Principal Investigator: LUKE MAESE
Keywords: Clinical Trial , Pediatrics , Adolescents , Cancer , Oncology Department: Pediatric Administration
IRB Number: 00103319
Specialty: Oncology, Pediatrics, General, Pediatrics, General, Adolescent Medicine
Sub Specialties: Adolescent Medicine,
Recruitment Status: Recruiting

Contact Information

Amy Holman
amy.holman@hsc.utah.edu
8015859155

Brief Summary

The primary objectives of the study:

  • Evaluate the safety of venetoclax monotherapy
  • Determine dose limiting toxicities (DLT) and the recommended Phase 2 dose
    (RPTD) of venetoclax monotherapy 
  • Assess the pharmacokinetics (PK) of venetoclax monotherapy

The secondary objectives of the study:

  • Determine the preliminary efficacy of venetoclax monotherapy
  • Evaluate the safety of venetoclax in combination with chemotherapy
  • Assess the preliminary efficacy of venetoclax in combination with chemotherapy

The exploratory objectives of the study:

  • Evaluate pharmacodynamic and predictive biomarkers
  • Assess minimal residual disease (MRD) in the peripheral blood and bone marrow

Detailed Description

Will be performed at Primary Children's Hospital.

Inclusion Criteria

1. The patient, parent or guardian must voluntarily sign and date an informed consent approved (in addition to pediatric assent, if required) by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures.

2. Is< 25 years of age at time of enrollment.

  • Enrollment of patients ≥ 18 years of age may be halted at any time during the study to ensure adequate enrollment of pediatric patients (< 18 years)

3. Has adequate hepatic function, as defined below. Alternatives should be discussed with AbbVie

  • AST and ALT must be < 3 × institutional upper limit of normal
  • Total bilirubin must be ≤ 1.5 × institutional upper limit of normal
  • For patients on inotuzumab, ozogamicin or gemtuzumab ozogamicin who have completed a 30 day wash out period, AST, ALT and bilirubin must be < ULN prior to the first dose of study drug

4. Has a normal creatinine for age or have a calculated creatinine clearance ≥ 60 mL/min/1.73 m2.

5. For patients ≤ 16 years of age, has performance status of Lansky ≥ 50%; patients > 16 years of age must have performance status of Karnofsky > 50%.

6. In Part 1 (the dose determination portion) of the study, must have relapsed or refractory cancer with no alternative curative regimens available.

7. In Part 1 (the dose determination portion) of the study, patients with solid tumors (with the exception of neuroblastoma), must have adequate bone marrow function as defined by ANC ≥ 1000/μl and platelets > 75,000/μl (with transfusion independence defined as not receiving platelet transfusion within 7 days prior to enrollment). 

In Part 2 (the cohort expansion portion) of the study, must meet the following criteria in addition to those listed above:

8. For relapsed/refractory acute leukemia (myeloid or lymphoblastic), patients must have

  • histologically confirmed diagnosis 
  • ≥ 5% blast (M2 or M3 marrow) in the bone marrow aspirate or biopsy sample, as assessed by morphology, immunohistochemistry, flow cytometry, karyotype, cytogenetic testing such as FISH, or other molecular evaluation
  • refractory disease is defined as persistent disease after at least two induction cycles
  • relapsed disease is defined as second or subsequent relapse or any relapse refractory to salvage chemotherapy

9. Confirmation of TCF3-HLF positive ALL by FISH or PCR (RT-PCR or genomic PCR of breakpoints) must be made during induction and patients must have hepatic function as described below:

  • AST and ALT must be < 10 × institutional upper limit of normal
  • Total bilirubin must be ≤ 3 × institutional upper limit of normal

10. For relapsed/refractory non-Hodgkin lymphoma, patient must

  • have histologic verification at initial diagnosis

  • have measurable disease documented by radiographic criteria or bone marrow disease

  • have a history of progression, recurrence, or failure to respond to prior standard therapy

11. For relapsed/refractory neuroblastoma, patients must

  • have histologic verification of neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased urinary catecholamines at initial diagnosis

  • have evaluable (microscopic marrow metastasis, MIBG or PET scans) or measurable (CT, MRI) disease.  Archived radiographic scans within 42 days of enrollment are allowed.

  • have a history of progression, recurrence or failure to respond to prior standard therapy

12. Patients with high-risk neuroblastoma who have refractory disease (defined by no response or stable disease as best response since diagnosis and completion of at least 4 cycles of induction therapy) are eligible to enroll in Part 2.

13. For Part 2 of study – for enrollment into the fifth cohort (other tumors), patients must have evidence of BCL-2 expression determined locally in either archived tumor tissue or tumor tissue available at relapse. Exception: patients with TCF3-HLF ALL enrolled in the fifth cohort are not required to have evidence of BCL-2 expression.

Added hepatic function criteria for patients who previously received inotuzumab ozogamicin within 30 days of the first dose of the study drug.

 

 

 

Exclusion Criteria

1. Has a primary brain tumor or disease metastatic to the brain.

2. For patients with leukemia, has CNS disease with cranial involvement (CNS 3 status) confirmed by lumbar puncture and defined by CSF white blood cells (WBC) > 5 cells per high power field (hpf) with blasts on cytospin or any cranial nerve palsy regardless of cell count. The Steinherz/Bleyer Algorithm should be utilized to interpret traumatic lumbar punctures (> 10 red blood cells/hpf with > 5 WBC):

  • CSF specimens with > 10 RBC/hpf and > 5 WBC/hpf should be treated as CNS-3 if CSF WBC/CSF RBC > 2× blood WBC/blood RBC
  • All other CSF specimens with > 10 RBC/hpf and > 5 WBC/hpf in CSF specimen should be treated as CNS2.

3. Patients should be excluded who were treated with inotuzumab ozogamicin within 30 days of the first dose of study drug and to add exception for Ph+ ALL patients receiving TKI anti-cancer therapies Has received any of the following within the listed time frame, prior to the first dose of study drug

  • Inotuzumab ozogamicin or gemtuzumab ozogamicin within 30 days
  • Biologic agent (i.e., antibodies) for anti-neoplastic intent within 30 days or 5 half-lives, whichever is shorter

  • CAR-T infusion or other cellular therapy within 30 days

  • Anticancer therapy including chemotherapy, radiation therapy, targeted small molecule agents, investigational agents within 14 days or 5 half-lives, whichever is shorter- Exception: Exception: TCF3-HLF ALL patients are allowed to have received chemotherapy within 14 days or 5 half-lives, whichever is shorter

  • Steroid therapy for anti-neoplastic intent within 5 days- Exception: TCF3-HLF ALL patients are allowed to have received steroid therapy for anti-neoplastic intent within 5 days.

  • Requires ongoing hydroxyurea (hydroxyurea permitted up to first dose) 

4. Is less than 100 days post-transplant, or > 100 days post-transplant with active GVHD, or is still continuing post-transplant immunosuppressant therapy within 7 days prior to first dose of study drug.

5. Is less than 6 weeks post-I-131 MIBG therapy for neuroblastoma patients.

6. In Part 1, (the dose determination portion) of the study, patient who has received strong and moderate CYP3A inhibitors within 7 days prior to the first dose of studydrug.

7. In Part 1 and Part 2, patient has received strong and moderate CYP3A inducers within 7 days prior to the first dose of study drug.

8. Has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit within 3 days prior to the first dose of study drug.

9. Has active hepatitis.

10. Has an active, uncontrolled infection.

11. Has not recovered from grade 2 clinically significant adverse effect(s)/toxicity(s) of the previous therapy. Exception: Chemotherapy-induced side effects that are expected to return to baseline in TCF3-HLF ALL patients.

12. Has malabsorption syndrome or any other condition that precludes enteral administration.

13. Female patient who is pregnant or breastfeeding. Female patient who is considering becoming pregnant during the study, or within approximately 30 days after the last dose of venetoclax. If on venetoclax plus chemotherapy, also see the relevant chemotherapy product label for pregnancy precautions.

14. Male patient who is considering fathering a child within approximately 30 days or donating sperm during the study, within approximately 90 days after the last dose to venetoclax. If on venetoclax plus chemotherapy, also see the relevant chemotherapy product label for not fathering a child and donating sperm

15. For Part 1 – Dose Escalation/De-escalation Cohorts S1, S2, S-1and S-2 – Neuroblastoma and solid tumor patients with bone marrow involvement.

16. Patients with recent positive test for SARS-CoV-2 (COVID-19) and no follow up test with negative result cannot be enrolled. Patients with contact to persons with COVID-19 and persons with signs and symptoms for COVID-19 infection must be tested before enrolling.

● A negative result is defined as at least 2 negative viral tests in a row, ≥ 24 hours apart after at least 10 days have passed since recovery, defined as resolution of fever without use of antipyretics and improvement in respiratory symptoms (e.g., cough, shortness of breath). 

Frequency or timing of COVID-19 testing and interval between testing for the above viral clearance criteria may be adjusted to account for epidemiological
trends, updated information regarding infectivity and local/institutional guidelines.