ASH 2020: TRANSCEND-CLL-004 Study: Results of CAR-T Combination in R/R CLL or SLL

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 or 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 TRANSCEND-CLL-004 Study?

Imbruvica (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. 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 allow B cells to survive and multiply.⁶ 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 initial treatments of CLL and in patients with previous treatment.

Because ibrutinib is given as continuous therapy for the treatment of CLL, long-term safety and efficacy data are important to help doctors make informed decisions.

Preclinical data have suggested that combination therapy may provide marked improvements in treatment responses for patients with R/R CLL or SLL.^7,8

Lisocabtagene maraleucel (liso-cel) is a type of chimeric antigen receptor (CAR)-T cell therapy in which T cells are taken from a patient’s blood, programmed in a laboratory to bind to and attack cancer cells, and given to the patient by infusion.⁹

ASH 2020: TRANSCEND-CLL-004 Study: Results of CAR-T Combination in R/R CLL or SLL

The TRANSCEND-CLL-004 study is a phase 1/2 clinical trial that looked at the safety and efficacy of liso-cel in combination with ibrutinib for adult patients with previously treated R/R CLL or SLL.^10,11

Figure 2 illustrates the participant eligibility and trial design.11 Overall, patients enrolled had a median of four prior treatments. In the study, 19 patients (median age, 60 years) received infusions of liso-cel and started or continued ibrutinib for 90 days or more. Patients received liso-cel at a dose of either 50 × 106 (dose level 1; n = 4) or 100 × 106 (dose level 2; n = 15) CAR-T cells.¹¹

The efficacy end points of this study included overall response rate (ORR) noted as a complete response (CR), a CR with incomplete blood count recovery (CRi) or a partial response. All overall responses were obtained by day 30 post-infusion. An overall response was achieved in 18 patients for an ORR of 95% (ORR was 100% with dose level 2 and 75% with dose level 1). Of those who achieved a response, nine patients (47%) achieved a CR or CRi (Figure 3).¹¹ The disease was stable in one patient. Of the 18 patients who achieved a response, 15 (83%) maintained it to treatment at their three-month follow-up.¹¹

The primary end points of the study were safety and to determine the recommended dose of liso-cel in combination with ibrutinib for R/R CLL/SLL. Preliminary pharmacokinetics (PK) data showed a median time to peak liso-cel expansion of 11 days across dose levels (dose level 1, 12 days; dose level 2, 11 days).¹¹

The combination therapy of liso-cel with ibrutinib exhibited no dose-limiting toxicities; however, six patients who received dose level 2 exhibited grade 2 (moderate) and 3 (severe) lung infections. The most common severe or medically significant, but not immediately life-threatening, treatment-emergent side effects were neutropenia (neutrophil count decrease) in 17 patients (89%), anemia in nine patients (47%) and febrile neutropenia in five patients (26%). Side effects specific to ibrutinib treatment were diarrhea, atrial fibrillation, hypertension and rash. Notably, 74% and 32% of patients experienced cytokine release syndrome and neurological events, respectively.¹¹

In conclusion, the preliminary data from the TRANSCEND study showed promising efficacy results in patients with R/R CLL or SLL treated with liso-cel in combination with ibrutinib. There were incidences of grade 3 cytokine release syndrome and grade 3 or higher neurological events. No clear safety differences were observed between the treatment groups who received liso-cel at a dose of either 50 × 106 or 100 × 106 CAR-T cells. For future studies, 100 × 106 CAR-T cells will be selected for investigation for liso-cel in combination with ibrutinib for adult patients with R/R CLL or SLL.¹¹

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

FOR YOUR REFERENCE:

Glossary of Terms^1-11

Anemia: a condition in which the number of red blood cells is below normal

Atrial fibrillation: an irregular heartbeat that occurs when the electric signal in the atria (the two upper chambers of the heart) fires rapidly at the same time, causing the heart to beat faster than normal

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

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

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

Chemotherapy: treatment that uses drugs to stop the growth of cancer cells by either killing the cells or 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.

Chimeric antigen receptor T (CAR-T) cell therapy: a type of immunotherapy in which T cells are taken from a patient’s blood, programmed in a laboratory to bind to and attack cancer cells and given to the patient by infusion. Lisocabtagene maraleucel (liso-cel) is a type of CAR-T cell therapy.

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

Complete response (CR): the disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured. Also called complete remission.

Complete remission with incomplete count recovery (CRi): CR with incomplete blood count recovery

Cytokine release syndrome (CRS): a condition that may occur after treatment with some types of immunotherapy in which a great number of cytokines (immune substances) are rapidly released into the blood from immune cells affected by immunotherapy. CRS signs and symptoms include fever, nausea, headache, rash, rapid heartbeat, low blood pressure and trouble breathing.

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

End point: an event or outcome that can be measured to determine whether the treatment being studied in a clinical trial is beneficial

Febrile neutropenia: a condition marked by fever and a lower-than-normal number of neutrophils (a type of white blood cell) in the blood

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

Imbruvica (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.

Lisocabtagene maraleucel (liso-cel): a type of CAR-T cell therapy in which T cells are taken from a patient’s blood, programmed in a laboratory to bind to and attack cancer cells, and given to the patient by infusion.

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

Median: the middle value of a sorted list of numbers placed in value order from highest to lowest

Median follow-up: the median time between treatment and when data outcomes are gathered

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

Overall response rate (ORR): the percentage of people in a study or treatment group who have a partial or complete response to the treatment within a certain period of time

Partial response: a decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment. Also called partial remission.

Pharmacokinetics (PK): the activity of drugs in the body over a period of time, including the processes by which drugs are absorbed, distributed in the body, localized in the tissues and excreted

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

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

White blood cell: 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 types of white blood cells

References

1. What are clinical trials and studies? National Institute on Aging. Updated April 9, 2020. 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. Chronic lymphocytic leukemia. Leukemia and Lymphoma Society. Updated 2014. Accessed March 15, 2021. https://www.lls.org/sites/default/files/file_assets/cll.pdf

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

7. Ruella M, Kenderian SS, Shestova O, et al. Kinase inhibitor ibrutinib to prevent cytokine-release syndrome after anti-CD19 chimeric antigen receptor T cells for B-cell neoplasms. Leukemia. 2017;31(1):246-248. doi:10.1038/leu.2016.262

8. Fraietta JA, Beckwith KA, Patel PR, et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood. 2016;127(9):1117-1127. doi:10.1182/blood-2015-11-679134

9. NCI Dictionary of Cancer Terms. National Cancer Institute. Accessed March 22, 2021. https://www.cancer.gov/publications/dictionaries/cancer-terms

10. Study evaluating safety and efficacy of JCAR017 in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Clinical Trials.gov. Updated August 28, 2020. Accessed March 15, 2021. https://clinicaltrials.gov/ct2/show/NCT03331198

11. Wierda WG, Dorritie KA, Munoz J, et al. Transcend CLL 004: phase 1 cohort of lisocabtagene maraleucel (liso-cel) in combination with ibrutinib for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Blood. 2020;136(suppl 1):39-40. doi:10.1182/blood-2020-140622

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