Acalabrutinib + Obinutuzumab for Non-Hodgkin's Lymphoma

Overseen By Jonathon Cohen, MD, MS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Emory University

Must not be taking: CYP3A4 inhibitors, Proton pump inhibitors

Disqualifiers: High-grade lymphoma, CNS 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: 12

49 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of combining two treatments, acalabrutinib (a targeted therapy) and obinutuzumab (an antibody therapy), for certain types of non-Hodgkin's lymphoma, including follicular lymphoma and other slow-growing forms. Acalabrutinib may inhibit cancer cell growth, while obinutuzumab might enhance the immune system's ability to attack cancer cells. The goal is to determine if this combination can effectively kill more cancer cells. The trial seeks participants diagnosed with specific types of non-Hodgkin's lymphoma who have not yet received treatment. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take certain medications like strong CYP3A4 inhibitors/inducers, warfarin, or proton pump inhibitors. If you are on proton pump inhibitors, you may switch to H2-receptor antagonists or antacids to participate.

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

Research has shown that the combination of acalabrutinib and obinutuzumab has been tested for safety in other studies. Acalabrutinib is generally well-tolerated. For example, in one study with a follow-up period of 42 months, 89% of patients continued using acalabrutinib, and only 5% stopped due to side effects like other cancers or infections.

Obinutuzumab, used as a type of immunotherapy, can cause side effects, but these are usually manageable. It works with the body's immune system to fight cancer, which can sometimes cause reactions. However, researchers typically monitor and treat these reactions during the study.

Overall, previous research suggests that both acalabrutinib and obinutuzumab are generally well-tolerated by patients. Safety data from earlier studies provide a good idea of what to expect. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of acalabrutinib and obinutuzumab for treating Non-Hodgkin's Lymphoma because it offers a fresh approach compared to standard treatments like R-CHOP or bendamustine plus rituximab. Acalabrutinib is a next-generation Bruton's tyrosine kinase (BTK) inhibitor, which specifically targets and blocks signals that help cancer cells grow. Obinutuzumab, on the other hand, is a monoclonal antibody that binds to cancer cells, marking them for destruction by the immune system. This dual-action strategy could potentially lead to more effective cancer cell eradication, offering hope for better outcomes in patients who have limited options.

What evidence suggests that acalabrutinib and obinutuzumab might be effective for non-Hodgkin's lymphoma?

Research has shown that using acalabrutinib and obinutuzumab together, as studied in this trial, may help treat non-Hodgkin's lymphoma. In earlier studies, acalabrutinib reduced the risk of disease progression by 27% compared to standard treatments for some types of lymphoma. Obinutuzumab, a type of immunotherapy, enhances the immune system's ability to attack cancer cells. Together, these treatments might more effectively stop cancer from growing and spreading. Although specific data for non-Hodgkin's lymphoma is limited, success in similar conditions suggests potential benefits. ^{1 5 6 7 8}

Who Is on the Research Team?

Jonathon B Cohen, MD, MS

Principal Investigator

Emory University

Are You a Good Fit for This Trial?

This trial is for adults with untreated follicular lymphoma or other indolent non-Hodgkin lymphomas. Participants must be willing to use contraception, have no active high-grade cancers, and not require certain medications that could interfere with the study drugs. They should not have major health issues like uncontrolled autoimmune diseases, significant infections within 14 days before starting the trial, or a history of severe allergic reactions to similar drugs.

Inclusion Criteria

You have certain types of untreated slow-growing lymphomas.

Willing and able to participate in all required evaluations and procedures in this study protocol

Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information

Exclusion Criteria

You have had cancer that needed ongoing treatment, unless there are specific exceptions.

You have uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP).

Major surgical procedure within 28 days of first dose of study drug

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive acalabrutinib orally twice daily and obinutuzumab intravenously. Treatments repeat every 28 days for up to 12 cycles.

48 weeks

Multiple visits per cycle for drug administration

Follow-up

After cycle 12, patients are monitored for safety and effectiveness. Patients in complete response may discontinue or continue acalabrutinib. Follow-up includes regular assessments.

1 year

Every 12 weeks for 1 year, then every 6 months

Long-term Follow-up

Patients are monitored every 6 months until disease progression or next anti-lymphoma treatment.

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Obinutuzumab

Trial Overview The trial is testing acalabrutinib combined with obinutuzumab in patients who haven't been treated before for their lymphoma. Acalabrutinib targets enzymes needed by cancer cells to grow while obinutuzumab works by helping the immune system affect cancer cell growth and spread.

How Is the Trial Designed?

Group I: Treatment (acalabrutinib, obinutuzumab) Experimental Treatment 4 Interventions

INDUCTION PHASE: Patients receive acalabrutinib PO BID on days 1-28. Patients also receive obinutuzumab IV on days 1, 8, and 15 of cycle 3, then on day 1 of cycles 4-8. Treatments repeat every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. FOLLOW-UP PHASE: After cycle 12, patients who are in CR are randomized to either discontinue acalabrutinib or to continue acalabrutinib monotherapy in the absence of disease progression or unacceptable toxicity. Patients with PR or SD after cycle 12 continue acalabrutinib monotherapy in the absence of disease progression or unacceptable toxicity. Patients with disease progression after cycle 12 discontinue study treatment. Patients with disease progression at any time prior to the conclusion of cycle 12 may continue study therapy if they are felt to be benefiting by the treating physician, but not past cycle 12.

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?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

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

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study involving 573 patients with B-cell malignancies, acalabrutinib showed no significant relationship between its systemic exposure levels and the efficacy outcomes, such as progression-free survival or tumor regression.

The findings support the use of a fixed dose of 100 mg twice daily for acalabrutinib, as pharmacokinetic exposure did not correlate with safety outcomes, indicating consistent safety across different patient responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure-response analysis of acalabrutinib and its active metabolite, ACP-5862, in patients with B-cell malignancies. Edlund, H., Buil-Bruna, N., Vishwanathan, K., et al.[2022]

Obinutuzumab is an effective treatment for chronic lymphocytic leukemia (CLL) and rituximab-refractory follicular lymphoma (FL), showing promise in combination with both chemotherapy and novel targeted therapies.

Future treatment strategies are likely to focus on chemotherapy-free regimens using obinutuzumab, aiming to enhance efficacy and improve patient safety through innovative combinations with other therapeutic agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination therapy with the type II anti-CD20 antibody obinutuzumab. Klein, C., Bacac, M., Umana, P., et al.[2017]

In a phase II study involving 217 patients with relapsed/refractory follicular lymphoma, the combination of zanubrutinib and obinutuzumab (ZO) showed a significantly higher overall response rate (ORR) of 69% compared to 46% for obinutuzumab alone, indicating greater efficacy.

The safety profile of ZO was manageable, with common side effects including thrombocytopenia and neutropenia, and serious adverse events like atrial fibrillation occurring in only 3% of patients, suggesting that ZO could be a promising treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ROSEWOOD: A Phase II Randomized Study of Zanubrutinib Plus Obinutuzumab Versus Obinutuzumab Monotherapy in Patients With Relapsed or Refractory Follicular Lymphoma. Zinzani, PL., Mayer, J., Flowers, CR., et al.[2023]

Obinutuzumab, combined with bendamustine, significantly prolonged progression-free survival (PFS) in patients with indolent non-Hodgkin's lymphoma, particularly benefiting those with follicular lymphoma, as shown in the phase III GADOLIN study.

The treatment was generally well-tolerated, with mild to moderate infusion-related reactions being the most common side effects, while neutropenia was the most frequent severe adverse event, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab: A Review in Rituximab-Refractory or -Relapsed Follicular Lymphoma. Dhillon, S.[2018]

In a study of 56 patients with relapsed/refractory follicular lymphoma, obinutuzumab combined with chemotherapy (either G-CHOP or G-FC) resulted in high response rates of 93% to 96%, indicating strong efficacy for this treatment approach.

The safety profile was acceptable, with most adverse events being mild infusion-related reactions; however, G-FC was associated with more adverse events compared to G-CHOP, suggesting that while both regimens are effective, G-CHOP may be better tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000). Radford, J., Davies, A., Cartron, G., et al.[2022]

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 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]

Acalabrutinib maleate tablets (AT) show comparable pharmacokinetics to the original acalabrutinib capsules (AC), making them a viable alternative for patients, especially since AT can be taken with food or proton-pump inhibitors (PPIs) without affecting drug absorption.

The safety profile of acalabrutinib remains favorable, with most adverse events being mild and no new safety concerns identified, indicating that AT is a safe option for treating chronic lymphocytic leukemia and other related conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioequivalence and Relative Bioavailability Studies to Assess a New Acalabrutinib Formulation That Enables Coadministration With Proton-Pump Inhibitors. Sharma, S., Pepin, X., Burri, H., et al.[2023]

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 2 trial involving 124 patients with relapsed or refractory mantle cell lymphoma, acalabrutinib was associated with common treatment-related adverse events (AEs) like headache and diarrhea, but these did not lead to any treatment discontinuations.

Effective management strategies, including patient education and the use of over-the-counter medications for mild AEs, helped maintain treatment adherence and allowed for better tracking and management of nonadherence issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib: Managing Adverse Events and Improving Adherence in Patients With Mantle Cell Lymphoma. Badillo, M., Nava, D., Rosa, M., et al.[2022]

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]

The combination of obinutuzumab and atezolizumab was found to be safe and tolerable in a phase 1b study involving 49 patients with relapsed/refractory follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), with no new toxicities reported.

The treatment showed preliminary efficacy, achieving a 54% objective response rate in the FL cohort and a 17% response rate in the DLBCL cohort, with median progression-free survival of 9 months for FL and 3 months for DLBCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of Atezolizumab and Obinutuzumab in Patients with Relapsed/Refractory Follicular Lymphoma and Diffuse Large B-Cell Lymphoma: Results from a Phase 1b Study. Palomba, ML., Till, BG., Park, SI., et al.[2022]

Obinutuzumab is an effective treatment for B-cell malignancies, specifically approved in the US for chronic lymphocytic leukaemia (CLL) in combination with chlorambucil, showcasing its efficacy in targeting cancer cells.

Utilizing GlycoMAb® technology, obinutuzumab enhances immune-mediated cell death through increased antibody-dependent cellular cytotoxicity, making it a promising option in ongoing phase III trials for various B-cell lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab: first global approval. Cameron, F., McCormack, PL.[2021]

Citations

1. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2024/calquence-acalabrutinib-plus-chemoimmunotherapy-reduced-the-risk-of-disease-progression-or-death-by-27-percentage-vs-standard-of-care-in-patients-with-untreated-mantle-cell-lymphoma-in-echo-phase-iii-trial.html

CALQUENCE® (acalabrutinib) plus chemoimmunotherapy ... Results showed the CALQUENCE combination regimen reduced the risk of disease progression or death by 27% compared to standard-of-care chemoimmunotherapy.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6777435/

Evaluating Acalabrutinib In The Treatment Of Mantle Cell ... The median duration of response was 17.5 months with PFS and OS rates of 31% and 47%, respectively, at 2 years and are the highest reported for a single agent ...

3. ashpublications.org ashpublications.org/blood/article/134/Supplement_1/5261/425144/Clinical-Outcomes-of-Non-Hodgkin-Lymphoma-Patients

Clinical Outcomes of Non-Hodgkin Lymphoma Patients on ... The majority (65%) of pts received acala 100 mg twice daily, with the rest of the patients receiving 100 mg once daily. The median time to best ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO-24-02503

Phase II Study of Acalabrutinib, Venetoclax, and ... AVO was highly active and well tolerated in patients with previously untreated high-risk CLL, supporting its use as a new standard-of-care ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118631878

Clinical Outcomes of Non-Hodgkin Lymphoma Patients on ... Results: We identified 23 pts treated with acala at our institution. The cohort consisted of 83% males (n=19). Diagnoses were chronic ...

6. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/7744/528340/Real-World-Effectiveness-and-Safety-Outcomes-of

Real-World Effectiveness and Safety Outcomes of ... Results: Among 181 pts with MCL treated with acala, 127 were treated in the R/R setting (study cohort) (acala monotherapy: 94 pts; combination ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8162209/

Acalabrutinib: A Selective Bruton Tyrosine Kinase Inhibitor for ... After 42 months of follow-up (range, 1–48 months), 89% of patients remained on acalabrutinib. Discontinuations were due to AEs (5%: second malignancies, sepsis, ...

8. ema.europa.eu ema.europa.eu/en/documents/variation-report/calquence-h-c-005299-ii-0028-epar-assessment-report-variation_en.pdf

Calquence- INN; Acalabrutinib - European Medicines Agency The AMPLIFY study (also referred to as ACE-CL-311) was designed to assess the efficacy and safety of a fixed-duration therapy of acalabrutinib ...