BTX-A51 for Liposarcoma

Recruiting at 2 trial locations

Overseen By Michael Wagner, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Michael Wagner

Must not be taking: Investigational agents

Disqualifiers: Infection, CHF, Cirrhosis, CNS disease, others

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

Compensation: Varies

Number of Visits: 5

Duration: Until disease progression or unacceptable toxicity

12 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot use other investigational or anticancer agents while participating in the trial, except for certain hormonal therapies for breast or prostate cancer.

What data supports the effectiveness of the drug BTX-A51 for treating liposarcoma?

The research highlights the effectiveness of small molecule protein kinase inhibitors in cancer therapy, which are similar to BTX-A51. These inhibitors have shown success in treating various cancers by targeting specific proteins involved in cancer growth, suggesting potential effectiveness for BTX-A51 in treating liposarcoma. ^{1 2 3 4 5}

What makes the drug BTX-A51 unique for treating liposarcoma?

BTX-A51 is unique because it is a proteolysis-targeting chimera (PROTAC) that targets specific proteins for degradation, potentially offering a novel mechanism of action compared to traditional treatments that inhibit protein function. This approach may provide a more effective way to treat liposarcoma by directly reducing the levels of proteins that contribute to tumor growth. ^{6 7 8 9 10}

What is the purpose of this trial?

This study is testing if the recommended dose of BTX-A51 is safe and tolerable in participants with liposarcoma. The name of the study drug used in this research study is: -BTX-A51 (a type of kinase inhibitor)

Research Team

Michael J Wagner, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

Adults with specific subtypes of liposarcoma that have spread or returned, and who haven't had cancer treatment in the last 14 days. They must be able to swallow pills, not be pregnant, agree to use two contraception methods during and after the study, have stable vital organ functions, and an ECOG performance status ≤2.

Inclusion Criteria

My organ and bone marrow functions meet the required levels for the study.

I am a woman able to have children and have a recent negative pregnancy test.

I can take care of myself but might not be able to do heavy physical work.

Exclusion Criteria

I cannot swallow pills or have issues absorbing medication.

Patient with current evidence of specific medical conditions that could compromise safety and/or assessment of efficacy

I do not have an active hepatitis B or C infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive BTX-A51 3 times weekly in 28-day cycles, with tumor biopsies and radiologic imaging

Until disease progression or unacceptable toxicity

Day 1 of each 28-day cycle, radiologic imaging every 2 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Every 3 months

Treatment Details

Interventions

• BTX-A51

Trial Overview The trial is testing BTX-A51 (a kinase inhibitor) for safety and tolerability in patients with liposarcoma. Participants will receive a recommended dose to see how well they handle it and if there are any beneficial effects on their condition.

Participant Groups

Group I: BTX-A51 Experimental Treatment 1 Intervention

Participants will be enrolled and will complete study procedures as follows: * Baseline visit with tumor biopsy. * Tumor biopsy at the end of Cycle 1. * Radiologic imaging every 2 cycles. * Cycle 1 through End of Treatment: --Day 1 of 28 day cycle: Predetermined dose of BTX-A51 3x weekly. * End of Treatment visit with radiologic imaging. * Follow-up: every 3 months for 1 year.

Who Is Running the Clinical Trial?

Michael Wagner

Lead Sponsor

Trials

1

Recruited

10+

Michael Wagner, MD

Lead Sponsor

Trials

1

Recruited

10+

Edgewood Oncology Inc.

Industry Sponsor

Trials

3

Recruited

200+

Findings from Research

Targeted protein-tyrosine kinase inhibitors (PTKIs), like imatinib and gefitinib, are effective anticancer drugs that work by selectively inhibiting specific kinases involved in cancer development, with ongoing research into other PTKIs for various cancer types.

The success of PTKI therapy relies on identifying appropriate molecular targets for each patient, highlighting the need for advanced diagnostic tools to ensure effective treatment and to address issues of drug resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging roles of targeted small molecule protein-tyrosine kinase inhibitors in cancer therapy. Smith, JK., Mamoon, NM., Duhé, RJ.[2019]

The combination of the Tyr-kinase inhibitors PP1 and GL-2003 effectively suppresses the growth of human pancreatic cancer xenografts in mice, showing similar efficacy to established treatments like gemcitabine.

This approach targets the PAK1 signaling pathway, which is crucial for RAS-induced cancer growth, suggesting a promising new therapeutic strategy for treating pancreatic cancer and potentially other cancers resistant to current therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Signal therapy of human pancreatic cancer and NF1-deficient breast cancer xenograft in mice by a combination of PP1 and GL-2003, anti-PAK1 drugs (Tyr-kinase inhibitors). Hirokawa, Y., Levitzki, A., Lessene, G., et al.[2014]

Recent advancements have led to the development of small molecules that directly target the G12C mutant of oncogenic RAS proteins, which are implicated in about 24% of human cancers, marking a significant step in addressing previously considered 'undruggable' targets.

New strategies are emerging that not only focus on mutant RAS proteins but also consider the role of wild-type RAS and its interactions, suggesting that disrupting RAS activation pathways could be a viable therapeutic approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RAS, wanted dead or alive: Advances in targeting RAS mutant cancers. Stalnecker, CA., Der, CJ.[2021]

NRAS mutations are common in several cancers, including melanoma and acute myelogenous leukemia (AML), and have historically been difficult to target with therapies.

Recent developments in targeting the MAP/ERK kinase (MEK) pathway have shown promise, with MEK inhibitors demonstrating clinical efficacy as monotherapy and in combination with other agents, indicating a potential new approach for treating NRAS-mutant tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular pathways: targeting NRAS in melanoma and acute myelogenous leukemia. Johnson, DB., Smalley, KS., Sosman, JA.[2022]

In 2019, the FDA approved four new small molecule protein kinase antagonists (entrectinib, erdafitinib, pexidartinib, and fedratinib) that target specific genetic alterations in various cancers, demonstrating their efficacy in treating conditions like solid tumors and bladder cancers.

Overall, 52 small molecule protein kinase inhibitors have been approved, primarily for cancer treatment, with many showing effectiveness against multiple diseases, although resistance to these therapies remains a significant challenge.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Properties of FDA-approved small molecule protein kinase inhibitors: A 2020 update. Roskoski, R.[2021]

UBX-382, a novel proteolysis-targeting chimera (PROTAC), effectively degrades both wild-type and mutant Bruton tyrosine kinase (BTK) proteins, showing strong potential for treating B-cell lymphomas with a half-maximal degradation concentration in the single-digit nanomolar range.

In murine xenograft models, UBX-382 led to complete tumor regression after less than 2 weeks of oral dosing, outperforming other BTK inhibitors like ibrutinib, indicating its promising efficacy in targeting B-cell-related blood cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Orally bioavailable BTK PROTAC active against wild-type and C481 mutant BTKs in human lymphoma CDX mouse models. Lim, YS., Yoo, SM., Patil, V., et al.[2023]

In a study involving 12 healthy subjects, the new tablet (P22-TAB) and capsule (P22-CAP) formulations of CC-292, a BTK inhibitor, demonstrated similar or improved bioavailability compared to the original capsule formulation (P01-CAP).

All formulations were well tolerated at a 250 mg dose, indicating a favorable safety profile for CC-292 across different formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An open-label, phase 1, randomized, three treatments, three-period, crossover, relative bioavailability study of CC-292, a potent and orally available inhibitor of bruton tyrosine kinase. Cheng, Y., Liu, L., Xue, Y., et al.[2022]

The study identified new oxindole sulfonamide derivatives as promising inhibitors of Bruton's tyrosine kinase (BTK), which is crucial for the survival of B-cell malignancies like Burkitt's lymphoma.

Among the compounds tested, PID-4 demonstrated significant cytotoxicity against Burkitt's lymphoma cells while showing negligible effects on non-BTK cancerous and non-cancerous cell lines, indicating its potential as a targeted therapy with fewer side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and Biological Evaluation of Oxindole Sulfonamide Derivatives as Bruton's Tyrosine Kinase Inhibitors. Koraboina, CP., Maddipati, VC., Annadurai, N., et al.[2023]

A series of novel compounds were developed as dual inhibitors of Btk and PI3Kδ kinases, showing effectiveness in suppressing leukemia cell proliferation at low micromolar concentrations in vitro.

Among these compounds, 16b demonstrated the strongest inhibitory activity against Btk and PI3Kδ, with IC50 values of 139 nM and 275 nM respectively, indicating its potential as a promising candidate for further development in leukemia treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design and synthesis of benzofuro[3,2-b]pyridin-2(1H)-one derivatives as anti-leukemia agents by inhibiting Btk and PI3Kδ. Liu, L., Shi, B., Li, X., et al.[2019]

Compound 24a is a newly developed covalent BTK inhibitor that shows strong inhibition of BTK activity with an IC50 of 4.0 nM and high selectivity over ITK and EGFR, reducing the risk of adverse effects associated with off-target inhibition.

In preclinical U-937 xenograft models, compound 24a significantly inhibited tumor growth by 57.85% at a dosage of 50 mg/kg, indicating its potential as an effective treatment for cancers involving BTK.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery of Pteridine-7(8H)-one Derivatives as Potent and Selective Inhibitors of Bruton's Tyrosine Kinase (BTK). Dou, D., Diao, Y., Sha, W., et al.[2022]

References

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

Emerging roles of targeted small molecule protein-tyrosine kinase inhibitors in cancer therapy. [2019]

2. Ireland pubmed.ncbi.nlm.nih.gov

Signal therapy of human pancreatic cancer and NF1-deficient breast cancer xenograft in mice by a combination of PP1 and GL-2003, anti-PAK1 drugs (Tyr-kinase inhibitors). [2014]

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

RAS, wanted dead or alive: Advances in targeting RAS mutant cancers. [2021]

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

Molecular pathways: targeting NRAS in melanoma and acute myelogenous leukemia. [2022]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Properties of FDA-approved small molecule protein kinase inhibitors: A 2020 update. [2021]

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

Orally bioavailable BTK PROTAC active against wild-type and C481 mutant BTKs in human lymphoma CDX mouse models. [2023]

7. England pubmed.ncbi.nlm.nih.gov

An open-label, phase 1, randomized, three treatments, three-period, crossover, relative bioavailability study of CC-292, a potent and orally available inhibitor of bruton tyrosine kinase. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

Synthesis and Biological Evaluation of Oxindole Sulfonamide Derivatives as Bruton's Tyrosine Kinase Inhibitors. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Design and synthesis of benzofuro[3,2-b]pyridin-2(1H)-one derivatives as anti-leukemia agents by inhibiting Btk and PI3Kδ. [2019]

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

Discovery of Pteridine-7(8H)-one Derivatives as Potent and Selective Inhibitors of Bruton's Tyrosine Kinase (BTK). [2022]