CLL - Episode 1

ASH 2020: Results From the Phase 1/2 BRUIN Trial

April 23, 2021

FOR YOUR REFERENCE: What Are Clinical Trials?

Clinical trials determine whether a drug works in humans and whether it is safe and effective. To find out whether a drug can 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 3,000 for a phase 3 trial (Figure 1).1

  • Phase 1: tests an experimental treatment on a small group of often healthy people to judge its 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 use of the drug 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 into 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:

  1. Watchful waiting.
  2. Radiation therapy.
  3. Chemotherapy.
  4. Immunotherapy.
  5. Targeted therapy.
  6. 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.5 Refractory CLL refers to CLL that does not respond to treatment, or result in the disappearance of signs of disease (but might be stable), or CLL that worsens within six months of the last treatment.5

FOR YOUR REFERENCE: What Agents Were Investigated in the BRUIN Trial?

Bruton tyrosine kinase (BTK) inhibitors block the enzyme BTK, which plays a key role in the development and survival of white blood cells. BTK inhibitors are taken orally and are very important agents in the treatment of CLL. There are some gene mutations that reduce the effectiveness of BTK inhibitors and mechanisms, and treatment failure can occur if the patient develops resistance to the therapy. In some patients, treatment may need to be discontinued due to side effects.6,7

Patients with CLL who have received multiple prior therapies have fewer options available to them and worsened survival outcomes. Clinical trial results are helpful for assessing treatment options that are in development so that patients with R/R CLL who have received many previous treatments can have more safe and effective options available.

A highly selective BTK inhibitor called LOXO-305 (pirtobrutinib) was developed to help address the challenge of resistance to therapy in patients with CLL who have failed or are intolerant to standard of care. LOXO-305 is not an FDA-approved drug, but it is currently being studied in clinical trials

ASH 2020: Results From the Phase 1/2 BRUIN Trial

Data collected as of April 30, 2020, were presented at the 2020 American Society of Hematology Annual Meeting and Exposition regarding the safety and efficacy of LOXO-305 in 94 patients with previously treated CLL or small lymphocytic lymphoma (SLL).7,8

The BRUIN trial was an open-label, multicenter phase 1/2 study that aimed to find the highest dose of LOXO-305 that doesn’t cause unacceptable side effects and to assess its anti-tumor activity in patients with R/R CLL who have received two or more previous treatments.7,8 The majority of the study’s participants had received prior treatment with a BTK inhibitor (84%); other therapies included Venclexta (venetoclax; 31%) or a PI3K inhibitor (21%). And 69% of patients had received an anti-CD20 antibody, chemotherapy and a BTK inhibitor.8

The BRUIN trial was broken into three parts7,8:

  • Phase 1: LOXO-305 monotherapy dose escalation and dose expansion.
  • Phase 1b: LOXO-305 combination therapy dose expansion.
  • Phase 2: LOXO-305 monotherapy dose expansion.

In phase 1, the starting dose of LOXO-305 was 25 mg each day in an oral tablet form. Patients were treated with seven increasing dose levels of LOXO-305 that ranged from 25 mg to 300 mg daily until the highest dose with acceptable side effects — also known as the maximum tolerated dose — was determined. This LOXO-305 dose was then continued into phase 2, during which patients were assigned to different groups depending on disease type and prior treatment.8

In phase 2 of the trial, the primary outcome was overall response rate, which is the proportion of patients who experienced a response to LOXO-305 measured by a decrease in the number of cancer cells or the total disappearance of cancer cells. Of the 94 total patients treated with LOXO-305, 88 remained on treatment at the time of data collection. A total of 65 patients had their tumors assessed for response to LOXO-305.

At a median follow up of 6.7 months, the overall response rate was 57% with LOXO-305. Of these patients, 23 achieved a partial response and 14 patients achieved a partial response with lymphocytosis, which means no signs of progressive disease other than lymphocytosis.The longest-followed responding patient had ongoing response after 13.5 months of treatment.

Responses to LOXO-305 were not affected by classes of prior therapy, which means responses were achieved in patients who had prior treatment with a BTK inhibitor, had prior treatment with a BCL2 inhibitor or never received a BTK inhibitor. Additionally, patients who discontinued a BTK inhibitor previously achieved response for intolerance due to side effects or progressed on therapy. Moreover, the common mutation that confers resistance to BTK inhibitors was present in some patients who achieved response, indicating that this previous mutation did not affect response to LOXO-305.

There were no treatment-related toxicities that led to dose reductions or dose restrictions for the study’s participants. The most commonly reported side effects that occurred as a result of LOXO-305 treatment were fatigue (tiredness) in 29 patients and diarrhea in 28 patients.8

LOXO-305 demonstrated promising efficacy in patients with CLL or SLL who had received multiple lines of prior therapy and who generally had a poorer prognosis.8 In March 2021, the final results of the BRUIN phase 1/2 trial were published within the journal, Lancet.

LOXO-305 (pirtobrutinib) will continue to be evaluated in the phase 3 BRUIN CLL-321 trial, comparing LOXO-305 to either idelalisib or bendamustine in combination with rituximab in patients with CLL or SLL who have had prior treatment with a BTK inhibitor.

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 Terms2-5

Adverse event (AE): an unexpected medical problem that happens during treatment with a drug or other therapy. AEs may be mild, moderate, or severe. AEs may be caused by something other than the treatment given in a clinical trial. Also called adverse effect or side effect

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

Bone marrow: spongy tissue inside of 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: anti-cancer drugs that kill or control cancer cells. These drugs are taken by mouth or injected and enter the bloodstream so they can help cancers that spread throughout the body (like CLL).

Chronic lymphocytic leukemia: a type of cancer that affects white blood cells (called lymphocytes) found in the bone marrow

Clinical trials: research investigations in which people volunteer to test experimental treatments; these trials evaluate the safety and efficacy of experimental treatments

Efficacy: the ability to produce a desired outcome; in the case of cancer treatments, the desired outcome is a decrease in the number of cancer cells or the disappearance of cancer cells

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 only target 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 tissues

Lymphocytosis: a higher-than-normal amount of lymphocytes in the body

Maximum tolerated dose: the highest dose of a drug that does not cause unacceptable side effects.

Overall response rate: the proportion of patients who have a decrease in the number of cancer cells or the disappearance of cancer cells

Phase I study: tests an experimental treatment on a small group of often healthy people

Phase II study: uses more people and emphasizes effectiveness

Phase III study: gathers more information about safety and effectiveness, studying different populations and different dosages, using the drug in combination with other drugs

Phase IV study: usually occurs after FDA approval of the treatment; monitors safety and effectiveness in large, diverse populations; and collects information on long-term side effects.

PI3K inhibitor: a targeted therapy that works by blocking a specific protein in B cells, called PI3K delta, that contributes to CLL and SLL growth. PI3K inhibitors may delay or prevent the growth of leukemia cells

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: are turn of signs and symptoms of cancer after a period of treatment or 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 effects: Any undesirable experience associated with the use of a medical product in a patient

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

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 a type of white blood cell.


1. What are clinical trials and studies? National Institute on Aging. Accessed March 15, 2021.

2. What is chronic lymphocytic leukemia? American Cancer Society. Updated May 10, 2018. Accessed March 15, 2021.

3. Signs and symptoms of chronic lymphocytic leukemia. American Cancer Society. Updated May 10, 2018. Accessed March 15, 2021.

4. Chronic lymphocytic leukemia treatment (PDQ)-patient version. National Cancer Institute. Updated November 25, 2020. Accessed March 15, 2021.

5. Chronic lymphocytic leukemia. Leukemia and Lymphoma Society. Updated 2014. Accessed March 15, 2021.

6. LOXO-305. LOXO Oncology. Accessed March 15, 2021.

7. A study of oral LOXO-305 in patients with previously treated CLL/SLL or NHL. November 14, 2018. Accessed March 15, 2021.

8. Mato AR, Pagel JM, Coombs CC, et al. LOXO-305, a next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: results from the phase 1/2 BRUIN study. Presented at: 62nd ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 542.

Supported by Bristol Myers Squibb

Sponsored by Loxo Oncology at Lilly

Funding provided by an unrestricted educational grant from Pharmacyclics, an AbbVie Company and Janssen Biotech, Inc.