AC676 for B-Cell Malignancies

Recruiting at 10 trial locations

Overseen By Accutar Biotechnology

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Accutar Biotechnology Inc

Must not be taking: Small molecule, Biologics

Disqualifiers: CNS lymphoma, Active bleeding, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug, AC676, for individuals with certain types of B-cell blood cancers that have returned or do not respond to treatment. The study aims to determine the safest dose, understand the drug's behavior in the body, and evaluate its effectiveness. It suits those who have undergone at least two previous treatments for B-cell cancers like Chronic Lymphocytic Leukemia (CLL) or Mantle Cell Lymphoma (MCL) without relief from standard therapies. Participants will receive their assigned dose in a 28-day cycle. As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its effects in people.

Will I have to stop taking my current medications?

The trial requires stopping certain medications before participating. You must stop small molecule anti-cancer drugs at least 5 half-lives or 2 days before, systemic chemotherapy and radiation therapy 14 days before, biologics 28 days before, and radioimmunoconjugates 12 weeks before. Prior CAR T cell therapy and stem cell transplants also have specific time restrictions.

Is there any evidence suggesting that AC676 is likely to be safe for humans?

Research has shown that AC676 is an experimental drug tested for safety in people with certain blood cancers called B-cell malignancies. AC676 breaks down a protein called Bruton tyrosine kinase, which cancer cells need to survive.

As this is an early-stage clinical trial, detailed safety information remains limited. The study's main goal is to find a safe dose and understand how the body processes the drug. Researchers closely monitor participants' reactions to the treatment and any side effects.

Early trials like this emphasize safety, so any serious side effects are carefully recorded and addressed. For those considering participation, it may be reassuring to know that safety is a top priority in these trials. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard care options for B-cell malignancies, which often include chemotherapy, targeted therapies, or immunotherapy, AC676 is unique because it introduces a new mechanism of action. AC676 specifically targets and inhibits a critical protein involved in the survival and proliferation of malignant B-cells, potentially offering a more direct approach to halting cancer growth. Researchers are excited about AC676 because it may offer a more precise treatment with fewer side effects compared to traditional therapies, improving the quality of life for patients with B-cell malignancies.

What evidence suggests that AC676 might be an effective treatment for B-cell malignancies?

Research has shown that AC676 targets a protein called Bruton tyrosine kinase (BTK), crucial for the survival of certain blood cells. This makes AC676 a promising option for treating some blood cancers. Studies have found that BTK degraders, like AC676, might be effective for patients who have already tried other treatments. Early results suggest that AC676 could help manage blood cancers that have returned or are not responding to other treatments. Although more research is needed, the mechanism of AC676 offers hope for people dealing with these challenging cancers. ^{4 5 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults with certain types of B-cell malignancies that have come back or didn't respond to treatment. They must have tried at least two treatments already, or be unable to use standard therapies. People can't join if they've had recent cancer treatments, stem cell transplants, CAR-T therapy (for DLBCL patients), active bleeding issues, or are within a specific timeframe after receiving other specific therapies.

Inclusion Criteria

My cancer is one of the specified types and has come back or didn't respond to treatment.

I have undergone at least 2 treatments or cannot take standard treatments according to my doctor.

Exclusion Criteria

Medical history of active bleeding within 2 months prior to study entry or susceptible to bleeding by the judgement of investigator

My CNS lymphoma/leukemia has been in remission for less than 2 years.

I haven't taken any cancer drugs within the last 2 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive an assigned dose of AC676 in a 28-day cycle

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• AC676

Trial Overview

The study tests AC676 in participants with relapsed/refractory B-cell malignancies. It aims to find the safest dose, understand side effects and how the body processes the drug (pharmacokinetics), and assess its effectiveness against these blood cancers.

How Is the Trial Designed?

Group I: AC676 Dose Escalation Experimental Treatment 1 Intervention

Participants will receive an assigned dose of AC676 in a 28-days cycle.

Who Is Running the Clinical Trial?

Accutar Biotechnology Inc

Lead Sponsor

Trials

6

Recruited

180+

Published Research Related to This Trial

Acalabrutinib demonstrated a high overall response rate of 97% in treatment-naive patients with chronic lymphocytic leukemia (CLL), with a median follow-up of 53 months, indicating its strong efficacy as a monotherapy.

The treatment was generally safe, with serious adverse events reported in 38% of patients, but only 6% discontinued due to adverse effects, suggesting that acalabrutinib can be a durable and manageable option for patients with CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib in treatment-naive chronic lymphocytic leukemia. Byrd, JC., Woyach, JA., Furman, RR., et al.[2022]

The study reviews the clinical outcomes of newly approved drugs for chronic lymphocytic leukemia (CLL), indicating their effectiveness in treating this condition.

It also discusses promising investigational therapies that may offer new treatment options for patients with CLL in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Pharmacotherapies in Chronic Lymphocytic Leukemia. Olin, JL., Canupp, K., Smith, MB.[2020]

In a study of 178 patients with chronic lymphocytic leukemia (CLL) who discontinued B-cell receptor kinase inhibitor (KI) therapy, the most common reason for discontinuation was toxicity (51%), followed by disease progression (29%).

Patients who stopped KI therapy due to toxicity had a 50% overall response rate to subsequent salvage therapy with an alternate KI, indicating that these patients can still achieve durable responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience. Mato, AR., Nabhan, C., Barr, PM., et al.[2021]

In a study of 52 B-lymphoblastic leukemia cases, 12% showed BCL6 protein expression, particularly in those with the t(1;19) translocation, indicating a potential link between BCL6 and this specific genetic alteration.

The findings suggest that testing for TCF3(E2A)-PBX1 rearrangements could be beneficial in identifying BCL6-positive B-lymphoblastic leukemia, which may help in understanding the disease's biology and guiding treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BCL6 expression correlates with the t(1;19) translocation in B-lymphoblastic leukemia. Deucher, AM., Qi, Z., Yu, J., et al.[2016]

Histone deacetylase 6 (HDAC6) is found to be upregulated in chronic lymphocytic leukemia (CLL) patients and targeting it with the inhibitor ACY738 shows promising therapeutic effects, including reduced proliferation of CLL B cells and delayed disease onset in preclinical models.

Combining ACY738 with ibrutinib enhances the effectiveness of treatment, leading to improved survival rates in CLL models, suggesting that HDAC6 inhibitors could be a valuable addition to current CLL therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Silencing of HDAC6 as a therapeutic target in chronic lymphocytic leukemia. Maharaj, K., Powers, JJ., Achille, A., et al.[2021]

B7-H6 is highly expressed in B-cell lymphomas, and its downregulation significantly inhibits tumor growth, migration, and invasion, suggesting it plays a crucial role in lymphoma progression.

Silencing B7-H6 not only increases apoptosis in lymphoma cells but also enhances their sensitivity to chemotherapy drugs like vincristine and dexamethasone, indicating its potential as a therapeutic target in treating B-cell lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Knockdown of B7-H6 inhibits tumor progression and enhances chemosensitivity in B-cell non-Hodgkin lymphoma. Wu, F., Wang, J., Ke, X.[2022]

Acadesine was found to have a manageable safety profile in a phase I/II study involving 24 CLL patients, with a maximum tolerated dose of 210 mg/kg established, indicating it can be safely administered at this level.

While trends of efficacy were observed, such as reductions in CLL cells and lymphadenopathy, the variability in results suggests further investigation is needed to confirm its effectiveness as a treatment for relapsed/refractory CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acadesine for patients with relapsed/refractory chronic lymphocytic leukemia (CLL): a multicenter phase I/II study. Van Den Neste, E., Cazin, B., Janssens, A., et al.[2021]

Rituximab, an anti-CD20 chimeric monoclonal antibody, has significantly improved treatment outcomes for patients with B cell malignancies, but some patients still experience resistance to this therapy.

Next-generation anti-CD20 monoclonal antibodies are being explored to enhance treatment efficacy by targeting the mechanisms of action of rituximab, with ongoing clinical trials needed to determine their effectiveness in overcoming resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evolution of anti-CD20 monoclonal antibody therapeutics in oncology. Oflazoglu, E., Audoly, LP.[2023]

In a study of 133 diffuse large B-cell lymphoma (DLBCL) cases, BCL6 translocations were found in 18.8% of cases, with higher frequencies in the primary mediastinal (33%) and activated B-cell-like (24%) subgroups compared to the germinal center B-cell-like subgroup (10%).

BCL6 mutations were present in 61% of DLBCL cases, significantly more common in the germinal center and primary mediastinal subgroups (>70%) than in the activated B-cell-like subgroup (44%), and higher BCL6 expression was associated with better overall survival for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphoma. Iqbal, J., Greiner, TC., Patel, K., et al.[2018]

Acalabrutinib, a Bruton's tyrosine kinase inhibitor, has been shown to be effective and safe for treating chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), with significant improvements in efficacy observed in both monotherapy and combination treatments.

In clinical studies, acalabrutinib demonstrated a high rate of molecular remission when combined with venetoclax, while maintaining an acceptable safety profile, although some adverse events occurred in over 20% of patients, including myelosuppression and gastrointestinal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib and its use in the treatment of chronic lymphocytic leukemia. Egyed, M., Lueff, S., Borbely, J., et al.[2022]

In a study of 96 children with acute leukemia, CD96 expression was found to be significantly higher in leukemia patients compared to healthy controls, indicating its potential as a reliable diagnostic marker for acute leukemia, especially acute myeloid leukemia (AML).

The study also revealed that higher levels of CD96 were associated with poorer treatment response, as patients with non-complete remission had significantly higher CD96 levels compared to those who achieved complete remission, suggesting its potential use as a prognostic marker.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cluster of Differentiation 96 in Children with Acute Leukemia: A Single Center Cohort Study. Mohammad, H., Wahba, Y., Gouida, M., et al.[2021]

Acalabrutinib, a selective BTK inhibitor, has shown improved progression-free survival in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) compared to standard treatments, indicating its efficacy as a treatment option.

The safety profile of acalabrutinib is favorable, with most side effects being mild (grade 1/2), such as headache and diarrhea, and a low rate of treatment discontinuation due to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib: A Selective Bruton Tyrosine Kinase Inhibitor for the Treatment of B-Cell Malignancies. Abbas, HA., Wierda, WG.[2023]

Bruton's tyrosine kinase (BTK) inhibitors, such as ibrutinib, acalabrutinib, and zanubrutinib, have shown excellent efficacy in treating non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), marking a significant advancement in treatment options over the past two decades.

While BTK inhibitors are generally better tolerated than traditional chemoimmunotherapy, they come with specific safety concerns, including risks of rash, diarrhea, and cardiovascular events, necessitating careful long-term monitoring and management to ensure patient quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How We Manage Patients with Indolent B-Cell Malignancies on Bruton's Tyrosine Kinase Inhibitors: Practical Considerations for Nurses and Pharmacists. Nixon, S., Duquette, D., Doucette, S., et al.[2023]

New chemotherapy agents like fludarabine and DCF have shown promising response rates in chronic lymphocytic leukemia (CLL) patients, with fludarabine achieving over 50% response in previously treated patients and over 70% in untreated patients.

Ongoing clinical trials are exploring combinations of these new agents with standard treatments, adhering to strict guidelines to ensure safety and efficacy, with plans for a phase III trial to compare the best new regimens against standard chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current approaches to the chemotherapy of B-cell chronic lymphocytic leukemia: a review. Cheson, BD.[2019]

Predictive biomarkers can identify a subgroup of patients with chronic lymphocytic leukemia (CLL) who respond exceptionally well to the front-line therapy of fludarabine, cyclophosphamide, and rituximab (FCR).

This finding suggests that using these biomarkers could help tailor treatment plans for CLL patients, potentially improving outcomes by identifying those who are likely to benefit the most from FCR therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

So FCR, so good. Dearden, C.[2021]

Citations

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IBCL-147 AC676, an Orally Bioavailable BTK Chimeric ...

Study background: Bruton tyrosine kinase (BTK) is a key signaling molecule that plays a central role in B-cell receptor transduction.

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IBCL-147 AC676, an Orally Bioavailable BTK Chimeric ...

AC676-001 is a phase 1 dose-escalation study of AC676 administered orally once daily as monotherapy in patients with relapsed/refractory B-cell malignancies.

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onclive.com

onclive.com/view/btk-degraders-look-to-fill-unmet-need-for-patients-with-pretreated-b-cell-malignancies

BTK Degraders Look to Fill Unmet Need for Patients With ...

A promising direction for BTK degraders appears to be in the treatment of patients with previously treated B-cell malignancies.

4.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11817010/

A Review of BTK-Degrader Drug Development, Clinical Data ...

Notably, higher rates of cytokine release syndrome (85%) and neurotoxicity (45%) were reported compared with patients with large B cell lymphoma receiving the ...

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withpower.com

withpower.com/trial/phase-1-neoplasms-3-2023-69948

AC676 for B-Cell Malignancies

The study reviews the clinical outcomes of newly approved drugs for chronic lymphocytic leukemia (CLL), indicating their effectiveness in treating this ...

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clinicaltrials.gov

clinicaltrials.gov/study/NCT05780034

NCT05780034 | A Study of AC676 for the Treatment ...

AC676 is an investigational medicinal product that is an orally bioavailable BTK degrader for the treatment of B-cell malignancies. Official Title. A Phase I ...

7.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/39941922/?utm_source=FeedFetcher&utm_medium=rss&utm_campaign=None&utm_content=1x9bY_ZPGMIcWPrw0p3mx7r52T1x_jeUgpmmwcedlWKv4e7E7t&fc=None&ff=20250213234712&v=2.18.0.post9+e462414

A Review of BTK-Degrader Drug Development, Clinical ...

We focus on four agents which are under investigation in B-cell malignancies in early clinical trials: BGB-16673, NX-2127, NX-5948, and AC676.

8.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S0006497124091249

A Phase 1 Study of AC676, a Novel BTK Chimeric ...

AC676-001 is a Phase 1 dose-escalation study of AC676 administered orally once daily as monotherapy in patients with relapsed and refractory B-cell ...