocols
Description
ClinicalTrials Open at St. Jude

Learn more about this trial

Trial Treating Relapsed Acute Lymphoblastic Leukemia With Venetoclax and Navitoclax

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