Emavusertib (+ Venetoclax) for Acute Myeloid Leukemia

Recruiting at 21 trial locations

Overseen By Catherine Wang, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Curis, Inc.

Must not be taking: Chemotherapy, Immunomodulatory drugs

Disqualifiers: APL, CNS leukemia, CML, others

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

Compensation: Varies

Number of Visits: Unknown

366 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a multicenter, open-label, Phase 1/2a dose escalation and expansion study of orally administered emavusertib (CA-4948) monotherapy in adult patients with AML or higher- risk Myelodysplastic Syndrome (hrMDS). Patients enrolling in the Phase 1 dose escalation of the study must meet one of the following criteria prior to consenting to the study: * Relapse/refractory (R/R) AML with FMS-like tyrosine kinase-3 (FLT3) mutations who have been previously treated with a FLT3 inhibitor * R/R AML with spliceosome mutations of splicing factor 3B subunit 1 (SF3B1) or U2AF1 * R/R hrMDS with spliceosome mutations of SF3B1 or U2 small nuclear RNA auxiliary factor 1 (U2AF1) * Number of pretreatments: 1 or 2 The Phase 2a Dose Expansion will be in 3 Cohorts of patients: 1. R/R AML with FLT3 mutations who have been previously treated with a FLT3 inhibitor; 2. R/R AML with spliceosome mutations of SF3B1 or U2AF1; and 3. R/R hrMDS (Revised International Prognostic Scoring System \[IPSS-R\] score \> 3.5) with spliceosome mutations of SF3B1 or U2AF1. All patients above have had ≤ 2 lines of prior systemic anticancer treatment. In previous versions of this protocol there was a Phase 1b portion of the study, in which patients with AML or hrMDS received CA-4948 in combination with venetoclax. This part of the study is no longer open for enrollment.

Will I have to stop taking my current medications?

The trial requires that you stop any prior systemic anti-cancer treatment at least 3 weeks before starting emavusertib. Other medications are not specifically mentioned, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Emavusertib and Venetoclax for treating Acute Myeloid Leukemia?

Research shows that venetoclax, when combined with other treatments like azacitidine, has been effective in improving response rates and survival in patients with acute myeloid leukemia, especially in those who are older or have relapsed. This suggests that combining venetoclax with other drugs, like Emavusertib, could also be beneficial. ^{1 2 3 4 5}

Is the combination of Emavusertib and Venetoclax safe for treating Acute Myeloid Leukemia?

Venetoclax, when combined with other agents like alvocidib, homoharringtonine, and cytarabine, has been found to be generally safe and tolerable in treating Acute Myeloid Leukemia, though some patients experienced significant side effects like gastrointestinal issues and blood-related problems. No fatal drug-related adverse events were reported, but dose adjustments are often needed due to therapy-related toxicity. ^{1 5 6 7 8}

What makes the drug Emavusertib combined with Venetoclax unique for treating acute myeloid leukemia?

Emavusertib combined with Venetoclax is unique because it introduces a novel component, Emavusertib, which may offer a new mechanism of action compared to existing treatments that primarily use Venetoclax with other agents. This combination could potentially address resistance issues seen with current Venetoclax-based therapies. ^{1 2 3 4 9}

Eligibility Criteria

Adults with Acute Myelogenous Leukemia (AML) or high-risk Myelodysplastic Syndrome (MDS) who have had ≤2 prior cancer treatments can join this trial. They must be able to take oral medication, not be pregnant, agree to use contraception, and have a life expectancy of at least 3 months. People with CNS leukemia, recent anti-cancer treatments, unresolved toxicity from past therapies, certain infections like HIV or hepatitis B/C, severe heart disease or other serious health issues cannot participate.

Inclusion Criteria

You are expected to live for at least three more months.

My AML has specific genetic changes in SF3B1 or U2AF1.

I have had 1 or 2 treatments for my condition.

Exclusion Criteria

I had a stem cell transplant within the last 60 days or have significant GVHD needing more medication before starting emavusertib.

I haven't had cancer treatments like chemotherapy in the last 14 days.

I haven't had major surgery in the last 28 days or minor surgery in the last 14 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Dose Escalation

Determine the maximum tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D) for emavusertib in monotherapy

28 days per cycle

Multiple visits for dose escalation and monitoring

Phase 2a Dose Expansion

Assess anti-cancer activity of CA-4948 at the RP2D in patients with R/R AML or hrMDS

24 months

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Azacitidine
• CA-4948
• Venetoclax

Trial Overview The study is testing emavusertib as a single agent in patients with AML/MDS. It's an open-label Phase 1/2a trial where the dose will be increased gradually to find the safest and most effective level for treatment expansion. Previously there was a combination therapy part with venetoclax which is no longer accepting participants.

Participant Groups

Group I: Emavusertib monotherapy dose expansion Experimental Treatment 1 Intervention

The Expansion phase will begin once the RP2D from Phase 1 Dose Escalation phase has been identified. There will be 3 Cohorts and patients will be assigned to each Cohort based on baseline disease.

Group II: Emavusertib dose escalation + Venetoclax Experimental Treatment 2 Interventions

The starting dose for emavusertib will be 200 mg BID for 21 days of a 28-day Cycle. Anticipated emavusertib doses will be 200 and 300 mg BID. Venetoclax will be administered at 100 mg orally (Day 1) per the product label at the same time each day with a ramp up over 3 days to 400 mg for 21days of a 28-day Cycle. Second and subsequent cycles start with target dose level. This arm of the study has been closed to enrollment.

Group III: Emavusertib (CA-4948) dose escalation Experimental Treatment 1 Intervention

Patients receive emavusertib monotherapy BID daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

Curis, Inc.

Lead Sponsor

Trials

17

Recruited

1,100+

Findings from Research

In a study of 26 adult patients with relapsed/refractory acute myeloid leukemia (R/R AML), the combination of venetoclax (VEN) with demethylating agents (azacitidine or decitabine) resulted in a 57.7% overall response rate, including 13 complete responses, indicating its efficacy as a salvage therapy.

Patients who achieved minimal residual disease negativity had significantly better overall survival and event-free survival, highlighting the importance of this outcome in improving long-term prognosis for R/R AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Observation of Venetoclax Combined with Demethylating Agents on the Treatment of Relapsed/Refractory Acute Myeloid Leukemia]. Wang, Y., Huang, SL., Zhang, XX., et al.[2023]

Venetoclax combined with hypomethylators and low-dose cytarabine has shown high response rates and improved overall survival in older, untreated patients with acute myeloid leukemia, based on preliminary data from small, uncontrolled studies.

The efficacy of venetoclax appears to stem from its ability to target leukemia stem cells by altering the metabolic environment, which is particularly effective in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Why are hypomethylating agents or low-dose cytarabine and venetoclax so effective? Pollyea, DA., Jordan, CT.[2020]

In a study of 56 adult patients with acute myeloid leukemia (AML) treated with the BCL-2 inhibitor venetoclax (VEN), the overall response rate was 51.8%, with median overall survival of 13.3 months for first-line treatment, indicating its efficacy in improving outcomes for AML patients.

Patients with specific mutations, such as NPM1, showed a significant survival advantage when treated with VEN, while those with FLT3-ITD mutations had a notably reduced median overall survival, highlighting the importance of genetic profiling in treatment planning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with venetoclax in patients with newly diagnosed, relapsed, or refractory acute myeloid leukemia. Fleischmann, M., Scholl, S., Frietsch, JJ., et al.[2022]

In a phase III study involving 127 treatment-naïve patients with acute myeloid leukemia and poor-risk cytogenetics, the combination of venetoclax and azacitidine significantly improved remission rates and overall survival in patients with TP53 wild-type (CRc of 70% and OS of 23.4 months) compared to azacitidine alone (CRc of 23% and OS of 11.3 months).

For patients with TP53 mutations, while venetoclax plus azacitidine improved remission rates (41% vs. 17% with azacitidine alone), it did not significantly enhance the duration of remission or overall survival, indicating that the treatment's efficacy may vary based on TP53 status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes in Patients with Poor-Risk Cytogenetics with or without TP53 Mutations Treated with Venetoclax and Azacitidine. Pollyea, DA., Pratz, KW., Wei, AH., et al.[2023]

Venetoclax-based combinations have shown significant efficacy and improved survival rates in older patients with acute myeloid leukemia (AML) who are ineligible for conventional chemotherapy, addressing a critical need in this population.

Further research is necessary to optimize the use of venetoclax in frontline treatment, manage cases where patients do not respond, and evaluate its effectiveness in relapsed or refractory AML situations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evaluation of venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine as therapy for acute myeloid leukemia. Othman, TA., Tenold, ME., Moskoff, BN., et al.[2022]

The combination of venetoclax and alvocidib was found to be safe and tolerable in patients with relapsed/refractory Acute Myeloid Leukemia (AML), with no maximum tolerated dose reached, although significant gastrointestinal side effects were common.

The overall response rate to this treatment was modest, with only 11.4% achieving complete or incomplete remission, indicating that while the combination is safe, it may not significantly enhance efficacy compared to using each drug alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b study of venetoclax and alvocidib in patients with relapsed/refractory acute myeloid leukemia. Jonas, BA., Hou, JZ., Roboz, GJ., et al.[2023]

In a study of 13 patients with de novo adverse-risk acute myeloid leukemia (AML), the combination of venetoclax, homoharringtonine, and cytarabine (VHA regimen) resulted in a high complete remission rate of 84.6%, with all responders showing no measurable residual disease.

While the VHA regimen was effective, it was associated with significant side effects, including grade 3-4 neutropenia and febrile neutropenia in 30.8% of patients, indicating that while promising, careful monitoring for adverse events is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of venetoclax combined with homoharringtonine and cytarabine in fit adults patients with de novo adverse-risk acute myeloid leukaemia: A single-centre retrospective analysis. Song, BQ., Kong, X., Pu, Y., et al.[2023]

A lower dosage of Venetoclax (100 mg) combined with Azacitidine showed favorable outcomes in newly diagnosed acute myeloid leukemia (AML) patients, with a median overall survival of 17 months and an overall response rate of 69.4% based on a study of 36 patients.

The study suggests that even with dose reductions of Venetoclax, the combination therapy remains effective, indicating a potential strategy to manage therapy-related toxicity while still achieving significant treatment responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced duration and dosage of venetoclax is efficient in newly diagnosed patients with acute myeloid leukemia. Cui, J., Chen, X., Li, C., et al.[2023]

Venetoclax, especially when combined with hypomethylating agents, has significantly improved treatment outcomes for older or unfit patients with newly diagnosed acute myeloid leukemia (AML), making it the standard therapy in this group.

While venetoclax shows high response rates in younger patients and specific genetic mutations, it can lead to severe side effects like cytopenias and infections, necessitating careful management strategies to mitigate these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How We Incorporate Venetoclax in Treatment Regimens for Acute Myeloid Leukemia. Maiti, A., Konopleva, MY.[2023]

References

1. China pubmed.ncbi.nlm.nih.gov

[Clinical Observation of Venetoclax Combined with Demethylating Agents on the Treatment of Relapsed/Refractory Acute Myeloid Leukemia]. [2023]

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

Why are hypomethylating agents or low-dose cytarabine and venetoclax so effective? [2020]

3. Germany pubmed.ncbi.nlm.nih.gov

Clinical experience with venetoclax in patients with newly diagnosed, relapsed, or refractory acute myeloid leukemia. [2022]

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

Outcomes in Patients with Poor-Risk Cytogenetics with or without TP53 Mutations Treated with Venetoclax and Azacitidine. [2023]

5. England pubmed.ncbi.nlm.nih.gov

An evaluation of venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine as therapy for acute myeloid leukemia. [2022]

6. England pubmed.ncbi.nlm.nih.gov

A phase 1b study of venetoclax and alvocidib in patients with relapsed/refractory acute myeloid leukemia. [2023]

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

Outcomes of venetoclax combined with homoharringtonine and cytarabine in fit adults patients with de novo adverse-risk acute myeloid leukaemia: A single-centre retrospective analysis. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Reduced duration and dosage of venetoclax is efficient in newly diagnosed patients with acute myeloid leukemia. [2023]

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

How We Incorporate Venetoclax in Treatment Regimens for Acute Myeloid Leukemia. [2023]