Entrectinib + ASTX727 for Acute Myeloid Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: OHSU Knight Cancer Institute

Must not be taking: Investigational agents

Disqualifiers: HIV, Hepatitis B/C, Heart failure, others

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

Compensation: Varies

Number of Visits: 4

Duration: 28 days per cycle

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safest and most effective doses of two medications, entrectinib and ASTX727, for treating acute myeloid leukemia (AML) that has returned or isn't responding to treatment. ASTX727, a combination of cedazuridine and decitabine, helps the body produce normal blood cells and eliminate abnormal ones. Entrectinib blocks signals that promote cancer cell growth, potentially slowing or stopping cancer spread. This trial may suit those with relapsed or treatment-resistant AML who have a specific genetic mutation in the TP53 gene. Participants should be able to take oral medication and have documented AML with a TP53 mutation. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you have taken an investigational drug recently, you may need to wait before starting the trial.

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

Research has shown that the combination of entrectinib and ASTX727 is generally safe for people with acute myeloid leukemia (AML) who have a TP53 gene mutation. One study found that this combination was well-tolerated in patients with a difficult-to-treat type of AML, with most participants not experiencing serious side effects.

ASTX727, a mix of cedazuridine and decitabine, has undergone safety testing in other blood-related conditions. These studies found it to be safe, with most patients experiencing only mild side effects.

Overall, existing research suggests that the treatment is fairly safe, with manageable side effects for most people. However, as this is an early phase trial, researchers are still collecting more information to ensure its safety for everyone. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for AML?

Researchers are excited about the combination of entrectinib and ASTX727 for treating acute myeloid leukemia (AML) because it introduces new mechanisms that aren't typically used in standard treatments. Entrectinib targets specific genetic mutations in cancer cells, potentially offering a more personalized approach to treatment. Meanwhile, ASTX727 combines two drugs, cedazuridine and decitabine, to enhance the effectiveness of chemotherapy by helping decitabine to remain active longer in the body. This combination could mean a more effective attack on cancer cells with potentially fewer side effects compared to current options.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

Research has shown that using entrectinib and ASTX727 together might effectively treat acute myeloid leukemia (AML) with a TP53 mutation. In this trial, participants will receive a combination of entrectinib, which blocks proteins that help cancer cells grow, and ASTX727, which combines cedazuridine and decitabine to produce normal blood cells and kill abnormal ones. Studies have found this combination safe for patients whose AML has returned or is difficult to treat. The goal of using these two treatments together is to stop cancer cell growth more effectively. ^{1 2 3 4 6}

Who Is on the Research Team?

Ronan T. Swords

Principal Investigator

OHSU Knight Cancer Institute

Are You a Good Fit for This Trial?

Adults with relapsed/refractory AML and a TP53 mutation can join this trial. They must understand the study, be able to take oral meds, have decent organ function, and use contraception. Excluded are those with certain leukemia types, active infections like HIV or hepatitis B/C, uncontrolled diseases, recent investigational drugs usage or conditions affecting drug absorption.

Inclusion Criteria

My kidney function is within the required range.

My AML has a confirmed TP53 mutation.

My AML has returned or didn't respond to treatment, with at least 20% cancer cells in my blood or bone marrow.

Exclusion Criteria

I haven't taken any experimental drugs recently or still have side effects from one.

I have taken entrectinib for another cancer, but not decitabine.

I do not have a history of conditions like short gut syndrome that affect medication absorption.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive entrectinib orally once daily on days 1-28 and ASTX727 orally once daily on days 1-5. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

Cycle 1: 4 visits (in-person) on Day 1, Day 8, Day 28; subsequent cycles as needed

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and then every 3 months for up to 1 year.

12 months

Follow-up visits every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Cedazuridine
• Decitabine
• Entrectinib

Trial Overview The trial is testing entrectinib combined with ASTX727 (cedazuridine plus decitabine) for safety and effectiveness in AML patients. Entrectinib blocks cancer cell growth signals; cedazuridine increases decitabine's availability which helps produce normal blood cells and kills abnormal ones.

How Is the Trial Designed?

Group I: Treatment (ASTX727, entrectinib) Experimental Treatment 3 Interventions

Patients receive entrectinib PO QD on days 1-28 and ASTX727 PO QD on days 1-5. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

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

Approved in United States as ASTX727 for:

• Acute Myeloid Leukemia (AML)

Who Is Running the Clinical Trial?

OHSU Knight Cancer Institute

Lead Sponsor

Trials

239

Recruited

2,089,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Taiho Oncology, Inc.

Industry Sponsor

Trials

79

Recruited

12,700+

Tim Whitten

Taiho Oncology, Inc.

Chief Executive Officer since 2018

MBA and Pharmacy degree

Harold Keer

Taiho Oncology, Inc.

Chief Medical Officer

MD, PhD

Taiho Oncology

Collaborator

Trials

2

Recruited

30+

Oregon Health and Science University

Collaborator

Trials

1,024

Recruited

7,420,000+

Published Research Related to This Trial

In a phase 3 trial involving 319 patients aged 60 and older with relapsed/refractory acute myeloid leukemia (AML), enasidenib, an oral IDH2 inhibitor, showed significant improvements in event-free survival (EFS), time to treatment failure (TTF), overall response rate (ORR), hematologic improvement (HI), and transfusion independence (TI) compared to conventional care regimens.

Although the primary endpoint of overall survival (OS) did not show a significant difference between enasidenib and conventional care (6.5 vs 6.2 months), enasidenib demonstrated meaningful clinical benefits in a heavily pretreated population, suggesting its potential as an effective treatment option for older patients with mutant-IDH2 AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enasidenib vs conventional care in older patients with late-stage mutant-IDH2 relapsed/refractory AML: a randomized phase 3 trial. de Botton, S., Montesinos, P., Schuh, AC., et al.[2023]

Glasdegib, a small-molecule inhibitor targeting the hedgehog pathway, was approved by the FDA for treating newly diagnosed acute myeloid leukemia (AML) in patients over 75 or those unable to undergo intensive chemotherapy, showing significant promise in improving patient outcomes.

In a phase II trial, the combination of glasdegib with low-dose cytarabine (LDAC) nearly doubled the median overall survival of patients compared to LDAC alone, highlighting its efficacy in a vulnerable patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glasdegib for the treatment of adult patients with newly diagnosed acute myeloid leukemia or high-grade myelodysplastic syndrome who are elderly or otherwise unfit for standard induction chemotherapy. Goldsmith, SR., Lovell, AR., Schroeder, MA.[2019]

In a phase 2 study involving 58 older patients with acute myeloid leukemia (AML) and either TP53 mutations or complex karyotypes, the combination of entospletinib and decitabine showed low complete remission rates of 13.3% for TP53 mutation patients and 30.8% for those with complex karyotypes.

Despite being acceptably tolerated, the treatment resulted in short overall survival rates of 6.5 months for TP53 mutation patients and 11.5 months for those with complex karyotypes, indicating a need for more effective therapies for this high-risk group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Entospletinib with decitabine in acute myeloid leukemia with mutant TP53 or complex karyotype: A phase 2 substudy of the Beat AML Master Trial. Duong, VH., Ruppert, AS., Mims, AS., et al.[2023]

Midostaurin combined with intensive chemotherapy is now the standard treatment for younger patients with acute myeloid leukemia (AML) who have FLT3 mutations, highlighting the importance of genetic testing in treatment planning.

For older patients, the combination of venetoclax with hypomethylating agents or low-dose AraC has significantly improved treatment outcomes, showcasing the advancements in targeted therapies for AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

What to use to treat AML: the role of emerging therapies. Thol, F.[2022]

Glasdegib, an oral Hedgehog pathway inhibitor, has shown promising response rates in treating acute myeloid leukemia (AML) in elderly patients, with moderate toxicity and reduced early mortality compared to standard treatments.

Approved by the FDA and EMA for use with low-dose cytarabine in patients aged 75 and older or those unfit for intensive chemotherapy, glasdegib represents a significant advancement in AML therapy options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on glasdegib in acute myeloid leukemia - broadening horizons of Hedgehog pathway inhibitors. Fersing, C., Mathias, F.[2023]

The BCL2 inhibitor venetoclax, when combined with low-dose cytarabine or hypomethylating agents, is both safe and effective for older patients with newly diagnosed acute myeloid leukemia (AML) who cannot undergo intensive chemotherapy.

New targeted therapies, such as glasdegib and CPX-351, have shown improved survival rates in specific patient populations, highlighting the importance of genomic characterization in selecting the most effective treatment for AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-agent and combination biologics in acute myeloid leukemia. Richard-Carpentier, G., DiNardo, CD.[2022]

Acute myeloid leukemia (AML) treatment has seen little change in 40 years, but new agents like IDH inhibitors and antibody-drug conjugates show promise in improving outcomes, either alone or with traditional chemotherapy.

A variety of novel therapies, including cytotoxic agents, epigenetic modifiers, and targeted inhibitors, are currently being tested in clinical trials, indicating a potential shift in AML management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging therapies for acute myeloid leukemia. Saygin, C., Carraway, HE.[2023]

Oral azacitidine (CC-486) has been shown to improve overall survival as maintenance therapy for older patients with acute myeloid leukemia who are in complete remission, highlighting its efficacy in this specific patient population.

The combination of decitabine and cedazuridine (ASTX727) is approved for treating adult patients with myelodysplastic syndromes and chronic myelomonocytic leukemia, particularly those with intermediate-1 or higher risk, indicating its targeted therapeutic application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The path to approval for oral hypomethylating agents in acute myeloid leukemia and myelodysplastic syndromes. Kipp, D., H Wei, A.[2022]

The phase 2 study found that oral cedazuridine/decitabine (100 mg/35 mg) provided similar systemic exposure and DNA demethylation compared to standard IV decitabine (20 mg/m2) in patients with myelodysplastic syndromes or chronic myelomonocytic leukemia, indicating comparable efficacy.

Clinical responses were observed in 60% of patients, with 21% achieving a complete response, while the most common serious side effects included neutropenia (46%) and thrombocytopenia (38%), highlighting the treatment's safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Garcia-Manero, G., Griffiths, EA., Steensma, DP., et al.[2021]

The optimal biologic dose (OBD) of decitabine for treating acute myeloid leukemia (AML) was determined to be 20 mg/m²/day, which showed limited nonhematologic toxicity and promising clinical activity, with a response rate of 44% among 25 patients.

Combining decitabine with valproic acid (VA) resulted in dose-limiting encephalopathy at lower doses of VA, indicating safety concerns, while the clinical responses were similar whether patients received decitabine alone or in combination with VA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. Blum, W., Klisovic, RB., Hackanson, B., et al.[2019]

In a study of 8 geriatric patients with acute myeloid leukemia, treatment with decitabine, with or without low-dose cytarabine, resulted in a 50% overall response rate, with 25% achieving complete remission and 25% achieving partial remission.

The treatment showed a median overall survival time of 9.5 months, with some patients surviving over a year, although it was associated with significant side effects, including severe myelosuppression in 87.5% of patients and pneumonia in 50%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of Decitabine Combined with or without Cytarabine-based Low Dose Regimen for Senile patients with Acute Myeloid Leukemia]. Zhou, HW., Zhou, MH., Wang, ZH., et al.[2019]

A new low-intensity treatment regimen combining cladribine and low-dose cytarabine alternating with decitabine showed promising results in elderly or unfit patients with acute myeloid leukaemia (AML), with a median disease-free survival of 10.8 months and a median overall survival of 13.8 months based on a study of 118 patients.

The regimen was well tolerated, with only 1% of patients experiencing early death within the first 4 weeks, indicating a favorable safety profile compared to traditional therapies, which often have higher toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cladribine and low-dose cytarabine alternating with decitabine as front-line therapy for elderly patients with acute myeloid leukaemia: a phase 2 single-arm trial. Kadia, TM., Cortes, J., Ravandi, F., et al.[2019]

Citations

1. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-02156

Entrectinib in Combination with ASTX727 for the Treatment ... This phase I trial tests the safety, side effects, and best dose of entrectinib when given with ASTX727 in treating patients with acute myeloid leukemia (AML)

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124042459

Phase 1 Trial Testing the Novel Combination Therapy of ... Combined therapy of entrectinib and oral DEC-C was safe for pts with R/R mTP53 AML, a nearly fatal diagnosis.

3. withpower.com withpower.com/trial/phase-1-leukemia-myeloid-acute-5-2022-a91c5

Entrectinib + ASTX727 for Acute Myeloid Leukemia This trial tests a combination of two medications for patients with a tough-to-treat type of leukemia. One drug stops cancer cells from growing, ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12131698/

TP53‐Mutated Acute Myeloid Leukemia: Unanswered Questions The Phase III MIRROS trial explored the efficacy of idasanutlin in combination with cytarabine in RR ANML patients. A total of 447 patients ...

5. adisinsight.springer.com adisinsight.springer.com/trials/700336705

A Phase I Study of Entrectinib in Combination With ASTX727 ... This phase I trial tests the safety, side effects, and best dose of entrectinib when given with ASTX727 in treating patients with acute myeloid leukemia ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11665714/

Nontransplant treatment approaches for myeloid neoplasm ... This review summarizes the current approaches for myeloid disease with TP53 mutation and provides an overview of emerging nontransplant approaches.