Acalabrutinib + Obinutuzumab for Chronic Lymphocytic Leukemia
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: M.D. Anderson Cancer Center
Must not be taking: Warfarin, Vitamin K antagonists
Disqualifiers: Pregnancy, HIV, Hepatitis B/C, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This phase II trial investigates the how well acalabrutinib and obinutuzumab work in treating patients with chronic lymphocytic leukemia (CLL). Acalabrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with obinutuzumab may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving acalabrutinib and obinutuzumab may help to control disease progression in CLL patients who have not received treatment for CLL.
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 warfarin (a blood thinner) and must switch to a different type of blood thinner if needed. Also, you cannot use strong CYP3A4 inhibitors/inducers (types of drugs that affect how your body processes medications).
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, with high response rates and a significant number of patients remaining free from disease progression after 36 months. This combination has been shown to be well-tolerated and provides durable responses in both newly diagnosed and previously treated patients.
12345Is the combination of Acalabrutinib and Obinutuzumab safe for treating chronic lymphocytic leukemia?
The combination of Acalabrutinib and Obinutuzumab has been shown to be generally safe for treating chronic lymphocytic leukemia, with common side effects including headache, diarrhea, neutropenia (low white blood cell count), nausea, and infections. Infusion-related reactions are more common with Obinutuzumab, but these are usually mild to moderate and manageable. Overall, the safety profile is considered acceptable.
12567What 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 well-tolerated and effective, providing durable responses in patients with chronic lymphocytic leukemia, both in those who are newly diagnosed and those whose disease has returned.
12458Eligibility Criteria
This trial is for patients with chronic lymphocytic leukemia (CLL) who haven't been treated before. They should have a creatinine clearance over 30 mL/min, normal liver function tests, and no prior malignancies within the last 2 years except certain skin cancers or 'in situ' carcinomas. Participants must be willing to use effective birth control and not be pregnant or breastfeeding. People with previous CLL treatments, significant infections, uncontrolled heart conditions, recent strokes or surgeries are excluded.Inclusion Criteria
Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) except for patients with bilirubin elevation due to Gilbert's disease who will be allowed to participate
I have been diagnosed with CLL/SLL and have not received any treatment.
I am able to care for myself and perform daily activities.
+6 more
Exclusion Criteria
I have not had major surgery or a serious injury in the last 28 days.
I need treatment with a strong medication that affects liver enzymes.
I can't swallow pills or have a stomach condition affecting medication absorption.
+17 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive acalabrutinib orally twice a day and obinutuzumab intravenously, with treatment repeating every 28 days for up to 24 cycles
24 months
Monthly visits for each cycle
Follow-up
Participants are monitored for safety and effectiveness after treatment completion
4 years
1 visit at 30 days post-treatment, then every 3 months
Optional Extension
Participants who do not achieve a complete response may receive additional cycles of acalabrutinib and obinutuzumab
6 months
Participant Groups
The trial is testing how well acalabrutinib combined with obinutuzumab works in treating CLL. Acalabrutinib blocks enzymes needed for tumor growth while obinutuzumab may help the immune system interfere with tumor cell growth and spread. The goal is to see if this combination can better manage disease progression in untreated CLL patients.
1Treatment groups
Experimental Treatment
Group I: Treatment (acalabrutinib, obinutuzumab)Experimental Treatment2 Interventions
Patients receive acalabrutinib PO BID every 12 hours starting on day 1 of cycle 1, and obinutuzumab IV over 4-6 hours on days 1 and 2 of cycle 3, and day 1 of cycles 4-8. Patients who do not achieve a complete response or remission after cycle 8 may receive single-agent acalabrutinib therapy PO BID for an additional 6 cycles at the discretion of their treating physician. Patients who are in partial response or who have stable disease receive an additional 6 cycles of acalabrutinib PO BID and obinutuzumab IV. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.
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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
M D Anderson Cancer CenterHouston, TX
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Who Is Running the Clinical Trial?
M.D. Anderson Cancer CenterLead Sponsor
National Cancer Institute (NCI)Collaborator
References
Matching-adjusted indirect comparisons of safety and efficacy of acalabrutinib versus other targeted therapies in patients with treatment-naïve chronic lymphocytic leukemia. [2021]Acalabrutinib is a highly selective, potent, next-generation, covalent Bruton tyrosine kinase inhibitor with minimal off-target activity. Matching-adjusted indirect comparisons (MAICs) were performed to estimate the safety and efficacy of acalabrutinib compared to other targeted therapies for treatment-naïve patients with chronic lymphocytic leukemia (CLL). Individual patient data for acalabrutinib (ELEVATE-TN trial) were matched to aggregate baseline characteristics for comparators. After matching, acalabrutinib (with or without obinutuzumab) showed improved safety outcomes, except for increased risk of neutropenia (p < 0.001) for acalabrutinib plus obinutuzumab versus ibrutinib and increased risk of leukopenia (p < 0.05) for acalabrutinib (with or without obinutuzumab) versus venetoclax plus obinutuzumab. There was no statistically significant difference in progression-free survival between acalabrutinib (with or without obinutuzumab) and any of the comparators. This MAIC demonstrated a favorable safety profile for acalabrutinib-based therapy compared with other targeted therapies in treatment-naïve patients with CLL, without compromising efficacy.
EMA Review of Acalabrutinib for the Treatment of Adult Patients with Chronic Lymphocytic Leukemia. [2021]On November 5, 2020, a marketing authorization valid through the European Union (EU) was issued for acalabrutinib monotherapy or acalabrutinib in combination with obinutuzumab (AcalaObi) in adult patients with treatment-naïve (TN) chronic lymphocytic leukemia (CLL) and also for acalabrutinib monotherapy in adult patients with relapsed or refractory (RR) CLL. Acalabrutinib inhibits the Bruton tyrosine kinase, which plays a significant role in the proliferation and survival of the disease. Acalabrutinib was evaluated in two phase III multicenter randomized trials. The first trial (ACE-CL-007) randomly allocated acalabrutinib versus AcalaObi versus chlorambucil plus obinutuzumab (ChlObi) to elderly/unfit patients with TN CLL. The progression-free survival (PFS), as assessed by an independent review committee, was superior for both the AcalaObi (hazard ratio [HR], 0.1; 95% confidence interval [CI], 0.06-0.17) and acalabrutinib (HR, 0.2; 95% CI, 0.13-0.3) arms compared with the ChlObi arm. The second trial (ACE-CL-309) randomly allocated acalabrutinib versus rituximab plus idelalisib or bendamustine to adult patients with RR CLL. Also in this trial, the PFS was significantly longer in the acalabrutinib arm (HR, 0.31; 95% CI, 0.20-0.49). Adverse events for patients receiving acalabrutinib varied across trials, but the most frequent were generally headache, diarrhea, neutropenia, nausea, and infections. The scientific review concluded that the benefit-risk ratio of acalabrutinib was positive for both indications. This article summarizes the scientific review of the application leading to regulatory approval in the EU. IMPLICATIONS FOR PRACTICE: Acalabrutinib was approved in the European Union for the treatment of adult patients with chronic lymphocytic leukemia who have not received treatment before and for those who have received therapy but whose disease did not respond or relapsed afterward. Acalabrutinib resulted in a clinically meaningful and significant lengthening of the time from treatment initiation to further disease relapse or patient's death compared with standard therapy. The overall safety profile was considered acceptable, and the benefit-risk ratio was determined to be positive.
U.S. Food and drug administration approval: obinutuzumab in combination with chlorambucil for the treatment of previously untreated chronic lymphocytic leukemia. [2022]On November 1, 2013, the U.S. Food and Drug Administration (FDA) approved obinutuzumab (GAZYVA; Genentech, Inc.), a CD20-directed cytolytic antibody, for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). In stage 1 of the trial supporting approval, patients with previously untreated CD20-positive CLL were randomly allocated (2:2:1) to obinutuzumab + chlorambucil (GClb, n = 238), rituximab + chlorambucil (RClb, n = 233), or chlorambucil alone (Clb, n = 118). The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall response rate (ORR). Only the comparison of GClb to Clb was relevant to this approval and is described herein. A clinically meaningful and statistically significant improvement in PFS with medians of 23.0 and 11.1 months was observed in the GClb and Clb arms, respectively (HR, 0.16; 95% CI, 0.11-0.24; P
Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. [2021]Acalabrutinib is a selective, covalent Bruton tyrosine-kinase inhibitor with activity in chronic lymphocytic leukaemia. We compare the efficacy of acalabrutinib with or without obinutuzumab against chlorambucil with obinutuzumab in patients with treatment-naive chronic lymphocytic leukaemia.
Acalabrutinib plus Obinutuzumab in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia. [2022]Acalabrutinib is a selective irreversible Bruton tyrosine kinase (BTK) inhibitor that does not affect IL2-associated tyrosine kinase or antibody-dependent cellular cytotoxicity, making it an attractive candidate for combination therapy with anti-CD20 antibodies. We investigated acalabrutinib plus obinutuzumab in a phase Ib/II study (NCT02296918) of patients with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia (CLL). Nineteen treatment-naïve and 26 relapsed/refractory patients were treated with acalabrutinib (100 mg twice daily) until progression and obinutuzumab (cycle 1: 100 mg day 1, 900 mg day 2, 1000 mg days 8 and 15; cycles 2-6: 1,000 mg day 1). Grade 3/4 adverse events occurred in 71% of patients. Overall response rates were 95% (treatment-naïve) and 92% (relapsed/refractory). Thirty-two percent of treatment-naïve and 8% of relapsed/refractory patients achieved complete remission. At 36 months, 94% (treatment-naïve) and 88% (relapsed/refractory) were progression free. Acalabrutinib plus obinutuzumab was well tolerated, producing high and durable responses in treatment-naïve and relapsed/refractory CLL. SIGNIFICANCE: Rituximab plus the less selective BTK inhibitor ibrutinib has not shown benefit in CLL; however, the selective BTK inhibitor acalabrutinib plus the antibody-dependent cellular cytotoxicity-enhanced antibody obinutuzumab yielded durable responses that deepened over time in treatment-naïve and relapsed/refractory CLL, supporting the evaluation of this approach in larger, comparative studies in CLL.This article is highlighted in the In This Issue feature, p. 327.
Obinutuzumab: a review of its use in patients with chronic lymphocytic leukaemia. [2018]Obinutuzumab (Gazyva(®); Gazyvaro(®)) is an intravenously administered, glycoengineered, humanized, type II, anti-CD20 monoclonal antibody of the IgG1 subclass. It is available in the EU and the USA as combination therapy with oral chlorambucil in adults with previously untreated chronic lymphocytic leukaemia (CLL). In a multinational phase III study in this patient population, obinutuzumab plus chlorambucil significantly prolonged progression-free survival compared with oral chlorambucil alone and intravenous rituximab plus oral chlorambucil. Significant advantages with obinutuzumab plus chlorambucil over chlorambucil alone and rituximab plus chlorambucil were also observed in event-free survival, the time to a new anti-leukaemia treatment and overall response. The overall survival benefit with obinutuzumab plus chlorambucil is as yet unclear, although the most recent analysis suggests a benefit over chlorambucil alone. In the phase III study, obinutuzumab plus chlorambucil had a manageable tolerability profile in accordance with what would be expected for an anti-CD20 antibody. Neutropenia and infusion-related reactions were the most frequently reported grade 3 or higher treatment-emergent adverse events. In the majority of patients, infusion-related reactions were mild to moderate in severity and occurred predominantly during the first infusion and were managed by slowing or temporarily halting the infusion. Thus, current evidence suggests that obinutuzumab plus chlorambucil is a welcome addition to the treatment options currently available for adults with previously untreated CLL and is recommended by the National Comprehensive Cancer Network guidelines as the preferred first option for some, including those with comorbidities.
Managing Infusion-Related Reactions for Patients With Chronic Lymphocytic Leukemia Receiving Obinutuzumab. [2017]In patients with previously untreated chronic lymphocytic leukemia (CLL) and comorbidities, treatment with the glycoengineered, type II anti-CD20 monoclonal antibody obinutuzumab (Gazyva®) (GA101) plus chlorambucil (Leukeran®) was associated with superior outcomes to rituximab (Rituxan®) plus chlorambucil, with a similar safety profile. However, a higher occurrence of infusion-related reactions (IRRs) was reported with obinutuzumab. These reactions typically require additional management.
ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. [2021]Acalabrutinib, a highly selective, potent, Bruton tyrosine kinase inhibitor, was evaluated in this global, multicenter, randomized, open-label, phase III study in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).