What side effects are associated with this type of intervention?

Common treatments for Chronic Lymphocytic Leukemia (CLL) include Venetoclax (a BCL-2 inhibitor), BTK inhibitors like Ibrutinib and Acalabrutinib, and combination therapies such as Venetoclax plus Obinutuzumab. Known side effects of Venetoclax include neutropenia, diarrhea, and tumor lysis syndrome (TLS). Ibrutinib and Acalabrutinib can cause side effects such as hypertension, atrial fibrillation, bleeding, and infections. Combination therapies like Venetoclax plus Obinutuzumab may lead to neutropenia, thrombocytopenia, infections, and TLS. Patients should discuss these potential side effects with their healthcare provider to make informed treatment decisions.

What prior FDA approvals exist?

The FDA has approved several treatments for Chronic Lymphocytic Leukemia (CLL) that are similar to Venetoclax, a BCL-2 inhibitor. Venetoclax itself is approved for use in combination with obinutuzumab for previously untreated CLL and with rituximab for relapsed or refractory CLL. Other targeted therapies include Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib and acalabrutinib, which are approved for CLL treatment either as monotherapy or in combination with other agents like obinutuzumab. These therapies offer alternatives to traditional chemoimmunotherapy regimens and are particularly beneficial for patients with high-risk CLL or those with specific genetic mutations.

What other types of research exist?

Promising alternatives to Venetoclax for CLL patients include Bruton tyrosine kinase (BTK) inhibitors such as acalabrutinib and zanubrutinib, which have shown efficacy and better tolerability compared to ibrutinib. Additionally, the combination of ibrutinib or acalabrutinib with venetoclax is being studied for high-risk CLL patients. These alternatives offer targeted approaches with potential for improved outcomes.

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Bruton's Tyrosine Kinase Inhibitor

Venetoclax + BTK Inhibitors for Chronic Lymphocytic Leukemia

Phase 2

Recruiting

Led By Philip A Thompson

Research Sponsored by M.D. Anderson Cancer Center

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Patients must have received at least 12 months of ibrutinib or acalabrutinib therapy and have measurable CLL

Patients must have a diagnosis of CLL/CLL and have high-risk cytogenetic features or molecular features, defined as: del(17p), mutated TP53, complex metaphase karyotype

Must not have

Grade 3 or 4 hemorrhage within the past 3 weeks

Malabsorption syndrome or other condition that precludes enteral route of administration

Timeline

Screening 3 weeks

Treatment Varies

Follow Up through study completion, an average of 1 year

Awards & highlights

No Placebo-Only Group

Summary

This trial looks at venetoclax + ibrutinib to treat high-risk CLL. Both drugs work differently to stop cancer cell growth.

Who is the study for?

Adults with high-risk Chronic Lymphocytic Leukemia (CLL) who've had at least a year of Ibrutinib or Acalabrutinib treatment. They should be relatively healthy, with good kidney and liver function, no severe heart issues, and able to follow the study plan. Pregnant women can't join, nor those with other active cancers or infections.

What is being tested?

The trial is testing if adding Venetoclax to ongoing Ibrutinib or Acalabrutinib therapy improves outcomes for CLL patients who haven't fully responded after 12 months of treatment. It's an open-label phase II study where everyone knows what treatments are given.

What are the potential side effects?

Venetoclax may cause tumor lysis syndrome (a rapid release of cells into the blood), gastrointestinal symptoms like nausea and diarrhea, low blood cell counts increasing infection risk, fatigue, and possibly liver problems.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

Select...

I have been on ibrutinib or acalabrutinib for over a year for my CLL.

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My CLL diagnosis includes high-risk features like del(17p), mutated TP53, or a complex karyotype.

Select...

I am 18 years old or older.

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I am able to care for myself and perform daily activities.

Select...

My bone marrow is working well.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have not had severe bleeding in the last 3 weeks.

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I cannot take medications by mouth due to a digestive condition.

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I haven't had major treatments or experimental therapy in the last 3 weeks.

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I have an active hepatitis B infection.

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I have been treated with venetoclax or a similar drug before.

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I am currently taking warfarin.

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My condition has progressed to Richter's syndrome.

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I need steroids for an uncontrolled autoimmune condition.

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I haven't taken strong CYP3A affecting drugs in the last week.

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I have active hepatitis C.

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I am not pregnant or breastfeeding.

Select...

I do not have any untreated or uncontrolled infections.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ through study completion, an average of 1 year

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~through study completion, an average of 1 year

This trial's timeline: 3 weeks for screening, Varies for treatment, and through study completion, an average of 1 year for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

The primary endpoint will be the rate of MRD-negativity in the bone marrow, using an assay method with at least 0.01% sensitivity after 12 cycles of combination therapy. One cycle is 4 weeks of treatment.

Secondary study objectives

Determine complete remission CR/complete remission with incomplete hematologic recovery CRi rate of combination therapy in patients who were not in CR/Cri at study initiation and estimate the time to best response with this combination.

Determine the safety of combined ibrutinib and venetoclax.

Side effects data

From 2022 Phase 3 trial • 389 Patients • NCT02005471

33%

Neutropenia

11%

SARS-CoV-2 test positive

11%

Sepsis

11%

Abdominal pain

11%

Pneumonia

11%

Rhinovirus infection

11%

COVID-19

11%

Gastroenteritis

11%

Pneumonia pseudomonal

11%

Electrocardiogram QT prolonged

11%

Anaemia

11%

Neutrophil count decreased

11%

Hypokalaemia

11%

Febrile neutropenia

11%

Supraventricular tachycardia

11%

Blood creatinine increased

11%

White blood cell count decreased

11%

Dermatitis

100%

80%

60%

40%

20%

Study treatment Arm

Bendamustine + Rituximab Crossover Substudy

Venetoclax + Rituximab Re-Treatment Substudy

Venetoclax + Rituximab Main Study

Bendamustine + Rituximab Main Study

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: Treatment (venetoclax, ibrutinib, acalabarutinib)Experimental Treatment3 Interventions

Patients receive venetoclax PO QD and ibrutinib PO QD and acalabrutinib PO BID. Treatment repeat every 4 weeks for up to 24 cycles in the absence of disease progression or unaccepted toxicity.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Ibrutinib

2014

Completed Phase 4

~2060

Venetoclax

2019

Completed Phase 3

~2240

Acalabrutinib

2020

Completed Phase 2

~2110

0 / 17Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Chronic Lymphocytic Leukemia (CLL) include Bruton tyrosine kinase (BTK) inhibitors like ibrutinib and acalabrutinib, and BCL-2 inhibitors like venetoclax. BTK inhibitors work by blocking the BTK enzyme, which is crucial for the survival and proliferation of CLL cells. This inhibition disrupts the signaling pathways that CLL cells rely on, leading to their death. Venetoclax, a BCL-2 inhibitor, targets the BCL-2 protein that prevents apoptosis (programmed cell death) in CLL cells. By inhibiting BCL-2, venetoclax promotes the death of these cancerous cells. These targeted therapies are significant for CLL patients as they offer more effective and less toxic treatment options compared to traditional chemotherapy, improving both survival rates and quality of life.