Phase 3 Randomized Study of Pirtobrutinib vs. Bendamustine and Rituximab in Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
- Trial ID
- 2024-511599-33-00
- Protocol
- LOXO-BTK-20023
- Sponsor
- Loxo Oncology Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3 study is to evaluate the **progression-free survival (PFS)** of pirtobrutinib as monotherapy (Arm A) compared to the combination of bendamustine plus rituximab (Arm B) in patients with **Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)**. This objective is clinically relevant as PFS is a critical endpoint in assessing the efficacy of cancer treatments, providing insights into the duration a patient lives without disease progression.
Secondary objectives include:
- Evaluating the effectiveness of Arm A compared to Arm B based on the overall response rate (ORR) and time to event(s) outcomes.
- Assessing the effectiveness of Arm A compared to Arm B based on patient-reported outcomes.
- Evaluating the safety and tolerability of each treatment arm.
Participants
The clinical trial involves a total of **116 participants** diagnosed with **Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma**. The study population includes both male and female subjects, aged **18 years or older**, as per local regulations at the time of enrollment. Participants were selected based on a confirmed diagnosis of CLL/SLL, with specific disease characteristics as defined by iwCLL 2018 criteria. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. Participants must have adequate organ function and meet specific washout periods for prior treatments. The trial population is diverse, including vulnerable populations, and requires adherence to contraception guidelines for women of childbearing potential and their partners. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, controlled study to evaluate the efficacy of **pirtobrutinib** compared to a combination of **bendamustine hydrochloride** and **rituximab** in patients with untreated **Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma** (CLL/SLL). The trial aims to assess progression-free survival (PFS) as the primary endpoint, with evaluations conducted according to the iwCLL 2018 response criteria. The study is expected to span approximately four years, with an estimated end date in January 2026.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, diagnosis, and organ function. Following successful screening, participants will be randomized into one of two treatment arms: Arm A receiving pirtobrutinib monotherapy, or Arm B receiving bendamustine plus rituximab. The treatment period for Arm A is up to 52 weeks, while Arm B is limited to 6 cycles, each cycle lasting 28 days. Study visits will occur regularly to monitor safety, efficacy, and adherence to the treatment protocol.
Follow-up visits will be scheduled to assess ongoing response to treatment and to monitor for any adverse events. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the overall treatment outcomes. Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination, such as significant adverse reactions, withdrawal of consent, or non-compliance with study procedures.
Participant involvement is anticipated to last up to 52 weeks for those in Arm A and approximately 6 months for those in Arm B, with additional follow-up as required. Conditions that may lead to early termination include the development of unacceptable toxicity, disease progression, or any other medical condition that, in the investigator's judgment, warrants discontinuation of the study treatment.
Treatment
The clinical trial involves the administration of **RITUXIMAB**, a monoclonal antibody used in the treatment of certain types of cancer. RITUXIMAB is administered in the form of an intravenous infusion. The dosage is calculated based on body surface area, with a maximum daily dose of 500 mg/m² and a total maximum dose of 2875 mg/m² over a treatment period of up to 6 months. The pharmaceutical form is designated as PHF00230MIG, and the product is specifically relabeled and repackaged for clinical trial use only. Participant compliance is monitored through regular assessments during the treatment period.
**BENDAMUSTINE HYDROCHLORIDE** is another experimental medication used in this trial. It is a chemotherapy agent administered intravenously, with a dosage also based on body surface area. The maximum daily dose is 90 mg/m², and the total maximum dose is 1080 mg/m² over a 6-month treatment period. Similar to RITUXIMAB, BENDAMUSTINE is relabeled and repackaged for exclusive use in the clinical trial. The pharmaceutical form is PHF00230MIG, and compliance is monitored through scheduled evaluations.
**PIRTOBRUTINIB** is the experimental medication being tested as a monotherapy in this trial. It is administered orally in the form of film-coated tablets. The maximum daily dose is 200 mg, with a total maximum dose of 316600 mg over a treatment period of up to 52 weeks. PIRTOBRUTINIB is not subject to relabeling or repackaging for the trial, and participant adherence to the dosing schedule is closely monitored throughout the study duration.
The trial compares the efficacy of PIRTOBRUTINIB monotherapy against the combination of BENDAMUSTINE and RITUXIMAB in patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. The study aims to evaluate progression-free survival (PFS) as the primary endpoint. No additional non-experimental treatments, such as placebo or standard-of-care therapy, are utilized in this study. Compliance and safety are assessed through regular clinical evaluations and laboratory tests.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of **Progression-Free Survival (PFS)**, as determined by an Independent Review Committee (IRC) using the iwCLL 2018 response criteria. This endpoint is critical in comparing the efficacy of **pirtobrutinib** as monotherapy (Arm A) against the combination of **bendamustine** plus **rituximab** (Arm B) in patients with untreated Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).
The trial is designed as a Phase 3 open-label, randomized study, with the primary objective of evaluating PFS. The assessment of PFS will be conducted at specified intervals throughout the trial duration, which is estimated to conclude by January 2026. The trial will adhere to the iwCLL 2018 criteria, ensuring that the evaluation of disease progression and response is consistent and standardized across all participants.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age 18 years or older per local regulations at time of enrollment. Type of Patient and Disease Characteristics
- Confirmed diagnosis by redacted local laboratory report of CLL/SLL as defined by iwCLL 2018 criteria including the following: a) B-cells co-express CD5 and CD23; express at least one B-cell antigen (CD19 or CD20) and be either κ or λ light-chain restricted. Atypical cases may be considered with Sponsor approval. b) ≥ 5 × 109 B lymphocytes/L (5000/μL) in the peripheral blood for CLL patients. For SLL patients, <5 × 109 B cells/L (5000/μL) in the peripheral blood is allowed. c) Prolymphocytes may comprise ≤ 55% of blood lymphocytes (for CLL patients).
- A requirement for therapy consistent with iwCLL 2018 criteria for initiation of therapy such that at least 1 of the following should be met: a) Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (such as hemoglobin < 10 g/dL) and/or thrombocytopenia (such as platelets ≤ 100 × 109/L). b) Massive (i.e., spleen edge ≥ 6 cm below the left costal margin) or progressive or symptomatic splenomegaly (> 13 cm). c) Massive nodes (i.e., ≥ 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy. d) Progressive lymphocytosis with an increase of > 50% over a 2-month period, or lymphocyte doubling time < 6 months. Factors contributing to lymphocytosis other than CLL/SLL (e.g., infections, steroid administration) should be excluded. e) Autoimmune complications including anemia or thrombocytopenia poorly responsive to corticosteroids. f) Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine). g) Disease-related symptoms (also known as B-symptoms) as defined by any of the following: i) Unintentional weight loss ≥ 10% within the previous 6 months. ii) Significant fatigue (i.e., Eastern Cooperative Oncology Group [ECOG] performance scale 2 or worse; cannot work or unable to perform usual activities). iii) Fevers ≥ 100.5°F or 38.0°C for 2 or more weeks without evidence of infection. iv) Night sweats for ≥ 1 month without evidence of infection.
- Eastern Cooperative Oncology Group (ECOG) 0-2.
- Must have adequate organ function, as defined below. Results from the most recent laboratory tests prior to enrollment will be used for eligibility.
- Patients are required the have had the following washout periods prior to planned C1D1: a) Palliative limited field radiation: 7 days b) Broad field radiation (≥ 30% of bone marrow or whole brain radiotherapy): 28 days Contraception
- Willingness women of childbearing potential (WOCBP), and their partners, to both observe barrier method and highly effective birth control methods as outlined in Section 10.2 (Appendix 2; and below) for the duration of treatment and for 1 month following the last dose of pirtobrutinib or 12 months after the last dose of rituximab, whichever is later. WOCBP are defined as women following menarche, and who are not postmenopausal (or 2 years of non-therapy-induced amenorrhea, or surgically sterile). WOCBP must utilize 2 effective contraception methods with at least 1 form of highly effective contraception method as outlined below. In addition, male partners must use a barrier method (condoms) for the duration of treatment and for 1 month following the last dose of study treatment or 12 months after the last dose of rituximab. Male patients enrolled in Arm B with partners who are WOCBP must use a barrier method (condoms) and their partner must also use a highly effective form of contraception as listed below for the duration of treatment and for 12 months after the last dose of rituximab. For further please refer to Protocol.
Exclusion Criteria
- Known or suspected Richter's transformation to diffuse large B-cell lymphoma (DLBCL), prolymphocytic leukemia, or Hodgkin lymphoma at any time preceding enrollment.
- Presence of 17p deletion by fluorescence in-situ hybridization (FISH) (refer to Section 8.10.2)
- Known or suspected history of central nervous system (CNS) involvement by CLL/SLL.
- Active second malignancy. Patients with treated second malignancy who are in remission with life expectancy > 2 years and with documented Sponsor approval are eligible. Examples include: a) Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current evidence of disease. b) Adequately treated cervical carcinoma in situ without current evidence of disease. c) Localized (e.g., lymph node negative) breast cancer treated with curative intent with no evidence of active disease present for more than 3 years and receiving adjuvant hormonal therapy. d) Localized prostate cancer undergoing active surveillance. e) History of treated and cured Hodgkin's disease or NHL within 5 years from diagnosis.
- Major surgery, within 4 weeks of planned start of study treatment.
- A significant history of renal, neurologic, psychiatric, endocrine, metabolic or immunologic, that, in the opinion of the Investigator, would adversely affect the patient's participation in this study or interpretation of study outcomes.
- Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP]) not on a stable regimen and dose for at least 4 weeks prior to study enrollment
- Significant cardiovascular disease defined as any of the following: a) Unstable angina or acute coronary syndrome within the past 2 months, b) History of myocardial infarction within 3 months prior to planned start of study drug, c) Documented LVEF by any method of ≤ 40% d) ≥ Grade 3 NYHA functional classification system of heart failure, uncontrolled or symptomatic arrhythmias
- Prolongation of the QT interval corrected (QTc) for heart rate using Fredericia's Formula (QTcF) > 470 msec on at least 2 of 3 consecutive ECGs, and mean QTcF > 470 msec on all 3 ECGs, during Screening. a) QTcF is calculated using Fredericia's Formula (QTcF = QT/(RR^0.33) b) Correction of suspected drug-induced QTcF prolongation or prolongation due to electrolyte abnormalities can be attempted at the Investigator's discretion, and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation or electrolyte supplementation. c) Correction of QTc for underlying bundle branch block (BBB) permissible.
- Hepatitis B or hepatitis C testing indicating active/ongoing infection based on Screening laboratory tests as defined as: a) Hepatitis B virus (HBV): Patients with positive hepatitis B surface antigen (HBsAg) are excluded. Patients with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require hepatitis B Polymerase chain reaction (PCR) evaluation before randomization. Patients who are hepatitis B PCR positive will be excluded. b) Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody result, patient will need to have a negative result for hepatitis C ribonucleic acid (RNA) before randomization. Patients who are hepatitis C RNA positive will be excluded. c) For optional crossover, repeat testing is not required.
- Active cytomegalovirus (CMV) infection.
- Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, or fungal) or other clinically significant active disease process which in the opinion of the Investigator and Medical Monitor may pose a risk for patient participation. Screening for chronic conditions is not required.
- Known Human Immunodeficiency Virus (HIV) infection, regardless of CD4 count. Patients with unknown or negative status are eligible.
- Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the oral administered study treatments. Please refer to Protocol.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 28 Mar 2022 | 6 |
 Bulgaria | Not Recruiting | 28 Mar 2022 | 11 |
 Czechia | Not Recruiting | 28 Mar 2022 | 7 |
 France | Not Recruiting | 28 Mar 2022 | 2 |
 Hungary | Not Recruiting | 28 Mar 2022 | 5 |
 Italy | Not Recruiting | 28 Mar 2022 | 23 |
 Poland | Not Recruiting | 28 Mar 2022 | 93 |
 Portugal | Not Recruiting | 28 Mar 2022 | 4 |
 Romania | Not Recruiting | 28 Mar 2022 | 7 |
 Spain | Not Recruiting | 28 Mar 2022 | 8 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
PIRTOBRUTINIB | Test | — | ORAL USE | 200 | 52 | SUB215610 |
PIRTOBRUTINIB | Test | — | ORAL USE | 200 | 52 | SUB215610 |
BENDAMUSTINE | Comparator | PHF00230MIG | INTRAVENOUS USE | 90 | 6 | SCP20211730 |
RITUXIMAB | Comparator | PHF00230MIG | INTRAVENOUS USE | 500 | 6 | SCP24437829 |