Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma
Conditions
Keywords
Hematologic Disease, Lymphoma, non-Hodgkin's, Lymphoma, B-cell, Lymphoma, Bruton's tyrosine kinase inhibitor, Ibrutinib, Acalabrutinib, Zanubrutinib, Pirtobrutinib
Brief summary
This is a study for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have previously received treatment with at least a BTK inhibitor. The main purpose is to compare LOXO-305 to idelalisib plus rituximab or bendamustine plus rituximab. Participation could last up to four years, and possibly longer, if the disease does not progress.
Detailed description
This is a Phase 3 global, randomized, open-label study comparing LOXO-305 (Arm A) to investigator's choice of either idelalisib plus rituximab or bendamustine plus rituximab (Arm B) in CLL/SLL patients who have been treated with at least a covalent BTK inhibitor (BTKi). Patients may have discontinued the prior covalent BTKi due to disease progression (PD) or intolerance. Patients who have received venetoclax are eligible for the study. Eligible patients will be randomized in 1:1 to Arm A or Arm B.
Interventions
DRUGPirtobrutinib
Oral Pirtobrutinib
DRUGIdelalisib
Oral
DRUGBendamustine
IV
DRUGRituximab
IV
Sponsors
Loxo Oncology, Inc.
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Eligible patients will be randomized in 1:1 into Arm A or Arm B. Patients randomized to Arm B who have disease progression (PD) confirmed by independent review committee (IRC) may be eligible to crossover into Arm A. Patients who discontinue treatment for toxicity may still be evaluated for cross over at the time of IRC-confirmed PD.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of CLL/SLL requiring therapy as defined by iwCLL 2018 criteria. * Previously treated with a covalent BTK inhibitor. * Eastern Cooperative Oncology Group (ECOG) 0-2. * Absolute neutrophil count ≥ 0.75 × 10\^9/L without granulocyte-colony-stimulating factor support, or ≥ 0.50 × 10\^9/L in patients with documented bone marrow involvement considered to impair hematopoiesis. Granulocyte-colony-stimulating factor support is permitted in patients with documented bone marrow involvement. * Hemoglobin ≥ 8 g/dL or ≥ 6 g/dL in patients with documented bone marrow involvement considered to impair hematopoiesis. Transfusion support is permitted in patients with bone marrow involvement. * Platelets ≥ 50 × 10\^9/L. If an investigator has chosen bendamustine/rituximab as the Arm B treatment, platelets must be ≥ 75 × 10\^9/L. Patients may enroll below these thresholds if the Investigator determines the cytopenia is related to bone marrow involvement considered to impair hematopoiesis. Patients with a platelet count \< 30 x 10\^9/L are excluded. * AST and ALT ≤ 3.0 x upper limit of normal (ULN). * Total bilirubin ≤ 1.5 x ULN. * Estimated creatinine clearance of ≥ 30 mL/min.
Exclusion criteria
* Known or suspected Richter's transformation at any time preceding enrollment. * Known or suspected history of central nervous system (CNS) involvement by CLL/SLL. * Ongoing drug-induced liver injury. * Active uncontrolled auto-immune cytopenia. * Significant cardiovascular disease. * History of allogeneic or stem cell transplantation (SCT) or chimeric antigen receptor-modified T cells (CAR-T) therapy within the past 60 days. * Active hepatitis B or hepatitis C. * Known active cytomegalovirus (CMV) infection. * Active uncontrolled systemic bacterial, viral, fungal or parasitic infection. * Known Human Immunodeficiency Virus (HIV) infection, regardless of CD4 count. * Clinically significant active malabsorption syndrome or inflammatory bowel disease * Prior exposure to non-covalent (reversible) BTK inhibitor. * Patients requiring therapeutic anticoagulation with warfarin or another Vitamin K antagonist. * Current treatment with strong cytochrome P450 (CYP) 3A4 (CYP3A4) inhibitors or inducers. * Vaccination with a live vaccine within 28 days prior to randomization. * Patients with the following hypersensitivity: 1. Known hypersensitivity, including anaphylaxis, to any component or excipient of LOXO-305. For patients planned to receive idelalisib, known hypersensitivity, including anaphylaxis, to any component or excipient of idelalisib. For patients planned to receive bendamustine, known hypersensitivity, including anaphylaxis, to any component or excipient of bendamustine. 2. Prior significant hypersensitivity to rituximab.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Assessed by Independent Review Committee (IRC) | Randomization to Disease Progression or Death Due to Any Cause (Up to 29 Months) | PFS is defined as the time from the date of randomization to the date of first documentation of progressive disease (PD) or death from any cause, as evaluated by an IRC according to International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PFS Assessed by Investigator | Randomization to Disease Progression or Death Due to Any Cause (Up to 36 Months) | PFS is defined as time from the date of randomization to the date of first documentation of PD or death from any cause, as evaluated by an investigator according to iwCLL 2018. |
| Overall Survival (OS) | Randomization to Death from Any Cause (Up to 36 months) | OS was defined as time from randomization to death due to any cause. |
| Time to Next Treatment (TTNT) | Randomization to Subsequent Anticancer Therapy, Therapy of Pirtobrutinib or Death Due to Any Cause (Up to 36 Months) | TTNT was defined as time from the date of randomization to the date of initiation of the subsequent anticancer therapy for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), therapy of pirtobrutinib for Arm B patients, or death due to any cause, whichever occurs first. |
| Event Free Survival (EFS) | Randomization to Disease Progression, Subsequent Anticancer Therapy, Unacceptable Toxicity Leading to Treatment Discontinuation, or Death Due to Any Cause (Up to 36 Months) | EFS is defined as the time from randomization to the first occurrence of: * Documented disease progression per iwCLL 2018 criteria as assessed by Investigator; or * Initiation of subsequent anticancer therapy for CLL/SLL; or * Unacceptable toxicity leading to treatment discontinuation as assessed by the Investigator; or * Death (due to any cause). |
| Percentage of Participants With Overall Response Rate (ORR) Assessed by Investigator | Randomization to Subsequent Anticancer Therapy, Disease Progression or Death Due to Any Cause (Up to 36 Months) | ORR according to investigator-assessed best overall response (BOR) based on iwCLL 2018 is defined as the number of participants who achieve a BOR of complete response (CR), complete response with incomplete bone marrow recovery (CRi), nodular partial response (nPR) or partial response (PR) at or before the initiation of subsequent anticancer therapy divided by the total number of participants randomized to each treatment arm. |
| Time to Worsening (TTW) of CLL/SLL Related Symptoms | Baseline up to Week 25 (Arm A and Arm B - Idelalisib plus Rituximab) & Baseline up to Week 21 + Safety Follow-Up of up to 5 Weeks (Arm B - Bendamustine plus Rituximab) | TTW was defined as a change in score greater than the meaningful within-person change for worsening in score. Scores were furthermore required to be sustained. To meet the requirement for sustained change, the assessment following the first observation of a meaningful worsening of the score (event date) was also required to show a meaningful worsening compared to baseline. The event date was defined as the first of these consecutive events. The European Organization for Research and Treatment of Cancer Item Library 87 was used, which is scored from 0-100, with higher scores reflecting more symptoms. The time to sustained patient-reported outcome (PRO) deterioration was calculated using all on-treatment assessment time points up to the Week 25 (Arm A \& Arm B - Idelalisib plus Rituximab) and up to Week 21 + Safety follow-up of up to 5 weeks (Arm B - Bendamustine plus Rituximab) assessment time point prior to disease progression. |
| Time to Worsening (TTW) of Physical Function | Baseline up to Week 25 (Arm A and Arm B - Idelalisib plus Rituximab) & Baseline up to Week 21 + Safety Follow-Up of up to 5 Weeks (Arm B - Bendamustine plus Rituximab) | Time of worsening was defined as a change in score greater than the meaningful within-person change for worsening in score. Scores were furthermore required to be sustained. To meet the requirement for sustained change, the assessment following the first observation of a meaningful worsening of the score (event date) was also required to show a meaningful worsening compared to baseline. The event date was defined as the first of these consecutive events. The European Organization for Research and Treatment of Cancer Item Library 87 was used, which is scored from 0-100, with higher scores reflecting more symptoms. The time to sustained PRO deterioration was calculated using all on-treatment assessment time points up to the Week 25 (Arm A and IdelaR) and up to Week 21 + Safety follow-up (BR) assessment time point prior to disease progression. |
Countries
Australia, Austria, Belgium, Canada, China, Croatia, Czechia, France, Germany, Hungary, Ireland, Israel, Italy, Japan, Poland, Russia, Singapore, South Korea, Spain, Switzerland, Taiwan, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORMarisa Hill, MD
Loxo Oncology, Inc.
Participant flow
Pre-assignment details
A total of 238 participants were randomized 1:1 to receive either Arm A - pirtobrutinib or Arm B - Idelalisib plus Rituximab or Bendamustine plus Rituximab. The results were reported based on a data cut off from 29 Aug 2024.
Participants by arm
| Arm | Count |
|---|---|
| Arm A - Pirtobrutinib Participants received 200 mg of pirtobrutinib administered orally QD on Days 1 through 28 of a 28-day cycle. The treatment was continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. | 119 |
| Arm B - Idelalisib Plus Rituximab or Bendamustine Plus Rituximab Participants received either 150 mg of idelalisib administered BID orally on Days 1 through 28 of a 28-day cycle in combination with 375 mg/m\^2 of rituximab by IV infusion on day 1 of cycle 1, then 4 IV infusions of rituximab 500 mg/m\^2 Q2W and 3 IV infusions of rituximab 500 mg/m\^2 Q4W or 70 mg/m\^2 of bendamustine administered IV on day 1 and 2 of each 28-day cycle from cycles 1 to 6 in combination with 375 mg/m\^2 of rituximab IV on day 1 of cycle 1, then 500 mg/m\^2 of rituximab on day 1 of each 28-day cycle from cycles 2 to 6. | 119 |
| Total | 238 |
Baseline characteristics
| Characteristic | Arm B - Idelalisib Plus Rituximab or Bendamustine Plus Rituximab | Total | Arm A - Pirtobrutinib |
|---|---|---|---|
| Age, Continuous | 67.00 years STANDARD_DEVIATION 8.52 | 67.00 years STANDARD_DEVIATION 8.91 | 66.90 years STANDARD_DEVIATION 9.32 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 10 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 108 Participants | 215 Participants | 107 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 13 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 15 Participants | 29 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 6 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 10 Participants | 6 Participants |
| Race (NIH/OMB) White | 95 Participants | 193 Participants | 98 Participants |
| Region of Enrollment Australia | 2 participants | 7 participants | 5 participants |
| Region of Enrollment Austria | 1 participants | 2 participants | 1 participants |
| Region of Enrollment Belgium | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Canada | 6 participants | 10 participants | 4 participants |
| Region of Enrollment China | 14 participants | 24 participants | 10 participants |
| Region of Enrollment Croatia | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Czechia | 1 participants | 3 participants | 2 participants |
| Region of Enrollment France | 4 participants | 9 participants | 5 participants |
| Region of Enrollment Germany | 4 participants | 6 participants | 2 participants |
| Region of Enrollment Hungary | 4 participants | 7 participants | 3 participants |
| Region of Enrollment Ireland | 1 participants | 3 participants | 2 participants |
| Region of Enrollment Israel | 0 participants | 2 participants | 2 participants |
| Region of Enrollment Italy | 19 participants | 42 participants | 23 participants |
| Region of Enrollment Japan | 0 participants | 3 participants | 3 participants |
| Region of Enrollment Poland | 17 participants | 31 participants | 14 participants |
| Region of Enrollment Russia | 1 participants | 1 participants | 0 participants |
| Region of Enrollment South Korea | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Spain | 2 participants | 6 participants | 4 participants |
| Region of Enrollment Switzerland | 1 participants | 3 participants | 2 participants |
| Region of Enrollment Taiwan | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Turkey | 1 participants | 2 participants | 1 participants |
| Region of Enrollment United Kingdom | 6 participants | 20 participants | 14 participants |
| Region of Enrollment United States | 33 participants | 53 participants | 20 participants |
| Sex: Female, Male Female | 36 Participants | 72 Participants | 36 Participants |
| Sex: Female, Male Male | 83 Participants | 166 Participants | 83 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 38 / 119 | 32 / 119 |
| other Total, other adverse events | 94 / 116 | 103 / 109 |
| serious Total, serious adverse events | 60 / 116 | 53 / 109 |
Outcome results
Primary
Progression-free Survival (PFS) Assessed by Independent Review Committee (IRC)
PFS is defined as the time from the date of randomization to the date of first documentation of progressive disease (PD) or death from any cause, as evaluated by an IRC according to International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018.
Time frame: Randomization to Disease Progression or Death Due to Any Cause (Up to 29 Months)
Population: All randomized participants, even if a participant did not take the assigned treatment, did not receive the correct treatment, or otherwise did not follow the protocol. Participants were analyzed according to the treatment arm they were assigned to regardless of what actual treatment they received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - Pirtobrutinib | Progression-free Survival (PFS) Assessed by Independent Review Committee (IRC) | 13.96 Months |
| Arm B - Idelalisib Plus Rituximab or Bendamustine Plus Rituximab | Progression-free Survival (PFS) Assessed by Independent Review Committee (IRC) | 8.74 Months |
p-value: 0.000295% CI: [0.385, 0.746]Log Rank
Secondary
Event Free Survival (EFS)
EFS is defined as the time from randomization to the first occurrence of: * Documented disease progression per iwCLL 2018 criteria as assessed by Investigator; or * Initiation of subsequent anticancer therapy for CLL/SLL; or * Unacceptable toxicity leading to treatment discontinuation as assessed by the Investigator; or * Death (due to any cause).
Time frame: Randomization to Disease Progression, Subsequent Anticancer Therapy, Unacceptable Toxicity Leading to Treatment Discontinuation, or Death Due to Any Cause (Up to 36 Months)
Population: All randomized participants, even if a participant did not take the assigned treatment, did not receive the correct treatment, or otherwise did not follow the protocol. Participants were analyzed according to the treatment arm they were assigned to regardless of what actual treatment they received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - Pirtobrutinib | Event Free Survival (EFS) | 14.06 Months |
| Arm B - Idelalisib Plus Rituximab or Bendamustine Plus Rituximab | Event Free Survival (EFS) | 7.62 Months |
p-value: <0.000195% CI: [0.28, 0.534]Log Rank
Secondary
Overall Survival (OS)
OS was defined as time from randomization to death due to any cause.
Time frame: Randomization to Death from Any Cause (Up to 36 months)
Population: All randomized participants, even if a participant did not take the assigned treatment, did not receive the correct treatment, or otherwise did not follow the protocol. Participants were analyzed according to the treatment arm they were assigned to regardless of what actual treatment they received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - Pirtobrutinib | Overall Survival (OS) | 29.67 Months |
| Arm B - Idelalisib Plus Rituximab or Bendamustine Plus Rituximab | Overall Survival (OS) | NA Months |
p-value: 0.720295% CI: [0.679, 1.749]Log Rank
Secondary
Percentage of Participants With Overall Response Rate (ORR) Assessed by Investigator
ORR according to investigator-assessed best overall response (BOR) based on iwCLL 2018 is defined as the number of participants who achieve a BOR of complete response (CR), complete response with incomplete bone marrow recovery (CRi), nodular partial response (nPR) or partial response (PR) at or before the initiation of subsequent anticancer therapy divided by the total number of participants randomized to each treatment arm.
Time frame: Randomization to Subsequent Anticancer Therapy, Disease Progression or Death Due to Any Cause (Up to 36 Months)
Population: All randomized participants, even if a participant did not take the assigned treatment, did not receive the correct treatment, or otherwise did not follow the protocol. Participants were analyzed according to the treatment arm they were assigned to regardless of what actual treatment they received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A - Pirtobrutinib | Percentage of Participants With Overall Response Rate (ORR) Assessed by Investigator | 66.4 percentage of participants |
| Arm B - Idelalisib Plus Rituximab or Bendamustine Plus Rituximab | Percentage of Participants With Overall Response Rate (ORR) Assessed by Investigator | 48.7 percentage of participants |
Secondary
PFS Assessed by Investigator
PFS is defined as time from the date of randomization to the date of first documentation of PD or death from any cause, as evaluated by an investigator according to iwCLL 2018.
Time frame: Randomization to Disease Progression or Death Due to Any Cause (Up to 36 Months)
Population: All randomized participants, even if a participant did not take the assigned treatment, did not receive the correct treatment, or otherwise did not follow the protocol. Participants were analyzed according to the treatment arm they were assigned to regardless of what actual treatment they received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - Pirtobrutinib | PFS Assessed by Investigator | 15.28 Months |
| Arm B - Idelalisib Plus Rituximab or Bendamustine Plus Rituximab | PFS Assessed by Investigator | 9.20 Months |
p-value: <0.000195% CI: [0.338, 0.669]Log Rank
Secondary
Time to Next Treatment (TTNT)
TTNT was defined as time from the date of randomization to the date of initiation of the subsequent anticancer therapy for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), therapy of pirtobrutinib for Arm B patients, or death due to any cause, whichever occurs first.
Time frame: Randomization to Subsequent Anticancer Therapy, Therapy of Pirtobrutinib or Death Due to Any Cause (Up to 36 Months)
Population: All randomized participants, even if a participant did not take the assigned treatment, did not receive the correct treatment, or otherwise did not follow the protocol. Participants were analyzed according to the treatment arm they were assigned to regardless of what actual treatment they received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - Pirtobrutinib | Time to Next Treatment (TTNT) | 23.95 Months |
| Arm B - Idelalisib Plus Rituximab or Bendamustine Plus Rituximab | Time to Next Treatment (TTNT) | 10.91 Months |
p-value: <0.000195% CI: [0.254, 0.524]Log Rank
Secondary
Time to Worsening (TTW) of CLL/SLL Related Symptoms
TTW was defined as a change in score greater than the meaningful within-person change for worsening in score. Scores were furthermore required to be sustained. To meet the requirement for sustained change, the assessment following the first observation of a meaningful worsening of the score (event date) was also required to show a meaningful worsening compared to baseline. The event date was defined as the first of these consecutive events. The European Organization for Research and Treatment of Cancer Item Library 87 was used, which is scored from 0-100, with higher scores reflecting more symptoms. The time to sustained patient-reported outcome (PRO) deterioration was calculated using all on-treatment assessment time points up to the Week 25 (Arm A & Arm B - Idelalisib plus Rituximab) and up to Week 21 + Safety follow-up of up to 5 weeks (Arm B - Bendamustine plus Rituximab) assessment time point prior to disease progression.
Time frame: Baseline up to Week 25 (Arm A and Arm B - Idelalisib plus Rituximab) & Baseline up to Week 21 + Safety Follow-Up of up to 5 Weeks (Arm B - Bendamustine plus Rituximab)
Population: All randomized participants, even if a participant did not take the assigned treatment, did not receive the correct treatment, or otherwise did not follow the protocol. Participants were analyzed according to the treatment arm they were assigned to regardless of what actual treatment they received. Here, Overall Number of Participants Analyzed signifies participants who were evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - Pirtobrutinib | Time to Worsening (TTW) of CLL/SLL Related Symptoms | NA Months |
| Arm B - Idelalisib Plus Rituximab or Bendamustine Plus Rituximab | Time to Worsening (TTW) of CLL/SLL Related Symptoms | NA Months |
Secondary
Time to Worsening (TTW) of Physical Function
Time of worsening was defined as a change in score greater than the meaningful within-person change for worsening in score. Scores were furthermore required to be sustained. To meet the requirement for sustained change, the assessment following the first observation of a meaningful worsening of the score (event date) was also required to show a meaningful worsening compared to baseline. The event date was defined as the first of these consecutive events. The European Organization for Research and Treatment of Cancer Item Library 87 was used, which is scored from 0-100, with higher scores reflecting more symptoms. The time to sustained PRO deterioration was calculated using all on-treatment assessment time points up to the Week 25 (Arm A and IdelaR) and up to Week 21 + Safety follow-up (BR) assessment time point prior to disease progression.
Time frame: Baseline up to Week 25 (Arm A and Arm B - Idelalisib plus Rituximab) & Baseline up to Week 21 + Safety Follow-Up of up to 5 Weeks (Arm B - Bendamustine plus Rituximab)
Population: All randomized participants, even if a participant did not take the assigned treatment, did not receive the correct treatment, or otherwise did not follow the protocol. Participants were analyzed according to the treatment arm they were assigned to regardless of what actual treatment they received. Here, Overall Number of Participants Analyzed signifies participants who were evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - Pirtobrutinib | Time to Worsening (TTW) of Physical Function | NA Months |
| Arm B - Idelalisib Plus Rituximab or Bendamustine Plus Rituximab | Time to Worsening (TTW) of Physical Function | NA Months |