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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safest dose of a new drug, ASTX727 (also known as Decitabine/Cedazuridine), for individuals with IDH mutant gliomas, a specific type of brain cancer. Participants take the drug orally for several days in a cycle, with some undergoing surgery after starting the medication. Ideal candidates have an IDH mutant glioma that has worsened or returned and have previously received treatments such as chemotherapy or radiation. 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 treatment.

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.

Is there any evidence suggesting that ASTX727 is likely to be safe for humans?

Research has shown that ASTX727, a combination of cedazuridine and decitabine, has been studied for safety in other conditions. In patients with chronic myelomonocytic leukemia, a type of blood cancer, ASTX727 caused side effects like low blood cell counts, increasing infection risk, as well as nausea and tiredness. Most patients handled the treatment well, though some experienced more serious side effects.

Another study tested ASTX727 in people with brain tumors before surgery to assess its safety when combined with another treatment. Results indicated that some patients experienced manageable side effects like tiredness and nausea.

In this trial, researchers are testing ASTX727 specifically for brain cancer to find the highest dose patients can safely take. Since the trial is in an early stage, the main goal is to determine a safe dose rather than its effectiveness. Because testing is still early, complete safety data for this specific use is not yet available. However, studies so far suggest that while ASTX727 can cause side effects, many are manageable. ^{1 2 3 4 5}

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

Unlike the standard treatments for brain cancer, which often involve invasive chemotherapy and radiation, ASTX727 is unique because it combines two active ingredients, Cedazuridine and the antimetabolite Decitabine, to be taken orally. This new delivery method aims to improve patient convenience and reduce the need for hospital visits. Additionally, ASTX727 targets cancer cells in a novel way, potentially enhancing the effectiveness of the treatment while minimizing side effects. Researchers are excited about this approach because it could offer a less disruptive and more targeted therapy option for patients with brain cancer.

What evidence suggests that ASTX727 might be an effective treatment for brain cancer?

Research has shown that ASTX727 may effectively treat certain blood cancers, such as chronic myelomonocytic leukemia (CMML) and myelodysplastic syndromes (MDS). Studies found that the pill form of ASTX727 provides nearly the same drug levels in the body as the IV version, enhancing its effectiveness. ASTX727 combines two drugs, decitabine and cedazuridine, to increase the drug's availability in the body, potentially boosting its efficacy. This treatment interferes with specific processes in cancer cells, slowing their growth. In this trial, participants will receive ASTX727 to evaluate its effects on brain cancer. Although research on its impact on brain cancer continues, the mechanism of ASTX727 suggests it might benefit patients with IDH mutant gliomas, a type of brain tumor. ^{1 4 5 6 7}

Who Is on the Research Team?

Isabel Arrillaga-Romany, MD, Ph.D

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04872543

A Study of ASTX727 in People With Malignant Peripheral ... The purpose of this study is to see whether the study drug ASTX727 is an effective treatment for people who have MPNST with a PCR2 mutation.

2. withpower.com withpower.com/trial/phase-1-central-nervous-system-neoplasms-6-2019-f636b

ASTX727 for Brain Cancer 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).

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8701430/

Efficacy of Oral Decitabine/Cedazuridine (ASTX727) in the ... Here, we present outcome data for this study for the enrolled subpopulation of patients with CMML. Methods: We used a randomized cross over ...

4. isrctn.com isrctn.com/ISRCTN30298528

Assessment of the safety of a combined drug treatment ... Assessment of the safety of a combined drug treatment of ASTX727 and Nivolumab, in patients with newly diagnosed brain tumours before tumour removal surgery.

5. onclive.com onclive.com/view/oral-decitabine-cedazuridine-is-a-game-changer-for-mds-and-cmml-treatment

Oral Decitabine-Cedazuridine Is a Game Changer for ... Critically, the primary end point of total drug exposure was met, with the oral formulation achieving 98.93% (90% CI, 92.66%-105.60%) of the IV ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04872543

A Study of ASTX727 in People With Malignant Peripheral ... The purpose of this study is to see whether the study drug ASTX727 is an effective treatment for people who have MPNST with a PCR2 mutation.

7. cancer.gov cancer.gov/clinicaltrials/NCI-2019-05495

ASTX727 for the Treatment of IDH Mutant Recurrent Glioma This phase I trial studies the side effects and best dose of ASTX727 in treating patients with IDH mutant glioma that has come back (recurrent).