BTX-A51 for Cancer

Recruiting at 3 trial locations

Overseen By Zung Thai, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Edgewood Oncology Inc.

Must not be taking: Antineoplastics, Corticosteroids

Disqualifiers: CNS disease, Cardiac disease, Infections, others

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

Compensation: Varies

Number of Visits: Unknown

112 Participants Needed

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. ^{1 2 3 4 5}

What 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. ^{6 7 8 9 10}

Research Team

Zung Thai, MD

Principal Investigator

Edgewood Oncology Inc.

Eligibility 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.

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.

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

Treatment Details

Interventions

• BTX-A51

Trial Overview 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.

Participant Groups

Group I: BTX-A51 in Combination with Fulvestrant Cohort 2 Experimental Treatment 1 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 1 Experimental Treatment 1 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 6 Experimental Treatment 1 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 5 Experimental Treatment 1 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 4 Experimental Treatment 1 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 3 Experimental Treatment 1 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 2 Experimental Treatment 1 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 1 Experimental Treatment 1 Intervention

Starting dose (SD) of BTX-A51 administered orally 5 times per week in a 28-day cycle

Who Is Running the Clinical Trial?

Edgewood Oncology Inc.

Lead Sponsor

Trials

3

Recruited

200+

BioTheryX, Inc.

Lead Sponsor

Trials

3

Recruited

200+

Findings from Research

The study found that CK2 inhibitors (DMAT, MPT, AEAT) combined with pentabromobenzylisothioureas (ZKK-3, ZKK-9, ZKK-13) produced a synergistic pro-apoptotic effect against the KG-1 acute myelogenous leukemia cell line, indicating a promising treatment strategy.

Among the CK2 inhibitors tested, AEAT showed the highest apoptotic activity, suggesting it may be the most effective option for targeting leukemia cells in this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic anti-leukemic effects of CK2 inhibitors and pentabromobenzylisothioureas in vitro. Koronkiewicz, M., Chilmonczyk, Z., Kazimierczuk, Z.[2014]

Hematein, a novel CK2 inhibitor, effectively suppressed lung cancer cell growth and induced apoptosis in a murine xenograft model without causing significant toxicity to the mice.

Molecular docking studies revealed that hematein binds to CK2α at durable sites, indicating its role as an allosteric inhibitor of protein kinase CK2, which contributes to its antitumor activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematein, a casein kinase II inhibitor, inhibits lung cancer tumor growth in a murine xenograft model. Hung, MS., Xu, Z., Chen, Y., et al.[2021]

CX-4945 is the first orally bioavailable small molecule inhibitor of casein kinase 2 (CK2), which plays a significant role in cancer cell proliferation and tumor progression.

In preclinical studies, CX-4945 demonstrated anti-proliferative effects by inhibiting the cell cycle and the PI3K/Akt signaling pathway, while also reducing angiogenesis and inflammation in breast cancer cells, suggesting its potential as an effective anti-cancer treatment in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Druggability of the CK2 inhibitor CX-4945 as an anticancer drug and beyond. Kim, J., Kim, SH.[2021]

Two new inhibitors targeting casein kinase 1δ/ε were developed, showing low nanomolar potency in reducing the growth of MDA-MB-231 triple negative breast cancer cells in laboratory tests.

These inhibitors also demonstrated favorable pharmacokinetic properties, making them suitable for further testing in animal models to evaluate their effectiveness against human cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of dual casein kinase 1δ/1ε (CK1δ/ε) inhibitors for treatment of breast cancer. Monastyrskyi, A., Nilchan, N., Quereda, V., et al.[2021]

The study found that tetra-bromo-cinnamic acid (TBCA), a selective CK2 inhibitor, effectively reduced cell proliferation and induced G2/M cell cycle arrest in prostate cancer cell lines, suggesting its potential as a therapeutic agent.

TBCA was shown to block the nuclear translocation of the androgen receptor (AR) and inhibit AR-mediated gene expression, indicating that CK2 subunits α and α' play a significant role in AR signaling in prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Casein kinase 2 inhibition attenuates androgen receptor function and cell proliferation in prostate cancer cells. Yao, K., Youn, H., Gao, X., et al.[2012]

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]

Bruton's tyrosine kinase (BTK) has become a key target for developing new therapies for cancer and autoimmune disorders, with five irreversible BTK inhibitors already available on the market.

Recent research highlights the potential of reversible BTK inhibitors, which may have fewer side effects and be more suitable for long-term use in autoimmune conditions, along with new tunable irreversible inhibitors and PROTAC molecules that could enhance treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Development of BTK Inhibitors: A Five-Year Update. Tasso, B., Spallarossa, A., Russo, E., et al.[2022]

A new PROTAC molecule, 15-271, was developed to target BTK and shows improved solubility and bioavailability compared to ibrutinib, which is important for treating B-cell malignancies.

15-271 also demonstrates better liver microsomal stability and a longer half-life in vivo, suggesting it could be a more effective treatment option for patients with BTKC481S mutation-induced drug resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design, synthesis, and evaluation of BTK-targeting PROTACs with optimized bioavailability in vitro and in vivo. Sun, Y., Yang, Z., Zhang, Z., et al.[2023]

Bruton's tyrosine kinase (BTK) inhibitors, already approved by the FDA, show promise as new treatments for patients with solid tumors that are resistant to traditional chemotherapy.

Emerging evidence suggests that BTK inhibitors could be combined with other therapies to create effective treatment regimens for metastatic and therapy-refractory solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting Solid Tumors With BTK Inhibitors. Uckun, FM., Venkatachalam, T.[2021]

The combination of AT-101 and topotecan was found to be safe for patients with relapsed and refractory small cell lung cancer (SCLC), with a recommended dose of 40 mg AT-101 and 1.25 mg/m² topotecan.

Although the study did not meet the predefined response rate criteria for further enrollment, many patients experienced stable disease, and the median time to progression was 17.4 weeks for sensitive-relapsed patients and 11.7 weeks for refractory patients, suggesting potential benefits in disease management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II study of AT-101 with topotecan in relapsed and refractory small cell lung cancer. Heist, RS., Fain, J., Chinnasami, B., et al.[2013]

References

1. Greece pubmed.ncbi.nlm.nih.gov

Synergistic anti-leukemic effects of CK2 inhibitors and pentabromobenzylisothioureas in vitro. [2014]

2. Greece pubmed.ncbi.nlm.nih.gov

Hematein, a casein kinase II inhibitor, inhibits lung cancer tumor growth in a murine xenograft model. [2021]

3. Korea (South) pubmed.ncbi.nlm.nih.gov

Druggability of the CK2 inhibitor CX-4945 as an anticancer drug and beyond. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Development of dual casein kinase 1δ/1ε (CK1δ/ε) inhibitors for treatment of breast cancer. [2021]

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

Casein kinase 2 inhibition attenuates androgen receptor function and cell proliferation in prostate cancer cells. [2012]

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. Switzerland pubmed.ncbi.nlm.nih.gov

The Development of BTK Inhibitors: A Five-Year Update. [2022]

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

Design, synthesis, and evaluation of BTK-targeting PROTACs with optimized bioavailability in vitro and in vivo. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Targeting Solid Tumors With BTK Inhibitors. [2021]

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

Phase I/II study of AT-101 with topotecan in relapsed and refractory small cell lung cancer. [2013]