Acalabrutinib + Venetoclax +/- Obinutuzumab for Chronic Lymphocytic Leukemia

(AMPLIFY Trial)

Recruiting at 161 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

984 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to evaluate the efficacy and safety of acalabrutinib in combination with venetoclax and acalabrutinib in combination with venetoclax with and without obinutuzumab compared to chemoimmunotherapy in subjects with previously untreated CLL

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.

What data supports the effectiveness of the drug combination Acalabrutinib, Venetoclax, and Obinutuzumab for treating Chronic Lymphocytic Leukemia?

Research shows that the combination of Venetoclax and Obinutuzumab is effective for treating Chronic Lymphocytic Leukemia, leading to longer progression-free survival and higher rates of undetectable disease compared to other treatments. Acalabrutinib, when used with Venetoclax and Obinutuzumab, is hypothesized to induce deep and lasting remissions. ^{1 2 3 4 5}

How is the drug combination of Acalabrutinib, Venetoclax, and Obinutuzumab unique for treating chronic lymphocytic leukemia?

This drug combination is unique because it combines continuous therapy with acalabrutinib and fixed-duration therapy with venetoclax and obinutuzumab, aiming for deep and durable remissions by guiding treatment based on minimal residual disease (MRD) status, which is a measure of how much cancer remains after treatment. ^{2 3 4 5 6}

Research Team

Jennifer Brown

Principal Investigator

Dana Farber Mass General Brigham Cancer Care Inc

Barbara Eichhorst

Principal Investigator

Universitätsklinikum Köln

Arnon Kater

Principal Investigator

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

Paolo Ghia, MD

Principal Investigator

OSPEDALE S. RAFFAELE - MILANO

John Seymour

Principal Investigator

Peter MacCallum Cancer Ctr

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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]

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]

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]

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]

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]

References

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

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

2. England pubmed.ncbi.nlm.nih.gov

Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. [2021]

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

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

4. France pubmed.ncbi.nlm.nih.gov

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

5. England 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. [2020]

6. England 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. [2022]