Results From the Phase 2 CAPTIVATE Study

FOR YOUR REFERENCE: What Are Clinical Trials?

Clinical trials determine whether a drug works in humans and whether it is safe and effective. For a drug to be approved for use, the Food and Drug Administration (FDA) requires four phases of a clinical trial. The number of participants increases in each phase, starting from 20 to 80 people for a phase 1 trial to up to several thousand for a phase 3 trial (Figure 1).¹

• Phase 1: tests an experimental treatment on a small group of often healthy people to judge the drug’s safety and side effects and find the correct dosage.
• Phase 2: focuses on effectiveness and obtains preliminary data on whether the drug works in people who have a certain disease or condition.
• Phase 3: gathers more information about safety and effectiveness, studies different populations and dosages and examines the drug’s use in combination with other drugs.
• Phase 4: occurs after FDA approval; monitors safety and effectiveness in large, diverse populations; and collects information on long-term side effects.
• FOR YOUR REFERENCE:

What Is Chronic Lymphocytic Leukemia?

Chronic lymphocytic leukemia (CLL) is a form of cancer that starts in the blood-forming cells in bone marrow that become certain white blood cells, called lymphocytes. In CLL, cancer occurs in B cells, a type of lymphocyte, which defends your body against infection. These cells change and become cancer cells, or leukemia cells, that can grow out of control and spread by traveling in the blood to other parts of the body.²

Patients with CLL may experience symptoms such as weakness, fatigue, weight loss, chills, fever, night sweats, swollen lymph nodes, pain and a sense of fullness in the belly. Although these signs and symptoms can point to CLL, tests are needed for a diagnosis. Many people with CLL do not have any symptoms at the time of their diagnosis; their leukemia is found during blood tests for unrelated health issues or routine checkups.³ CLL is usually recognized when blood counts performed for unrelated reasons reveal lymphocytosis, or a higher-than-normal amount of lymphocytes in the body.

Treatment options for patients with CLL include the following⁴:

• Watchful waiting.
• Radiation therapy.
• Chemotherapy.
• Immunotherapy.
• Targeted therapy.
• Clinical trials.

Patients undergoing CLL treatment often experience a complete or partial response to initial therapy — but not always. Consequently, CLL can be classified as relapsed or refractory (R/R), depending on how the disease responds to treatment. Relapsed CLL describes CLL that responded to therapy initially but stopped responding after six or more months. CLL is called refractory if treatment does not result in the total disappearance of CLL cells (though the patient may have stable disease) or if the patient experiences worsening of CLL within six months of the last treatment.⁵

FOR YOUR REFERENCE:

What Agents Were Investigated in the CAPTIVATE CLL Study?

Ibrutinib and venetoclax are FDA-approved drugs for treating CLL.^5,6 In previous trials, a combination of these drugs showed anti-tumor activity and good responses.

Ibrutinib is an FDA-approved targeted treatment for adult patients with CLL or small lymphocytic lymphoma (SLL) and patients with CLL or SLL with specific mutations.⁵ It blocks the activity of Bruton tyrosine kinase (also known as tyrosine-protein kinase or BTK), a protein in B cells that sends “signals” that help B cells stay alive and multiply.⁵ Ibrutinib blocks BTK signaling to help stop B cells from surviving and multiplying. Ibrutinib may slow the spread of CLL or SLL. It is used in the initial treatment of patients with CLL and in patients with previous treatment.5 Venetoclax is a BCL2 inhibitor. BCL2 proteins help CLL cells survive.^6,7

Phase 2 CAPTIVATE Study

The CAPTIVATE trial is a phase 2 clinical trial evaluating the effectiveness of the combination of venetoclax and ibrutinib in patients with CLL in the frontline setting, meaning the first treatment in those who have not received prior treatment for their CLL.8 Patients who were younger than 70 with previously untreated CLL/SLL received an initial three cycles of ibrutinib followed by 12 cycles of ibrutinib in combination with venetoclax.⁸

Following the initial treatment, 86 patients achieved confirmed undetectable minimal residual disease (uMRD), defined as those patients who had a small number of leukemia cells remaining in their body after initial treatment, serially over at least three cycles in both peripheral blood and bone marrow. Of those, 43 patients were randomly assigned to receive placebo and 43 received ibrutinib.⁸

The 63 patients who did not achieve confirmed uMRD continued treatment with either ibrutinib (31 patients) or ibrutinib in combination with venetoclax (32 patients).⁸

Results

In the confirmed uMRD group, there were similar rates of one-year disease-free survival among patients who received the placebo and those who continued with ibrutinib treatment (95.3% vs. 100%) after the initial 12 cycles of ibrutinib in combination with venetoclax.⁸

For participants who did not achieve confirmed uMRD, continued treatment with ibrutinib alone or in combination with venetoclax improved their rates of progression-free survival (PFS).⁸

The PFS study outcomes are represented below and in Figure 2 as the percentage of patients who did not have cancer spread over the 30-month study period⁸:

• Patients with confirmed uMRD who received placebo: 95.3%.
• Patients with confirmed uMRD who were treated with ibrutinib: 100.0%.
• Patients without confirmed uMRD who were treated with ibrutinib: 95.2%.
• Patients without confirmed uMRD who were treated with ibrutinib in combination with venetoclax: 96.7%.

The safety profile of ibrutinib in combination with venetoclax was consistent with known side effects for each drug. Most side effects were mild in severity and occurred when patients were being treated with early cycles of ibrutinib in combination with venetoclax. Serious side effects reported by 5% or more of patients included neutropenia (36%), hypertension (10%), thrombocytopenia (5%) and diarrhea (5%).⁸

First-line treatment with ibrutinib in combination with venetoclax shows promise as a chemotherapy-free treatment option for patients with CLL and demonstrated high rates of uMRD.⁸

Not all patients qualify for certain clinical trials. If you are interested in enrolling in a trial, talk to your doctor about which treatment options would be most appropriate for you.

FOR YOUR REFERENCE:

Glossary of Terms^1-9

B cell: a type of white blood cell that is an important part of your immune system (the body’s defense against infection)

BCL-2: proteins that help CLL cells survive

Bone marrow: spongy tissue inside bones; cells that make blood cells are found in the bone marrow

Bruton tyrosine kinase (BTK): a protein in B cells that sends signals, which help B cells survive and multiply

Chemotherapy: treatment that uses drugs to stop the growth of cancer cells either by killing the cells or by stopping them from dividing. These drugs are taken by mouth or injected and enter the bloodstream so they can help fight cancers that spread throughout the body (like CLL). This can affect cancer cells and normal cells.

Chronic lymphocytic leukemia (CLL): a slow-growing cancer in which too many immature lymphocytes (white blood cells) are found mostly in the blood and bone marrow

Clinical trial: a research study in which one or more human patients are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of the intervention(s) on health-related biomedical or behavioral outcomes

Efficacy: the ability of a therapy to produce the expected result under ideal circumstances

Hypertension: a blood pressure reading of 140/90 mm Hg or higher; also called high blood pressure

Ibrutinib: an FDA-approved BTK inhibitor indicated for the treatment of adult patients with CLL or SLL with or without 17p deletion. Ibrutinib may slow the spread of CLL or SLL.

Immunotherapy: type of therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection and other diseases. Some types of immunotherapy target only certain cells of the immune system. Others affect the immune system in a general way.

Leukemia: cancer that starts in blood-forming tissue, such as bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the bloodstream

Lymphocytes: a type of white blood cell that is made in the bone marrow and found in the blood and lymph tissue

Minimal residual disease: patients who have a small number of cancer cells that remain in their body during or after treatment

Neutropenia: a condition in which there is a lower-than-normal number of neutrophils (a type of white blood cell) in the blood

Phase 1: trial that tests an experimental treatment on a small group of often healthy people to judge its safety and side effects and to find the correct drug dosage

Phase 2: trial that focuses primarily on effectiveness of the drug and obtains preliminary data on whether it works in people who have a certain disease or condition

Phase 3: trial that gathers more information about safety and effectiveness, studies different populations and different dosages, and examines use of the drug in combination with other drugs

Phase 4: trial that occurs after FDA approval; monitors safety and effectiveness in large, diverse populations; and collects information on long-term side effects

Progression-free survival: the length of time during and after the treatment that a patient lives with the disease, but it does not get worse

Radiation therapy: type of cancer treatment that uses beams of intense energy to kill cancer cells

Refractory: a disease state or condition that does not respond to treatment or medication. Refers to when the lymphoma does not respond to treatment (the cancer cells continue to grow) or when the response to treatment does not last very long.

Relapsed: a return of signs and symptoms of cancer after undergoing treatment and/or taking medication. Relapsed is the disease that returns or grows again after a period of remission following one or more treatments. Marked by an initial response to treatment that is no longer present after six months or more.

Side effect: an unintended reaction to, or result of, a treatment

Small lymphocytic lymphoma (SLL): a slow-growing type of lymphoma in which too many immature lymphocytes (white blood cells) are found mostly in the lymph nodes

Targeted therapy: a cancer treatment that uses drugs to target specific aspects of the cancer cells

Thrombocytopenia: a condition marked by a low number of platelet cell levels in the blood. Platelets help the blood to clot and stop bleeding

Venetoclax: a drug used on its own or in combination with other drugs to treat chronic lymphocytic leukemia. Venetoclax works by binding to a protein called BCL2, a protein that helps chronic lymphocytic leukemia cells survive.

Watchful waiting: a strategy in which treatment is not started right away; instead, symptoms are observed and time is allowed to pass before medical intervention or therapy is used

White blood cells: a type of cell that is found in the blood and lymph tissue that helps fight infections and other diseases. Lymphocytes (T and B cells) are typesof white blood cells.

References

1. What are clinical trials and studies? National Institute on Aging. Accessed March 15, 2021. https://www.nia.nih.gov/health/what-are-clinical-trials-and-studies

2. What is chronic lymphocytic leukemia? American Cancer Society. Updated May 10, 2018. Accessed March 15, 2021. https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/what-is-cll.html

3. Signs and symptoms of chronic lymphocytic leukemia. American Cancer Society. Updated May 10, 2018. Accessed March 15, 2021. https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/detection-diagnosis-staging/signs-symptoms.html

4. Chronic lymphocytic leukemia treatment (PDQ)-patient version. National Cancer Institute. Updated November 25, 2020. Accessed March 15, 2021. https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq

5. Imbruvica. Prescribing information. Janssen Biotech Inc; 2020. Accessed March 22, 2021. https://imbruvica.com/files/prescribing-information.pdf

6. Venclexta. Prescribing information. AbbVie Inc; 2020. Accessed March 17, 2021. https://www.rxabbvie.com/pdf/venclexta.pdf

7. Targeted therapy drugs for chronic lymphocytic leukemia. American Cancer Society. Accessed March 18, 2021. https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/treating/targeted-therapy.html

8. Wierda WG, Tam CS, Allan JN, et al. Imbruvica (Ibr) plus Venclexta (Ven) for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): 1-year disease-free survival (DFS) results from the MRD cohort of the phase 2 CAPTIVATE study. Abstract presented at: 62nd ASH Annual Meeting and Exposition; December 5-8, 2020. Accessed May 10, 2021. https://ash.confex.com/ash/2020/webprogram/Paper134446.html

9. NCI Dictionary of Cancer Terms. National Cancer Institute. Accessed April 17, 2021. https://www.cancer.gov/publications/dictionaries/cancer-terms

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