CLL : Episode 1

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


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


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 treatment failure can occur if the patient develops resistance to the therapy. In some patients, treatment may need to be discontinued because of 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 experienced treatment failure or are not able to tolerate standard-of-care therapies. As of May 2021, pirtobrutinib was not FDA approved drug, but it is currently being studied in clinical trials.

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

The BRUIN trial was an open-label, multicenter phase 1/2 study that aimed to find the highest dose of pirtobrutinib 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

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

The BRUIN trial was broken into three parts7,8:

  • Phase 1: pirtobrutinib monotherapy dose escalation and dose expansion.
  • Phase 1b: pirtobrutinib combination therapy dose expansion.
  • Phase 2: pirtobrutinib monotherapy dose expansion.

In phase 1, the starting dose of pirtobrutinib was 25 milligrams each day in an oral tablet form. Patients were treated with seven increasing dose levels of pirtobrutinib that ranged from 25 milligrams to 300 milligrams daily until the highest dose with acceptable side effects — also known as the maximum tolerated dose — was determined. This pirtobrutinib 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 pirtobrutinib measured by a decrease in the number of cancer cells or the total disappearance of cancer cells. Of the 94 total patients treated with pirtobrutinib, 88 remained on treatment at the time of data collection. A total of 65 patients had their tumors assessed for response to pirtobrutinib.

At a median follow up of 6.7 months, the overall response rate was 57% with pirtobrutinib (Figure 2).8 Of these patients, 23 achieved a partial response and 14 achieved a partial response with lymphocytosis, which means no signs of progressive disease other than lymphocytosis. The longest-followed responding patient was still responding to treatment after 13.5 months.

Responses to pirtobrutinib 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. Patients who previously discontinued a BTK inhibitor because of disease progression or intolerance of side effects demonstrated a response to pirtobrutinib in the BRUIN trial. Moreover, the 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 pirtobrutinib.

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 pirtobrutinib treatment were fatigue (tiredness) in 29 patients and diarrhea in 28 patients.8

Pirtobrutinib demonstrated promising efficacy in patients with CLL or SLL who had received multiple lines of prior therapy and who generally had a poorer prognosis. In March 2021, the final results of the BRUIN phase 1/2 trial were published in the medical journal Lancet.9 Pirtobrutinib will continue to be evaluated in the phase 3 BRUIN CLL-321 trial, comparing pirtobrutinib to either idelalisib or bendamustine in combination with rituximab in patients with CLL/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.


Glossary of Terms1-8

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

BTK inhibitors: BTK inhibitors are medications that are taken orally and block a the BTK protein in B cells. FDA-approved BTK inhibitors used for patients with CLL/SLL are Imbruvica (ibrutinib), Calquence (acalabrutinib), and Brukinsa (zanubrutinib).

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.

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 trials: 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 those interventions 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

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

LOXO 305 (pirtobrutinib): a highly selective BTK inhibitor being investigated in clinical trials to help address the challenge of resistance to therapy in patients with CLL who have experienced treatment failure or are not able to tolerate standard of care therapies.

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

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

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

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

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: 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

Venclexta (venetoclax): an oral prescription medicine used to treat adults with CLL/SLL. It targets specific proteins (BCL-2) on CLL cells and signals these cells to self‑destruct.

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 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.


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. Accessed May 19, 2021.

9. Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901. doi:10.1016/S0140-6736(21)00224-5