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

NCT03236857 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: M13-8332017-000439-14
• Study Type: interventional
• Target: 143
• Locations: 8 countries
• Sites: 31

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.

Conditions

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

Keywords

Cancer; Venetoclax; pediatric; relapsed or refractory; Venclexta

Outcome Measures

Primary Outcomes (6)

• Number of Participants Experiencing Adverse Events

  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.

  Up to 9 months

• Number of Participants With Dose Limiting Toxicities (DLT) of Venetoclax Monotherapy

  A DLT is any Grade 3 or higher non-hematologic adverse event (AE) with exceptions outlined in the protocol.

  First 21 days venetoclax monotherapy

• Recommended Phase 2 dose (RPTD) of Venetoclax

  Venetoclax RPTD is the dose determined based on adverse event reporting and dose-limiting toxicity information from all participants.

  First 21 days venetoclax monotherapy

• Cmax of Venetoclax

  Maximum plasma concentration (Cmax) of venetoclax.

  Up to approximately 2 weeks

• Tmax of venetoclax

  Time to maximum plasma concentration (Tmax) of venetoclax.

  Up to approximately 2 weeks

• AUC0-24 Post-Dose of Venetoclax

  Area under the plasma concentration-time curve from 0 to 24 hours (AUC24) post-dose of venetoclax.

  Up to approximately 2 weeks

Secondary Outcomes (3)

• Objective Response Rate (ORR)

  Up to 9 months

• Partial Response (PR) Rate

  Up to 9 months

• Complete Response (CR) Rate

  Up to 9 months

Study Arms (1)

Venetoclax with or without chemotherapy

EXPERIMENTAL

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.

Drug: chemotherapy; Drug: venetoclax

Interventions

chemotherapy DRUG

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

Venetoclax with or without chemotherapy

venetoclax DRUG

Oral tablet for participants; Tablet for oral suspension (participants who cannot swallow a tablet)

Also known as: ABT-199, GDC-0199, Venclexta

Venetoclax with or without chemotherapy

Eligibility Criteria

• Age: 0 Years - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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).

You may not qualify if:

• 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).

Sponsors & Collaborators

• AbbVie: lead
• Roche-Genentech: collaborator

Study Sites (31)

Univ California, San Francisco /ID# 163460

San Francisco, California, 94143-2204, United States

Location

Children's Hospital Colorado /ID# 161551

Aurora, Colorado, 80045, United States

Location

Children's Healthcare of Atlan /ID# 161552

Atlanta, Georgia, 30322, United States

Location

Dana-Farber Cancer Institute /ID# 163440

Boston, Massachusetts, 02215, United States

Location

Memorial Sloan Kettering Cancer Center-Koch Center /ID# 163444

New York, New York, 10065-6007, United States

Location

Cincinnati Children's Hospital /ID# 161550

Cincinnati, Ohio, 45229, United States

Location

Children's Hospital of Philadelphia /ID# 163445

Philadelphia, Pennsylvania, 19104, United States

Location

St Jude Children's Research Hospital /ID# 163447

Memphis, Tennessee, 38105, United States

Location

Primary Children's /ID# 164399

Salt Lake City, Utah, 84113, United States

Location

Seattle Children's Hospital /ID# 163459

Seattle, Washington, 98105, United States

Location

Medical College of Wisconsin /ID# 163461

Milwaukee, Wisconsin, 53226-3522, United States

Location

Sydney Children's Hospital /ID# 163148

Randwick, New South Wales, 2031, Australia

Location

Queensland Children's Hospital /ID# 163146

South Brisbane, Queensland, 4101, Australia

Location

Women and Childrens Hospital /ID# 163147

North Adelaide, South Australia, 5006, Australia

Location

Royal Children's Hospital /ID# 163104

Parkville, Victoria, 3052, Australia

Location

Hospital for Sick Children /ID# 163726

Toronto, Ontario, M5G 1X8, Canada

Location

CHU Sainte-Justine /ID# 163725

Montreal, Quebec, H3T 1C5, Canada

Location

AP-HM - Hopital de la Timone /ID# 161465

Marseille, Bouches-du-Rhone, 13385, France

Location

Centre Leon Berard /ID# 163707

Lyon, Rhone, 69373, France

Location

AP-HP - Hopital Armand-Trousseau /ID# 163728

Paris, 75012, France

Location

Robert Debre Hopital, FR /ID# 161464

Paris, 75019, France

Location

CHU Toulouse - Hôpital des enfants /ID# 163727

Toulouse, 31059, France

Location

Universitaetsklinikum Freiburg /ID# 164206

Freiburg im Breisgau, Baden-Wurttemberg, 79106, Germany

Location

Universitaetsklinikum Schleswig-Holstein Campus Kiel /ID# 161729

Kiel, Schleswig-Holstein, 24105, Germany

Location

Charite Universitaetsklinikum Berlin - Campus Virchow /ID# 161730

Berlin, 13353, Germany

Location

Universitaetsklinikum Essen /ID# 164207

Essen, 45147, Germany

Location

Erasmus MC - Sophia /ID# 161579

Rotterdam, 3015 GD, Netherlands

Location

Prinses Maxima Centrum /ID# 162670

Utrecht, 3584 CS, Netherlands

Location

Kinderspital Zurich - Eleonorenstiftung /ID# 163037

Zurich, Canton of Zurich, 8032, Switzerland

Location

Great Ormond Street Hospital for Children /ID# 169238

London, London, City of, WC1N 3JH, United Kingdom

Location

The Newcastle Upon Tyne Hospitals NHS Foundation Trust /ID# 162938

Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

Related Publications (5)

• Karol SE, Khaw SL, Zwaan CM, Baruchel A, Bittencourt H, Cooper TM, Flotho C, Fraser C, Forlenza CJ, Goldsmith KC, Macy ME, Morgenstern DA, O'Brien MM, Petit A, Ziegler DS, Reinhardt D, Opferman JT, Rubnitz JE, Onishi M, Dunshee DR, Dunbar F, Vishwamitra D, Ross JA, Chen X, Unnebrink K, Kammerlander M, Salem AH, Palenski TL, Sunkersett G, Place AE. Venetoclax Alone or in Combination With Chemotherapy in Paediatric and Adolescent/Young Adult Patients With Relapsed/Refractory Acute Myeloid Leukaemia. Pediatr Blood Cancer. 2025 Jul;72(7):e31714. doi: 10.1002/pbc.31714. Epub 2025 Apr 23.

  PMID: 40266036 DERIVED

• Place AE, Karol SE, Forlenza CJ, Cooper TM, Fraser C, Cario G, O'Brien MM, Gerber NU, Bourquin JP, Reinhardt D, Rubnitz JE, Opferman JT, Sunkersett G, Onishi M, Dunshee DR, Chen X, Unnebrink K, Vishwamitra D, Dunbar F, Badawi M, Ross JA, Loh ML. Venetoclax Combined With Chemotherapy in Pediatric and Adolescent/Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. Pediatr Blood Cancer. 2025 Jun;72(6):e31630. doi: 10.1002/pbc.31630. Epub 2025 Mar 10.

  PMID: 40062648 DERIVED

• Badawi M, Gopalakrishnan S, Engelhardt B, Palenski T, Karol SE, Rubnitz JE, Menon R, Salem AH. Dosing of Venetoclax in Pediatric Patients with Relapsed Acute Myeloid Leukemia: Analysis of Developmental Pharmacokinetics and Exposure-Response Relationships. Clin Ther. 2024 Oct;46(10):759-767. doi: 10.1016/j.clinthera.2024.09.008. Epub 2024 Oct 5.

  PMID: 39368878 DERIVED

• 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.

  PMID: 34088831 DERIVED

• 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.

  PMID: 29595064 DERIVED

MeSH Terms

Conditions

Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Neuroblastoma; Recurrence

Interventions

Drug Therapy; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid; Lymphoma; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Therapeutics

Study Officials

• ABBVIE INC.

  AbbVie

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: July 31, 2017
• First Posted: August 2, 2017
• Study Start: November 8, 2017
• Primary Completion: April 19, 2023
• Study Completion: April 19, 2023
• Last Updated: May 22, 2023

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will not share

Locations

CA (2); FR (5); AU (4); DE (4); CH (1); GB (2); US (11); NL (2)