Venetoclax + Omacetaxine for Blood Cancer

(VEN-OM Trial)

Overseen By Kristen Kitsch, BS

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Illinois at Chicago

Must be taking: Venetoclax

Must not be taking: CYP3A inducers/inhibitors

Disqualifiers: HIV, CNS AML, CHF, others

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

Compensation: Varies

Number of Visits: 5

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of two treatments, Omacetaxine and Venetoclax, for individuals with acute myeloid leukemia (AML) that hasn't responded to other treatments. The goal is to determine the safest and most effective dose. Participants will receive both drugs in cycles, with Omacetaxine administered as an injection and Venetoclax taken orally. Individuals with AML who have tried at least one treatment that included Venetoclax and still experience symptoms or progression might be suitable for this study. 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 combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you must stop taking Hydroxyurea at least 48 hours before registration. Also, you cannot have taken strong or moderate CYP3A inducers or inhibitors within 7 days before starting the study treatment.

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

Research has shown that combining omacetaxine and venetoclax has been used in patients with certain blood cancers, such as AML (acute myeloid leukemia) and MDS (myelodysplastic syndromes). Previous studies found that patients did not experience severe side effects requiring treatment cessation, known as dose-limiting toxicities. This suggests the combination is generally well-tolerated. However, since this trial is still in its early stages, researchers are closely monitoring safety. While the treatment appears promising, further research is necessary to fully understand any potential risks. ^{1 2 3 4 5}

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

Researchers are excited about the combination of Venetoclax and Omacetaxine for blood cancer because it offers a novel approach compared to current treatments. Unlike standard therapies, which often focus on traditional chemotherapy or targeted therapies like tyrosine kinase inhibitors, this combination leverages Venetoclax's ability to target and inhibit a protein called BCL-2 that helps cancer cells survive. Additionally, Omacetaxine, given via subcutaneous injection, works alongside Venetoclax by disrupting protein synthesis in cancer cells, which is a unique mechanism of action. This dual strategy could potentially enhance treatment effectiveness and overcome resistance seen with other options, providing new hope for patients with challenging blood cancers.

What evidence suggests that the combination of Venetoclax and Omacetaxine could be effective for blood cancer?

This trial will evaluate the combination of omacetaxine and venetoclax for individuals with certain blood cancers, such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Studies have shown that this combination may benefit these patients. Research suggests that omacetaxine can enhance venetoclax's ability to kill cancer cells, particularly the myeloblasts common in these diseases. In previous studies, some patients with MDS responded well to this treatment combination. However, for AML, the results showed only small improvements in survival rates. Overall, these findings suggest that while the treatment might help some patients, more research is needed to fully understand its potential. ^{1 4 5 6 7}

Who Is on the Research Team?

John G. Quigley

Principal Investigator

University of Illinois at Chicago

Are You a Good Fit for This Trial?

Adults aged 18-75 with Acute Myeloid Leukemia (AML) that has returned or didn't respond to treatment, including a regimen with Venetoclax. Participants must have finished previous cancer treatments at least 21 days before and recovered from their effects, be able to perform daily activities with minimal assistance (ECOG score 0-2), not be pregnant or breastfeeding, agree to use contraception, and have adequate organ function.

Inclusion Criteria

Females of childbearing potential and males must be willing to use effective contraception during treatment and for at least 30 days after the last dose of Venetoclax

I finished my last cancer treatment over 3 weeks ago and have recovered from its side effects.

My kidney and liver functions are within the required range.

Exclusion Criteria

Pregnant or breastfeeding

I do not have any severe or uncontrolled infections.

I do not have any severe health or mental conditions that could make this study risky for me.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Induction Treatment

Participants receive Omacetaxine and Venetoclax with dose escalation to find the MTD

4 weeks per cycle

Day 1 and Day 28 of each cycle (in-person)

Consolidation Treatment

Participants may receive additional cycles of treatment if applicable

4 weeks per cycle

Safety Follow-up

Participants are monitored for safety 14 days after the last dose of treatment

2-3 weeks

1 visit (in-person)

Long Term Follow-up

Participants are monitored every 2 months for 12 months for long-term safety and survival outcomes

12 months

Every 2 months (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Omacetaxine
• Venetoclax

Trial Overview The trial is testing the safety and effectiveness of combining two drugs: Venetoclax and Omacetaxine in escalating doses for AML patients who haven't responded well to previous treatments. It's an open-label study where everyone gets the same treatment, starting with induction then consolidation phases if needed.

How Is the Trial Designed?

Group I: Cohort 4 Experimental Treatment 2 Interventions

Omacetaxine 2.5 mg/m2 SQ injection q12h days 1-7 with Venetoclax 400 mg orally daily on days 4-28 Cycles are 28 days

Group II: Cohort 3 Experimental Treatment 2 Interventions

Omacetaxine 2.0 mg/m2 SQ injection q12h days 1-7 with Venetoclax 400 mg orally daily on days 4-28 Cycles are 28 days

Group III: Cohort 2 Experimental Treatment 2 Interventions

Omacetaxine 1.25 mg/m2 SQ injection q12h days 1-7 with Venetoclax 400 mg orally daily on days 4-28 Cycles are 28 days

Group IV: Cohort 1 Experimental Treatment 2 Interventions

Omacetaxine 0.625 mg/m2 SQ injection q12h days 1-7 with Venetoclax 400 mg orally daily on days 4-28 Cycles are 28 days

Omacetaxine is already approved in United States, European Union for the following indications:

Approved in United States as Synribo for:

• Chronic myeloid leukemia (CML), accelerated phase
• Chronic myeloid leukemia (CML), blast phase

Approved in European Union as Synribo for:

• Chronic myeloid leukemia (CML), accelerated phase
• Chronic myeloid leukemia (CML), blast phase

Who Is Running the Clinical Trial?

University of Illinois at Chicago

Lead Sponsor

Trials

653

Recruited

1,574,000+

Published Research Related to This Trial

In a study of 94 patients aged 70 and older with advanced colorectal cancer, both CAPOX and CAPIRI treatments showed similar overall response rates (38% for CAPOX and 36% for CAPIRI), indicating comparable efficacy as first-line treatments.

CAPOX was better tolerated than CAPIRI, with fewer severe side effects such as diarrhea and neutropenia, suggesting it may be a safer option for elderly patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capecitabine in combination with oxaliplatin or irinotecan in elderly patients with advanced colorectal cancer: results of a randomized phase II study. Rosati, G., Cordio, S., Bordonaro, R., et al.[2020]

In a phase II trial involving 48 patients with untreated advanced colorectal cancer, the combination of irinotecan and raltitrexed showed an overall response rate of 27%, with a median duration of response of 10 months.

Despite its activity, the treatment was associated with significant side effects, including grade III-IV diarrhea and neutropenia, leading to a dose reduction and highlighting the need for careful patient selection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of irinotecan and raltitrexed in chemotherapy-naive advanced colorectal cancer. Chiara, S., Nobile, MT., Tomasello, L., et al.[2018]

In a phase II trial involving 46 patients with untreated metastatic colorectal cancer, the combination of irinotecan and raltitrexed showed a promising overall response rate of 46%, indicating significant efficacy in this patient population.

While the treatment was effective, it also presented notable toxicities, including severe diarrhea in 26% of patients and neutropenia in 20%, suggesting that while the regimen is active, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan and raltitrexed: an active combination in advanced colorectal cancer. Carnaghi, C., Rimassa, L., Garassino, I., et al.[2020]

Premetrexed disodium (MTA) shows promising anti-proliferative effects against colon cancer, especially when combined with oxaliplatin or SN38, demonstrating synergistic activity in both standard and 5-fluorouracil-resistant cancer cells.

The combination of MTA with oxaliplatin resulted in additive antitumor effects with minimal toxicity in mouse models, suggesting a potential for safer and more effective chemotherapy regimens for colon cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed disodium combined with oxaliplatin, SN38, or 5-fluorouracil, based on the quantitation of drug interactions in human HT29 colon cancer cells. Raymond, E., Louvet, C., Tournigand, C., et al.[2018]

The XELOX30 regimen, which combines capecitabine and a shorter 30-minute infusion of oxaliplatin, was tested in 70 patients with advanced colorectal cancer resistant to irinotecan, showing a response rate of 17% and a median survival of 9.5 months.

The treatment demonstrated a moderate level of neurotoxicity, with 56% of patients experiencing grade 1 and 17% grade 2 neuropathy, indicating that XELOX30 is a convenient and effective second-line therapy with a safety profile comparable to longer infusion schedules.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-time infusion of oxaliplatin in combination with capecitabine (XELOX30) as second-line therapy in patients with advanced colorectal cancer after failure to irinotecan and 5-fluorouracil. Pfeiffer, P., Sørbye, H., Ehrsson, H., et al.[2020]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40979071/

Omacetaxine and venetoclax in relapsed/refractory acute ... We investigated the safety and efficacy of OM + VEN in relapsed/refractory RUNX1 mut MDS/AML in a Bayesian Optimal Interval design. VEN 400 mg ...

2. ashpublications.org ashpublications.org/bloodneoplasia/article/2/4/100145/546357/Omacetaxine-and-venetoclax-in-relapsed-refractory

Omacetaxine and venetoclax in relapsed/refractory acute ... Omacetaxine can synergize with VEN to promote loss of viability of myeloblasts. Responses were seen in patients with MDS, suggesting that dose optimization ...

3. targetedonc.com targetedonc.com/view/omacetaxine-and-venetoclax-show-benefits-in-mds-no-improvement-in-aml

Omacetaxine and Venetoclax Show Benefits in MDS, No ... The median overall survival (OS) among the total number of patients was 4 months (95% CI, 3–9), and the 1-year OS rate was 17% (95% CI,7%–41%).

4. sciencedirect.com sciencedirect.com/science/article/pii/S2950328025000809

Omacetaxine and venetoclax in relapsed/refractory acute ... Omacetaxine can synergize with venetoclax to promote loss of viability of myeloblasts. •. Clinical responses were seen in MDS patients, ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04874194

NCT04874194 | Omacetaxine and Venetoclax for the ... This phase Ib/II trial best dose, possible benefits and/or side effects of omacetaxine and venetoclax in treating patients with acute myeloid leukemia or ...

6. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/4283/534024/The-Efficacy-and-Safety-of-Homoharringtonine-Added

The Efficacy and Safety of Homoharringtonine Added to ... The endpoint of the study was to evaluate the rate of overall response, composite complete remission (CRc), measurable residual disease (MRD), ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04926285

Safety and Efficacy of Venetoclax With Escalating Doses ... This will be a single arm, open label Phase Ib dose-escalation study of the combination of VEN and OM, conducted using an innovative Bayesian Optimal ...