Accelerating Drug Development in Pediatric Cancer: A Novel Phase I Study Design of Venetoclax in Relapsed/Refractory Malignancies

Abstract

Venetoclax is a highly selective, potent BCL-2 inhibitor that is approved for some patients previously treated for chronic lymphocytic leukemia, and has shown promising activity in adult studies across several hematologic malignancies. Preclinical studies have demonstrated venetoclax activity in pediatric patient-derived xenograft models and cell lines; however, clinical studies in pediatric patients have yet to be conducted. The prognosis is poor for children with most relapsed/refractory malignancies, and limited treatment options result in unmet clinical need. Herein, we describe the rationale and design of the first study of venetoclax in pediatric patients with relapsed/refractory malignancies: a Phase I trial investigating the safety and pharmacokinetics of venetoclax monotherapy followed by the addition of chemotherapy (Trial registration: EudraCT 2017-000439-14; NCT03236857).

Sequential combinations of chemotherapeutic agents with BH3 mimetics to treat rhabdomyosarcoma and avoid resistance

“…On the other hand, doxorubicin treatment lead to a marked decline in MCL-1 and BCL-xL levels, an increase in BCL-2 expression and a decrease in pro-apoptotic proteins BAK and BID (Supplementary Figure 2). From this first set of experiments we conclude that we can increase chemotherapeutic agents' efficacy by rationally combining them Alcon et al 9 with specific BH3 mimetics. Particularly, sequential vincristine treatment followed by S63845 stands out as the most effective therapy in vitro for CW9019 RMS cells ( Figure 2B).…”

“…Evasion of apoptosis is a hallmark of human cancers and it is often explained by anti-apoptotic proteins' increased expression 8,9 . In fact, high levels of BCL-2 and MCL-1 have been reported in RMS patients as a pro-survival mechanism 10,11 .…”

“…In fact, high levels of BCL-2 and MCL-1 have been reported in RMS patients as a pro-survival mechanism 10,11 . Therefore, targeting anti-apoptotic proteins represents a promising therapeutic approach to treat high-risk or relapsed RMS patients 9,12 . In this regard, BH3 mimetics, a novel class of therapeutics that mimic the action of sensitizer BH3-only proteins and selectively inhibit anti-apoptotic BCL-2 family members 7 , could be used to overcome apoptotic resistance.…”

Creating a New Cancer Therapeutic Agent by Targeting the Interaction between Bcl-2 and IP3Receptors

“…Currently, the only approved anti-Bcl-2 drug for use in cancer treatment is ABT-199/Venetoclax (Place et al 2018), and this approval is limited to chronic lymphocytic leukemia (CLL) with some additional approvals expected to come (Fig. 1).…”

Dodging the bullet: therapeutic resistance mechanisms in pediatric cancers

“…Venetoclax specifically has received FDA approval in adult AML and CLL, alone or in combination with one additional drug [164][165][166] . However, in the pediatric approach, monotherapy is not expected to be effective alone; as such, a novel Phase 1 study has been opened that rapidly allows evaluation of venetoclax in monotherapy and combination chemotherapy [167] This novel approach advocates for the advancement of a targeted therapeutic approach for pediatric cancer patients specifically.…”