ASTX727 for Brain Cancer

Recruiting at 2 trial locations

Overseen By Isabel Arrillaga-Romany, MD, Ph.D

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Massachusetts General Hospital

Must not be taking: Bevacizumab

Disqualifiers: Enhancing disease, Severe infection, Myocardial infarction, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 1 year

18 Participants Needed

Trial Summary

What is the purpose of this trial?

this research study is evaluating the highest dose of ASTX727 that can be administered safely to recurrent/progressive non-enhancing IDH mutant gliomas patients.

Do I need to stop taking my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must be on a stable or decreasing dose of glucocorticoids for 7 days before registration, and you cannot have received systemic anticancer therapy within 28 days prior to registration, except for lomustine/CCNU, which requires a 42-day wait.

What data supports the effectiveness of the drug ASTX727 for brain cancer?

The drug ASTX727, a combination of decitabine and cedazuridine, has shown effectiveness in treating myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) by increasing the availability of decitabine in the body. While it is being studied for other cancers, including brain cancer, its effectiveness in these conditions is still under investigation. ^{1 2 3 4 5}

How is the drug ASTX727 different from other brain cancer treatments?

ASTX727 is unique because it combines decitabine and cedazuridine, which allows for oral administration, potentially improving patient convenience compared to traditional intravenous chemotherapy. This combination is designed to enhance the effectiveness of decitabine by preventing its breakdown in the body, which may offer a novel approach for treating brain cancer. ^{6 7 8 9 10}

Research Team

Isabel Arrillaga-Romany, MD, Ph.D

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

Adults with recurrent/progressive non-enhancing IDH mutant gliomas who've completed radiation at least 12 weeks prior, understand the consent process, have good liver and kidney function, stable brain scans within 28 days of starting treatment, and a life expectancy over 6 months. Not for pregnant/breastfeeding individuals or those with certain medical conditions that could interfere with the trial.

Inclusion Criteria

My kidneys are working well.

I have saved samples from my initial cancer biopsy or surgery.

I am a woman who can have children and have a recent negative pregnancy test.

Exclusion Criteria

I have another cancer that is getting worse or needs treatment.

I do not have a severe infection or unexplained fever over 38.5°C.

My heart's electrical activity is normal and does not pose a risk for irregular heartbeats.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ASTX727 orally for 4 to 6 consecutive days every 28-day cycle, with surgical resection occurring 12 days after treatment initiation

1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment, with progression-free survival and overall survival assessed

Up to 5 years

Treatment Details

Interventions

• ASTX727

Trial Overview The study is testing ASTX727 to find the highest safe dose for patients with specific types of brain tumors (non-enhancing IDH mutant gliomas). It involves people who've had previous treatments as well as those untreated. Some participants may need accessible tumors for surgical evaluation.

Participant Groups

Group I: Expansion Cohort Experimental Treatment 1 Intervention

* Oral ASTX727 will be administered daily for 4, 5 or 6 consecutive days * Surgical resection will take place 12 days (+/- 1 day) after initiation of treatment

Group II: ASTX727 (Cedazuridine + Cytidine Antimetabolite Decitabine) Experimental Treatment 1 Intervention

-ASTX727 administered orally for 5 or 6 consecutive days every 28d cycle and will de-escalate to 4 consecutive days every 28 d cycle.

ASTX727 is already approved in United States, European Union for the following indications:

Approved in United States as Inqovi for:

• Myelodysplastic Syndromes (MDS)

Approved in European Union as Inqovi for:

• Myelodysplastic Syndromes (MDS)

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Astex Pharmaceuticals, Inc.

Industry Sponsor

Trials

97

Recruited

7,400+

Dr. Harren Jhoti

Astex Pharmaceuticals, Inc.

Chief Executive Officer since 2007

PhD in Biochemistry from Birkbeck College, London

Dr. Harold N. Keer

Astex Pharmaceuticals, Inc.

Chief Medical Officer since 2020

MD

Findings from Research

The fixed-dose oral combination of decitabine and cedazuridine (Inqovi®) has been approved for treating myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), enhancing the oral bioavailability of decitabine through the inhibition of cytidine deaminase by cedazuridine.

Decitabine is already an established treatment for MDS and CMML, and the combination therapy has shown promise in ongoing clinical studies for other cancers like acute myeloid leukaemia (AML), glioma, and solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine/Cedazuridine: First Approval. Dhillon, S.[2021]

In a phase 1 study involving 44 patients with myelodysplastic syndromes or chronic myelomonocytic leukaemia, the combination of oral decitabine and the CDA inhibitor cedazuridine successfully increased the bioavailability of decitabine, achieving pharmacokinetics similar to intravenous administration without increasing toxicity.

The study demonstrated that oral decitabine combined with cedazuridine produced effective dose-dependent demethylation and clinical responses comparable to intravenous decitabine, suggesting it could be a viable alternative treatment for myeloid disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. Savona, MR., Odenike, O., Amrein, PC., et al.[2019]

The phase 2 study found that oral cedazuridine/decitabine (100 mg/35 mg) provided similar systemic exposure and DNA demethylation compared to standard IV decitabine (20 mg/m2) in patients with myelodysplastic syndromes or chronic myelomonocytic leukemia, indicating comparable efficacy.

Clinical responses were observed in 60% of patients, with 21% achieving a complete response, while the most common serious side effects included neutropenia (46%) and thrombocytopenia (38%), highlighting the treatment's safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Garcia-Manero, G., Griffiths, EA., Steensma, DP., et al.[2021]

In a study of 44 patients with relapsed/refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), the combination of decitabine with the EIAG regimen resulted in a higher modified composite complete response (mCRc) rate of 72.7% compared to 40.9% in the CAG regimen group, indicating improved efficacy.

Both treatment regimens led to significant myelosuppression as a common adverse effect, but there was no increase in non-hematological toxicities, suggesting that decitabine combined with EIAG is a safe option that enhances remission rates without adding extra risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Decitabine Combined with Modified EIAG Regimen in the Treatment of Patients with Relapsed/Refractory Acute Myeloid Leukemia and High-risk Myelodysplastic Syndrome]. Mao, JP., Xue, LG., Zhu, YX., et al.[2023]

In a phase III trial with 170 patients suffering from myelodysplastic syndromes (MDS), decitabine significantly improved response rates compared to supportive care alone, achieving a 17% response rate with complete and partial responses, while supportive care had no responses (p < 0.001).

Decitabine's mechanism involves reactivating tumor suppressor genes, leading to cancer cell differentiation, but it is associated with myelosuppression as a main adverse effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine: in myelodysplastic syndromes. McKeage, K., Croom, KF.[2018]

The newly synthesized prodrug BGCNU is significantly more effective at inducing DNA interstrand cross-links (ICLs) in human glioma cells compared to traditional CENUs like ACNU and BCNU, suggesting enhanced anticancer efficacy.

BGCNU works by releasing O6-benzylguanine, which effectively inhibits the DNA repair enzyme AGT, allowing for greater accumulation of ICLs and increased cytotoxicity in AGT-proficient cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and Antitumor Activity Evaluation of a Novel Combi-nitrosourea Prodrug: BGCNU. Wang, Y., Ren, T., Lai, X., et al.[2020]

The preclinical drug development pipeline effectively identified the nucleoside analog 5-fluoro-2'-deoxycytidine (FdCyd) as having strong in vitro activity against pediatric brain tumors, significantly reducing cell proliferation at low concentrations.

Despite its promising in vitro results and adequate drug levels in the brain, FdCyd did not show a significant therapeutic response in vivo, leading to its deprioritization for clinical trials, highlighting the importance of comprehensive preclinical testing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical studies of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in pediatric brain tumors. Morfouace, M., Nimmervoll, B., Boulos, N., et al.[2018]

In a study involving 97 patients with malignant gliomas, temozolomide (TMZ) demonstrated a significantly higher response rate (35.71%) compared to lomustine (CCNU) (9.09%), indicating its greater efficacy in treating these aggressive brain tumors.

TMZ was found to have an acceptable safety profile, with common side effects being mild nausea and vomiting, suggesting it could be a preferred chemotherapy option for patients with refractory malignant brain gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A multicenter randomized controlled study of temozolomide in 97 patients with malignant brain glioma]. Qian, ZZ., Wang, HQ., Liu, XM., et al.[2018]

Lomustine, a chemotherapy drug, effectively induces DNA damage in glioblastoma cells by forming interstrand cross-links and double-strand breaks, which are crucial for triggering cell death pathways.

Inhibiting homologous recombination repair with Rad51 inhibitors like RI-1 significantly enhances the effectiveness of lomustine, leading to increased tumor cell death and reduced tumor growth in glioma models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting Homologous Recombination by Pharmacological Inhibitors Enhances the Killing Response of Glioblastoma Cells Treated with Alkylating Drugs. Berte, N., Piée-Staffa, A., Piecha, N., et al.[2020]

Pediatric CNS tumors like posterior fossa ependymoma and diffuse midline glioma share a common epigenetic vulnerability, which could be targeted with repositioned, already-approved drugs, potentially speeding up the development of new treatments.

Challenges in treating these tumors include their location, resistance to chemotherapy, and the need for drugs to effectively cross the blood-brain barrier, highlighting the importance of targeting both tumor cells and their supportive microenvironments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug Repurposing in Pediatric Brain Tumors: Posterior Fossa Ependymoma and Diffuse Midline Glioma under the Looking Glass. Servidei, T., Sgambato, A., Lucchetti, D., et al.[2023]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Decitabine/Cedazuridine: First Approval. [2021]

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

An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. [2019]

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

Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. [2021]

4. China pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Decitabine Combined with Modified EIAG Regimen in the Treatment of Patients with Relapsed/Refractory Acute Myeloid Leukemia and High-risk Myelodysplastic Syndrome]. [2023]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Decitabine: in myelodysplastic syndromes. [2018]

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

Synthesis and Antitumor Activity Evaluation of a Novel Combi-nitrosourea Prodrug: BGCNU. [2020]

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

Preclinical studies of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in pediatric brain tumors. [2018]

8. China pubmed.ncbi.nlm.nih.gov

[A multicenter randomized controlled study of temozolomide in 97 patients with malignant brain glioma]. [2018]

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

Targeting Homologous Recombination by Pharmacological Inhibitors Enhances the Killing Response of Glioblastoma Cells Treated with Alkylating Drugs. [2020]

10. Singapore pubmed.ncbi.nlm.nih.gov

Drug Repurposing in Pediatric Brain Tumors: Posterior Fossa Ependymoma and Diffuse Midline Glioma under the Looking Glass. [2023]