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Acute Lymphoblastic LeukemiaPhase 1/2ITALLI001NCT05054465

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

A Phase 1/2 study testing Navitoclax and Venetoclax in people with Acute Lymphoblastic Leukemia, run by Israeli Medical Association at 6 sites in Israel.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Acute Lymphoblastic Leukemia
What is being tested?
Navitoclax and Venetoclax
Could I receive a placebo?
No, everyone receives an active treatment
How many people
48 participants
Where
6 sitesIsrael
Study dates
1 Oct 2021to 1 Aug 2026
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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.
  • 9. 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).
  • 10. Male subjects with a female partner of childbearing potential must agree to the use of at least two physician-approved contraceptive methods throughout the course of the study and should avoid fathering a child during the course of the study and for 3 months following the last dose of study drug.
  • 11. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures being conducted.
  • 12. Able to adhere to the study visit schedule and other protocol requirements.

Who cannot join

  • 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.
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  • 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:
  • 1. 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
  • 6. Known Human Immunodeficiency Virus (HIV).
  • 7. No history of being positive for hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Inactive hepatitis carrier status or low viral hepatitis titers on antivirals (non-exclusionary medications) are not excluded.
  • 8. Known or suspected hypersensitivity to any of the study drugs.
  • 9. Pregnant or lactating females.
  • 10. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
  • 11. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
  • 12. Participation to an investigational drug trial in the last month before randomization.

Trial locations and contacts

6 sites in 1 country.

Ofir Wolach, MD contact

+972-50-4065590

owolach@gmail.com

6 sites in 1 country

Israel6 sites

  • Soroka Medical Center

    Beersheba, 84101

    Itai Levi, MD, +972-54-4851728, etail@CLALIT.org.il

  • Rambam Health Care Campus

    Haifa, 3109601

    Avraham Frisch, MD, +972-52-2667916, a_frisch@rambam.health.gov.il

  • Shaare Zedek Medical Center

    Jerusalem, 9103102

    Yishai Ofran, MD, ++972-50-2061524, yofran@szmc.org.il

  • Rabin Medical Center

    Petah Tikva, 49100

    Ofir Wolach, MD, ++972-50-4065590, owolach@gmail.com

  • Sheba Medical Center

    Ramat Gan, 52621

    Jonathan Canaani, MD, +972-52-6669169, Jonathan.Canaani@sheba.health.gov.il

  • Tel Aviv Sourasky Medical Center

    Tel Aviv, 6423906

    Yakir Moshe, MD PhD, +972-52-7360913, yakirm@tlvmc.gov.il

Other trials in Israel

About this study

Official title: 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

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:

Read more

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).

Read the 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.

Being tested
Navitoclax, Venetoclax
Medical subject headings
Precursor Cell Lymphoblastic Leukemia-Lymphoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • NavitoclaxDrug

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

  • VenetoclaxDrug

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

Study groups in NCT05054465
Study groupRoleWhat they receive
Pre-transplant consolidation and post-transplant maintnance with navitoclax and venetoclax.ExperimentalPatients 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.
Receives: Drug: Navitoclax; Drug: Venetoclax

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: 2 years

Secondary outcomes (4)

  1. Overall survival (OS)

    Measured: 2 years

  2. Frequency of AE's during therapy

    AE's based on CTCAE 5.0

    Measured: Recorded every 3 months for 2 years during follow up

  3. Rate of grade 3-4 GvHD events

    GvHD rate at 90 days - defined as Grade 3 or higher for aGvHD and moderate or severe for cGvHD as defined by the investigator following National Institutes of Health (NIH) criteria.

    Measured: 90 days

  4. Minimal Residual Disaease status

    Frequency of MRD negativity at the following time points: post induction II (week 12), after cycle 1 of-venetoclax and navitoclax therapy, after cycle 2 and before alloSCT and Q3 months post transplant (centrally assessed by PCR)

    Measured: Recorded every 3 months for 2 years during follow up

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Sep 2021
  2. Study start1 Oct 2021 (estimated)
  3. Primary completion1 Aug 2025 (estimated)
  4. Study completion1 Aug 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Model description
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.
Masking
None (open label)
Enrolment
48 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05054465
Sponsor's protocol ID
ITALLI001
Acronym
ITALLI001
Status last verified
Jun 2021
First submitted
10 Jun 2021
Last updated
23 Sep 2021
Results posted
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 33593877

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Navitoclax and Venetoclax in people with Acute Lymphoblastic Leukemia, run by Israeli Medical Association at 6 sites in Israel.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 18 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 23 Sep 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in Israel. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Ofir Wolach, MD (+972-50-4065590, owolach@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Event-free survival (EFS) (time frame: 2 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05054465, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Sep 2021.

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