Tomivosertib for Acute Myeloid Leukemia

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Northwestern University

Must not be taking: Investigational agents

Disqualifiers: Pregnancy, Uncontrolled infection, Cardiac arrhythmia, others

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

Compensation: Varies

Number of Visits: 1

Duration: Up to 18 months

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safest dose of tomivosertib for individuals with acute myeloid leukemia (AML) that has returned or is unresponsive to other treatments. The study combines tomivosertib with azacitidine, a chemotherapy drug, and venetoclax, a targeted therapy, to evaluate their combined effectiveness. It targets those who have already tried certain standard AML treatments. Participants should have AML that has recurred or not responded to therapies and must not have other conditions that could interfere with treatment. 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 therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are on other investigational agents or have had chemotherapy for AML within 14 days before starting tomivosertib.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that tomivosertib is under investigation for its effects on acute myeloid leukemia (AML). Early results suggest that tomivosertib can interfere with certain processes in leukemia cells, potentially slowing their growth.

In earlier studies, researchers tested tomivosertib to assess its safety for humans. Although these studies provide limited safety information, they help determine how well people tolerate the drug. Current research aims to find the optimal dose that is both effective and safe.

As this trial is in its early stages, it primarily focuses on identifying the safest dose for patients. Researchers are still learning about how people react to tomivosertib and what side effects might occur. Prospective participants should discuss any safety concerns or questions with the research team. ^{1 2 3 4 5}

Why are researchers excited about this possible treatment for acute myeloid leukemia?

Tomivosertib is unique because it targets a specific pathway in cancer cells known as MNK1/2, which is different from traditional treatments for acute myeloid leukemia (AML) that primarily focus on DNA damage or metabolism pathways. This novel mechanism of action may inhibit proteins that help cancer cells grow, making tomivosertib potentially more effective in stopping the progression of AML. Researchers are excited about tomivosertib because it could offer a new approach to treating AML, especially for patients who may not respond well to current therapies.

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

Studies have shown that tomivosertib looks promising for treating acute myeloid leukemia (AML). It blocks a process that helps cancer cells grow. Research indicates that tomivosertib reduces the survival and spread of leukemia cells, suggesting it could effectively control AML. These findings offer hope for its potential as a treatment option. Participants in this trial will receive tomivosertib continuously on days 1-28 of each 28-day cycle. ^{1 2 3 5 6}

Who Is on the Research Team?

Shira Dinner, MD

Principal Investigator

Northwestern University

Are You a Good Fit for This Trial?

Adults aged 18+ with newly diagnosed AML unsuitable for intensive chemotherapy due to age (75+), poor physical status, or severe heart/lung/liver conditions. Participants must not be pregnant/nursing and agree to use contraception. Those with controlled HIV/HBV/HCV are eligible.

Inclusion Criteria

I understand the study, am willing to follow its rules, and have signed the consent form.

People with sperm-producing reproductive capacity treated or enrolled on this protocol must also agree to use adequate contraception (or abstinence or vasectomy) and refrain from donating sperm from the time of informed consent, for the duration of study therapy, and 30 days after completion of study therapy

My hepatitis B virus is undetectable with treatment.

Exclusion Criteria

Patients who have conditions that would interfere with their ability to swallow oral medications

Patients who are pregnant or nursing

Patients who are receiving any other investigational agents

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Phase 1 dose finding using a Bayesian optimal interval (BOIN) design to determine the maximum pharmacologic activity (MPA) of tomivosertib

28 days per cycle

Continuous dosing on days 1-28 of each 28-day cycle

Treatment

Tomivosertib is administered continuously with dose adjustments based on BOIN design

Up to 18 months

Follow-up

Participants are monitored for safety, adverse events, and treatment effectiveness

Up to 18 months

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Tomivosertib
• Venetoclax

Trial Overview The trial is testing Tomivosertib's optimal dose in treating AML. It starts at 100mg daily taken orally with meals, adjusting based on safety/effectiveness. Patients will take the drug continuously over a 28-day cycle alongside biospecimen collection for analysis.

How Is the Trial Designed?

Group I: Treatment (tomivosertib) Experimental Treatment 2 Interventions

Tomivosertib will be dosed continuously on days 1-28 of each 28-day cycle.

Azacitidine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

EFFECTOR Therapeutics, Inc.

Collaborator

Trials

1

Recruited

20+

Published Research Related to This Trial

In patients with newly diagnosed unfit acute myeloid leukemia (AML), the combination of azacitidine and venetoclax is a standard first-line treatment.

However, patients with TP53-mutated AML and poor-risk cytogenetics do not benefit from adding venetoclax to azacitidine, suggesting that alternative treatment regimens should be considered for these individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TP53 or Not TP53: That Is the Question. Green, SD., Zeidner, JF.[2023]

In a phase 1/2 study involving six Japanese patients aged 60 and older with acute myeloid leukaemia, the combination of venetoclax and azacitidine demonstrated a high response rate, with 83% of patients achieving a response, including three complete remissions.

The treatment was generally well tolerated, with a median overall survival of 15.7 months, although some patients experienced serious adverse events, including grade 3 fungal pneumonia, which required treatment adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. Taniguchi, S., Yamauchi, T., Choi, I., et al.[2021]

In a Japanese subgroup of the phase 3 VIALE-A trial, venetoclax-azacitidine significantly improved overall survival rates compared to placebo-azacitidine, with 67% of patients alive at 12 months versus 46% in the placebo group.

The treatment also resulted in a high complete response (CR) and CR with incomplete hematologic recovery (CRi) rate of 67%, while maintaining a safety profile similar to the global study, indicating it is a viable first-line treatment for Japanese patients with acute myeloid leukemia ineligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. Yamamoto, K., Shinagawa, A., DiNardo, CD., et al.[2023]

In a study of 57 elderly patients (average age 69.9 years) with acute myeloid leukemia, the combination of venetoclax and azacitidine (VEN + AZA) showed a high overall response rate of 87.5% and a complete remission (CR) rate of 68.8%, indicating strong efficacy in this population.

The treatment was associated with a median overall survival (OS) of 11.5 months, and achieving minimal residual disease (MRD) negativity (<0.1%) was more common with VEN + AZA compared to traditional chemotherapy, although older patients (≥75 years) and those with higher ECOG scores faced more challenges in achieving MRD negativity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-institution experience of venetoclax combined with azacitidine in newly diagnosed acute myeloid leukemia patients. Yu, H., Wang, C., Lei, Y., et al.[2023]

In a study of nine AML patients with acquired resistance to venetoclax, the typical BCL2 mutation associated with resistance was not found, suggesting that this mutation is not necessary for developing resistance in AML.

The study identified that existing mutations, particularly the expansion of FLT3-ITD, were primarily responsible for venetoclax resistance, indicating that monitoring these mutations could help in developing strategies to prevent or overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Not BCL2 mutation but dominant mutation conversation contributed to acquired venetoclax resistance in acute myeloid leukemia. Zhang, X., Qian, J., Wang, H., et al.[2022]

Outpatient induction therapy using low-dose venetoclax combined with itraconazole and azacitidine is feasible and safe for newly diagnosed acute myeloid leukemia (ND-AML) patients, with 77.7% of participants completing the first treatment cycle as outpatients.

The treatment showed promising efficacy, with a composite complete response rate of 53.9% after the first cycle and 85.7% after the second cycle, indicating that this regimen could be a viable option for patients eligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low dose venetoclax plus itraconazole outpatient induction in newly diagnosed acute myeloid leukemia: A phase 2 study. De la Garza-Salazar, F., Colunga-Pedraza, PR., Gómez-Almaguer, D., et al.[2023]

In a study of 13 patients with acute leukemia treated with venetoclax and azacitidine, 46% developed COVID-19, highlighting a significant risk associated with this treatment during the pandemic.

The study found that 33% of those who contracted COVID-19 died from the virus, indicating that COVID-19 can lead to severe outcomes in patients receiving AZA-VEN therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution. Drozd-Sokołowska, J., Mądry, K., Barankiewicz, J., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8121614/

Inhibitory effects of Tomivosertib in acute myeloid leukemia We demonstrate that Tomivosertib suppresses eIF4E phosphorylation in AML cells and decreases leukemic cell survival and proliferation. We also ...

2. oncotarget.com oncotarget.com/news/pr/inhibitory-effects-of-tomivosertib-in-acute-myeloid-leukemia/

Inhibitory effects of Tomivosertib in acute myeloid leukemia Tomivosertib was highly effective at blocking eIF4E phosphorylation on serine 209 in AML cells.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05744739

Tomivosertib in Relapsed or Refractory Acute Myeloid ... Phase 1 of the study will open first with a (Bayesian optimal interval BOIN) dose finding design. The starting dose of tomivosertib is 100mgdaily (doses 24 ...

4. ajmc.com ajmc.com/view/tomivosertib-alone-in-combination-shows-promise-in-aml-say-researchers

Tomivosertib Alone, in Combination Shows Promise ... The researchers of the paper evaluated the data on the treatment in AML specifically, finding that tomivosertib was highly effective as blocking ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34012509/

Inhibitory effects of Tomivosertib in acute myeloid leukemia Tomivosertib was highly effective at blocking eIF4E phosphorylation on serine 209 in AML cells. Such inhibitory effects correlated with dose- ...

6. researchgate.net researchgate.net/publication/351218015_Inhibitory_effects_of_Tomivosertib_in_acute_myeloid_leukemia

Inhibitory effects of Tomivosertib in acute myeloid leukemia Overall, these findings demonstrate that Tomivosertib exhibits potent anti-leukemic properties on AML cells and support the development of ...