ONC201 for Leukemia

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

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

Compensation: Varies

Number of Visits: 1

Duration: 63 days

120 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and assess the side effects of a new drug, ONC201, for treating individuals with acute leukemia or high-risk myelodysplastic syndrome. These conditions have either recurred after improvement or have not responded to other treatments. ONC201 blocks certain enzymes necessary for cancer cell growth. The trial includes several groups, each testing different methods of administering the drug. Potential participants have experienced a return of leukemia or myelodysplastic syndrome or resistance to treatment. As a Phase 1 trial, this research focuses on understanding how ONC201 functions in people, offering participants the opportunity to be among the first to receive this new treatment.

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.

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

Research has shown that ONC201 has been safe in several studies. In one study, patients with glioblastoma, a type of brain cancer, tolerated ONC201 well, with no serious side effects. Another study involving patients with a specific brain tumor mutation found ONC201 both safe and effective. These results suggest that ONC201 was generally well-tolerated in past trials, providing some confidence in its safety. However, it is important to remember that ONC201 remains under investigation in this trial, so researchers continue to monitor for any new side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Researchers are excited about ONC201 for leukemia because it offers a novel approach by targeting the Akt/ERK pathway, a mechanism not commonly addressed by standard leukemia treatments like chemotherapy and targeted therapies such as tyrosine kinase inhibitors. Unlike typical treatments, ONC201 is an oral medication, providing a more convenient administration method. Additionally, one of its variations is combined with venetoclax, which may enhance its effectiveness and offer new hope for patients who haven't responded to existing therapies. This combination and unique mechanism of action have the potential to improve outcomes for those with resistant forms of leukemia.

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

Research shows that ONC201, also known as dordaviprone, may help treat certain cancers. In earlier studies, this drug stopped cancer cells from growing by blocking essential proteins needed for survival and multiplication. ONC201 was tested in patients with H3 K27M-mutant gliomas, a specific type of brain tumor, and demonstrated its ability to fight the tumor. Although limited data exists on its use for leukemia, these findings suggest potential effectiveness for other cancers. This trial will explore different dosing schedules of ONC201 to evaluate its effectiveness for leukemia. Its ability to disrupt cancer cell signals makes it a promising option for challenging cases like leukemia that has recurred or not responded to treatment. ^{2 3 4 6 7}

Who Is on the Research Team?

Gautam Borthakur, M.D.

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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

Women of child-bearing potential must use acceptable contraceptive methods

Must be able and willing to give written informed consent

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.

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• ONC201

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.

How Is the Trial Designed?

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+

Oncoceutics, Inc.

Industry Sponsor

Trials

10

Recruited

500+

Published Research Related to This Trial

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11066938/

ACTION: a randomized phase 3 study of ONC201 ... ONC201 (dordaviprone) has demonstrated antitumor efficacy in preclinical and clinical evaluations of H3 K27M-mutant glioma. ONC201 is a first-in-class small- ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.10017

Efficacy and safety of dordaviprone (ONC201) in ... 12-month PFS rate was not reached; 12-month OS rate was 27.3% (6.5, 53.9). One patient experienced a grade ≥3 TR-TEAE (9.1%); no TR-SAEs, ...

3. ejcancer.com ejcancer.com/article/S0959-8049(24)01772-6/fulltext

Real life data of ONC201 (dordaviprone) in pediatric and ... Median OS after ONC201 start was 143 days or 4,7 mo (1–711 days) for the whole cohort. Univariate and multivariable analysis identified site ( ...

4. karmanos.org karmanos.org/karmanos/blog/2269

Karmanos Researcher Co-discovered Compound, Led to ... Preclinical and clinical trials revealed that ONC201 worked in multiple ways: it shut down survival signals inside cancer cells (ERK and AKT), ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0959804924017726

Real life data of ONC201 (dordaviprone) in pediatric and ... Median OS after ONC201 start was 143 days or 4,7 mo (1–711 days) for the whole cohort. Univariate and multivariable analysis identified site ( ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11066921/

Safety and pharmacokinetics of ONC201 (dordaviprone ... Per preclinical data, sustained ONC201 exposure was associated with the death of newly diagnosed and recurrent glioblastoma cells. The present ...

7. academic.oup.com academic.oup.com/neuro-oncology/article/26/Supplement_8/viii225/7890111

NCOG-07. SAFETY OF ONC201 TREATMENT IN PATIENTS ... The present analysis reports safety data from ONC028, a compassionate use program (CUP) for patients with previously treated H3 K27M-mutant ...