TL-895 + KRT-232 for Acute Myeloid Leukemia

Not currently recruiting at 39 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for adults with a specific type of Acute Myeloid Leukemia (AML) that has a FLT3 mutation and has not responded well to other treatments. The study examines the effectiveness of TL-895, a targeted cancer drug, when combined with KRT-232 (also known as Navtemadlin), which blocks a protein that aids cancer cell survival. Researchers explore different dosage levels to find the optimal balance of effectiveness and safety. This trial targets individuals whose AML has returned or resisted previous treatments, particularly those who have previously tried a FLT-3 inhibitor. As a Phase 1, Phase 2 trial, it focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

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.

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

Earlier studies have shown that TL-895 and KRT-232 can be used together to treat acute myeloid leukemia (AML). Although detailed safety information for this combination isn't available yet, ongoing studies aim to find the optimal dose that balances efficacy and safety. As this is an early-stage trial, researchers are carefully testing the combination for safety. This process typically involves monitoring how well patients tolerate the treatment and observing any side effects. Before joining a trial, discussing potential risks and benefits with the research team or a doctor is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about TL-895 and KRT-232 for treating Acute Myeloid Leukemia (AML) because they offer a novel approach compared to the current standard treatments like chemotherapy and targeted therapy. TL-895 is a potent, selective Bruton's tyrosine kinase (BTK) inhibitor, which interferes with cancer cell signaling, potentially halting cancer progression. KRT-232 is a small molecule inhibitor targeting MDM2, a protein that usually suppresses the tumor-suppressor gene p53, thereby reactivating p53 to fight cancer cells. This combination aims to enhance the effectiveness of treatment by simultaneously attacking cancer through different pathways, offering hope for better outcomes in a condition that has been challenging to treat.

What evidence suggests that this trial's treatments could be effective for Acute Myeloid Leukemia?

Research has shown that TL-895, a type of drug, blocks certain proteins that help cancer cells grow. KRT-232 targets a protein called MDM2, which can prevent cancer cells from dying. This trial will explore various dosages of TL-895 combined with KRT-232 to determine their effectiveness in treating Acute Myeloid Leukemia (AML) with FLT3 mutations. Early findings suggest that these two drugs together may effectively attack cancer cells. Some initial studies showed promise in slowing cancer cell growth. However, more research is needed to confirm their combined effectiveness in people. ^{1 4 6 7 8}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04669067

TL-895 and KRT-232 Study in Acute Myeloid Leukemia This study evaluates TL-895, a potent, orally available and highly selective irreversible tyrosine kinase inhibitor combined with navtemadlin (KRT-232), ...

2. clinicaltrial.be clinicaltrial.be/en/details/49751?per_page=20&only_recruiting=0&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_eligible=0&only_active=0

TL-895 and KRT-232 Study in Acute Myeloid Leukemia This study evaluates TL-895, a potent, orally available and highly selective irreversible tyrosine kinase inhibitor combined with ...

3. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04669067/

Clinical Trial: NCT04669067 This study evaluates TL-895, a potent, orally available and highly selective irreversible tyrosine kinase inhibitor combined with KRT-232, a novel oral small ...

4. withpower.com withpower.com/trial/phase-2-leukemia-2-2021-ebaa6

TL-895 + KRT-232 for Acute Myeloid Leukemia This study evaluates TL-895, a potent, orally available and highly selective irreversible tyrosine kinase inhibitor combined with navtemadlin (KRT-232), ...

5. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2021-00124

TL-895 and KRT-232 Study in Acute Myeloid Leukemia - NCI This study evaluates TL-895, a potent, orally available and highly selective irreversible tyrosine kinase inhibitor combined with navtemadlin (KRT-232), ...

6. clinicaltrial.be clinicaltrial.be/en/details/49751?active_not_recruiting=1&completed=0&enrolling_by_invitation=1&only_active=0&only_eligible=0&only_recruiting=0&per_page=20

TL-895 and KRT-232 Study in Acute Myeloid Leukemia - Clin... The Safety Review Committee (SRC) will determine the RP2D based on safety data of the combination of TL-895 and KRT-232. ... The proportion of subjects who ...

7. sperimentazionicliniche.it sperimentazionicliniche.it/sito2021clinicmap/component/clinicmap/clinicmaps?single=NCT04669067

TL-895 and KRT-232 Study in Acute Myeloid Leukemia ... TL-895 combined with KRT-232. The Safety Review Committee (SRC) will determine the RP2D based on safety data of the combination of TL-895 and KRT-232.

8. clin.larvol.com clin.larvol.com/trial-detail/NCT04669067

TL-895 and KRT-232 Study in Acute Myeloid Leukemia ... TL-895 combined with KRT-232. The Safety Review Committee (SRC) will determine the RP2D based on safety data of the combination of TL-895 and KRT-232. 13 ...