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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug, TGRX-678, for individuals with chronic myelogenous leukemia (CML), a type of blood cancer. The trial aims to determine the safety and effectiveness of TGRX-678, particularly for those who cannot take or do not respond to current treatments known as TKIs. Individuals with CML who have experienced difficulties with TKI treatments might be suitable candidates for this study. As a Phase 1 trial, the research focuses on understanding how TGRX-678 works in people, offering participants the opportunity to be among the first to receive this new treatment.

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.

Is there any evidence suggesting that TGRX-678 is likely to be safe for humans?

A previous study found TGRX-678 to be safe for patients, with no new safety issues reported. Researchers determined the appropriate dose that patients could tolerate without serious side effects. The study also explored the drug's effectiveness in patients with various types of Chronic Myelogenous Leukemia. Results suggest that TGRX-678 could be a promising option for patients who have not responded well to other treatments. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for chronic myelogenous leukemia (CML), which usually involve drugs like imatinib that target specific proteins in cancer cells, TGRX-678 is unique because it offers a new approach. Researchers are excited about TGRX-678 because it targets a different part of the cancer cell's structure, potentially leading to improved effectiveness and fewer side effects. This new mechanism of action could provide an important alternative for patients who do not respond well to existing therapies.

What evidence suggests that TGRX-678 might be an effective treatment for Chronic Myelogenous Leukemia?

Research has shown that TGRX-678, the investigational drug in this trial, may effectively treat Chronic Myelogenous Leukemia (CML). In previous studies, patients with the T315I mutation experienced positive outcomes: 80% achieved normal blood counts, 76% saw a reduction in cancer cells, 69% had a complete decrease in cancer cells, and 50% showed a significant drop in cancer markers. TGRX-678 was well-tolerated, with no new safety issues reported. These results suggest it could be a good option for CML patients who haven't responded to other treatments. ^{1 2 3 4 6}

Who Is on the Research Team?

Elias Jabbour, MD

Principal Investigator

The University of Texas MD Anderson Cancer Center

Are You a Good Fit for This Trial?

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 have been diagnosed with chronic myeloid leukemia in the chronic phase recently.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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 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 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]

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, 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]

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]

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]

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]

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]

Citations

1. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/477/530699/Safety-and-Efficacy-of-Tgrx-678-a-Potent-BCR-ABL1

Safety and Efficacy of Tgrx-678, a Potent BCR::ABL1 allosteric ... Study TGRX-678-1001 (NCT05434312) is a phase Ia/Ib, first-in-human, open-label trial designed to evaluate the safety, efficacy and ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05434312

NCT05434312 | TGRX-678 Chinese Phase I in Chronic ... This is the first-in-human trial with TGRX-678 which aims to evaluate the safety profile and preliminary efficacy profile in advanced or refractory CML patients ...

3. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/867/502441/Safety-and-Efficacy-of-Tgrx-678-a-Potent-BCR-ABL

Safety and Efficacy of Tgrx-678, a Potent BCR-ABL Allosteric ... Of 14 CML-CP patients with T315I mutation, 9 (100%) achieved CHR, 9 (62%) MCyR, 8 (57%) CCyR and 7 (50%) MMR. Of 35 CML-CP patients without any ...

4. tjrbiosciences.com tjrbiosciences.com/en/index.php?m=content&c=index&a=show&catid=20&id=108

2024 ASH Oral | TGRX-678 Phase I Clinical Trial Results ... In patients with a single T315I mutation, 16/20 (80%) achieved CHR, the 18-month cumulative incidences of MCyR, CCyR, and MMR were 76%, 69%, and 50%, ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124032245

Safety and Efficacy of Tgrx-678, a Potent BCR::ABL1 ... TGRX-678 showed well tolerated with no new safety signals identified. The updated data indicate promising efficacy in both CP and AP patients.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06088888

Study Details | NCT06088888 | TGRX-678 US Phase I for ... The primary purpose of this study is to evaluate the safety profile of TGRX-678, including determination of the recommended dose for expansion (RDE) and other ...