TGRX-678 for Chronic Myelogenous Leukemia

Recruiting at 1 trial location

Overseen By Xinyi Zhu

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Shenzhen TargetRx, Inc.

Must not be taking: Antineoplastics, Immunosuppressants, Torsade drugs, others

Disqualifiers: Cardiovascular diseases, CNS disorder, HIV, others

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

Compensation: Varies

Number of Visits: 2

90 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this single-arm, open-label, dose escalation + cohort expansion study is to evaluate the safety, tolerability, pharmacokinetic and preliminary efficacy of TGRX-678 in Chronic Myelogenous Leukemia patients who had failure with or are intolerant to TKI treatments.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot have taken other cancer treatments or investigational drugs within 14 days before starting the trial. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug TGRX-678 for chronic myelogenous leukemia?

The effectiveness of TGRX-678 for chronic myelogenous leukemia may be supported by the success of tyrosine kinase inhibitors (TKIs) like imatinib, nilotinib, and dasatinib, which have significantly improved patient outcomes by targeting the BCR-ABL1 protein involved in the disease. These drugs have shown high rates of response and improved survival, suggesting that TGRX-678, if similar, could potentially offer benefits in treating this condition. ^{1 2 3 4 5}

Is TGRX-678 safe for humans?

Tyrosine kinase inhibitors (TKIs), like TGRX-678, generally have a favorable safety profile, with most side effects being mild to moderate and manageable. However, there can be serious long-term effects on vital organs like the heart and lungs, especially in patients with other health issues. ^{6 7 8 9 10}

How is the drug TGRX-678 different from other treatments for chronic myelogenous leukemia?

The drug TGRX-678 may offer a unique approach by targeting leukemic stem cells that are resistant to current treatments like tyrosine kinase inhibitors (TKIs). This could potentially help achieve treatment-free remission by eradicating these resistant cells, which is a challenge with existing therapies. ^{2 3 11 12 13}

Research Team

Elias Jabbour, MD

Principal Investigator

The University of Texas MD Anderson Cancer Center

Eligibility Criteria

This trial is for adults with Chronic Myelogenous Leukemia (CML) who haven't responded to or can't tolerate TKI treatments. Participants must have good kidney and liver function, stable heart health, and not be pregnant. They should agree to use effective birth control during the study.

Inclusion Criteria

My kidney and liver are working well.

I can take care of myself and perform light activities.

I am 18 years old or older.

Exclusion Criteria

I have symptoms of graft versus host disease.

I have been diagnosed with a brain or spinal cord disorder.

I haven't taken any Traditional Chinese medicine for cancer in the last 2 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive escalating doses of TGRX-678 to determine the recommended dose for expansion (RDE)

1 year

Visits on Day 1, 7, 21, 28 of each 28-day cycle

Cohort Expansion

Participants receive the recommended dose of TGRX-678 to further evaluate safety and efficacy

1 year

Visits on Day 1, 7, 21, 28 of each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• TGRX-678

Trial Overview The trial tests TGRX-678's safety and early effectiveness in CML patients resistant or intolerant to standard therapies. It's an open-label study where everyone gets TGRX-678, starting with low doses that increase over time.

Participant Groups

Group I: TGRX-678 Experimental Treatment 1 Intervention

Subjects to be treated with the investigational drug TGRX-678

Who Is Running the Clinical Trial?

Shenzhen TargetRx, Inc.

Lead Sponsor

Trials

12

Recruited

1,100+

M.D. Anderson Cancer Center

Collaborator

Trials

3,107

Recruited

1,813,000+

Findings from Research

Second-generation tyrosine kinase inhibitors (TKIs) like nilotinib and dasatinib have significantly improved outcomes for chronic myelogenous leukemia (CML) patients compared to the first-line TKI, imatinib, by achieving faster and deeper molecular remissions.

Combining interferon alpha with TKI therapy may enhance the immune response against leukemia, and this approach is currently being investigated to potentially improve long-term treatment responses in CML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chronic myelogenous leukemia]. Hochhaus, A., La Rosée, P., Eigendorff, E., et al.[2018]

Imatinib, the first tyrosine kinase inhibitor (TKI) approved for chronic myelogenous leukemia (CML), has greatly improved patient outcomes, but resistance occurs in 40% to 50% of cases due to mutations affecting its binding to the Bcr-Abl kinase.

Novel TKIs, such as dasatinib and nilotinib, have been developed to overcome resistance mechanisms, and combination therapies are being explored to enhance treatment efficacy by targeting multiple pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New targeted therapies for chronic myelogenous leukemia: opportunities to overcome imatinib resistance. Jabbour, E., Cortes, J., O'Brien, S., et al.[2022]

Tyrosine kinase inhibitors (TKIs) have significantly improved outcomes for patients with chronic myelogenous leukemia (CML), making treatment-free remission (TFR) a realistic goal.

Despite the benefits of TKIs, about 50% of patients experience a molecular relapse after stopping treatment, indicating that leukemic stem cells (LSCs) are resistant to TKIs, highlighting the need for additional therapies like immunotherapy to eliminate these resistant cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Treatment Strategies Utilizing Immune Reactions against Chronic Myelogenous Leukemia Stem Cells. Matsushita, M.[2021]

The introduction of tyrosine kinase inhibitors (TKIs) like imatinib has significantly improved outcomes for chronic myelogenous leukemia (CML) patients, but about 35% may develop resistance or intolerance to this treatment.

Second-generation TKIs such as dasatinib and nilotinib have been developed to effectively treat patients who experience imatinib failure, and ponatinib specifically targets the T315I mutation associated with resistance, showcasing the evolution of targeted therapies in CML management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evolution of therapies for chronic myelogenous leukemia. Santos, FP., Kantarjian, H., Quintás-Cardama, A., et al.[2021]

Imatinib, a targeted therapy for chronic myelogenous leukemia (CML), has significantly improved treatment outcomes, achieving over 80% complete cytogenetic response in newly diagnosed patients and leading to excellent long-term survival with minimal side effects.

Despite its effectiveness, some patients may not respond to imatinib or may develop resistance, but second-generation tyrosine kinase inhibitors can restore response in about half of these cases, highlighting ongoing advancements in targeted therapies for CML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New agents in the treatment of chronic myelogenous leukemia. Pinilla-Ibarz, J., Quintas-Cardama, A.[2023]

Imatinib and newer tyrosine kinase inhibitors (TKIs), including asciminib, have significantly improved the prognosis for patients with chronic myelogenous leukemia in chronic phase, highlighting their high efficacy.

Understanding the toxicity profiles of these TKIs is crucial for optimizing treatment, as dose modifications can help minimize chronic toxicities and improve patients' quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events and dose modifications of tyrosine kinase inhibitors in chronic myelogenous leukemia. Yoshifuji, K., Sasaki, K.[2022]

In a study of 450 patients with chronic-phase chronic myeloid leukemia (CML-CP) treated with tyrosine kinase inhibitors (TKIs) from 2004 to 2014, the 5-year overall survival rate was 95.1%, indicating high efficacy of TKIs in this patient population.

Severe adverse events (AEs) during first-line TKI therapy were linked to lower overall survival and event-free survival rates, suggesting that timely modifications to treatment are crucial when patients experience significant AEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe adverse events by tyrosine kinase inhibitors decrease survival rates in patients with newly diagnosed chronic-phase chronic myeloid leukemia. Ota, S., Matsukawa, T., Yamamoto, S., et al.[2022]

In a Phase IIIb study involving 20 patients with chronic phase chronic myeloid leukemia (CML-CP) who were intolerant to previous treatments, switching to nilotinib 300 mg twice daily resulted in a 50% rate of achieving a deep molecular response (MR4.5) within 24 months.

Most non-hematological adverse events from prior treatments resolved within 12 weeks after switching to nilotinib, indicating that nilotinib has minimal cross-intolerance and can be a safe alternative for patients with previous treatment-related toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of nilotinib 300 mg twice daily in patients with chronic myeloid leukemia in chronic phase who are intolerant to prior tyrosine kinase inhibitors: Results from the Phase IIIb ENESTswift study. Hiwase, D., Tan, P., D'Rozario, J., et al.[2022]

In the LAST study involving 172 patients with chronic myeloid leukemia (CML), discontinuation of tyrosine kinase inhibitors (TKIs) was found to be safe, with 60.8% of patients achieving treatment-free remission (TFR) after stopping their medication.

Patients who discontinued TKIs reported significant improvements in quality of life, including reductions in fatigue (80.4%), depression (34.8%), and diarrhea (87.5%), highlighting the potential benefits of stopping TKIs beyond just cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of Outcomes After Stopping Tyrosine Kinase Inhibitors Among Patients With Chronic Myeloid Leukemia: A Nonrandomized Clinical Trial. Atallah, E., Schiffer, CA., Radich, JP., et al.[2022]

Tyrosine kinase inhibitors (TKIs) have significantly improved long-term survival rates for patients with chronic myeloid leukemia (CML), but treatment must be carefully managed due to potential adverse events that can occur, especially early in therapy.

While TKIs generally have a favorable safety profile, new-generation TKIs may pose long-term risks to vital organs like the heart and lungs, particularly in patients with existing health issues, necessitating a careful selection of treatment based on individual patient factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of adverse events associated with tyrosine kinase inhibitors in chronic myeloid leukemia. Rea, D.[2022]

The bcr-abl fusion protein, which is crucial for the development of chronic myelogenous leukemia, is effectively targeted by the tyrosine kinase inhibitor ST1571, showing selective toxicity to bcr-abl-expressing cells in both laboratory and animal studies.

Early clinical trials of ST1571 have yielded promising results, indicating that it may soon be integrated into treatment plans for patients with chronic myelogenous leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Status of bcr-abl tyrosine kinase inhibitors in chronic myelogenous leukemia. O'Dwyer, ME., Druker, BJ.[2019]

In a phase 2 trial involving 62 chronic myeloid leukemia (CML) patients with the T315I mutation, omacetaxine mepesuccinate demonstrated significant efficacy, achieving a complete hematologic response in 77% of patients and a median response duration of 9.1 months.

While omacetaxine was effective, it was associated with manageable grade 3/4 hematologic toxicities, such as thrombocytopenia (76%) and neutropenia (44%), indicating that while it is a promising treatment option, monitoring and dose adjustments may be necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Cortes, J., Lipton, JH., Rea, D., et al.[2021]

A novel compound, 20g (AP24534), has been designed to effectively inhibit both the native BCR-ABL and the resistant T315I mutant, showing low nanomolar IC(50) values in laboratory tests.

In mouse models, daily oral administration of 20g significantly improved survival in mice with BCR-ABL(T315I) expressing cells, suggesting its potential as a new treatment option for chronic myeloid leukemia, especially for patients who do not respond to existing therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant. Huang, WS., Metcalf, CA., Sundaramoorthi, R., et al.[2013]

References

1. Germany pubmed.ncbi.nlm.nih.gov

[Chronic myelogenous leukemia]. [2018]

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

New targeted therapies for chronic myelogenous leukemia: opportunities to overcome imatinib resistance. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Novel Treatment Strategies Utilizing Immune Reactions against Chronic Myelogenous Leukemia Stem Cells. [2021]

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

Evolution of therapies for chronic myelogenous leukemia. [2021]

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

New agents in the treatment of chronic myelogenous leukemia. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Adverse events and dose modifications of tyrosine kinase inhibitors in chronic myelogenous leukemia. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Severe adverse events by tyrosine kinase inhibitors decrease survival rates in patients with newly diagnosed chronic-phase chronic myeloid leukemia. [2022]

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

Efficacy and safety of nilotinib 300 mg twice daily in patients with chronic myeloid leukemia in chronic phase who are intolerant to prior tyrosine kinase inhibitors: Results from the Phase IIIb ENESTswift study. [2022]

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

Assessment of Outcomes After Stopping Tyrosine Kinase Inhibitors Among Patients With Chronic Myeloid Leukemia: A Nonrandomized Clinical Trial. [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

Management of adverse events associated with tyrosine kinase inhibitors in chronic myeloid leukemia. [2022]

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

Status of bcr-abl tyrosine kinase inhibitors in chronic myelogenous leukemia. [2019]

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

Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. [2021]

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

Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant. [2013]