NCT05054465

A Phase 1b-2 Trial to Assess Venetoclax and Navitoclax Consolidation and Post-transplant Maintenance in High-risk Patients With T-ALL

A Phase 1b-2 Trial to Assess the Safety and Efficacy of a Venetoclax and Navitoclax Consolidation in High-risk Patients With T- Cell Acute Lymphoblastic Leukemia Prior to Allogeneic Transplantation Followed by Venetoclax and Navitoclax Post-transplant Maintenance

• Status: Not Yet Recruiting
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 48 (estimated)
• Sponsor: Israeli Medical Association · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

This is a national, multicenter, phase II clinical trial to evaluate the potential benefit of pre-transplant consolidation and post-transplant maintenance with navitoclax and venetoclax in patients with T-ALL, LBL and MPAL T/M in first complete remission designated for allogeneic transplantation. Pre-transplantation consolidation with venetoclax and navitoclax: Patients in CR designated for transplantation will be treated with venetoclax 400 mg QD and navitoclax 50mg QD according to the RP2D presented by Pullarkat et al. (Cancer Discov . 2021 Feb 16;candisc.1465.2020. doi: 10.1158/2159-8290.CD-20-1465.) for two 28 day cycles. Following 2 cycles re-staging marrow including MRD assessment and imaging as need will be followed by alloSCT according to local protocol. Post-transplantation maintenance with venetoclax and navitoclax: Within 90 days from alloSCT patients will be started on venetoclax and navitoclax maintenance. Due to lack of data regarding the toxicity of navitoclax and venetoclax in the ALL post alloSCT maintenance setting a dose escalation scheme based on the BOIN design will be applied as outlined (TBD) with a maximal dose of venetoclax 400 mg QD and navitoclax 50mg QD according to the RP2D presented by Pullarkat et al. (Cancer Discov . 2021 Feb 16;candisc.1465.2020. doi: 10.1158/2159-8290.CD-20-1465).

Detailed description

Despite several therapeutic advancements, the outcome of adults with T-cell acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) remains unsatisfactory, especially in those patients with high-risk disease features. In such high-risk patients, allogenic transplantation is usually recommended, when feasible. Interventions to increase response and survival are needed for this high-risk subset of patients. In pre-clinical studies, certain T-cell ALL cell lines were shown to be particularly sensitive to BCL2 inhibition (Peirs et al, Blood 2014). Recent reports demonstrate that venetoclax in combination with navitoclax is an effective approach to patients with relapsed/refractory ALL (Lacayo. ASH 2019. Abstr 285). Venetoclax in combination with chemotherapy in elderly patients with ALL also demonstrated promising efficacy with preliminary reasonable safety signals (Jain. ASH 2019. Abstr 3867). We hypothesize that adding venetoclax and navitoclax as a pre-transplant intervention and as maintenance may improve post-transplant outcome for these patients. The primary objectives of this study are: 1. To evaluate the efficacy of venetoclax in combination with navitoclax consolidation in newly diagnosed T-ALL patients prior to alloSCT. 2. To evaluate the safety and potential benefit of post-transplant venetoclax and navitoclax maintenance therapy in patients with T-ALL. The secondary objectives of this study are: 1\. To evaluate the impact of pre-transplant venetoclax/navitoclax consolidation. This is a national, multicenter, phase II clinical trial to evaluate the potential benefit of pre-transplant consolidation and post-transplant maintenance with navitoclax and venetoclax in patients with T-ALL, LBL and MPAL T/M in first complete remission designated for allogeneic transplantation. Pre-transplantation consolidation with venetoclax and navitoclax: Patients in CR designated for transplantation will be treated with venetoclax 400 mg QD and navitoclax 50mg QD according to the RP2D presented by Jabbour et al. (EHA25; S116) for two 28 day cycles. Following 2 cycles re-staging marrow including MRD assessment and imaging as need will be followed by alloSCT according to local protocol. Post-transplantation maintenance with venetoclax and navitoclax: Within 90 days from alloSCT patients will be started on venetoclax and navitoclax maintenance. Due to lack of data regarding the toxicity of navitoclax and venetoclax in the ALL post alloSCT maintenance setting a dose escalation scheme based on the BOIN design will be applied as outlined (TBD) with a maximal dose of venetoclax 400 mg QD and navitoclax 50mg QD according to the RP2D presented by Jabbour et al. (EHA25; S116). The BOIN design will be based on the cumulative number of subjects who experience a dose-limiting toxicity (DLT) at a particular dose level. Dose escalation decisions will be based on 3-6 DLT-evaluable subjects at each dose level. At least 6 subjects will be treated during dose escalation and assessed for safety at what is ultimately used for expansion. Planned follow up is durring maintnance every 3 months for 2 years.

Conditions

• Acute Lymphoblastic Leukemia

Interventions

Type	Name	Description
DRUG	Navitoclax	P.O 50mg QD Q28 days for 2 cycles pre-transplant Up to 50mg QD Q28 days maintnance post-transplant based on MTD
DRUG	Venetoclax	P.O 400mg QD Q28 days for 2 cycles pre-transplant Up to 400mg QD Q28 days maintnance post-transplant based on MTD

Timeline

• Start date: 2021-10-01
• Primary completion: 2025-08-01
• Completion: 2026-08-01
• First posted: 2021-09-23
• Last updated: 2021-09-23

Locations

6 sites across 1 country: Israel

Regulatory

• FDA-regulated drug study