TL-895 + KRT-232 for Acute Myeloid Leukemia

Recruiting at 35 trial locations

Overseen By Evelyn Hang

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Telios Pharma, Inc.

Must not be taking: MDM2 antagonists

Disqualifiers: AML subtype 3, HSCT eligible, others

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

Compensation: Varies

Number of Visits: 28

Duration: 41 months

18 Participants Needed

Trial Summary

What is the purpose of this trial?

This study evaluates TL-895, a potent, orally available and highly selective irreversible tyrosine kinase inhibitor combined with navtemadlin (KRT-232), a novel oral small molecule inhibitor of MDM2 for the treatment of adults with FLT3 mutated Acute Myeloid Leukemia. Participants must be relapsed/refractory (e.g., having failed prior therapy) to be eligible for this study.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug KRT-232 (Navtemadlin) for treating acute myeloid leukemia?

Research on a similar drug, AMG 232, which also targets the MDM2 protein, showed some promising results in patients with acute myeloid leukemia, with a few patients achieving remission or a leukemia-free state. This suggests that drugs targeting MDM2, like KRT-232, may have potential in treating this condition. ^{1 2 3 4 5}

What safety data exists for TL-895 and KRT-232 in humans?

There is no specific safety data available for TL-895 and KRT-232 in the provided research articles. ^{1 4 6 7 8}

How is the drug TL-895 + KRT-232 unique for treating acute myeloid leukemia?

The drug TL-895 + KRT-232 is unique because it combines two components that may target different pathways in acute myeloid leukemia, potentially offering a novel approach compared to existing treatments that often face resistance issues. While specific details about this combination are not provided, it may offer a new mechanism of action or synergy that is not present in current standard therapies. ^{9 10 11 12 13}

Eligibility Criteria

Adults with a specific type of leukemia (FLT3 mutated Acute Myeloid Leukemia) who have tried other treatments without success can join this trial. They should not have had prior MDM2 antagonist therapies, be eligible for stem cell transplant, or have subtype 3 AML. Good overall function and no severe issues with blood, liver, or kidneys are required.

Inclusion Criteria

My blood, liver, and kidney functions are all within normal ranges.

My condition did not improve after treatment, including a FLT-3 inhibitor.

I am able to care for myself and perform daily activities.

Exclusion Criteria

My leukemia is classified as AML subtype 3.

I am eligible for a stem cell transplant.

I have previously been treated with MDM2 antagonist therapies.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive TL-895 and KRT-232 in various dose levels across 28-day cycles

41 months

Monthly visits for each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

13 months

Treatment Details

Interventions

• KRT-232
• TL-895

Trial Overview The study tests TL-895 combined with KRT-232 in patients. TL-895 is an oral drug that blocks certain proteins involved in cancer growth while KRT-232 targets a protein that helps cancer cells survive.

Participant Groups

Group I: Phase 2 - Dose Expansion Experimental Treatment 2 Interventions

Dose expansion of the recommended phase 2 dose of TL-895 in combination with KRT-232 as determined in Phase 1b.

Group II: Phase 1b - Dose Level 5 Experimental Treatment 2 Interventions

Cycle 1 only: KRT-232 360 mg QD orally administered on Days 1 through 7 of the first 28-day cycle in combination with TL-895 450 mg BID continuously for the first 28-day cycle. Cycle 2 and beyond: KRT-232 300 mg QD orally administered on Days 1 through 7 of each 28-day cycle in combination with TL-895 450 mg BID continuously for each 28-day cycle.

Group III: Phase 1b - Dose Level 4 Experimental Treatment 2 Interventions

Cycle 1 only: KRT-232 360 mg QD orally administered on Days 1 through 7 of the first 28-day cycle in combination with TL-895 300 mg BID continuously for the first 28-day cycle. Cycle 2 and beyond: KRT-232 300 mg QD orally administered on Days 1 through 7 of each 28-day cycle in combination with TL-895 300 mg BID continuously for each 28-day cycle.

Group IV: Phase 1b - Dose Level 3 Experimental Treatment 2 Interventions

Cycle 1 only: KRT-232 360 mg QD orally administered on Days 1 through 7 of the first 28-day cycle in combination with TL-895 150 mg BID continuously for the first 28-day cycle Cycle 2 and beyond: KRT-232 300 mg QD orally administered on Days 1 through 7 of each 28-day cycle in combination with TL-895 150 mg BID continuously for each 28-day cycle.

Group V: Phase 1b - Dose Level 2 Experimental Treatment 2 Interventions

KRT-232 300mg QD, orally administered on days 1 through 7 of each 28-day cycle in combination with TL-895 150mg BID continuously for each 28-day cycle.

Group VI: Phase 1b - Dose Level 1 Experimental Treatment 2 Interventions

KRT-232 240mg QD, orally administered on days 1 through 7 of each 28-day cycle in combination with TL-895 150mg BID continuously for each 28-day cycle.

Who Is Running the Clinical Trial?

Telios Pharma, Inc.

Lead Sponsor

Trials

11

Recruited

1,700+

Kartos Therapeutics, Inc.

Industry Sponsor

Trials

17

Recruited

2,100+

Findings from Research

AMG 232, an investigational drug for relapsed/refractory acute myeloid leukemia (AML), was found to have acceptable safety and pharmacokinetics, with no dose-limiting toxicities at doses up to 360 mg when used alone, although gastrointestinal side effects were noted at higher doses.

In terms of efficacy, 1 out of 30 evaluable patients achieved complete remission, and 31% of patients with wild-type TP53 responded to treatment, indicating potential effectiveness, especially in specific patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia. Erba, HP., Becker, PS., Shami, PJ., et al.[2023]

In a pooled analysis of treatment-naïve patients with FLT3-mutant acute myeloid leukemia, the combination of venetoclax and azacitidine resulted in a significantly higher composite complete remission rate (67%) compared to azacitidine alone (36%), with a median overall survival of 12.5 months versus 8.6 months.

The treatment was found to be safe, with no unexpected toxicities reported, indicating that venetoclax + azacitidine is a promising option for older patients or those with comorbidities who are ineligible for intensive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of FLT3 Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia. Konopleva, M., Thirman, MJ., Pratz, KW., et al.[2023]

A new compound, SID7969543, was identified as a selective inhibitor that effectively targets KMT2A-rearranged leukemia cells, particularly in infants, without harming normal cells or other types of leukemia.

This compound works by inducing apoptosis in KMT2A-r leukemia cells and shows potential for synergy with existing chemotherapy treatments, making it a promising candidate for further research in treating aggressive leukemias.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic In Vitro Evaluation of a Library of Approved and Pharmacologically Active Compounds for the Identification of Novel Candidate Drugs for KMT2A-Rearranged Leukemia. Karsa, M., Ronca, E., Bongers, A., et al.[2022]

In a phase 1 study involving 23 patients with relapsed/refractory acute myeloid leukemia (AML), the combination of selinexor with mitoxantrone, etoposide, and cytarabine showed an overall response rate of 43%, with 26% of patients achieving complete remission.

The maximum tolerated dose of selinexor was determined to be 30 mg/m2 due to dose-limiting side effects, including hyponatremia, indicating that while the treatment is promising, careful monitoring for toxicity is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of selinexor in combination with salvage chemotherapy in Adults with relapsed or refractory Acute myeloid leukemia. Bhatnagar, B., Zhao, Q., Mims, AS., et al.[2023]

A study involving 31 primary high-risk AML samples identified gilteritinib as the most effective drug to combine with venetoclax, showing increased apoptosis and reduced cell viability, even in resistant cell lines.

The combination of gilteritinib and venetoclax works by inhibiting FLT3 and AXL signaling, leading to the degradation of the antiapoptotic protein MCL-1, suggesting this combination could be a promising treatment for patients with high-risk FLT3 wild-type AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax synergizes with gilteritinib in FLT3 wild-type high-risk acute myeloid leukemia by suppressing MCL-1. Janssen, M., Schmidt, C., Bruch, PM., et al.[2023]

The combination of vosaroxin and venetoclax synergistically induces apoptosis in acute myeloid leukemia (AML) cell lines and primary patient samples, suggesting a potent anti-leukemic effect.

This combination treatment effectively targets AML progenitor cells while sparing normal hematopoietic progenitor cells, indicating a potentially safer therapeutic option for elderly patients with AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax Synergistically Enhances the Anti-leukemic Activity of Vosaroxin Against Acute Myeloid Leukemia Cells Ex Vivo. Liu, F., Knight, T., Su, Y., et al.[2020]

The combination of 225 Ac-lintuzumab and venetoclax showed a synergistic effect in killing tumor cells in venetoclax-resistant acute myeloid leukemia (AML) models, indicating a potential new treatment strategy.

This combination therapy not only induced DNA damage but also reduced MCL-1 protein levels, which is linked to resistance against venetoclax, leading to better tumor control and prolonged survival in preclinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models. Garg, R., Allen, KJH., Dawicki, W., et al.[2021]

References

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

Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia. [2023]

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

Impact of FLT3 Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia. [2023]

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

Mezigdomide is effective alone and in combination with Menin inhibition in pre-clinical models of KMT2A-r and NPM1c AML. [2023]

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

Murine double minute 2 inhibition alone or with cytarabine in acute myeloid leukemia: Results from an idasanutlin phase 1/1b study⋆. [2021]

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

Multi-institutional phase 2 clinical and pharmacogenomic trial of tipifarnib plus etoposide for elderly adults with newly diagnosed acute myelogenous leukemia. [2021]

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

Systematic In Vitro Evaluation of a Library of Approved and Pharmacologically Active Compounds for the Identification of Novel Candidate Drugs for KMT2A-Rearranged Leukemia. [2022]

7. Italy pubmed.ncbi.nlm.nih.gov

A novel regimen for relapsed/refractory adult acute myeloid leukemia using a KMT2A partial tandem duplication targeted therapy: results of phase 1 study NCI 8485. [2020]

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

Phase 1 study of selinexor in combination with salvage chemotherapy in Adults with relapsed or refractory Acute myeloid leukemia. [2023]

9. Italy pubmed.ncbi.nlm.nih.gov

AXL/MERTK inhibitor ONO-7475 potently synergizes with venetoclax and overcomes venetoclax resistance to kill FLT3-ITD acute myeloid leukemia. [2022]

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

Venetoclax synergizes with gilteritinib in FLT3 wild-type high-risk acute myeloid leukemia by suppressing MCL-1. [2023]

11. France pubmed.ncbi.nlm.nih.gov

Venetoclax Synergistically Enhances the Anti-leukemic Activity of Vosaroxin Against Acute Myeloid Leukemia Cells Ex Vivo. [2020]

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

SOHO State of the Art Updates and Next Questions:Harnessing Apoptosis in AML. [2022]

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

225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models. [2021]