BTX-A51 for Cancer
Recruiting in Palo Alto (17 mi)
+3 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Edgewood Oncology Inc.
Must not be taking: Antineoplastics, Corticosteroids
Disqualifiers: CNS disease, Cardiac disease, Infections, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This is a multicenter, open label, nonrandomized, sequential dose escalation/dose ranging, multiple dose study designed to evaluate the safety, toxicity, and PK as well as preliminary efficacy of BTX-A51 alone and in combination with fulvestrant in subjects with advanced solid tumors. The study will be done in three phases, described below.
Phase 1a (Dose Escalation Phase):
The Phase 1a portion is designed to determine the dose limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of orally administered BTX-A51. BTX-A51 will be administered once daily on a weekly schedule of 5 days on/2 days off. Dose escalation will proceed according to a modified 3+3 design. Each cycle will consist of 28 days (4 weeks), and the DLT observation period will be the first cycle (i.e., 28 days after initiation of dosing). A DLT may be observed in no more than 0 out of 3 or 1 out of 6 subjects who have completed the DLT observation period before the next cohort initiates accrual. Barring DLT, sequential dose escalation of BTX-A51 is planned with up to a total of 6 dose levels; on the basis of these an MTD will be identified. The MTD is defined as the highest dose level with a subject incidence of DLTs of 0 or 1 out of 6 during the first 28 days of study drug dosing. A minimum of 6 subjects needs to be treated at a dose level before this dose level can be deemed as the MTD.
Phase 1b (Monotherapy Dose Ranging Phase):
Dose expansion may begin when the RP2D has been determined. Up to 40 additional subjects at each of the 2 dose levels will be enrolled to evaluate safety and preliminary efficacy of BTX-A51 in subjects with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-), GATA3 mutant (mt) and wild-type (wt) metastatic breast cancer (mBC). Dosing in this phase of the study consists of the first cycle of therapy (i.e., 28 days).
Phase 1c (Combination Safety Phase):
The Phase 1c portion will evaluate the safety and tolerability of orally administered BTX-A51 at two dose levels combined with fulvestrant. The first combo cohort may be initiated after DEC review of the 6 subject lead-in phase of the high dose monotherapy cohort in Phase 1b. Dose escalation will proceed according to a 3+3 design. Each cycle will consist of 28 days (4 weeks), and the DLT observation period will be the first cycle (i.e., 28 days after initiation of dosing).
Do I need to stop my current medications to join the trial?
The trial requires that you stop any local or systemic cancer treatments, including chemotherapy, hormonal therapy, or radiation, at least 3 weeks before starting the study drug. Chronic use of corticosteroids above a certain dose must also be stopped 4 weeks prior to the trial.
What safety data exists for BTX-A51 or similar CK2 inhibitors in humans?
There is limited safety data specifically for BTX-A51, but similar CK2 inhibitors like hematein have shown to inhibit tumor growth in mice without significant toxicity, suggesting potential safety in humans.
12345What makes the drug BTX-A51 unique for cancer treatment?
BTX-A51 is unique because it is a PROTAC (proteolysis-targeting chimera) that targets and degrades specific proteins involved in cancer cell growth, offering a novel mechanism compared to traditional inhibitors that only block protein activity.
678910Eligibility Criteria
Adults with advanced solid tumors or B cell Non-Hodgkin Lymphoma that's resistant to standard treatments can join. They must have measurable disease, not be pregnant, agree to use contraception, and have good organ function. Those with MYC amplified/overexpressed tumors are eligible for the expansion phase.Inclusion Criteria
Demonstration of understanding and voluntarily signing of an informed consent form
My organs are functioning well.
My cancer can be measured using scans.
+5 more
Exclusion Criteria
Life expectancy <3 months, as determined by the Investigator
I haven't taken more than 10 mg of steroids daily in the last month.
I have a serious heart condition.
+11 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Phase 1a (Dose Escalation Phase)
Determine the dose limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of BTX-A51
4 weeks
Weekly visits for dosing and monitoring
Phase 1b (Monotherapy Dose Ranging Phase)
Evaluate safety and preliminary efficacy of BTX-A51 in subjects with ER+, HER2- metastatic breast cancer
4 weeks
Weekly visits for dosing and monitoring
Phase 1c (Combination Safety Phase)
Evaluate the safety and tolerability of BTX-A51 combined with fulvestrant
4 weeks
Weekly visits for dosing and monitoring
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The trial is testing BTX-A51, an oral drug given on a weekly schedule (5 days on/2 days off). It has two phases: Phase 1a finds the safest dose by slowly increasing amounts; Phase 1b expands this dose to more patients focusing on those with specific genetic tumor features.
8Treatment groups
Experimental Treatment
Group I: BTX-A51 in Combination with Fulvestrant Cohort 2Experimental Treatment1 Intervention
Up to 2-times the SD of BTX-A51 administered orally 3 times per week in a 28-day cycle; fulvestrant administered as a 500-mg intramuscular injection on days 1 and 15 of cycle 1 and on day 1 of subsequent 28-day cycles.
Group II: BTX-A51 in Combination with Fulvestrant Cohort 1Experimental Treatment1 Intervention
Starting dose (SD) of BTX-A51 administered orally 3 times per week in a 28-day cycle; fulvestrant administered as a 500-mg intramuscular injection on days 1 and 15 of cycle 1 and on day 1 of subsequent 28-day cycles.
Group III: BTX-A51 Dose Cohort 6Experimental Treatment1 Intervention
Up to 10-times the SD of BTX-A51 administered orally 5 times per week in a 28-day cycle
Group IV: BTX-A51 Dose Cohort 5Experimental Treatment1 Intervention
Up to 7-times the SD of BTX-A51 administered orally 5 times per week in a 28-day cycle
Group V: BTX-A51 Dose Cohort 4Experimental Treatment1 Intervention
Up to 5-times the SD of BTX-A51 administered orally 5 times per week in a 28-day cycle
Group VI: BTX-A51 Dose Cohort 3Experimental Treatment1 Intervention
Up to 3.5-times the SD of BTX-A51 administered orally 5 times per week in a 28-day cycle
Group VII: BTX-A51 Dose Cohort 2Experimental Treatment1 Intervention
Up to 2-times the SD of BTX-A51 administered orally 5 times per week in a 28-day cycle
Group VIII: BTX-A51 Dose Cohort 1Experimental Treatment1 Intervention
Starting dose (SD) of BTX-A51 administered orally 5 times per week in a 28-day cycle
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Florida Cancer SpecialistsLake Mary, FL
The University of Texas MD Anderson Cancer CenterHouston, TX
SCRI Oncology PartnersNashville, TN
Florida Cancer SpecialistsSarasota, FL
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Who Is Running the Clinical Trial?
Edgewood Oncology Inc.Lead Sponsor
BioTheryX, Inc.Lead Sponsor
References
Synergistic anti-leukemic effects of CK2 inhibitors and pentabromobenzylisothioureas in vitro. [2014]Casein kinase-2 (CK2) inhibitors and pentabromobenzylisothioureas are promising anti-leukemic agents for treatment, both alone and in combination. In this study, we examined pro-apoptotic and cytostatic effects of three CK2 inhibitors: one known, 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT) and two new: 2-(4-methylpiperazin-1-yl)-4,5,6,7-tetrabromo-1H-benzimidazole (MPT) and 2-aminoethyleneamino-4,5,6,7-tetrabromo-1H-benzimidazole (AEAT), as well as of certain S-2,3,4,5,6-pentabromobenzylisothiouronium bromides: ZKK-3, ZKK-9, ZKK-13, against the human acute myelogenous leukemia cell line (KG-1). Cells were treated with CK2 inhibitors alone and in combination with the pentabromobenzylisothioureas.
Hematein, a casein kinase II inhibitor, inhibits lung cancer tumor growth in a murine xenograft model. [2021]Casein kinase II (CK2) inhibitors suppress cancer cell growth. In this study, we examined the inhibitory effects of a novel CK2 inhibitor, hematein, on tumor growth in a murine xenograft model. We found that in lung cancer cells, hematein inhibited cancer cell growth, Akt/PKB Ser129 phosphorylation, the Wnt/TCF pathway and increased apoptosis. In a murine xenograft model of lung cancer, hematein inhibited tumor growth without significant toxicity to the mice tested. Molecular docking showed that hematein binds to CK2α in durable binding sites. Collectively, our results suggest that hematein is an allosteric inhibitor of protein kinase CK2 and has antitumor activity to lung cancer.
Druggability of the CK2 inhibitor CX-4945 as an anticancer drug and beyond. [2021]Casein kinase 2 (CK2) is involved in multiple cellular processes such as proliferation, apoptosis, and cell cycle. In particular, its over-expression in human cancers is associated with angiogenesis and tumor progression. As a first orally bioavailable small molecule inhibitor of CK2, CX-4945 exerts anti-proliferative activity in human cancer cells by inhibiting the cell cycle and the PI3K/Akt signaling pathway. Additionally, CX-4945 reduces angiogenesis via blockade of hypoxia-inducible factor-1α transcription and suppresses the inflammatory interleukin-6 production in human breast cancer cells. These effects are supported by results from mouse xenograft model investigations. Here, we discuss the druggability of CX-4945 and its potential to be developed as an anti-cancer drug in clinical trials.
Development of dual casein kinase 1δ/1ε (CK1δ/ε) inhibitors for treatment of breast cancer. [2021]Casein kinase 1δ/ε have been identified as promising therapeutic target for oncology application, including breast and brain cancer. Here, we described our continued efforts in optimization of a lead series of purine scaffold inhibitors that led to identification of two new CK1δ/ε inhibitors 17 and 28 displaying low nanomolar values in antiproliferative assays against the human MDA-MB-231 triple negative breast cancer cell line and have physical, in vitro and in vivo pharmacokinetic properties suitable for use in proof of principle animal xenograft studies against human cancers.
Casein kinase 2 inhibition attenuates androgen receptor function and cell proliferation in prostate cancer cells. [2012]Casein kinase 2 (CK2) is constitutively active with dual specificity and exists as a hetero-tetrameric complex of α, α', and β subunits. Its aberrant expression and elevated activity have been linked to many human cancers, including prostate cancer. As an effort to develop new chemotherapy for prostate cancers, in this study, we tested the effects of tetra-bromo-cinnamic acid (TBCA), a newly synthetic CK2-selective CK2 inhibitor, on androgen receptor (AR) transactivation, cell proliferation, and viability in multiple prostate cancer cell lines.
Orally bioavailable BTK PROTAC active against wild-type and C481 mutant BTKs in human lymphoma CDX mouse models. [2023]Bruton tyrosine kinase (BTK) is an important signaling hub that activates the B-cell receptor (BCR) signaling cascade. BCR activation can contribute to the growth and survival of B-cell lymphoma or leukemia. The inhibition of the BCR signaling pathway is critical for blocking downstream events and treating B-cell lymphomas. Herein, we report potent and orally available proteolysis-targeting chimeras (PROTACs) that target BTK to inactivate BCR signaling. Of the PROTACs tested, UBX-382 showed superior degradation activity for wild-type (WT) and mutant BTK proteins in a single-digit nanomolar range of half-maximal degradation concentration in diffuse large B-cell lymphoma cell line. UBX-382 was effective on 7 out of 8 known BTK mutants in in vitro experiments and was highly effective in inhibiting tumor growth in murine xenograft models harboring WT or C481S mutant BTK-expressing TMD-8 cells over ibrutinib, ARQ-531, and MT-802. Remarkably, oral dosing of UBX-382 for
The Development of BTK Inhibitors: A Five-Year Update. [2022]Bruton's tyrosine kinase (BTK) represented, in the past ten years, an important target for the development of new therapeutic agents that could be useful for cancer and autoimmune disorders. To date, five compounds, able to block BTK in an irreversible manner, have been launched in the market, whereas many reversible BTK inhibitors (BTKIs), with reduced side effects that are more useful for long-term administration in autoimmune disorders, are under clinical investigation. Despite the presence in the literature of many articles and reviews, studies on BTK function and BTKIs are of great interest for pharmaceutical companies as well as academia. This review is focused on compounds that have appeared in the literature from 2017 that are able to block BTK in an irreversible or reversible manner; also, new promising tunable irreversible inhibitors, as well as PROTAC molecules, have been reported. This summary could improve the knowledge of the chemical diversity of BTKIs and provide information for future studies, particularly from the medicinal chemistry point of view. Data reported here are collected from different databases (Scifinder, Web of Science, Scopus, Google Scholar, and Pubmed) using "BTK" and "BTK inhibitors" as keywords.
Design, synthesis, and evaluation of BTK-targeting PROTACs with optimized bioavailability in vitro and in vivo. [2023]Ibrutinib is a first-line drug for the treatment of B-cell malignancies. BTKC481S mutation has led to drug resistance during clinical application. Herein, a novel BTK-targeting PROTAC molecule with better solubility and bioavailability was developed. Compound 15-271 has better solubility than ibrutinib and some reported BTK PROTACs. 15-271 has better liver microsomal stability than its analogues in multiple species. More importantly, 15-271 has a longer half-life and better bioavailability in vivo. The development strategy of compound 15-271 can be a general procedure for the optimization of other PROTACs.
Targeting Solid Tumors With BTK Inhibitors. [2021]The repurposing of FDA-approved Bruton's tyrosine kinase (BTK) inhibitors as therapeutic agents for solid tumors may offer renewed hope for chemotherapy-resistant cancer patients. Here we review the emerging evidence regarding the clinical potential of BTK inhibitors in solid tumor therapy. The use of BTK inhibitors may through lead optimization and translational research lead to the development of new and effective combination regimens for metastatic and/or therapy-refractory solid tumor patients.
Phase I/II study of AT-101 with topotecan in relapsed and refractory small cell lung cancer. [2013]AT-101 is an oral, pan Bcl-2 family protein inhibitor that has demonstrated activity in small cell lung cancer (SCLC) models. A phase I/II study was conducted combining AT-101 with topotecan in relapsed and refractory SCLC.