ABL001 Combo Therapy for Leukemia

Recruiting at 5 trial locations

Overseen By Marlise R. Luskin, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Marlise R. Luskin

Must be taking: ABL001, Dasatinib, Prednisone

Must not be taking: Dasatinib, ASCIMINIB, CYP3A4/5 inducers

Disqualifiers: ABL T315I mutation, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 6 cycles of 42 days each

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug combination for certain types of leukemia, specifically B-cell Acute Lymphoblastic Leukemia and Chronic Myeloid Leukemia, both with specific genetic markers (BCR-ABL positive). The study aims to determine if combining ABL001 (Asciminib or Scemblix) with dasatinib (Sprycel), prednisone, and later adding blinatumomab can improve treatment outcomes. The trial seeks participants with these types of leukemia who have not received standard chemotherapy or have conditions that make intense chemotherapy unsuitable. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial requires that certain medications be stopped before starting the study. Specifically, any TKI therapy must be discontinued for 5 half-lives before starting the trial, and other chemotherapy must be stopped 2 weeks prior, except for certain exceptions like steroids. Additionally, medications that strongly affect certain liver enzymes should be stopped unless medically necessary, in which case a review with the study investigator is needed.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ABL001 combined with dasatinib, prednisone, and blinatumomab can be safely managed in patients with Philadelphia chromosome positive (Ph+) acute leukemia. The combination of dasatinib and blinatumomab has yielded promising results, with good overall survival rates in previous studies. Although limited data exists on using ABL001 with dasatinib and prednisone in adults with Ph+ B-ALL or CML, these drugs have been well-studied in various combinations.

Dasatinib, a key drug in this mix, is already effective for Ph+ acute leukemia. However, some patients may develop resistance to it. Adding blinatumomab addresses this issue, as it has improved survival chances for older patients.

While the complete safety profile of this specific drug mix is still under investigation, existing research is encouraging. The drugs involved have been used safely in other combinations for similar conditions. Further studies will provide more detailed safety information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the ABL001 combo therapy for leukemia because it combines several potent treatments in a novel way. Unlike standard therapies, this trial includes Blinatumomab, which is given as a continuous infusion and targets specific proteins on cancer cells, potentially improving precision in treatment. Additionally, ABL001 is an oral medication, which could make it more convenient for patients compared to some intravenous treatments. Together, these features might provide a new approach to managing leukemia, potentially leading to improved outcomes for patients.

What evidence suggests that this trial's treatments could be effective for leukemia?

Research has shown that dasatinib effectively treats Philadelphia chromosome-positive acute leukemia, but some patients may stop responding to it. In this trial, participants will receive a combination of dasatinib with two other drugs, asciminib (ABL001) and prednisone, which studies suggest might help when resistance occurs. Additionally, blinatumomab, a type of antibody therapy, will be added to the treatment regimen starting from cycle 2, potentially enhancing effectiveness. Although specific data on using all these drugs together is limited, early research indicates that this combination might work better than using each drug individually. ^{1 2 3 5 6}

Who Is on the Research Team?

Marlise R Luskin, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

Adults with BCR-ABL+ B-cell ALL or CML in lymphoid blast crisis, who are unsuitable for standard chemotherapy due to age, comorbidities, or relapse. Participants must have normal organ function and agree to use effective contraception. Excluded are those suitable for standard therapy, with certain mutations or recent treatments, active infections like hepatitis/HIV, significant heart/lung issues, gastrointestinal disorders affecting drug absorption.

Inclusion Criteria

I am 18-49, have not had intense chemo, and cannot handle it due to health issues.

I am over 18 and my disease did not respond to at least one round of intense chemotherapy.

My organs are functioning normally.

Exclusion Criteria

I have a history of high blood pressure in the lungs.

I have liver disease.

I have a stomach or intestine problem that affects how I absorb medicine.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ABL001, Dasatinib, and Prednisone. Blinatumomab is introduced from cycle 2. Dose escalation follows a 3+3 scheme to determine the recommended phase 2 dose.

6 cycles of 42 days each

Regular visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• ABL001
• Dasatinib
• Prednisone

Trial Overview

The trial is testing ABL001 combined with dasatinib (Sprycel®) and prednisone as a treatment option for Philadelphia chromosome positive Acute Lymphoblastic Leukemia (Ph+ ALL) and Chronic Myeloid Leukemia (CML) in blast crisis phase. The study aims to enroll 25-40 people to assess the effectiveness of this drug combination.

How Is the Trial Designed?

Group I: ABL001, Dasatinib, Prednisone, Blinatumomab Experimental Treatment 4 Interventions

\- Dose escalation will occur conventional Fibonocci 3+3 dose escalation scheme to determine a recommended phase 2 dose (RP2D) * Dasatinib-Fixed doses oral once a day per cycle * ABL001 is administered orally daily per cycle * Prednisone-Fixed doses oral once a day per cycle. \--- Prednisone will be tapered and stop during cycle 2. * Blinatumomab - intravenous continuous infusion beginning no earlier than cycle 2 day 1 * Blinatumomab - Day 1-28 of each 42-day cycle, cycles 2-6, total of 5 cycles

ABL001 is already approved in United States, European Union for the following indications:

Approved in United States as Scemblix for:

• Chronic myeloid leukemia (CML) in patients with a resistance or intolerance to two or more tyrosine kinase inhibitors

Approved in European Union as Scemblix for:

• Chronic myeloid leukemia (CML) in patients with a resistance or intolerance to two or more tyrosine kinase inhibitors

Who Is Running the Clinical Trial?

Marlise R. Luskin

Lead Sponsor

Trials

1

Recruited

40+

Marlise Luskin, MD

Lead Sponsor

Trials

1

Recruited

40+

Novartis

Industry Sponsor

Trials

1,646

Recruited

2,778,000+

Vasant Narasimhan

Novartis

Chief Executive Officer since 2018

MD from Harvard Medical School, Bachelor's in Biological Sciences from University of Chicago, Master's in Public Policy from John F. Kennedy School of Government

Shreeram Aradhye

Novartis

Chief Medical Officer since 2022

MD from Yale University, MSc in Clinical Epidemiology from University of Pennsylvania

Published Research Related to This Trial

The combination of imatinib with Src/Abl inhibitors (AP23848 and BMS-354825) shows potential in effectively treating chronic myeloid leukemia (CML) by overcoming resistance from common Bcr-Abl mutations, as demonstrated in assays with Ba/F3 cells and primary CML cells.

While imatinib enhances the effects of Src/Abl inhibitors against wild-type and marginally resistant Bcr-Abl mutants, it has limited impact on highly resistant mutants like Y253F and E255K, indicating the need for tailored treatment strategies in CML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined Abl inhibitor therapy for minimizing drug resistance in chronic myeloid leukemia: Src/Abl inhibitors are compatible with imatinib. O'Hare, T., Walters, DK., Stoffregen, EP., et al.[2015]

Dasatinib, approved by the FDA for treating chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL), showed a major cytogenetic response rate of 45% in chronic phase CML and significant hematologic response rates in other phases of CML and Ph(+) ALL, indicating its efficacy in patients resistant to prior therapies.

The treatment was associated with common side effects such as myelosuppression, bleeding, and fluid retention, highlighting the importance of monitoring patient safety during dasatinib therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. Brave, M., Goodman, V., Kaminskas, E., et al.[2023]

ABL001 (asciminib) is a novel allosteric ABL1 inhibitor that works differently from traditional ABL1 kinase inhibitors by binding to a specific pocket on the ABL1 protein, leading to an inactive form of the kinase, which may help overcome resistance seen with other treatments.

In combination with nilotinib, ABL001 demonstrated complete disease control in mice with chronic myeloid leukaemia (CML), suggesting that this combination therapy could be a promising strategy for effectively managing CML and preventing recurrence after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Wylie, AA., Schoepfer, J., Jahnke, W., et al.[2022]

In the phase 3 DASISION trial, dasatinib (100 mg daily) showed faster and deeper responses in patients with newly diagnosed chronic-phase chronic myeloid leukaemia (CML) compared to imatinib (400 mg daily), although long-term survival rates were similar for both treatments.

Dasatinib is also effective for patients with imatinib-resistant or intolerant chronic-phase CML and advanced-phase CML or Ph+ acute lymphoblastic leukaemia, demonstrating a favorable benefit-risk profile and acceptable tolerability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dasatinib: A Review in Chronic Myeloid Leukaemia and Ph+ Acute Lymphoblastic Leukaemia. Keating, GM.[2022]

Imatinib is a safe and effective treatment for chronic myeloid leukemia (CML), but some patients develop resistance due to mutations in the Bcr-Abl kinase domain, prompting the use of second-generation inhibitors like nilotinib and dasatinib.

Despite the effectiveness of imatinib, nearly all CML patients still have detectable disease, highlighting the need for strategies that target leukemic stem cells to achieve complete disease eradication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New strategies for the first-line treatment of chronic myeloid leukemia: can resistance be avoided? Snead, JL., O'Hare, T., Eide, CA., et al.[2009]

Dasatinib, a multiple kinase inhibitor, is rapidly absorbed in the body after oral administration, with a peak concentration reached in about 30 minutes and a short elimination half-life of less than 4 hours, indicating efficient absorption and metabolism.

Most of dasatinib is eliminated through feces (85%), and while several metabolites are formed, they are not expected to significantly contribute to the drug's therapeutic effects, as the active metabolites do not show strong inhibitory activity against key kinases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolism and disposition of dasatinib after oral administration to humans. Christopher, LJ., Cui, D., Wu, C., et al.[2015]

Asciminib is the first drug that specifically targets the ABL myristoyl pocket, showing promising efficacy and safety in patients with chronic myeloid leukemia (CML) who have previously been treated with multiple tyrosine kinase inhibitors (TKIs).

The ongoing phase III trial (ASC4FIRST) is comparing asciminib to standard TKIs in newly diagnosed CML patients, with the primary goal of achieving a major molecular response by week 48, highlighting its potential as a new treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Asciminib monotherapy for newly diagnosed chronic myeloid leukemia in chronic phase: the ASC4FIRST phase III trial. Cortes, JE., Hochhaus, A., Takahashi, N., et al.[2023]

Dasatinib is an effective targeted therapy for chronic myelogenous leukemia and Philadelphia positive acute lymphoblastic leukemia, showing strong hematologic, cytogenetic, and molecular responses in patients resistant or intolerant to imatinib.

Despite its efficacy, dasatinib can cause significant side effects like myelosuppression and pleural effusions, particularly in advanced-phase patients; however, recent dose optimization has reduced these adverse events without affecting the drug's effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Guidelines for the management of dasatinib (Sprycel)-induced side effects in chronic myelogenous leukemia and Philadelphia positive acute lymphoblastic leukemias]. Cony-Makhoul, P., Bergeron, A., Corm, S., et al.[2015]

A clinical study involving 56 volunteers demonstrated that the generic dasatinib tablet (YiNiShu®) is bioequivalent to the branded version (Sprycel®) under both fasting and fed conditions, indicating similar pharmacokinetic profiles.

Both dasatinib formulations showed a good safety profile, confirming that patients can expect comparable efficacy and safety when using either version of the medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of dasatinib and its generic: a phase I bioequivalence study in healthy Chinese subjects. Wang, Y., Xue, J., Su, Z., et al.[2023]

Citations

1.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.6509

A phase I study of asciminib in combination with dasatinib ...

Dual ABL1 inhibition with ASC and DAS can be safely combined with blin in Ph+ acute leukemia. An additional 25-pt cohort is planned with blin in combination ...

2.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03595917

Study Details | NCT03595917 | ABL001 + Dasatinib + ...

There is currently no clinical data on the effects of ABL001 in combination with dasatinib and prednisone among adults with Ph+ B-ALL or CML in lymphoid blast ...

3.

ashpublications.org

ashpublications.org/blood/article/145/6/577/518092/Asciminib-plus-dasatinib-and-prednisone-for

Asciminib plus dasatinib and prednisone for Philadelphia ...

Dasatinib is an effective treatment for Philadelphia chromosome–positive (Ph+) acute leukemia, but some patients develop resistance.

4.

ashpublications.org

ashpublications.org/blood/article/142/Supplement%201/965/502282/A-Phase-I-Study-of-Asciminib-ABL001-in-Combination

A Phase I Study of Asciminib (ABL001) in Combination with ...

Second generation TKIs such as dasatinib (DAS) are more effective than imatinib (Foa et al. Blood 2011) but patients may develop resistance.

5.

cancer.gov

cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2018-02377

ASCIMINIB, Dasatinib, Prednisone, and Blinatumomab in ...

Giving ASCIMINIB, dasatinib, prednisone, and blinatumomab may work better in treating patients with BCR-ABL1 positive B-cell acute lymphoblastic leukemia, mixed ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10090098/

Dasatinib/prednisone induction followed by blinatumomab ...

The combination of dasatinib and blinatumomab has impressive overall survival and disease-free survival in older patients with Ph + ALL.