Tuspetinib for Acute Myeloid Leukemia

(TUSCANY Trial)

Recruiting at 39 trial locations

Overseen By Rafael Bejar, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Hanmi Pharmaceutical Company Limited

Must not be taking: HMA, BCL-2 inhibitors

Disqualifiers: Acute promyelocytic leukemia, BCR-ABL-positive leukemia, active malignancy, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

240 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests tuspetinib, a new drug for blood cancers such as acute myeloid leukemia (AML), myelodysplastic syndromes (MDS-IB2), and chronic myelomonocytic leukemia (CMML). The goal is to determine a safe and effective dose of tuspetinib, either alone or in combination with other drugs, for these conditions. Individuals whose cancers have returned after treatment or who are newly diagnosed with AML may be suitable candidates. Participants should be able to take oral medication and have a gap after their last treatment. As a Phase 1 trial, the 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 requires a break from certain medications before starting the study drug. You need to wait at least 2 weeks after stopping cytotoxic agents, 4 weeks for biologic or cellular immunotherapies, or at least 5 half-lives for other experimental or noncytotoxic agents. Discuss with the study team for specific guidance on your medications.

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

Research has shown that tuspetinib, used alone or with drugs like venetoclax and azacitidine, is well-tolerated by patients with acute myeloid leukemia (AML). Studies have reported positive responses in various groups of AML patients. Early results suggest that tuspetinib, whether used alone or with other treatments, is generally safe.

Earlier studies described tuspetinib as a well-tolerated oral drug targeting specific proteins in cancer cells. This has been confirmed at different doses and in combination with other treatments, providing reassurance about its safety in humans. However, since this treatment is still under evaluation, its full safety profile is yet to be determined. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Tuspetinib is unique because it targets the FLT3 protein, which is often mutated in acute myeloid leukemia (AML) cells, potentially stopping cancer growth more effectively than some existing treatments like chemotherapy or other FLT3 inhibitors. Researchers are excited about tuspetinib because it can be used alone or in combination with drugs like venetoclax and azacitidine, which might enhance its effectiveness. Unlike other treatments that may take longer to work, tuspetinib has shown promise in rapidly reducing cancer cell levels, offering hope for quicker patient responses.

What evidence suggests that tuspetinib might be an effective treatment for acute myeloid leukemia?

Research has shown that tuspetinib may effectively treat acute myeloid leukemia (AML). In studies, 70% of patients treated with tuspetinib alone showed no detectable cancer, outperforming other treatments. In this trial, some participants will receive tuspetinib as a single agent, while others will receive it with venetoclax and azacitidine. When combined with these drugs, some patients experienced complete remission, meaning their cancer was entirely gone. These findings suggest that tuspetinib could be especially effective when used with other medications. The treatment is also generally well-tolerated, causing no severe side effects for most patients. ^{1 2 6 7 8}

Who Is on the Research Team?

Naval Daver, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with Acute Myeloid Leukemia (AML) that has come back or didn't respond to previous treatments. They should be in a condition to take oral medication, have an acceptable level of organ function, and not be pregnant or breastfeeding. Participants must use effective contraception and can't join other studies simultaneously.

Inclusion Criteria

-- Must use highly effective contraception starting at screening and throughout the study period and for 90 days after the final study drug administration.

Patient must meet the following criteria as indicated on the clinical laboratory tests

I am surgically sterile or had a hysterectomy at least one month ago.

Exclusion Criteria

I have had a stem cell transplant.

My leukemia is BCR-ABL positive.

I have significant heart rhythm issues as shown on an ECG.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation and Exploration

Participants receive tuspetinib as a single agent or in combination with other drugs to determine the maximum tolerated dose and recommended Phase 2 dose

Cycle 1 (at least 28 days)

Dose Expansion

Participants receive tuspetinib at determined dose levels to further assess safety, tolerability, and preliminary efficacy

Cycle 1 (at least 28 days)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 years

What Are the Treatments Tested in This Trial?

Interventions

• Tuspetinib

Trial Overview The study tests Tuspetinib's safety and how the body responds to it at different doses in AML patients. It's given alongside Venetoclax tablets in an open-label format where everyone knows what treatment they're getting.

How Is the Trial Designed?

Group I: Part D Dose Exploration (tuspetinib plus venetoclax and azacitidine) [ACTIVE, RECRUITING - US Sites] Experimental Treatment 3 Interventions

Part D dose exploration of tuspetinib in combination with venetoclax and azacitidine is planned for up to 6 dose levels. The initial tuspetinib dose will be 40 mg.

Group II: Part C Dose Expansion (tuspetinib plus venetoclax) [COMPLETE] Experimental Treatment 2 Interventions

Part C dose expansion of tuspetinib in combination with venetoclax is planned for 2 dose levels. The initial tuspetinib dose will be 80 mg.

Group III: Part C Dose Expansion (tuspetinib as a single agent) [COMPLETE] Experimental Treatment 1 Intervention

Part C dose expansion of tuspetinib as a single agent is planned for 2 dose levels. Study participants will be randomly assigned to either arm based on the number of slots available. The initial tuspetinib dose will be 120 mg.

Group IV: Part B Dose Exploration [ACTIVE, NOT RECRUITING] Experimental Treatment 1 Intervention

Part B dose exploration of tuspetinib as a single agent is planned for up to 4 dose levels.

Group V: Part A Dose Escalation [COMPLETED] Experimental Treatment 1 Intervention

Part A dose escalation of tuspetinib as a single agent is planned for up to 6 dose levels. If a study participant in dose escalation at any dose level achieves clinical response, then the dose level will continue to enroll in Part B. If one DLT or less is observed in the 6 participants (\<1/6 DLT observed) in Part A, up to 20 evaluable participants can be enrolled in Part B at that dose level.

Tuspetinib is already approved in United States for the following indications:

Approved in United States as Tuspetinib for:

• Acute myeloid leukemia (AML)

Who Is Running the Clinical Trial?

Hanmi Pharmaceutical Company Limited

Lead Sponsor

Trials

196

Recruited

62,100+

Young Choi

Hanmi Pharmaceutical Company Limited

Chief Medical Officer since 2023

PhD in Pharmacology from Yonsei University

Jae-Hyun Park

Hanmi Pharmaceutical Company Limited

Chief Executive Officer since 2024

MD from Seoul National University

Aptose Biosciences Inc.

Lead Sponsor

Trials

8

Recruited

850+

Published Research Related to This Trial

Recent advancements in high-throughput sequencing have improved our understanding of acute myeloid leukemia (AML) by identifying key genetic mutations involved in the disease, paving the way for more targeted therapies.

In the last two years, the FDA has approved eight new therapies for AML, including those targeting specific mutations like FLT3 and IDH, which represent a significant shift towards personalized treatment options for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

From DNA Sequencing to Clinical Trials: Finding New Targeted Drugs for Acute Myeloid Leukemia. Yilmaz, M., Daver, N.[2020]

Acute myeloid leukemia (AML) has a low long-term survival rate of about 30% in adults, highlighting the urgent need for new therapeutic strategies to improve patient outcomes.

The review focuses on molecularly targeted therapies for AML, including investigational agents like FLT3 and IDH1 inhibitors, which represent promising advancements in precision medicine aimed at enhancing treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

From Bench to Bedside and Beyond: Therapeutic Scenario in Acute Myeloid Leukemia. Gurnari, C., Voso, MT., Maciejewski, JP., et al.[2020]

Recent advancements in genomics and molecular biology have significantly enhanced our understanding of acute myeloid leukemia (AML), a disease known for its clinical and genetic diversity and poor prognosis.

Since 2017, there have been new drug approvals for AML, particularly focusing on epigenetic-targeted therapies that are currently in pre-clinical and clinical development, marking a significant shift in treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent advances in the understanding and treatment of acute myeloid leukemia. Watts, J., Nimer, S.[2023]

Targeted therapies like venetoclax and ivosidenib, when combined with hypomethylating agents, significantly improve overall survival and event-free survival in patients with acute myeloid leukemia (AML) who cannot undergo first-line chemotherapy, with hazard ratios indicating a strong benefit.

While combination therapies generally resulted in more adverse events compared to control treatments, the combination of ivosidenib and azacitidine did not show this trend, suggesting it may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapies for acute myeloid leukemia in patients ineligible for standard induction chemotherapy: a systematic review. Heuser, M., Fernandez, C., Hauch, O., et al.[2023]

Gilteritinib is a newly approved second-generation FLT3 inhibitor specifically designed for treating relapsed or refractory acute myeloid leukemia (AML) in patients with FLT3 mutations, which are found in about one-third of AML cases.

This treatment targets the FLT3 mutation, which is associated with poor prognosis due to increased tumor growth and reduced cell differentiation, potentially improving outcomes for patients with this challenging form of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gilteritinib: A Novel FLT3 Inhibitor for Relapsed/Refractory Acute Myeloid Leukemia. Marjoncu, D., Andrick, B.[2021]

Midostaurin (PKC412) combined with standard chemotherapy (daunorubicin) shows a synergistic effect in inhibiting intracellular signaling in FLT3-mutated acute myeloid leukemia (AML) cells, which may enhance treatment efficacy.

In contrast, cytarabine appears to antagonize the effects of PKC412, leading to increased FLT3 receptor expression and potentially complicating treatment outcomes, highlighting the need for further research into optimal combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiplexed single-cell mass cytometry reveals distinct inhibitory effects on intracellular phosphoproteins by midostaurin in combination with chemotherapy in AML cells. Rörby, E., Adolfsson, J., Hultin, E., et al.[2021]

Trametinib, a MEK1/MEK2 inhibitor, demonstrated selective activity against RAS-mutated myeloid malignancies, with overall response rates of 20% in patients with NRAS or KRAS mutations, indicating its potential as a targeted therapy.

The treatment was generally well tolerated, with manageable side effects such as diarrhea and rash, and the recommended dose was established at 2 mg daily, suggesting a favorable safety profile for further clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in RAS-mutant relapsed or refractory myeloid malignancies. Borthakur, G., Popplewell, L., Boyiadzis, M., et al.[2022]

In a phase 1 trial involving 84 elderly patients with acute myelogenous leukemia, the combination of tipifarnib and etoposide showed promising results, achieving complete remission in 30% of patients receiving a 14-day regimen.

The combination therapy was well-tolerated, with dose-limiting toxicities noted primarily in the longer 21-day treatment, suggesting that a shorter duration may be more effective and safer for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide. Karp, JE., Flatten, K., Feldman, EJ., et al.[2021]

NUC-7738 effectively induces apoptosis in acute myeloid leukemia (AML) cell lines by targeting the PI3K/Akt/GSK3β pathway, leading to reduced levels of β-catenin and its associated oncogenes, which are crucial for leukemia stem cell survival.

In a study, NUC-7738 significantly decreased the population of leukemia stem cell-like cells (CD34+ CD38- CD123+) from 81% to 47%, demonstrating its potential to reduce the clonogenicity of AML cells and suggesting a promising therapeutic strategy for targeting AML stem cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NUC-7738 regulates β-catenin signalling resulting in reduced proliferation and self-renewal of AML cells. Shahid, AM., Um, IH., Elshani, M., et al.[2023]

Recent advancements in the treatment of acute myeloid leukemia (AML) have led to the FDA approval of four new targeted therapies that show improved responses and overall survival in specific patient populations, particularly those with certain genetic mutations.

These therapies include midostaurin for FLT3-mutated AML, gemtuzumab ozogamicin for CD33+ AML, CPX-351 for therapy-related AML, and enasidenib for IDH2-mutated AML, marking a significant shift in treatment options after decades of limited progress.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New and emerging therapies for acute myeloid leukaemia. Davis, JR., Benjamin, DJ., Jonas, BA.[2020]

Citations

1. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/4255/534292/Phase-1-Safety-and-Efficacy-of-Tuspetinib-Plus

Phase 1 Safety and Efficacy of Tuspetinib Plus Venetoclax ... CONCLUSIONS: Tuspetinib as monotherapy and in combination with VEN has been well- tolerated with objective responses among diverse AML patient ...

2. targetedonc.com targetedonc.com/view/promising-triplet-therapy-with-tuspetinib-shows-high-efficacy-in-newly-diagnosed-aml

Promising Triplet with Tuspetinib Shows Efficacy in Newly ... The TUSCANY trial shows a 100% complete remission rate at 80 mg and 120 mg doses of tuspetinib in combination with venetoclax and azacitidine.

3. cancernetwork.com cancernetwork.com/view/tuspetinib-exhibits-enhanced-efficacy-in-diverse-newly-diagnosed-aml-group

Tuspetinib Exhibits Enhanced Efficacy in Diverse Newly ... The addition of tuspetinib (HM-43239) to venetoclax (Venclexta) and azacitidine (Vidaza) exhibited enhanced efficacy outcomes in a diverse ...

4. aacrjournals.org aacrjournals.org/cancerrescommun/article/5/1/74/751014/Preclinical-Development-of-Tuspetinib-for-the

Preclinical Development of Tuspetinib for the Treatment of ... Tuspetinib (TUS) is a well-tolerated, once daily, oral kinase inhibitor in clinical development for treatment of acute myeloid leukemia ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03850574

Study Details | NCT03850574 | Clinical Trial to Evaluate ... The main purpose of this study is to identify a safe and potentially effective dose of tuspetinib to be used in future studies in study participants ...

6. aptose.com aptose.com/news-media/press-releases/detail/322/aptose-presents-safety-response-and-mrd-clinical-data

Aptose Presents Safety, Response, and MRD Clinical Data ... Aptose Presents Safety, Response, and MRD Clinical Data from TUSCANY Phase 1/2 Clinical Trial of Tuspetinib Triplet Therapy in Newly Diagnosed AML at the ...

7. ash.confex.com ash.confex.com/ash/2023/webprogram/Paper182296.html

162 Tuspetinib Myeloid Kinase Inhibitor Safety and Efficacy ... Tuspetinib is being evaluated clinically as monotherapy (TUS) and in combination (VEN/TUS) in a global Phase 1/2 trial of patients with R/R AML.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11725774/

Preclinical Development of Tuspetinib for the Treatment ... Tuspetinib (TUS) is a well-tolerated, once daily, oral kinase inhibitor in clinical development for treatment of acute myeloid leukemia (AML).