AC676 for B-Cell Malignancies

Recruiting at8 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Accutar Biotechnology Inc

Must not be taking: Small molecule, Biologics

Disqualifiers: CNS lymphoma, Active bleeding, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial is testing a new oral drug, AC676, in patients with blood cancers that have returned or are resistant to treatment. The drug aims to stop cancer cells from growing by targeting and destroying a specific protein they need.

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.

What data supports the effectiveness of the drug AC676 for B-cell malignancies?

The research highlights that new chemotherapy agents like fludarabine have shown significant response rates in treating chronic lymphocytic leukemia (CLL), a type of B-cell malignancy, with over 50% response in previously treated patients. Additionally, anti-CD20 monoclonal antibodies like rituximab have improved treatment outcomes in B-cell cancers, suggesting that similar mechanisms could support the effectiveness of AC676. ^{1 2 3 4 5}

What safety information is available for AC676 (acalabrutinib) in humans?

Acalabrutinib, also known as AC676, has been found to be generally safe in humans, with most side effects being mild to moderate, such as headache and diarrhea. Serious side effects can include infections, high blood pressure, and heart issues, but these are less common. ^{6 7 8 9 10}

What makes the drug AC676 unique for treating B-cell malignancies?

The drug AC676 is unique because it targets epigenetic modifications, specifically inhibiting the enzyme HDAC6, which is involved in the progression of B-cell malignancies. This approach is different from traditional treatments as it disrupts B-cell receptor signaling and enhances the effectiveness of other therapies, like ibrutinib, by making cancer cells more sensitive to treatment. ^{11 12 13 14 15}

Research Team

Eligibility Criteria

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 am an adult, 18 years or older, and can sign the consent form.

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.

Trial Timeline

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

Treatment Details

Interventions

• AC676 (Other)

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

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

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

Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience. [2021]

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

New Pharmacotherapies in Chronic Lymphocytic Leukemia. [2020]

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

So FCR, so good. [2021]

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

Evolution of anti-CD20 monoclonal antibody therapeutics in oncology. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Acalabrutinib and its use in the treatment of chronic lymphocytic leukemia. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

Acadesine for patients with relapsed/refractory chronic lymphocytic leukemia (CLL): a multicenter phase I/II study. [2021]

8. Switzerland 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. [2023]

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

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

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

Acalabrutinib in treatment-naive chronic lymphocytic leukemia. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphoma. [2018]

12. England pubmed.ncbi.nlm.nih.gov

BCL6 expression correlates with the t(1;19) translocation in B-lymphoblastic leukemia. [2016]

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

Silencing of HDAC6 as a therapeutic target in chronic lymphocytic leukemia. [2021]

14. India pubmed.ncbi.nlm.nih.gov

Cluster of Differentiation 96 in Children with Acute Leukemia: A Single Center Cohort Study. [2021]

15. Greece pubmed.ncbi.nlm.nih.gov

Knockdown of B7-H6 inhibits tumor progression and enhances chemosensitivity in B-cell non-Hodgkin lymphoma. [2022]