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

Trial Summary

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.

What data supports the effectiveness of the drug ABL001 Combo Therapy for Leukemia?

The drug dasatinib, a component of the ABL001 Combo Therapy, is effective in treating chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia, especially in patients who are resistant or intolerant to other treatments like imatinib. Additionally, asciminib, another component, has shown favorable results in patients with chronic myeloid leukemia in clinical trials. ^{1 2 3 4 5}

What safety data exists for ABL001 (Asciminib) and Dasatinib (Sprycel) in humans?

Asciminib has shown favorable safety in patients with chronic myeloid leukemia in clinical trials. Dasatinib, while effective, can cause side effects like myelosuppression (reduced bone marrow activity) and pleural effusions (fluid around the lungs), but dose optimization has helped reduce these issues. ^{1 2 3 4 6}

What makes the ABL001 Combo Therapy for Leukemia unique?

The ABL001 Combo Therapy is unique because it combines ABL001 (asciminib), an allosteric inhibitor that targets a different site on the BCR-ABL1 protein than traditional drugs, with dasatinib and prednisone. This combination aims to overcome resistance seen with other treatments by using different mechanisms to inhibit the cancer-driving protein, potentially leading to more effective disease control. ^{1 5 7 8 9}

What is the purpose of this trial?

This research study is evaluating a drug called ABL001 taken in combination with dasatinib (Sprycel®) and prednisone (a steroid) as a possible treatment for B-cell Acute Lymphoblastic Leukemia that is BCR-ABL positive (BCR-ABL+ B-ALL) or Chronic Myeloid Leukemia (CML) in lymphoid blast crisis. BCR-ABL+ B-ALL is also called Philadelphia chromosome positive Acute Lymphoblastic Leukemia (Ph+ ALL). It is expected that 40-65 people will take part in this research study. * ABL001 * Dasatinib (Sprycel®) * Prednisone * Blinatumomab

Research Team

Marlise R Luskin, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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

I have liver disease.

Timeline

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Metabolism and disposition of dasatinib after oral administration to humans. [2015]

2. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of dasatinib and its generic: a phase I bioequivalence study in healthy Chinese subjects. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Asciminib monotherapy for newly diagnosed chronic myeloid leukemia in chronic phase: the ASC4FIRST phase III trial. [2023]

5. New Zealand pubmed.ncbi.nlm.nih.gov

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

6. France 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]. [2015]

7. United States pubmed.ncbi.nlm.nih.gov

New strategies for the first-line treatment of chronic myeloid leukemia: can resistance be avoided? [2009]

8. England pubmed.ncbi.nlm.nih.gov

The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Combined Abl inhibitor therapy for minimizing drug resistance in chronic myeloid leukemia: Src/Abl inhibitors are compatible with imatinib. [2015]