What is the mechanism of action of this treatment?

The most common treatments for Chronic Lymphocytic Leukemia (CLL) include immunotherapy and enzyme inhibition. Immunotherapy drugs like ipilimumab and nivolumab enhance the body's immune system to recognize and attack cancer cells by blocking proteins (CTLA-4 and PD-1) that downregulate immune responses. Enzyme inhibitors like ibrutinib target Bruton's tyrosine kinase (BTK), a crucial enzyme for CLL cell growth and survival, thereby disrupting cancer cell proliferation. These targeted treatments are significant for CLL patients as they offer more precise control of the disease with potentially fewer side effects compared to traditional chemotherapy.

What side effects are associated with this type of intervention?

Common treatments for Chronic Lymphocytic Leukemia (CLL) include immunotherapies like Ipilimumab and Nivolumab, and enzyme inhibitors like Ibrutinib. Ipilimumab can cause immune-related adverse events such as colitis, hepatitis, and dermatitis. Nivolumab, another immunotherapy, may lead to side effects like fatigue, rash, and diarrhea. Ibrutinib, a BTK inhibitor, is associated with non-hematologic adverse effects such as atrial fibrillation, hypertension, and infections, as well as hematologic toxicities like neutropenia and thrombocytopenia. These side effects vary in severity and frequency, and management often involves supportive care and immunosuppressive therapies.

What prior FDA approvals exist?

The FDA has approved several treatments for Chronic Lymphocytic Leukemia (CLL) that involve immunotherapy and enzyme inhibition. Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, is approved for CLL and is often used in combination with other agents such as obinutuzumab, a monoclonal antibody. Obinutuzumab in combination with chlorambucil is another FDA-approved frontline treatment for CLL. While Ipilimumab and Nivolumab are primarily used in other cancers, their combination with Ibrutinib is being studied for potential efficacy in CLL. These treatments expand the therapeutic options for CLL, providing targeted and less-toxic alternatives to traditional chemotherapy.

What other types of research exist?

Promising novel alternatives for CLL treatment in 2024 include: 1) Acalabrutinib or Zanubrutinib (BTK inhibitors) which are better tolerated and have similar efficacy compared to Ibrutinib. 2) Venetoclax plus Obinutuzumab, which has shown high response rates and the potential for achieving undetectable minimal residual disease (MRD). 3) Combination therapies involving newer biologics targeting B-cells, such as Ocrelizumab or Veltuzumab, and novel strategies for regulatory T-cell modulation, like low-dose IL-2 therapy.

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Kinase Inhibitor

Triple Therapy for Chronic Lymphocytic Leukemia

Phase 1

Waitlist Available

Led By Nitin Jain

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

Eastern Cooperative Oncology Group (ECOG) performance status =< 2

Age 18 years or older

Must not have

Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor

Current or chronic hepatitis B or C infection, or known seropositivity for human immunodeficiency virus (HIV)

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 2 years

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing a combination of three drugs to help patients with chronic lymphocytic leukemia (CLL) and Richter transformation (RT). The drugs work by boosting the immune system to fight cancer and stopping cancer cells from growing.

Who is the study for?

Adults with chronic lymphocytic leukemia (CLL) or Richter transformation (RT), who have had prior treatments for CLL or are untreated with high-risk features, can join. They must be in good general health based on specific blood tests and agree to use effective contraception. Excluded are those with severe lung disease, certain heart conditions, uncontrolled hypertension, active infections, hepatitis B/C or HIV, recent major surgery or other cancer treatments.

What is being tested?

The trial is testing the combination of ipilimumab (an immune system booster) with ibrutinib alone or together with nivolumab for treating CLL and RT. It aims to find the safest dose that works best by seeing how these drugs affect cancer growth.

What are the potential side effects?

Possible side effects include immune-related reactions affecting organs like the liver and intestines, infusion reactions from the drug entering the body, fatigue, increased risk of infections due to a weakened immune system.

Eligibility Criteria

Inclusion Criteria

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

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I can take care of myself and am up and about more than half of the day.

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I am 18 years old or older.

Exclusion Criteria

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

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I need treatment with a strong medication that affects liver enzymes.

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I have hepatitis B or C, or I am HIV positive.

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I have not had a stroke or brain bleed in the last 2 months.

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I have not had an organ transplant.

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

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I am currently taking warfarin or similar blood thinners.

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I have not had a stem cell transplant in the last 6 months and do not have graft-versus-host disease.

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I do not have serious heart problems like recent heart attacks or uncontrolled heart rhythm issues.

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I do not have autoimmune diseases like Crohn's, ulcerative colitis, rheumatoid arthritis, lupus, or Wegener's.

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I do not have any ongoing serious infections.

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I have had interstitial lung disease or pneumonitis.

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I have an active blood disorder needing steroids.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 2 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 2 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 2 years for reporting.

Treatment Details

Study Objectives

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

Primary study objectives

Dose limiting toxicities

Secondary study objectives

Incidence of adverse events

Overall response rate

Overall survival

+1 more

Side effects data

From 2024 Phase 3 trial • 529 Patients • NCT02017717

80%

Fatigue

70%

Diarrhoea

70%

Headache

40%

Vomiting

40%

Aspartate aminotransferase increased

40%

Rash maculo-papular

40%

Alanine aminotransferase increased

40%

Lipase increased

30%

Partial seizures

30%

Hemiparesis

30%

Gait disturbance

30%

Fall

30%

Cough

30%

Dry skin

30%

Amylase increased

30%

Nausea

30%

Confusional state

20%

Malignant neoplasm progression

20%

Pyrexia

20%

Candida infection

20%

Mucosal infection

20%

Decreased appetite

20%

Back pain

20%

Dysphonia

20%

Hypotension

20%

Colitis

20%

Hyperthyroidism

20%

Oedema peripheral

20%

Muscular weakness

20%

Hypothyroidism

10%

Tinnitus

10%

Cushingoid

10%

Diabetic ketoacidosis

10%

Procedural haemorrhage

10%

Blood bilirubin increased

10%

Bradycardia

10%

Sinus tachycardia

10%

Hyperglycaemia

10%

Hypocalcaemia

10%

Neck pain

10%

Brain oedema

10%

Hydrocephalus

10%

Lethargy

10%

Seizure

10%

Hypertension

10%

Palpitations

10%

Cheilitis

10%

Presyncope

10%

Face oedema

10%

Oedema

10%

Conjunctivitis

10%

Enterocolitis infectious

10%

Oral candidiasis

10%

Pneumonia

10%

Sinusitis

10%

Staphylococcal infection

10%

Blood alkaline phosphatase increased

10%

Spinal pain

10%

Tremor

10%

Dizziness

10%

Dysarthria

10%

Urinary retention

10%

Dyspnoea exertional

10%

Nasal congestion

10%

Pneumonitis

10%

Dermatitis

10%

Erythema

10%

Rash

10%

Klebsiella infection

10%

Hypomagnesaemia

10%

Syncope

10%

Haemorrhage intracranial

10%

Pancreatitis

10%

Cholecystitis

10%

Upper respiratory tract infection

10%

Acute kidney injury

10%

Dermatitis bullous

10%

Lymphopenia

10%

Optic nerve disorder

10%

Visual impairment

10%

Dehydration

10%

Hypokalaemia

10%

Scoliosis

10%

Cognitive disorder

10%

Memory impairment

10%

Hallucination

10%

Insomnia

10%

Irritability

10%

Urinary incontinence

10%

Dyspnoea

10%

Dermatitis acneiform

10%

Pelvic venous thrombosis

10%

Sepsis

100%

80%

60%

40%

20%

Study treatment Arm

Cohort 1: Arm N1+I3

Cohort 2: Arm B

Part A Cohort 1c: Arm N3+RT+TMZ

Part A Cohort 1d: Arm N3+RT

Part B Cohort 1c: Arm N3+RT+TMZ

Part B Cohort 1d: Arm N3+RT

Cohort 1: Arm N3

Cohort 1b: Arm N3+I1

Cohort 2: Arm N3

Awards & Highlights

No Placebo-Only Group

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

Trial Design

2Treatment groups

Experimental Treatment

Group I: Part B (ipilimumab, nivolumab, ibrutinib)Experimental Treatment3 Interventions

Patients receive ipilimumab IV over 90 minutes and nivolumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning day 7 of cycle 1, patients also receive ibrutinib PO QD in the absence of disease progression or unacceptable toxicity. Patients who complete 4 doses of ipilimumab and nivolumab, and are deriving benefit from it, without severe toxicities, may continue to receive ipilimumab every 12 weeks and nivolumab every 4 weeks for up to a total of 2 years.

Group II: Part A (ipilimumab, ibrutinib)Experimental Treatment2 Interventions

Patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 3 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning day 1 of cycle 1, patients also receive ibrutinib PO QD in the absence of disease progression or unacceptable toxicity. Patients who complete 4 doses of ipilimumab and are deriving benefit from it, without severe toxicities, may continue to receive ipilimumab every 12 weeks for up to a total of 2 years.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Ibrutinib

2014

Completed Phase 4

~2060

Nivolumab

2015

Completed Phase 3

~4010

Ipilimumab

2015

Completed Phase 3

~3420

0 / 14Eligibility 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 immunotherapy and enzyme inhibition. Immunotherapy drugs like ipilimumab and nivolumab enhance the body's immune system to recognize and attack cancer cells by blocking proteins (CTLA-4 and PD-1) that downregulate immune responses. Enzyme inhibitors like ibrutinib target Bruton's tyrosine kinase (BTK), a crucial enzyme for CLL cell growth and survival, thereby disrupting cancer cell proliferation. These targeted treatments are significant for CLL patients as they offer more precise control of the disease with potentially fewer side effects compared to traditional chemotherapy.