Acalabrutinib + Obinutuzumab for Chronic Lymphocytic Leukemia

Recruiting at 10 trial locations

Overseen By Maria L Palomba, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Warfarin, QT prolongation drugs

Disqualifiers: Prior CLL therapy, CNS lymphoma, 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: Unknown

Duration: 26 cycles

55 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will test the safety of limiting treatment time with acalabrutinib and obinutuzumab in people who have chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The researchers want to find out whether stopping the study drugs when the cancer responds to the treatment, followed by a period of observation in which no treatment is given, is better than, the same as, or worse than the usual approach. A usual treatment for CLL and SLL is to give the study drugs continuously until the cancer progresses, even if the disease is in remission. But when people receive these drugs for long periods of time, they can have serious side effects and their cancer can become resistant to treatment.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that certain medications, like warfarin or those causing QT prolongation, should be used with caution or are not allowed. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Acalabrutinib plus Obinutuzumab for Chronic Lymphocytic Leukemia?

Research shows that Acalabrutinib, when used with Obinutuzumab, is effective in treating chronic lymphocytic leukemia (CLL). In studies, this combination led to high response rates and longer periods without disease progression compared to some other treatments, and it was generally well-tolerated by patients. ^{1 2 3 4 5}

Is the combination of Acalabrutinib and Obinutuzumab safe for treating chronic lymphocytic leukemia?

The combination of Acalabrutinib and Obinutuzumab is generally considered safe for treating chronic lymphocytic leukemia, with common side effects including headache, diarrhea, and infections. However, there is an increased risk of neutropenia (low white blood cell count) and infusion-related reactions, which are usually manageable. ^{3 4 5 6 7}

What makes the drug combination of Acalabrutinib and Obinutuzumab unique for treating chronic lymphocytic leukemia?

The combination of Acalabrutinib and Obinutuzumab is unique because Acalabrutinib is a highly selective Bruton tyrosine kinase inhibitor, which means it specifically targets a protein important for cancer cell survival, while Obinutuzumab is an antibody that enhances the immune system's ability to attack cancer cells. This combination has shown to be effective and well-tolerated, providing durable responses in patients with chronic lymphocytic leukemia. ^{1 3 4 5 8}

Research Team

Meghan Thompson, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for adults with untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who need treatment. Participants must be able to follow the study plan, have normal organ function, and if of childbearing potential, agree to use effective contraception. People can't join if they've had prior CLL therapy, bleeding disorders, severe heart conditions, recent major surgery or infections requiring hospitalization within 2 weeks before starting the study.

Inclusion Criteria

You must use a highly effective method of birth control, such as a tubal ligation, vasectomy, birth control pills that prevent ovulation, hormonal intrauterine devices, or copper intrauterine devices.

Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L.

My bilirubin levels are within normal limits, or I have a condition that explains higher levels.

Exclusion Criteria

I do not have active bleeding or a bleeding disorder like von Willebrand's disease or hemophilia.

You have taken any experimental medication within the last month, or within five half-lives of the medication, whichever is shorter.

I have received treatment for CLL before, not counting steroids for other reasons.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive acalabrutinib for a minimum of 13 cycles and maximum 26 cycles, with Obinutuzumab administered during Cycles 2-7

26 cycles

Observation

Participants undergo a treatment-free observation period through the 65th cycle

39 cycles

Retreatment

Participants who progress during the observation period receive 13 cycles of acalabrutinib in combination with obinutuzumab

13 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

36 months

Treatment Details

Interventions

• Acalabrutinib
• Obinutuzumab

Trial Overview The trial tests whether stopping acalabrutinib and obinutuzumab when cancer responds—followed by a watchful waiting period—is as effective as continuous treatment until disease progression. This approach aims to reduce long-term side effects and prevent resistance to treatment.

Participant Groups

Group I: Acalabrutinib Combined With Obinutuzumab Experimental Treatment 2 Interventions

Patients will receive acalabrutinib for a minimum of 13 cycles and maximum 26 cycles and Obinutuzumab will be administered during Cycles 2-7. This will be followed by treatment-free observation through the 65th cycle. Patients who progress during the observation period, per iwCLL criteria, will receive 13 cycles of acalabrutinib in combination with obinutuzumab in the retreatment phase of this study.

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?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

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

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Findings from Research

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]

Obinutuzumab, in combination with chlorambucil, significantly improved progression-free survival (PFS) in patients with previously untreated chronic lymphocytic leukemia (CLL), with a median PFS of 23.0 months compared to 11.1 months for chlorambucil alone.

The treatment also resulted in a higher overall response rate (ORR) of 75.9% for the obinutuzumab group versus 32.1% for the chlorambucil group, indicating its efficacy in treating CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

U.S. Food and drug administration approval: obinutuzumab in combination with chlorambucil for the treatment of previously untreated chronic lymphocytic leukemia. Lee, HZ., Miller, BW., Kwitkowski, VE., et al.[2022]

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 Ib/II study involving 45 patients with chronic lymphocytic leukemia (CLL), the combination of acalabrutinib and obinutuzumab resulted in high overall response rates of 95% for treatment-naïve patients and 92% for relapsed/refractory patients, demonstrating strong efficacy.

The treatment was well tolerated, with 94% of treatment-naïve and 88% of relapsed/refractory patients remaining progression-free at 36 months, indicating that this combination therapy could provide durable responses in CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib plus Obinutuzumab in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia. Woyach, JA., Blachly, JS., Rogers, KA., et al.[2022]

Obinutuzumab combined with chlorambucil shows better treatment outcomes for patients with untreated chronic lymphocytic leukemia compared to rituximab plus chlorambucil, while maintaining a similar safety profile.

Infusion-related reactions (IRRs) are more common with obinutuzumab, particularly during the first infusion, but these reactions are generally manageable with proper monitoring and management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing Infusion-Related Reactions for Patients With Chronic Lymphocytic Leukemia Receiving Obinutuzumab. Dawson, K., Moran, M., Guindon, K., et al.[2017]

In a multinational phase III study, obinutuzumab combined with chlorambucil significantly improved progression-free survival and event-free survival in adults with previously untreated chronic lymphocytic leukaemia (CLL) compared to chlorambucil alone and rituximab plus chlorambucil.

Obinutuzumab plus chlorambucil had a manageable safety profile, with neutropenia and infusion-related reactions being the most common serious side effects, primarily occurring during the first infusion and generally manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab: a review of its use in patients with chronic lymphocytic leukaemia. Hoy, SM.[2018]

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]

References

1. England 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. [2021]

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

U.S. Food and drug administration approval: obinutuzumab in combination with chlorambucil for the treatment of previously untreated chronic lymphocytic leukemia. [2022]

3. England pubmed.ncbi.nlm.nih.gov

EMA Review of Acalabrutinib for the Treatment of Adult Patients with Chronic Lymphocytic Leukemia. [2021]

4. United States 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. [2021]

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

Acalabrutinib plus Obinutuzumab in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia. [2022]

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

Managing Infusion-Related Reactions for Patients With Chronic Lymphocytic Leukemia Receiving Obinutuzumab. [2017]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Obinutuzumab: a review of its use in patients with chronic lymphocytic leukaemia. [2018]

8. United States 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. [2021]