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

NCT05054465 | Not Yet Recruiting Phase 1 FDA Drug

• 1 other identifier: ITALLI001
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 6

Brief 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).

Conditions

Acute Lymphoblastic Leukemia

Outcome Measures

Primary Outcomes (1)

• Event-free survival (EFS)

  EFS is defined for all patients and measured from the date of entry on study. It is measured until treatment failure defined as molecular or morphological relapse from CR, treatment discontinuation due to drug related toxicity or death from any cause, whichever occurs first.

  2 years

Secondary Outcomes (4)

• Overall survival (OS)

  2 years

• Frequency of AE's during therapy

  Recorded every 3 months for 2 years during follow up

• Rate of grade 3-4 GvHD events

  90 days

• Minimal Residual Disaease status

  Recorded every 3 months for 2 years during follow up

Study Arms (1)

Pre-transplant consolidation and post-transplant maintnance with navitoclax and venetoclax.

EXPERIMENTAL

Patients will be treated with VEN 400 mg QD and NAV 50mg QD according to the RP2D presented by Pullarkat et al. (doi: 10.1158/2159-8290.CD-20-1465) for two 28 day cycles. Following 2 cycles re-staging marrow including MRD assessment and imaging will be followed by alloSCT according to local protocol.Within 90 days from alloSCT patients will be started on VEN and NAV maintenance. For post-alloSCT maintenance a dose escalation scheme based on the BOIN design will be applied with a maximal dose of VEN 400 mg QD and NAV 50mg QD according to the RP2D presented by Pullarkat et al.

Drug: Navitoclax; Drug: Venetoclax

Interventions

Navitoclax DRUG

P.O 50mg QD Q28 days for 2 cycles pre-transplant Up to 50mg QD Q28 days maintnance post-transplant based on MTD

Pre-transplant consolidation and post-transplant maintnance with navitoclax and venetoclax.

Venetoclax DRUG

P.O 400mg QD Q28 days for 2 cycles pre-transplant Up to 400mg QD Q28 days maintnance post-transplant based on MTD

Pre-transplant consolidation and post-transplant maintnance with navitoclax and venetoclax.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years at the time of signing the informed consent document.
• Have a documented new diagnosis of T-ALL, T-LBL or MPAL T/Myeloid according to the WHO 2016 classification.
• Patients in first complete response that are planned for an alloSCT.
• Patient induction with a BFM backbone, asparginase containing induction.
• Adequate bone marrow reserve; • Absence of growth factors, thrombopoietic factors, or platelet transfusions in the week prior to day 1 of therapy with Navitoclax and venetoclax.
• Platelet count ≥ 50 × 109 /L
• Absolute neutrophil count (ANC) ≥ 1 × 109 /L.
• Hepatic function and enzymes:
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × upper limit of normal (ULN)
• Total bilirubin ≤ 1.5 × ULN (exception: subjects with Gilbert's Syndrome may have total bilirubin \> 1.5 × ULN)
• Coagulation: activated partial thromboplastin time (aPTT) and international normalized ratio (INR) ≤ 1.5 × ULN.
• Renal function: calculated creatinine clearance ≥ 30 mL/min
• For the post-transplant maintenance phase:Patient should satisfy all the above criteria.
• Patient must not have grade 2 or higher for aGvHD and moderate or severe for cGvHD.
• \. Females of childbearing potential (FCBP) may participate, providing they meet the following conditions: Agree to use at least two effective contraceptive methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) throughout the study, and for 3 months following EOT; and have a negative serum or urine pregnancy test (investigator's discretion; sensitivity at least 25 mIU/mL) at screening; and have a negative serum or urine pregnancy test (investigator's discretion) within 72 hours prior to starting study therapy in the treatment phase (note that the screening serum pregnancy test can be used as the test prior to starting study therapy in treatment phase if it is performed within the 72-hour timeframe).

You may not qualify if:

• Age \<18 at the time of signing the informed consent document.
• Ph-positive disease.
• Patient not regarded as candidates for allogeneic transplantation.
• Non-BFM based, asparginase containing induction (including HyperCVAD)
• Concomitant Medications:
• Subject must not have been treated with a medical product without any global regulatory approvals within 30 days or 5 half-lives of the drug (whichever is shorter) prior to Cycle 1 Day 1 and must not be currently receiving AML treatment in another clinical interventional study.
• Cytochrome P450 (CYP)3A inducers and grapefruit/grapefruit products: Subject must not have received a known strong or moderate CYP3A inducer 7 days prior to Cycle 1 Day 1. Subject must not have known medical conditions requiring chronic therapy of moderate CYP3A inducers.
• Cytochrome P450 (CYP)3A inhibitors: Subject must not have received a known strong or moderate CYP3A inhibitors 7 days prior to Cycle 1 Day 1. Subject must not have known medical conditions requiring chronic therapy of strong or moderate CYP3A inhibitors (appendix 2).
• Subject must not have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or starfruit within 3 days prior to Cycle 1 Day 1.
• Subject must not have received any live vaccine within 4 weeks prior to Cycle 1 Day 1.
• The subject must not be expected to need a live vaccination throughout study participation.
• The subject must not be expected to need a live vaccine in case of the following 7 conditions:
• \. Less than 24 months following transplantation 2. Active GvHD 3. Lymphocyte count \< 1,500/μL 4. Less than 12 months in remission 5. Less than 3 months after the last dose of oncological therapy 6. Less than 4 weeks after the most recent infusion of immunoglobulins 7. Less than 4 weeks after the most recent immunosuppressive therapy
• Subject must not have been treated with any investigational drug within 30 days prior to the first dose of study drug or is currently enrolled in another clinical study or was previously enrolled in this study
• \. Known Human Immunodeficiency Virus (HIV).

Sponsors & Collaborators

• Israeli Medical Association: lead
• Rabin Medical Center: collaborator
• Sheba Medical Center: collaborator
• Rambam Health Care Campus: collaborator
• Tel Aviv Medical Center: collaborator
• Soroka University Medical Center: collaborator
• Shaare Zedek Medical Center: collaborator
• Hadassah Medical Organization: collaborator

Study Sites (6)

Soroka Medical Center

Beersheba, 84101, Israel

Location

Rambam Health Care Campus

Haifa, 3109601, Israel

Location

Shaare Zedek Medical Center

Jerusalem, 9103102, Israel

Location

Rabin Medical Center

Petah Tikva, 49100, Israel

Location

Sheba Medical Center

Ramat Gan, 52621, Israel

Location

Tel Aviv Sourasky Medical Center

Tel Aviv, 6423906, Israel

Location

Related Publications (1)

• Pullarkat VA, Lacayo NJ, Jabbour E, Rubnitz JE, Bajel A, Laetsch TW, Leonard J, Colace SI, Khaw SL, Fleming SA, Mattison RJ, Norris R, Opferman JT, Roberts KG, Zhao Y, Qu C, Badawi M, Schmidt M, Tong B, Pesko JC, Sun Y, Ross JA, Vishwamitra D, Rosenwinkel L, Kim SY, Jacobson A, Mullighan CG, Alexander TB, Stock W. Venetoclax and Navitoclax in Combination with Chemotherapy in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma. Cancer Discov. 2021 Jun;11(6):1440-1453. doi: 10.1158/2159-8290.CD-20-1465. Epub 2021 Feb 16.

  PMID: 33593877 RESULT

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

navitoclax; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Central Study Contacts

Ofir Wolach, MD

CONTACT

+972-50-4065590; owolach@gmail.com

Study Design

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

Model Details: A national, multicenter, phase II clinical trial to evaluate the benefit of pre-transplant (alloSCT) consolidation (cons.) and post-alloSCT maintenance with navitoclax (NAV) and venetoclax (VEN) in patients with T-ALL, LBL and MPAL T/M in CR1 designated for alloSCT. Pre-alloSCT cons. with VEN and NAV: Patients will be treated with VEN 400 mg QD and NAV 50mg QD according to the RP2D presented by Pullarkat et al. (doi: 10.1158/2159-8290.CD-20-1465) for two 28 day cycles. Following 2 cycles re-staging marrow including MRD assessment and imaging will be followed by alloSCT according to local protocol. Post-alloSCT maintenance with VEN and NAV: Within 90 days from alloSCT patients will be started on VEN and NAV maintenance. For post-alloSCT maintenance a dose escalation scheme based on the BOIN design will be applied with a maximal dose of VEN 400 mg QD and NAV 50mg QD according to the RP2D presented by Pullarkat et al.

Study Record Dates

• First Submitted: June 10, 2021
• First Posted: September 23, 2021
• Study Start: October 1, 2021
• Primary Completion: August 1, 2025
• Study Completion (Estimated): August 1, 2026
• Last Updated: September 23, 2021

Record last verified: 2021-06

Data Sharing

• IPD Sharing: Will not share

Locations

IL (6)