A Study of the Safety and Pharmacokinetics of Venetoclax in Pediatric and Young Adult Patients With Relapsed or Refractory Malignancies

• ClinicalTrials.gov Identifier: NCT03236857
• Recruitment Status: Completed
• First Posted: August 2, 2017
• Last Update Posted: May 22, 2023
• Sponsor: AbbVie
• Collaborator: Roche-Genentech
• Information provided by (Responsible Party): AbbVie

Tracking Information

• First Submitted Date: July 31, 2017
• First Posted Date: August 2, 2017
• Last Update Posted Date: May 22, 2023
• Actual Study Start Date: November 8, 2017
• Actual Primary Completion Date: April 19, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 19, 2021)

• Number of Participants Experiencing Adverse Events [ Time Frame: Up to 9 months ]
  An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study.
• Number of Participants With Dose Limiting Toxicities (DLT) of Venetoclax Monotherapy [ Time Frame: First 21 days venetoclax monotherapy ]
  A DLT is any Grade 3 or higher non-hematologic adverse event (AE) with exceptions outlined in the protocol.
• Recommended Phase 2 dose (RPTD) of Venetoclax [ Time Frame: First 21 days venetoclax monotherapy ]
  Venetoclax RPTD is the dose determined based on adverse event reporting and dose-limiting toxicity information from all participants.
• Cmax of Venetoclax [ Time Frame: Up to approximately 2 weeks ]
  Maximum plasma concentration (Cmax) of venetoclax.
• Tmax of venetoclax [ Time Frame: Up to approximately 2 weeks ]
  Time to maximum plasma concentration (Tmax) of venetoclax.
• AUC0-24 Post-Dose of Venetoclax [ Time Frame: Up to approximately 2 weeks ]
  Area under the plasma concentration-time curve from 0 to 24 hours (AUC24) post-dose of venetoclax.

Original Primary Outcome Measures (submitted: July 31, 2017)

• Number of Participants with Dose limiting toxicities (DLT) of Venetoclax Monotherapy [ Time Frame: First 21 days venetoclax monotherapy ]
  A DLT is any Grade 3 or higher non-hematologic adverse event (AE) with exceptions outlined in the protocol.
• Recommended Phase 2 dose (RPTD) of venetoclax [ Time Frame: First 21 days venetoclax monotherapy ]
  Venetoclax RPTD is the dose determined based on adverse event reporting and dose-limiting toxicity information from all participants.
• Cmax of venetoclax [ Time Frame: Up to approximately 2 weeks ]
  Maximum plasma concentration (Cmax) of venetoclax
• Tmax of venetoclax [ Time Frame: Up to approximately 2 weeks ]
  Time to maximum plasma concentration (Tmax) of venetoclax
• AUC0-24 post-dose of venetoclax [ Time Frame: Up to approximately 2 weeks ]
  Area under the plasma concentration-time curve from 0 to 24 hours (AUC24) post-dose of venetoclax

Current Secondary Outcome Measures (submitted: April 19, 2021)

• Objective Response Rate (ORR) [ Time Frame: Up to 9 months ]
  ORR is defined as the proportion of participants who achieved a response according to established criteria described in detail in the study protocol.
• Partial Response (PR) Rate [ Time Frame: Up to 9 months ]
  PR is defined according to established criteria for each tumor type and is described in detail within the study protocol.
• Complete Response (CR) Rate [ Time Frame: Up to 9 months ]
  CR is defined according to established criteria for each tumor type and is described in detail within the study protocol.

Original Secondary Outcome Measures (submitted: July 31, 2017)

• Objective Response Rate (ORR) [ Time Frame: Up to 9 months ]
  ORR is defined as the proportion of participants who achieved a response according to established criteria described in detail in the study protocol.
• Complete Response (CR) rate [ Time Frame: Up to 9 months ]
  CR is defined according to established criteria for each tumor type and is described in detail within the study protocol.
• Partial Response (PR) rate [ Time Frame: Up to 9 months ]
  PR is defined according to established criteria for each tumor type and is described in detail within the study protocol.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of the Safety and Pharmacokinetics of Venetoclax in Pediatric and Young Adult Patients With Relapsed or Refractory Malignancies
• Official Title: A Phase 1 Study of the Safety and Pharmacokinetics of Venetoclax in Pediatric and Young Adult Patients With Relapsed or Refractory Malignancies
• Brief Summary: An open-label, global, multi-center study to evaluate the safety and pharmacokinetics of venetoclax monotherapy, to determine the dose limiting toxicity (DLT) and the recommended Phase 2 dose (RPTD), and to assess the preliminary efficacy of venetoclax in pediatric and young adult participants with relapsed or refractory malignancies.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Malignancies
• Acute Lymphoblastic Leukemia (ALL)
• Acute Myeloid Leukemia (AML)
• Non-Hodgkin's Lymphoma
• Neuroblastoma

Intervention

• Drug: chemotherapy
  Dexamethasone and/or vincristine and/or pegasparaginase OR cytarabine and/or etoposide and/or pegasparaginase; tyrosine kinase inhibitor; cytarabine OR azacitidine OR decitabine; rituximab and/or dexamethasone and/or vincristine; cyclophosphamide and/or topotecan
• Drug: venetoclax
  Oral tablet for participants; Tablet for oral suspension (participants who cannot swallow a tablet)
  Other Names:

  • ABT-199
  • GDC-0199
  • Venclexta

Study Arms

Experimental: Venetoclax with or without chemotherapy

Venetoclax administered orally once daily (QD) with various doses and dosing regimens with or without chemotherapy at the discretion of the investigator. Allowed chemotherapy regimens as outlined in the study protocol.

Interventions:

• Drug: chemotherapy
• Drug: venetoclax

Publications *

• Dalton KM, Krytska K, Lochmann TL, Sano R, Casey C, D'Aulerio A, Khan QA, Crowther GS, Coon C, Cai J, Jacob S, Kurupi R, Hu B, Dozmorov M, Greninger P, Souers AJ, Benes CH, Mosse YP, Faber AC. Venetoclax-based Rational Combinations are Effective in Models of MYCN-amplified Neuroblastoma. Mol Cancer Ther. 2021 Aug;20(8):1400-1411. doi: 10.1158/1535-7163.MCT-20-0710. Epub 2021 Jun 4.
• Place AE, Goldsmith K, Bourquin JP, Loh ML, Gore L, Morgenstern DA, Sanzgiri Y, Hoffman D, Zhou Y, Ross JA, Prine B, Shebley M, McNamee M, Farazi T, Kim SY, Verdugo M, Lash-Fleming L, Zwaan CM, Vormoor J. Accelerating drug development in pediatric cancer: a novel Phase I study design of venetoclax in relapsed/refractory malignancies. Future Oncol. 2018 Sep;14(21):2115-2129. doi: 10.2217/fon-2018-0121. Epub 2018 Mar 29.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 4, 2022): 143
• Original Estimated Enrollment (submitted: July 31, 2017): 135
• Actual Study Completion Date: April 19, 2023
• Actual Primary Completion Date: April 19, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Participants must have relapsed or refractory cancer.
• Participants must have adequate hepatic and kidney function.
• Participants less than or equal to 16 years of age must have performance status of Lansky greater than or equal to 50% and participants greater than 16 years of age must have performance status of Karnofsky greater than or equal to 50%.
• Participants with solid tumors (with the exception of neuroblastoma) must have adequate bone marrow function in Part 1.
• For the fifth cohort during Part 2 Cohort Expansion, participants with solid tumors must have evidence of BCL-2 expression (except participants with TCF3-HLF ALL).

Exclusion Criteria:

• Participants with primary brain tumors or disease metastatic to the brain.
• Participants who have central nervous system (CNS) disease with cranial involvement that requires radiation.

• Participants who have 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 (Exceptions: Ph+ALL participants on Tyrosine Kinase Inhibitor (TKI) at Screening may enroll and remain on TKI therapy to control disease and TCF3-HLF ALL participants 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 (with the exception of TCF3-HLF ALL participants).
  • Requires ongoing hydroxyurea (hydroxyurea permitted up to first dose)
• Participants who are less than 100 days post-transplant, or greater than or equal to 100 days post-transplant with active graft versus host disease (GVHD), or are receiving immunosuppressant therapy within 7 days prior to first dose of study drug.
• Participants who are less than 6 weeks post-131 I-metaiodobenzylguanidine (mIBG) therapy.

• Participants who have received the following within 7 days prior to the first dose of study drug:

  • Strong and moderate Cytochrome P450 3A (CYP3A) inhibitors (Part 1 Dose Determination);
  • Strong and moderate CYP3A inducers (Part 1 Dose Determination and Part 2 Cohort Expansion).
• Participants who have not recovered from 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 participants).
• Participants who have active, uncontrolled infections.

• Participants with malabsorption syndrome or any other condition that precludes enteral administration.

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 0 Years to 25 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, France, Germany, Netherlands, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT03236857
• Other Study ID Numbers: M13-833; 2017-000439-14 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: AbbVie
• Original Responsible Party: Same as current
• Current Study Sponsor: AbbVie
• Original Study Sponsor: Same as current
• Collaborators: Roche-Genentech

Investigators

• Study Director: ABBVIE INC.; AbbVie

• PRS Account: AbbVie
• Verification Date: November 2022