Acalabrutinib + Venetoclax +/- Obinutuzumab for Chronic Lymphocytic Leukemia

(AMPLIFY Trial)

Not currently recruiting at 193 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Acerta Pharma BV

Must not be taking: Warfarin, Vitamin K antagonists

Disqualifiers: HIV, Hepatitis B/C, Cardiovascular, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new treatments for individuals with chronic lymphocytic leukemia (CLL) who have not received prior treatment. It evaluates the effectiveness of combining the drugs acalabrutinib (a type of targeted therapy), venetoclax, and obinutuzumab compared to standard chemoimmunotherapy. The trial includes different groups: some receive acalabrutinib and venetoclax, others add obinutuzumab, and one group receives standard chemoimmunotherapy. Individuals with active CLL requiring treatment, who have not undergone CLL-specific therapies, might be suitable candidates. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants access to potentially groundbreaking treatments.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are on anticoagulation with warfarin or similar medications, you may not be eligible 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 venetoclax is generally well-tolerated by patients with chronic lymphocytic leukemia (CLL). The FDA has already approved this combination for CLL, indicating its safety. Most patients experienced manageable side effects, such as fatigue and low blood counts.

For the combination of acalabrutinib, venetoclax, and obinutuzumab, research also indicates safety. Studies found that this combination significantly reduced the risk of disease progression compared to other treatments, suggesting it is generally tolerable. Common side effects included low blood counts and nausea, but these were usually manageable.

Overall, extensive studies have shown that while side effects can occur, they are usually not severe and can be managed effectively. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using Acalabrutinib and Venetoclax, with or without Obinutuzumab, for treating Chronic Lymphocytic Leukemia (CLL) because these treatments bring something new to the table. Unlike traditional chemoimmunotherapy regimens like FCR (Fludarabine, Cyclophosphamide, and Rituximab) or BR (Bendamustine and Rituximab), Acalabrutinib and Venetoclax target specific proteins that help cancer cells survive. Acalabrutinib blocks BTK, a protein that helps CLL cells grow, while Venetoclax targets BCL-2, a protein that prevents cancer cells from dying. Adding Obinutuzumab, an antibody that attaches to cancer cells to mark them for destruction by the immune system, could potentially enhance these effects. This targeted approach could mean more effective treatments with potentially fewer side effects compared to traditional options.

What evidence suggests that this trial's treatments could be effective for chronic lymphocytic leukemia?

Research has shown that using acalabrutinib and venetoclax together holds promise for treating chronic lymphocytic leukemia (CLL). In this trial, one group of participants will receive this combination, which reduced the risk of disease progression or death by 58% compared to standard treatments in previous studies. Another group will receive acalabrutinib, venetoclax, and obinutuzumab, which demonstrated strong results, with many patients experiencing no disease progression for three years. These findings suggest that these treatment combinations could be more effective than traditional chemoimmunotherapy, used as a comparator in this trial, for patients with untreated CLL. Overall, the evidence supports the potential of these combinations to improve outcomes for people with CLL. ^{1 2 6 7 8}

Who Is on the Research Team?

Barbara Eichhorst

Principal Investigator

Universitätsklinikum Köln

John Seymour

Principal Investigator

Peter MacCallum Cancer Ctr

Arnon Kater

Principal Investigator

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Paolo Ghia, MD

Principal Investigator

OSPEDALE S. RAFFAELE - MILANO

Jennifer Brown

Principal Investigator

Dana Farber Mass General Brigham Cancer Care Inc

Are You a Good Fit for This Trial?

This trial is for adults over 18 with untreated Chronic Lymphocytic Leukemia (CLL) who need treatment. They must be in fairly good health, not pregnant or breastfeeding, and willing to use effective birth control. People can't join if they've had certain serious illnesses recently, like heart disease or stroke, infections like HIV or hepatitis B/C, bleeding disorders, brain lesions called PML, or any prior CLL treatments.

Inclusion Criteria

Participants must use highly effective birth control throughout the study

I can take care of myself and am up and about more than half of my waking hours.

My condition requires treatment according to the latest guidelines.

Exclusion Criteria

I have been diagnosed with HIV.

Concurrent participation in another therapeutic clinical trial.

Received any investigational drug within 30 days before first dose of study drug

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

5 weeks

Treatment

Participants receive randomized treatment with Acalabrutinib and Venetoclax, with or without Obinutuzumab, or chemoimmunotherapy until study drug discontinuation

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 years

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Chemoimmunotherapy
• Obinutuzumab
• Venetoclax

Trial Overview The study tests the effectiveness of Acalabrutinib combined with Venetoclax against standard chemoimmunotherapy for CLL. Some participants will also receive Obinutuzumab. The goal is to see which combination works best at treating CLL without previous treatment.

How Is the Trial Designed?

Group I: Acalabrutinib, Venetoclax, Obinutuzumab Experimental Treatment 3 Interventions

Acalabrutinib in combination with Venetoclax with Obinutuzumab

Group II: Acalabrutinib, Venetoclax Experimental Treatment 2 Interventions

Acalabrutinib in combination with Venetoclax

Group III: Chemoimmunotherapy Active Control 1 Intervention

Chemoimmunotherapy FCR: Fludarabine, Cyclophosphamide and Rituximab BR: Bendamustine and Rituximab

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?

Acerta Pharma BV

Lead Sponsor

Trials

46

Recruited

5,900+

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

Published Research Related to This Trial

In the phase III CLL14 trial, a 12-month treatment with venetoclax combined with obinutuzumab significantly improved progression-free survival and rates of undetectable minimal residual disease compared to traditional chemoimmunotherapy with chlorambucil and obinutuzumab in patients with untreated chronic lymphocytic leukaemia.

Venetoclax + obinutuzumab is a well-tolerated, chemotherapy-free treatment option for CLL, with manageable side effects like neutropenia, making it suitable for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. Blair, HA.[2021]

In a phase 2 trial involving 70 patients with chronic lymphocytic leukaemia, both 12 cycles of venetoclax consolidation and minimal residual disease-guided consolidation showed similar effectiveness, with around 50% of patients achieving undetectable minimal residual disease in bone marrow after treatment.

While consolidation treatment did not lead to treatment-related deaths, it was associated with a higher incidence of adverse events, particularly infections, indicating that while it may extend treatment duration, it does not significantly improve disease response or reduce relapse risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial. Kersting, S., Dubois, J., Nasserinejad, K., et al.[2022]

In a phase 2 study involving 37 patients with chronic lymphocytic leukaemia, the combination therapy of acalabrutinib, venetoclax, and obinutuzumab achieved a complete remission with undetectable minimal residual disease (MRD) in 38% of participants by cycle 16, indicating promising efficacy.

The treatment was generally well tolerated, with the most common serious adverse event being neutropenia, affecting 43% of patients, and no deaths reported during the study, suggesting a favorable safety profile for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. Davids, MS., Lampson, BL., Tyekucheva, S., et al.[2021]

Venetoclax is an effective oral treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), showing durable responses and a manageable safety profile in clinical trials, including patients with poor prognostic factors.

In combination with rituximab, venetoclax significantly improved progression-free survival and achieved undetectable minimal residual disease compared to bendamustine plus rituximab, with benefits lasting for at least 36 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. Scott, LJ.[2020]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

In a phase 3 trial involving 432 patients with untreated chronic lymphocytic leukaemia, the combination of venetoclax plus obinutuzumab resulted in significantly longer progression-free survival compared to chlorambucil plus obinutuzumab, with a hazard ratio of 0.31, indicating a strong treatment advantage.

After a median follow-up of 39.6 months post-treatment, patients receiving venetoclax plus obinutuzumab had not yet reached median progression-free survival, while those on chlorambucil plus obinutuzumab had a median of 35.6 months, highlighting the long-term efficacy of the venetoclax regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Al-Sawaf, O., Zhang, C., Tandon, M., et al.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03836261

NCT03836261 | Study of Acalabrutinib (ACP-196) in ... This randomized, global, multicenter, open-label, Phase 3 study will evaluate the efficacy and safety of AV and AVG versus chemoimmunotherapy (FCR or BR)

2. astrazeneca.com astrazeneca.com/media-centre/press-releases/2024/fixed-duration-calquence-plus-venetoclax-demonstrated-superior-pfs-vs-standard-care-previously-untreated-cll-with-77-of-patients-progression-free-3-years-amplify-phase-iii-trial.html

Fixed-duration Calquence plus venetoclax demonstrated ... Calquence plus venetoclax with obinutuzumab reduced the risk of disease progression or death by 58% versus standard of care in this setting

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

Phase II Study of Acalabrutinib, Venetoclax, and ... This investigator-sponsored, multicenter, phase II study enrolled patients with treatment-naïve CLL enriched for high-risk CLL, defined by TP53 aberration.

4. astrazenecaclinicaltrials.com astrazenecaclinicaltrials.com/study/ACE-CL-311

Study of Acalabrutinib (ACP-196) in combination with ... The purpose of this study is to evaluate the efficacy and safety of acalabrutinib in combination with venetoclax and acalabrutinib in combination with ...

5. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2024/fixed-duration-calquence-plus-venetoclax-demonstrated-superior-pfs-vs-standard-care-previously-untreated-cll-with-77-of-patients-progression-free-3-years-amplify-phase-iii-trial.html

Fixed-duration CALQUENCE® (acalabrutinib) plus ... CALQUENCE plus venetoclax with obinutuzumab reduced the risk of disease progression or death by 58% versus standard of care in this setting.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04941716

Study Details | NCT04941716 | Acalabrutinib in ... This phase II trial is to evaluate the effects of acalabrutinib in combination with venetoclax in treating patients with chronic lymphocytic leukemia or ...

7. news.abbvie.com news.abbvie.com/2025-07-29-AbbVie-Submits-for-U-S-FDA-Approval-of-Combination-Treatment-of-VENCLEXTA-R-venetoclax-and-Acalabrutinib-for-Previously-Untreated-Patients-with-Chronic-Lymphocytic-Leukemia-CLL

AbbVie Submits for U.S. FDA Approval of Combination ... VENCLEXTA is a prescription medicine used: to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). in ...

8. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2024/fixed-duration-calquence-acalabrutinib-plus-venetoclax-with-or-without-obinutuzumab-significantly-improved-progression-free-survival-in-first-line-chronic-lymphocytic-leukemia-in-amplify-phase-iii-trial.html

Fixed-duration CALQUENCE® (acalabrutinib) plus ... CALQUENCE is also indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).