Belinostat + Guadecitabine/ASTX727 for Chondrosarcoma

Recruiting at 43 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: UGT1A1 inhibitors

Disqualifiers: Pregnancy, Uncontrolled illness, Psychiatric illness, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 9

Duration: 28 days per cycle, repeated until disease progression or unacceptable toxicity

20 Participants Needed

Trial Summary

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must avoid chronic use of medications that strongly inhibit UGT1A1 and switch to alternatives 7-14 days before starting the trial treatment.

What data supports the effectiveness of the drug Belinostat + Guadecitabine/ASTX727 for treating chondrosarcoma?

Research shows that drugs similar to Belinostat and Guadecitabine, which target DNA and histone modifications, can slow down the growth of chondrosarcoma cells and trigger immune responses. These findings suggest that targeting the genetic and epigenetic changes in chondrosarcoma could be a promising treatment approach. ^{1 2 3 4 5}

Is the combination of Belinostat and Guadecitabine safe for humans?

Belinostat has been studied in combination with other drugs and found to be generally safe, though some patients experienced side effects, especially those with certain genetic variations. Guadecitabine, similar to decitabine, has been evaluated for safety in other conditions, but specific safety data for the combination with Belinostat in chondrosarcoma is not available. ^{6 7 8 9 10}

What makes the drug combination of Belinostat and Guadecitabine unique for treating chondrosarcoma?

This drug combination is unique because it targets the epigenetic changes in chondrosarcoma cells, using Belinostat to inhibit histone deacetylases (HDACs) and Guadecitabine to inhibit DNA methyltransferases (DNMTs). This approach aims to disrupt the tumor's growth and enhance immune signaling, offering a novel strategy for a cancer type that is typically resistant to conventional chemotherapy and radiotherapy. ^{1 2 3 11 12}

What is the purpose of this trial?

This phase II trial studies the effect of belinostat and SGI-110 (guadecitabine) or ASTX727 in treating patients with conventional chondrosarcoma that cannot be removed by surgery (unresectable) and has spread from where it first started (primary site) to other places in the body (metastatic). Belinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as guadecitabine and ASTX727, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving belinostat in combination with guadecitabine or ASTX727 may lower the chance of unresectable and metastatic chondrosarcoma growing or spreading.

Research Team

Mia Weiss

Principal Investigator

Yale University Cancer Center LAO

Eligibility Criteria

This trial is for adults (18+) with a type of bone cancer called conventional chondrosarcoma that can't be surgically removed and has spread. Participants must have at least one measurable tumor, may have had any number of prior treatments or none, but their disease should not be treatable by surgery. They need to be in fair health overall (ECOG <=2) and able to undergo biopsy.

Inclusion Criteria

My cancer diagnosis will be reviewed at the study site.

I have a tumor that can be measured and hasn't been treated with radiation.

I can safely undergo a biopsy as per my doctor's assessment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive guadecitabine or ASTX727 and belinostat in 28-day cycles

28 days per cycle, repeated until disease progression or unacceptable toxicity

5 visits (in-person) per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Every 3 months

Treatment Details

Interventions

• ASTX727
• Belinostat
• Guadecitabine

Trial Overview The study tests belinostat combined with either guadecitabine or ASTX727 on patients with advanced chondrosarcoma. Belinostat blocks enzymes needed for cell growth; guadecitabine and ASTX727 are chemotherapy drugs aiming to kill or stop the spread of cancer cells.

Participant Groups

Group I: Treatment (belinostat, guadecitabine, ASTX727) Experimental Treatment 7 Interventions

Patients receive guadecitabine SC or ASTX727 PO on days 1-5. Patients also receive belinostat IV over 30 minutes on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood during screening, tumor biopsy during screening and on study, and MRI or CT throughout the trial.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Chondrosarcoma, particularly in its metastatic or unresectable forms, is challenging to treat due to resistance to standard anticancer therapies, highlighting the need for novel treatments.

Recent research has identified promising biomarkers like IDH1/2 and COL2A1, and several targeted therapies and immunotherapies have shown encouraging antitumor activity in clinical studies for advanced chondrosarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic Targets and Emerging Treatments in Advanced Chondrosarcoma. Miwa, S., Yamamoto, N., Hayashi, K., et al.[2022]

The combination of belinostat with cisplatin and etoposide (C+E) is safe and shows activity in treating advanced small cell lung cancer (SCLC), with 39% of patients responding positively to the treatment.

The study identified a maximum tolerated dose for the combination therapy and highlighted the importance of genotyping patients for UGT1A1 variants, as those with more than three copies had higher serum levels of belinostat, which could influence treatment outcomes and adverse event risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of belinostat with cisplatin and etoposide in advanced solid tumors, with a focus on neuroendocrine and small cell cancers of the lung. Balasubramaniam, S., Redon, CE., Peer, CJ., et al.[2020]

In a phase I study involving 21 patients with advanced chondrosarcoma, ivosidenib treatment resulted in a significant reduction of the oncometabolite D-2-hydroxyglutarate (2-HG) in all patients, indicating effective targeting of the mutant IDH1 enzyme.

The treatment demonstrated minimal toxicity, with most adverse events being mild (grade 1 or 2), and a median progression-free survival of 5.6 months, suggesting potential for durable disease control in this challenging cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of the Mutant IDH1 Inhibitor Ivosidenib: Safety and Clinical Activity in Patients With Advanced Chondrosarcoma. Tap, WD., Villalobos, VM., Cote, GM., et al.[2021]

In a phase 2 study involving 47 patients with unresectable or metastatic conventional chondrosarcoma, pazopanib demonstrated a disease control rate of 43% at 16 weeks, indicating its potential effectiveness in managing this type of cancer.

The median overall survival for patients was 17.6 months, with manageable side effects, primarily hypertension (26%) and elevated liver enzymes (9%), suggesting that pazopanib is a relatively safe treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of a prospective phase 2 study of pazopanib in patients with surgically unresectable or metastatic chondrosarcoma. Chow, W., Frankel, P., Ruel, C., et al.[2021]

References

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

Growth Inhibition and Induction of Innate Immune Signaling of Chondrosarcomas with Epigenetic Inhibitors. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Beyond the Influence of IDH Mutations: Exploring Epigenetic Vulnerabilities in Chondrosarcoma. [2020]

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

Histone deacetylase inhibitors vorinostat and panobinostat induce G1 cell cycle arrest and apoptosis in multidrug resistant sarcoma cell lines. [2019]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Therapeutic Targets and Emerging Treatments in Advanced Chondrosarcoma. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Selective inhibition of mutant IDH1 by DS-1001b ameliorates aberrant histone modifications and impairs tumor activity in chondrosarcoma. [2022]

6. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Review: recent clinical trials in epigenetic therapy. [2019]

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

Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin's lymphomas. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Phase I trial of belinostat with cisplatin and etoposide in advanced solid tumors, with a focus on neuroendocrine and small cell cancers of the lung. [2020]

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

Cladribine in combination with entinostat synergistically elicits anti-proliferative/anti-survival effects on multiple myeloma cells. [2020]

10. England pubmed.ncbi.nlm.nih.gov

A phase I clinical trial of the histone deacetylase inhibitor belinostat in patients with advanced hematological neoplasia. [2014]

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

Phase I Study of the Mutant IDH1 Inhibitor Ivosidenib: Safety and Clinical Activity in Patients With Advanced Chondrosarcoma. [2021]

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

Results of a prospective phase 2 study of pazopanib in patients with surgically unresectable or metastatic chondrosarcoma. [2021]