AU2 for Chronic Lymphocytic Leukemia

Not currently recruiting at 2 trial locations

Overseen By Jennifer R Brown, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Jennifer R. Brown, MD, PhD

Must be taking: Anti-pneumocystis, Antiviral

Must not be taking: CYP3A4 inhibitors, Proton pump inhibitors

Disqualifiers: CNS involvement, Cardiac disease, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 1

Duration: 24 cycles (approximately 2 years)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for people with Chronic Lymphocytic Leukemia (CLL). It evaluates the effectiveness of the drugs acalabrutinib (AU2), umbralisib, and ublituximab when used together. Participants are divided into two groups: one for those whose CLL has returned after treatment and another for those who have never been treated. This trial may suit individuals diagnosed with CLL or a similar condition who have noticeable symptoms or measurable disease. As a Phase 2 trial, the research measures how well the treatment works in an initial, smaller group, offering participants a chance to contribute to significant advancements in CLL treatment.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does mention that you cannot take certain medications like strong inhibitors or inducers of CYP3A4 and proton pump inhibitors. It's best to discuss your current medications with the study team to see if any adjustments are needed.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that acalabrutinib is generally well-tolerated by patients with chronic lymphocytic leukemia (CLL). Studies have found it effective and safe, with manageable side effects for most people.

For umbralisib, the situation differs. The FDA has expressed concerns about a possible increased risk of death with this drug. Its use was even halted for some types of lymphoma due to safety issues. While some studies report it is well-tolerated when combined with other drugs, caution is advised.

Ublituximab, when used with umbralisib, demonstrated a good safety record in trials. It showed low rates of serious side effects like diarrhea and liver problems, which are common with similar drugs.

This study is in Phase 2, indicating that earlier stages tested the treatment's safety, and now larger groups are being studied to gather more safety information. Prospective participants should discuss these findings and any concerns with their doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for Chronic Lymphocytic Leukemia (CLL) because they bring innovative approaches to tackling the disease. Acalabrutinib is a next-generation Bruton’s tyrosine kinase (BTK) inhibitor, offering a more targeted attack on cancer cells with potentially fewer side effects than older BTK inhibitors like ibrutinib. Ublituximab, a glycoengineered anti-CD20 monoclonal antibody, and Umbralisib, a dual inhibitor targeting both PI3K-delta and CK1-epsilon, work in synergy to disrupt cancer cell survival pathways. This combination aims to improve treatment effectiveness while minimizing the harsh side effects often seen with traditional chemotherapy.

What evidence suggests that this trial's treatments could be effective for Chronic Lymphocytic Leukemia?

Research has shown that acalabrutinib is very effective in treating Chronic Lymphocytic Leukemia (CLL). In studies, 92% of people taking acalabrutinib with immunotherapy did not experience cancer growth, compared to 47% of those on other treatments. This trial will administer a combination of acalabrutinib and umbralisib, with ublituximab added later in the treatment cycle. The combination of umbralisib and ublituximab, known as U2, has also succeeded in previous studies. This combination has been more effective at treating both new and returning cases of CLL than some other treatments. Overall, these drugs together have a strong track record of controlling CLL with good response rates. ^{1 2 4 6 7}

Who Is on the Research Team?

Jennifer R Brown, MD, PhD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults with Chronic Lymphocytic Leukemia (CLL) who either have relapsed after treatment or haven't been treated before. Participants should be in relatively good health, able to take oral medication, and willing to use effective contraception. Those with more than two prior cancer treatments, recent major surgery, certain blood disorders, active infections like Hepatitis B/C or HIV are excluded.

Inclusion Criteria

My disease has not been treated before.

My heart function is classified as class 2B or better.

I have CLL that has come back or didn't respond to treatment, and I've had 2 or fewer prior treatments.

Exclusion Criteria

Allergic reactions attributed to study drugs or compounds of similar chemical or biologic composition

I am not taking strong drugs that affect liver enzyme CYP3A4.

I do not have active Hepatitis B or C, cytomegalovirus, or HIV.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Acalabrutinib, Umbralisib, and Ublituximab for a maximum of 24 cycles

24 cycles (approximately 2 years)

Visits at cycle 1 day 1, 8, and 15, cycle 2-6 and cycle 8-25 day 1, and cycle 7 day 1, 2 and 8

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Ublituximab
• Umbralisib

Trial Overview The study tests a combination of three drugs: Acalabrutinib (CALQUENCE®), Umbralisib (TGR-1202), and Ublituximab (TG-1101). It aims to determine their effectiveness in treating CLL when used together. The trial includes people who have had previous treatments as well as those who are untreated.

How Is the Trial Designed?

Group I: Cohort 2-Treatment Naive Experimental Treatment 3 Interventions

Participants with previously untreated disease * Treatment with Acalabrutinib \& Umbralisib beginning C1D1, * Ublituximab beginning C7D1 * Assessment of treatment response * Treatment continues for a maximum of 24 cycles. Participants followed post treatment for a maximum of 5 years

Group II: Cohort 1-Relapsed Disease Experimental Treatment 3 Interventions

Participants with relapsed disease * Treatment with Acalabrutinib \& Umbralisib beginning C1D1, * Ublituximab beginning C7D1 * Assessment of treatment response * Treatment continues for a maximum of 24 cycles. Participants followed post treatment for a maximum of 5 years

Acalabrutinib is already approved in United States, European Union for the following indications:

Approved in United States as Calquence for:

• Mantle cell lymphoma
• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma

Approved in European Union as Calquence for:

• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma
• Mantle cell lymphoma

Who Is Running the Clinical Trial?

Jennifer R. Brown, MD, PhD

Lead Sponsor

Trials

3

Recruited

140+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

TG Therapeutics, Inc.

Industry Sponsor

Trials

41

Recruited

6,900+

Published Research Related to This Trial

Acalabrutinib has been approved in the EU for treating both treatment-naïve and relapsed/refractory chronic lymphocytic leukemia (CLL), showing significant improvements in progression-free survival compared to standard therapies in two phase III trials involving adult patients.

The safety profile of acalabrutinib is generally acceptable, with common side effects including headache, diarrhea, and infections, and the overall benefit-risk ratio is considered positive for its use in CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EMA Review of Acalabrutinib for the Treatment of Adult Patients with Chronic Lymphocytic Leukemia. Delgado, J., Josephson, F., Camarero, J., et al.[2021]

Acalabrutinib, a selective Bruton tyrosine kinase inhibitor, showed improved safety outcomes compared to other targeted therapies for treatment-naïve chronic lymphocytic leukemia (CLL) patients, although it was associated with a higher risk of neutropenia and leukopenia in some cases.

The analysis indicated that acalabrutinib (with or without obinutuzumab) had similar efficacy in terms of progression-free survival compared to other treatments, suggesting it is a safe and effective option for CLL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Matching-adjusted indirect comparisons of safety and efficacy of acalabrutinib versus other targeted therapies in patients with treatment-naïve chronic lymphocytic leukemia. Davids, MS., Telford, C., Abhyankar, S., et al.[2021]

In a phase 3 study involving 535 patients with treatment-naive chronic lymphocytic leukaemia, acalabrutinib combined with obinutuzumab or as a monotherapy significantly improved progression-free survival compared to the standard treatment of obinutuzumab with chlorambucil, with median survival not reached for the acalabrutinib groups versus 22.6 months for the chlorambucil group.

The safety profile of acalabrutinib was favorable, with fewer infusion reactions and a lower incidence of grade 3 or higher adverse events compared to the obinutuzumab-chlorambucil group, indicating it is a viable chemotherapy-free treatment option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Sharman, JP., Egyed, M., Jurczak, W., et al.[2021]

In a phase III study involving 310 patients with relapsed/refractory chronic lymphocytic leukemia (CLL), acalabrutinib monotherapy significantly improved progression-free survival (PFS) compared to investigator's choice treatments, with a median PFS not reached for acalabrutinib versus 16.5 months for the comparator group.

Acalabrutinib demonstrated a favorable safety profile, with serious adverse events occurring in 29% of patients, compared to 56% for idelalisib plus rituximab and 26% for bendamustine plus rituximab, indicating it may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. Ghia, P., Pluta, A., Wach, M., et al.[2021]

In a pivotal phase 3 study with 310 patients, acalabrutinib significantly improved progression-free survival (PFS) compared to standard treatments (Idelalisib plus rituximab or bendamustine plus rituximab), with a median PFS not reached for acalabrutinib versus 16.8 months for IdR/BR.

After approximately 4 years of follow-up, acalabrutinib demonstrated a favorable safety profile, with lower rates of treatment discontinuation due to adverse events compared to IdR/BR, while maintaining similar rates of serious infections and other significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib Versus Investigator's Choice in Relapsed/Refractory Chronic Lymphocytic Leukemia: Final ASCEND Trial Results. Ghia, P., Pluta, A., Wach, M., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40736551/

Real-world efficacy and safety outcomes of acalabrutinib in ... NAOS, one of the largest real-world cohorts of acalabrutinib-treated CLL patients in Europe, showed effectiveness and safety consistent with ...

2. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/5151/503709/Real-World-Effectiveness-and-Safety-Outcomes-of

Real-World Effectiveness and Safety Outcomes of ... The 18-month OS rate was 90% and 85% for the 1L and 2L+ cohorts, respectively ( Figure 2). After initiation of acalabrutinib treatment, the ...

3. calquence.com calquence.com/why-calquence/how-effective-calquence-cll.html

How Effective Is CALQUENCE® (acalabrutinib)? | CLL 92% (165 of 179) of people on CALQUENCE + immunotherapy* had no cancer growth or spread compared to 47% (84 of 177) of people on chemoimmunotherapy.†. 80% Down ...

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa1509981

Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic ... At a median follow-up of 14.3 months, the overall response rate was 95%, including 85% with a partial response and 10% with a partial response ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39463596/

Assessment of the Efficacy and Safety of Acalabrutinib in ... Acalabrutinib is an active drug in treating CLL that induces significant clinical benefits concerning response rates and PFS.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04008706

NCT04008706 | Acalabrutinib Safety Study in Untreated ... To evaluate the safety and tolerability of acalabrutinib monotherapy in participants with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia.

7. sciencedirect.com sciencedirect.com/science/article/pii/S2950328024000645

Real-world safety profile of therapy with ibrutinib or ... Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial