ONC201 for Leukemia

Recruiting at1 trial location

Overseen by Gautam Borthakur, M.D.

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Strong CYP3A inhibitors

Disqualifiers: Uncontrolled illness, Active heart disease, CNS involvement, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This phase I/II trial studies the side effects and best dose of ONC201 and to see how well it works in treating patients with acute leukemia or high-risk myelodysplastic syndrome that has returned after a period of improvement (relapsed) or does not respond to treatment (refractory). ONC201 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Will I have to stop taking my current medications?

The trial requires that you stop taking any standard or investigational treatments for your blood cancer at least 2 weeks before starting the study drug. If you're taking hydroxyurea, you must stop it at least 24 hours before starting the trial. The protocol does not specify other medications, but you should discuss your current medications with the trial team.

What makes the drug ONC201 unique for treating leukemia?

ONC201 is unique because it targets a specific pathway in cancer cells, potentially offering a new approach for treating leukemia compared to traditional therapies. While other treatments like histone deacetylase inhibitors focus on altering gene expression, ONC201 works through a different mechanism, which may provide benefits in cases where other treatments are less effective. ^{1 2 3 4 5}

Research Team

Gautam Borthakur, M.D.

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults over 18 with acute leukemia or high-risk myelodysplastic syndrome that's relapsed or refractory. They must be in fair health (ECOG 0-2), able to consent, and have no severe persistent side effects from past treatments. No recent heart issues, other cancer treatments within 3 years (except certain low-risk cases), or active infections like HIV/Hepatitis B/C.

Inclusion Criteria

ALT or AST =< 3 x the ULN unless considered due to organ leukemic involvement

Must be able and willing to give written informed consent

Serum creatinine < 2.0 mg/dl

Exclusion Criteria

Known history of seropositive for HIV antibodies, hepatitis C antibody, or a hepatitis B carrier

Active drug use or alcoholism

I do not have any unmanaged ongoing illnesses.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Akt/ERK inhibitor ONC201 orally in various dosing schedules depending on the assigned arm. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity.

63 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• ONC201 (Small Molecule)

Trial Overview The trial is testing ONC201, a drug thought to block enzymes that cancer cells need to grow. It aims to find the safest dose and see how effective it is for patients whose disease has returned after treatment or hasn't responded at all.

Participant Groups

Group I: Arm E (Akt/ERK inhibitor ONC201) Experimental Treatment 2 Interventions

Arm E (Akt/ERK inhibitor ONC201) Patients receive Akt/ERK inhibitor ONC201 PO twice weekly for 4 weeks and venetoclax daily on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm D (Akt/ERK inhibitor ONC201) Experimental Treatment 2 Interventions

Patients receive Akt/ERK inhibitor ONC201 PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group III: Arm C (Akt/ERK inhibitor ONC201) Experimental Treatment 2 Interventions

Patients receive Akt/ERK inhibitor ONC201 PO on the first two consecutive days of every week. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group IV: Arm B (Akt/ERK inhibitor ONC201) Experimental Treatment 2 Interventions

Patients receive Akt/ERK inhibitor ONC201 PO once every week. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group V: Arm A (Akt/ERK inhibitor ONC201) Experimental Treatment 2 Interventions

Patients receive Akt/ERK inhibitor ONC201 PO once every 3 weeks. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Dr. Peter WT Pisters

M.D. Anderson Cancer Center

Chief Executive Officer since 2017

MD from University of Western Ontario

Dr. Jeffrey E. Lee

M.D. Anderson Cancer Center

Chief Medical Officer

MD from Stanford University School of Medicine

Oncoceutics, Inc.

Industry Sponsor

Trials

10

Recruited

500+

Findings from Research

The deacetylase inhibitor LAQ824 causes significant apoptosis in acute myeloid leukemia progenitor cells (AML-PC) and inhibits their ability to grow again, unlike the DACi valproic acid which does not have this effect.

LAQ824 also affects normal hematopoietic progenitor cells (HPC) by causing cell cycle arrest and apoptosis, particularly in committed HPC, while inducing changes in gene expression related to the notch pathway, which may explain its reversible hematotoxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The deacetylase inhibitor LAQ824 induces notch signalling in haematopoietic progenitor cells. Schwarz, K., Romanski, A., Puccetti, E., et al.[2010]

SK-7041, a novel histone deacetylase inhibitor, effectively inhibits the growth of chronic myeloid leukemia cells by altering key cell cycle regulators and activating apoptosis pathways.

When combined with STI571, SK-7041 enhances the treatment's effectiveness against chronic myeloid leukemia, suggesting it could help overcome resistance to STI571 in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of SK-7041, one of novel histone deacetylase inhibitors, and STI571-induced synergistic apoptosis in chronic myeloid leukemia. Kim, BS., Bae, E., Kim, YJ., et al.[2015]

The combination of the liposomal ATRA analog ATRA-IV and divalproex sodium was tested in a phase I trial involving nine patients with advanced solid tumors, showing manageable side effects like skin toxicity and thrombocytopenia, all rated as grade 2 or lower.

Although the trial could not determine the maximum tolerated dose due to early closure, one patient experienced disease stabilization, indicating potential efficacy of the treatment in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of ATRA-IV and Depakote in patients with advanced solid tumor malignancies. David, KA., Mongan, NP., Smith, C., et al.[2020]

In a study of 175 patients with Adult T-cell Leukemia/Lymphoma (ATL), 10 patients exhibited long-term survival of over 10 years, with 5 of them having been treated with valproic acid (VA), suggesting that VA may have a beneficial role as a histone deacetylase inhibitor in ATL treatment.

Patients treated with VA had significantly longer survival rates compared to those who were not treated, with chronic subtype patients surviving an average of 213 months versus 33 months for untreated patients, and lymphoma subtype patients surviving 144 months versus just 6 months for untreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characteristics of Adult T-Cell Leukemia/Lymphoma Patients with Long Survival: Prognostic Significance of Skin Lesions and Possible Beneficial Role of Valproic Acid. Yves, P., Stephane, M., Rishika, B., et al.[2020]

Histone deacetylase inhibitors (HDACi) like trichostatin A (TSA) and valproic acid (VPA) significantly enhance the effectiveness of etoposide in inducing apoptosis in HL60 leukemia cells, indicating a potential for improved cancer treatment strategies.

The synergistic effect of combining HDACi with etoposide on apoptosis is cell-type dependent, as similar results were not observed in U937 cells, highlighting the importance of considering specific cancer characteristics in treatment plans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of histone deacetylase inhibitors trichostatin A and valproic acid on etoposide-induced apoptosis in leukemia cells. Jasek, E., Lis, GJ., Jasinska, M., et al.[2013]

References

1. England pubmed.ncbi.nlm.nih.gov

The deacetylase inhibitor LAQ824 induces notch signalling in haematopoietic progenitor cells. [2010]

2. England pubmed.ncbi.nlm.nih.gov

Combination of SK-7041, one of novel histone deacetylase inhibitors, and STI571-induced synergistic apoptosis in chronic myeloid leukemia. [2015]

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

Phase I trial of ATRA-IV and Depakote in patients with advanced solid tumor malignancies. [2020]

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

Characteristics of Adult T-Cell Leukemia/Lymphoma Patients with Long Survival: Prognostic Significance of Skin Lesions and Possible Beneficial Role of Valproic Acid. [2020]

5. Greece pubmed.ncbi.nlm.nih.gov

Effect of histone deacetylase inhibitors trichostatin A and valproic acid on etoposide-induced apoptosis in leukemia cells. [2013]