KRT-232 + TKI for Chronic Myeloid Leukemia

Recruiting at 33 trial locations

Overseen By Emily Houlihan

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Kartos Therapeutics, Inc.

Must be taking: Tyrosine kinase inhibitors

Must not be taking: MDM2 antagonist therapies

Disqualifiers: CML-BC, T315I mutation, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

109 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called KRT-232 (Navtemadlin) for individuals with chronic myeloid leukemia (CML) who haven't found success with other treatments. The study evaluates the safety and effectiveness of KRT-232 when combined with existing medications, dasatinib or nilotinib. Candidates may be suitable if they have chronic or accelerated phase CML, have not responded well to Tyrosine Kinase Inhibitors (TKIs), and have a specific type of CML positive for certain markers, such as Ph+ and BCR-ABL+. As a Phase 1 trial, this research focuses on understanding how the treatment 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 need to stop taking your current medications, but it does require that you have been resistant or intolerant to at least one Tyrosine Kinase Inhibitor (TKI).

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

Research has shown that KRT-232, when combined with dasatinib or nilotinib, is under study for its safety and effectiveness in treating chronic myeloid leukemia (CML) in patients who haven't responded to other treatments. KRT-232 is a new drug that targets the protein MDM2, which aids cancer growth.

Studies have found that KRT-232 with dasatinib or nilotinib is generally well-tolerated. While dasatinib and nilotinib are approved for CML, they can cause side effects like heart issues and fluid buildup. Importantly, previous patients treated with these combinations did not report unexpected safety problems, suggesting the treatment is safe enough for further testing.

The study is in an early phase, focusing mainly on safety and dosage. Although more information is needed, early results are promising for those considering joining the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about KRT-232 for chronic myeloid leukemia (CML) because it offers a fresh approach to tackling the disease. Unlike standard treatments like dasatinib and nilotinib, which primarily inhibit BCR-ABL, a protein driving CML, KRT-232 targets MDM2, a protein that regulates the tumor-suppressing p53 pathway. By reactivating p53, KRT-232 may enhance the cancer-killing effects of existing therapies. This combination could potentially improve outcomes for patients who don't respond well to current treatments.

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

Research has shown that KRT-232, when combined with either dasatinib or nilotinib, may help treat certain cases of chronic myeloid leukemia (CML). In this trial, participants will receive KRT-232 along with one of these TKIs. KRT-232 blocks MDM2, a protein that aids cancer cell survival. Studies have found that this combination can improve survival rates in patients who do not respond well to standard treatments. Specifically, survival was 100% for patients who couldn't tolerate other therapies and 71% for those who were resistant. Dasatinib and nilotinib alone have already been effective in managing CML symptoms and improving survival. Together, these treatments aim to offer new hope for those who haven't responded to other options. ^{1 2 3 6 7}

Are You a Good Fit for This Trial?

This trial is for adults over 18 with Chronic Myeloid Leukemia who have not responded well to or cannot tolerate Tyrosine Kinase Inhibitor treatments. They must be in the chronic phase (CML-CP) or accelerated phase (CML-AP), without a specific mutation (T315I), and their body should be functioning well enough to participate.

Inclusion Criteria

I have had a cancer treatment that didn't work or I couldn't tolerate it.

I can care for myself and am up and about more than 50% of my waking hours.

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

Exclusion Criteria

My cancer has the T315I mutation.

I cannot tolerate my current TKI medication.

I have chronic myeloid leukemia in the accelerated phase and it's Ph+ and BCR-ABL+.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

KRT-232 is administered orally once daily on Days 1-7 in a 28-day cycle, combined with a Tyrosine Kinase Inhibitor (Dasatinib or Nilotinib) for patients with CML-CP and CML-AP

6 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

47 months

What Are the Treatments Tested in This Trial?

Interventions

• Dasatinib
• KRT-232
• Nilotinib

Trial Overview The study tests KRT-232, a new inhibitor targeting MDM2, in combination with existing drugs Dasatinib or Nilotinib, for patients whose leukemia has resisted previous treatments. It's an open-label trial meaning everyone knows what treatment they're getting.

How Is the Trial Designed?

Group I: Part 2, Arm C (KRT-232 combined with Dasatinib or Nilotinib in patients with CML-AP) Experimental Treatment 3 Interventions

KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 28-day cycle. Dasatinib or Nilotinib will be administered orally, per locally prescribed dose and schedule.

Group II: Part 2, Arm B (KRT-232 combined with Nilotinib in patients with CML-CP) Experimental Treatment 2 Interventions

KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 28-day cycle. Nilotinib will be administered orally, per locally prescribed dose and schedule.

Group III: Part 2, Arm A (KRT-232 combined with Dasatinib in patients with CML-CP) Experimental Treatment 2 Interventions

KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 28-day cycle. Dasastinib will be administered orally, per locally prescribed dose and schedule.

Group IV: Part 1, KRT-232 combined with TKI (Dasatinib or Nilotinib) in patients with CML-CP Experimental Treatment 3 Interventions

KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 28-day cycle. TKI (dasatinib or nilotinib) will be administered orally, per locally prescribed dose and schedule.

Who Is Running the Clinical Trial?

Kartos Therapeutics, Inc.

Lead Sponsor

Trials

17

Recruited

2,100+

Published Research Related to This Trial

Radotinib is a novel second-generation tyrosine kinase inhibitor (TKI) approved in Korea for treating chronic myeloid leukemia (CML) in both initial and resistant cases, highlighting its potential as a new treatment option.

The review emphasizes radotinib's efficacy and safety in patients with CML, suggesting it may offer significant benefits compared to existing treatments like imatinib and other TKIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radotinib and its clinical potential in chronic-phase chronic myeloid leukemia patients: an update. Eskazan, AE., Keskin, D.[2023]

The review highlights that the four available BCR-ABL1 tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML)—imatinib, nilotinib, dasatinib, and bosutinib—have different safety profiles, which are influenced by their specificity and selectivity in targeting the BCR-ABL1 protein.

Understanding the mechanisms behind adverse events, such as cardiovascular toxicity and gastrointestinal issues, is crucial for clinicians when selecting the most appropriate TKI for patients, especially in first-line treatment settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment-, patient-, and disease-related factors and the emergence of adverse events with tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia. Irvine, E., Williams, C.[2022]

The introduction of imatinib mesylate has significantly improved survival rates for chronic myeloid leukemia (CML) patients, making their outcomes comparable to those of the healthy population, especially with optimal responses.

For patients who do not respond to first-line imatinib, second-generation tyrosine kinase inhibitors (TKIs) can be beneficial, and about 40-60% of patients achieving deep molecular remission may have a chance for treatment-free remission (TFR).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contemporary treatment methods of adult patients with BCR/ABL1 positive chronic myeloid leukemia. Slezáková, K., Mistrík, M., Bátorová, A.[2020]

In a study involving 125 chronic myeloid leukemia (CML) patients, those who underwent low-dose de-escalation of tyrosine kinase inhibitors (TKIs) maintained a high major molecular response (MMR) rate of 88.32% after 12 months, compared to 59.98% in the discontinuation group.

The de-escalation of TKIs not only preserved MMR but also improved patients' quality of life, particularly in emotional functioning and fatigue, suggesting that reducing TKI dosage could be a beneficial new treatment strategy for patients with deep molecular response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

De-escalation or discontinuation of tyrosine kinase inhibitor in patients with chronic myeloid leukemia: A multicentral, open-label, prospective trial in China. Luo, J., Du, X., Lou, J., et al.[2022]

Tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia have similar effectiveness but vary in safety, making it crucial to choose treatments based on individual patient tolerability and adverse event profiles.

Specific TKIs like nilotinib and ponatinib should be avoided in patients with cardiovascular risks, while dasatinib is not recommended for those with lung damage, highlighting the need for personalized treatment plans based on patient comorbidities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of comorbidities on the choice of tyrosine kinase inhibitors in patients with chronic myeloid leukemia. Saydam, G., Ali, R., Demir, AM., et al.[2022]

In a study of 131 patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs), significant cytogenetic and molecular responses were observed, with 95.9% achieving major cytogenetic response after 12 months.

Switching to second-generation TKIs like nilotinib or dasatinib for patients who were resistant or intolerant to imatinib resulted in satisfactory responses, with early molecular responses (BCR-ABLIS levels) at 3 months being strong predictors for achieving deeper molecular remission (MR4.5).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Analysis of Efficacy and Related Factors of Acquired Deep Molecular Response in Chronic Myeloid Leukemia Patients Treated with TKI]. Jing, Y., Yang, L., Liu, DH.[2022]

Asciminib, a new treatment for chronic myeloid leukemia (CML), shows a good safety profile with a lower rate of adverse effects compared to previous tyrosine kinase inhibitors (TKIs), with 55% of patients reporting side effects and only 18% experiencing severe effects.

Despite its unique mechanism of action, asciminib does carry a risk of cross-toxicity with traditional TKIs, particularly for side effects like thrombocytopenia and anemia, indicating careful monitoring is still necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity of Asciminib in Real Clinical Practice: Analysis of Side Effects and Cross-Toxicity with Tyrosine Kinase Inhibitors. Pérez-Lamas, L., Luna, A., Boque, C., et al.[2023]

A 70-year-old female with chronic myeloid leukemia experienced significant facial edema after starting dasatinib, a tyrosine kinase inhibitor, highlighting a rare but impactful side effect of this treatment.

The patient showed marked improvement using a novel regimen of topical metronidazole and tacrolimus, allowing her to continue dasatinib therapy, suggesting a potential new management strategy for TKI-associated facial edema.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Facial Edema Associated with Dasatinib: Case Report with Successful Treatment. Nyckowski, T., Ambur, A., Vinokurov, A., et al.[2023]

Imatinib, a first-line treatment for chronic myeloid leukemia (CML), often leads to intolerance in patients, prompting the need for second- and third-generation tyrosine kinase inhibitors (TKIs) like ponatinib, which is effective against all BCR-ABL1 mutants, including those resistant to other TKIs.

There is a lack of consistent definitions of intolerance across clinical trials, which complicates the assessment of adverse events and their impact on patient quality of life, highlighting the need for better evaluation methods and consideration of ponatinib for patients who cannot tolerate other TKIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intolerance to tyrosine kinase inhibitors in chronic myeloid leukemia: the possible role of ponatinib. Breccia, M., Efficace, F., Iurlo, A., et al.[2019]

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]

The introduction of affordable generic imatinib allows global access to treatment for all chronic myeloid leukaemia patients, making it a crucial first-line therapy option.

Recent studies indicate that lower doses of tyrosine kinase inhibitors (TKIs), including dose-adjusted ponatinib, are not only effective but also safer, suggesting a shift in treatment strategies towards these lower doses for better patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The influence of drug prices, new availability of inexpensive generic imatinib, new approvals, and post-marketing research on the treatment of chronic myeloid leukaemia in the USA. Kantarjian, H., Paul, S., Thakkar, J., et al.[2022]

Tyrosine kinase inhibitors (TKIs) have significantly improved the life expectancy of patients with chronic myeloid leukemia (CML), but long-term use can lead to persistent adverse events that negatively affect quality of life.

The review highlights the potential benefits of TKI dose reduction to manage adverse events and maintain effective treatment responses, suggesting that dose modifications could be a viable strategy for both newly diagnosed patients and those experiencing side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose Optimization of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A New Therapeutic Challenge. Iurlo, A., Cattaneo, D., Bucelli, C., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04835584

KRT-232 and TKI Study in Chronic Myeloid Leukemia This study evaluates KRT-232, a novel oral small molecule inhibitor of MDM2, for the treatment of patients with Ph+ Chronic Myeloid Leukemia (CML) who have ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0006497121045092

A Phase 1b/2 Study of Navtemadlin (KRT-232), a Murine ... Background: BCR-ABL tyrosine kinase inhibitors (TKI) can provide symptom control and improve survival in patients with Ph+ chronic myeloid leukemia (CML), ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11534886/

Outcomes of chronic myeloid leukemia patients after ... With a median follow-up of 11.2 months, overall survival of the global cohort was 73%; 100% for intolerant patients, 71% for resistant patients ...

4. withpower.com withpower.com/trial/krt-232-tki-for-chronic-myeloid-leukemia-aefda

KRT-232 + TKI for Chronic Myeloid Leukemia This study is a global, open label Phase 1b/2 to determine the efficacy and safety of KRT-232 in patients with chronic phase CML (CML-CP) and accelerated phase ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10388268/

Insights into dasatinib use and outcomes in real-world ... The aim of this study was to investigate prescribing patterns, tolerability, and effectiveness of dasatinib in patients with CML in real-world clinical practice ...

6. ctv.veeva.com ctv.veeva.com/study/krt-232-and-tki-study-in-chronic-myeloid-leukemia

KRT-232 and TKI Study in Chronic Myeloid Leukemia This study is a global, open label Phase 1b/2 to determine the efficacy and safety of KRT-232 in patients with chronic phase CML (CML-CP) and ...

7. sprycel-hcp.com sprycel-hcp.com/safety-newly-diagnosed

SPRYCEL® (dasatinib) Safety Profile - Newly Diagnosed ... Find SPRYCEL® (dasatinib) safety profile for the management of newly diagnosed adult patients. See Important Safety Information and full PI.