The study consists of two parts. Part 1 determines the safety and tolerability of sonrotoclax monotherapy, the maximum tolerated dose, and the recommended Phase 2 dose of sonrotoclax monotherapy for relapsed or refractory mantle cell lymphoma. Part 2 evaluates efficacy of sonrotoclax monotherapy at the recommended Phase 2 dose with recommended ramp-up schedule from Part 1.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
125
Administered orally
Part 1: Number of Participants Experiencing Dose-limiting Toxicities (DLTs)
DLTs included the following events without a clear alternative cause other than study drug: Hematologic Toxicity: * Grade ≥ 3 febrile neutropenia; * Grade ≥ 3 thrombocytopenia lasting \> 7 days or resulting in clinically significant bleeding; * Any Grade ≥ 4 hematological toxicities, except for Grade 4 neutropenia lasting ≤ 7 days with or without treatment, Grade 4 lymphopenia, or Grade 4 leukopenia. Nonhematologic Toxicity: • Any Grade ≥ 3 nonhematologic toxicity with the following exceptions: * Laboratory tumor lysis syndrome (TLS) defined by the Howard criteria that resolves (≤ Grade 1 or baseline) in ≤ 3 days; * Individual TLS-related laboratory adverse events that resolve (≤ Grade 1or baseline) in ≤ 3 days with or without treatment; * Grade 3 gastrointestinal toxicity that resolves to ≤ Grade 2 following therapeutic intervention in ≤ 7 days; * Asymptomatic biochemical laboratory abnormalities that resolve (≤ Grade 1 or baseline) in ≤ 7 days with or without supportive care.
Time frame: From first dose in the ramp-up period through the first 3 weeks of treatment at the target dose (approximately 7 weeks)
Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events Leading to Treatment Discontinuation
An adverse event is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study drug, whether considered related to study drug or not. A serious adverse event is any untoward medical occurrence that, at any dose: * Resulted in death * Was life-threatening * Required hospitalization or prolongation of existing hospitalization. * Resulted in disability/incapacity. * Was a congenital anomaly/birth defect. * Was considered a significant medical adverse event by the investigator or sponsor based on medical judgment.
Time frame: From first dose of study drug up to 30 days after last dose or the primary analysis data cut-off date, whichever occurred earlier; maximum duration of treatment was 31 months.
Part 1: Number of Participants Experiencing Tumor Lysis Syndrome (TLS) Adverse Events
Tumor lysis syndrome (TLS) occurs when large numbers of cancer cells die rapidly, releasing their contents (such as potassium, phosphorus, and nucleic acids) into the bloodstream faster than the kidneys can filter them out. This rapid breakdown causes a dangerous chain reaction of metabolic and electrolyte imbalances.
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University of Alabama At Birmingham Hospital
Birmingham, Alabama, United States
Fort Wayne Medical Oncology and Hematology
Fort Wayne, Indiana, United States
Tulane Cancer Center
New Orleans, Louisiana, United States
Maryland Oncology Hematology, Pa
Columbia, Maryland, United States
Hackensack University Medical Center
Hackensack, New Jersey, United States
The University of Texas Md Anderson Cancer Center
Houston, Texas, United States
Hospital Aleman
Ciudad Autonoma Buenos Aires, Argentina
University Hospitals Leuven
Leuven, Belgium
Hospital Erasto Gaertner
Curitiba, Brazil
Hospital Mae de Deus
Porto Alegre, Brazil
...and 55 more locations
Time frame: From first dose of study drug up to 30 days after last dose or the primary analysis data cut-off date, whichever occurred earlier; maximum duration of treatment was 31 months.
Part 2: Overall Response Rate (ORR) as Assessed by the Independent Review Committee (IRC)
ORR is defined as the percentage of participants who achieved a complete response (CR) or partial response (PR) per the Lugano Classification for non-Hodgin lymphoma.
Time frame: Response was assessed 8 and 16 weeks after the first dose, then every 12 weeks up to 1 year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in Part 2 was 14.2 (0.3-24.9) months.
Part 1: Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUClast) of Sonrotoclax After a Single Dose
Time frame: Ramp-up Week 1 Day 1 at predose, 2, 4, 6, and 8 hours post-dose
Part 1: Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUClast) of Sonrotoclax at Steady-State
Time frame: Target Dose Week 4 Day 1 at predose, 2, 4, 6, and 8 hours post-dose
Part 1: Time to Maximum Observed Concentration of Sonrotoclax (Tmax) After a Single Dose
Time frame: Ramp-up Week 1 Day 1 at predose, 2, 4, 6, and 8 hours post-dose
Part 1: Time to Maximum Observed Concentration of Sonrotoclax (Tmax) at Steady State
Time frame: Target Dose Week 4 Day 1 at predose, 2, 4, 6, and 8 hours post-dose
Part 1: Maximum Observed Plasma Concentration (Cmax) of Sonrotoclax After a Single Dose
Time frame: Ramp-up Week 1 Day 1 at predose, 2, 4, 6, and 8 hours post-dose
Part 1: Maximum Observed Plasma Concentration (Cmax) at Steady State
Time frame: Target Dose Week 4 Day 1 at predose, 2, 4, 6, and 8 hours post-dose
Part 1: Trough Plasma Concentration (Ctrough) at Steady State
Time frame: Target Dose Week 4 Day 1 at predose
Part 1: Overall Response Rate Assessed by the Independent Review Committee (IRC)
ORR is defined as the percentage of participants who achieved a complete response (CR), or partial response (PR) per the Lugano classification for non-Hodgkin lymphoma. IRC review for response assessments was only performed for Part 1 participants assigned to the 320 mg dose level.
Time frame: Response was assessed 8 and 16 weeks after the first dose, then every 12 weeks up to one year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in Part 1 was 10.7 (0.1-31.6) months.
Part 1: Overall Response Rate Assessed by the Investigator
ORR is defined as the percentage of participants who achieved a complete response (CR), or partial response (PR) per Lugano classification for non-Hodgkin lymphoma.
Time frame: Response was assessed 8 and 16 weeks after the first dose, then every 12 weeks up to one year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in Part 1 was 10.7 (0.1-31.6) months.
Part 1: Duration of Response (DOR) Assessed by the IRC
DOR is defined as the time from the date of the first documented response (PR or better) after treatment initiation until the date of first documented disease progression or death due to any cause; whichever occurred first, per the Lugano classification for non-Hodgkin lymphoma. IRC review for response assessments was only performed for Part 1 participants assigned to the 320 mg dose level. DOR was estimated using the Kaplan-Meier method.
Time frame: Response was assessed 8 and 16 weeks after the first dose, then every 12 weeks up to one year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in Part 1 was 10.7 (0.1-31.6) months.
Part 1: Duration of Response Assessed by the Investigator
DOR is defined as the time from the date of the first documented response (PR or better) after treatment initiation until the date of first documented disease progression or death due to any cause, whichever occurred first. DOR was estimated using the Kaplan-Meier method.
Time frame: Response was assessed 8 and 16 weeks after the first dose, then every 12 weeks up to one year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in Part 1 was 10.7 (0.1-31.6) months.
Part 1: Progression Free Survival (PFS) Assessed by the IRC
PFS is defined as the time from the date of the first study dose until the date of first documented disease progression or death due to any cause, whichever occurred first. IRC review for response assessments was only performed for Part 1 participants assigned to the 320 mg dose level. PFS was estimated using the Kaplan-Meier method.
Time frame: From first dose until the data cut-off date; median (range) time on follow-up in efficacy-evaluable participants in Part 1 was 10.7 (0.1-31.6) months.
Part 1: Progression-free Survival Assessed by the Investigator
PFS is defined as the time from the date of the first study dose until the date of first documented disease progression or death due to any cause, whichever occurred first. PFS was estimated using the Kaplan-Meier method.
Time frame: From first dose until the data cut-off date; median (range) time on follow-up in efficacy-evaluable participants in Part 1 was 10.7 (0.1-31.6) months.
Part 1: Time to Response (TTR) as Assessed by the IRC
Time to response is defined as the time from start of treatment to first documentation of response (PR or better). IRC review for response assessments was only performed for Part 1 participants assigned to the 320 mg dose level.
Time frame: Response was assessed 8 and 16 weeks after the first dose, then every 12 weeks up to one year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in part 1 was 10.7 (0.1-31.6) months.
Part 1: Time to Response Assessed by the Investigator
TTR is defined as the time from start of treatment to first documentation of response (PR or better).
Time frame: Response was assessed 8 and 16 weeks after the first dose, then every 12 weeks up to one year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in Part 1 was 10.7 (0.1-31.6) months.
Part 1: Overall Survival (OS)
Overall survival is defined as the time from the start of treatment to the date of death due to any cause. OS was estimated using the Kaplan-Meier method.
Time frame: From first dose until the data cut-off date; median (range) time on follow-up in efficacy-evaluable participants in Part 1 was 10.7 (0.1-31.6) months.
Part 2: Overall Response Rate (ORR) Assessed by the Investigator
ORR is defined as the percentage of participants who achieved a complete response (CR) or partial response (PR) per the Lugano Classification for non-Hodgin lymphoma.
Time frame: Response was assessed at 8 and 16 weeks after the first dose, then every 12 weeks up to 1 year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in Part 2 was 14.2 (0.3-24.9) months.
Part 2: Duration of Response Assessed by the IRC
Duration of response is defined as the time from the date of the first documented response (PR or better) after treatment initiation until the date of first documented disease progression or death due to any cause, whichever occurred first. DOR was estimated using the Kaplan-Meier method.
Time frame: Response was assessed at 8 and 16 weeks after the first dose, then every 12 weeks up to 1 year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in Part 2 was 14.2 (0.3-24.9) months.
Part 2: Duration of Response Assessed by the Investigator
Duration of response is defined as the time from the date of the first documented response (PR or better) after treatment initiation until the date of first documented disease progression or death due to any cause, whichever occurred first. DOR was estimated using the Kaplan-Meier method.
Time frame: Response was assessed at 8 and 16 weeks after the first dose, then every 12 weeks up to 1 year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in Part 2 was 14.2 (0.3-24.9) months.
Part 2: Progression-free Survival Assessed by the IRC
PFS is defined as the time from the date of the first study dose until the date of first documented disease progression or death due to any cause, whichever occurred first. PFS was estimated using the Kaplan-Meier method.
Time frame: From first dose of study drug until the data cut-off date; median (range) time on follow-up in efficacy-evaluable participants in Part 2 was 14.2 (0.3-24.9) months.
Part 2: Progression-free Survival Assessed by the Investigator
PFS is defined as the time from the date of the first study dose until the date of first documented disease progression or death due to any cause, whichever occurred first. PFS was estimated using the Kaplan-Meier method.
Time frame: From first dose of study drug until the data cut-off date; median (range) time on follow-up in efficacy-evaluable participants in Part 2 was 14.2 (0.3-24.9) months.
Part 2: Time to Response Assessed by the IRC
Time to response is defined as the time from start of treatment to first documentation of response (PR or better).
Time frame: Response was assessed at 8 and 16 weeks after the first dose, then every 12 weeks up to 1 year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in Part 2 was 14.2 (0.3-24.9) months.
Part 2: Time to Response Assessed by the Investigator
Time to response is defined as the time from start of treatment to first documentation of response (PR or better).
Time frame: Response was assessed at 8 and 16 weeks after the first dose, then every 12 weeks up to 1 year, every 24 weeks for 2 years, and yearly thereafter; median (range) time on follow-up in efficacy-evaluable participants in Part 2 was 14.2 (0.3-24.9) months.
Part 2: Overall Survival
Overall survival is defined as the time from the start of treatment to the date of death due to any cause. OS was estimated using the Kaplan-Meier method.
Time frame: From first dose of study drug until the data cut-off date; median (range) time on follow-up in efficacy-evaluable participants in Part 2 was 14.2 (0.3-24.9) months.
Part 2: Change From Baseline in National Comprehensive Cancer Network - Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (NFlymSI-18) Disease Related Symptoms-Physical (DRS-P) Sub-scale Score
The NFlymSI-18 is a patient-reported outcome questionnaire that was developed to measure disease-specific symptoms and/or treatment-related concerns in patients with advanced lymphoma. The NFLymSI-18 questionnaire includes 18 separate questions about disease symptoms in the last 7 days; participants are asked to respond to each question on a scale from 0 (Not at all) to 4 (Very much). The 18 questions are grouped into 4 subscale scores: "Disease related symptoms - physical," "Disease related symptoms - emotional," "Treatment side effects," and "Function and wellbeing." The Disease Related Symptoms - Physical subscale score ranges from 0 to 36, where higher scores indicate better health-related quality of life (HRQoL).
Time frame: Baseline and Weeks 4, 12, and 24
Part 2: Change From Baseline in National Comprehensive Cancer Network - Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (NFlymSI-18) Treatment Side-Effects (TSE) Sub-scale Score
The NFlymSI-18 is a patient-reported outcome questionnaire that was developed to measure disease-specific symptoms and/or treatment-related concerns in patients with advanced lymphoma. The NFLymSI-18 questionnaire includes 18 separate questions about disease symptoms in the last 7 days; participants are asked to respond to each question on a scale from 0 (Not at all) to 4 (Very much). The 18 questions are grouped into 4 subscale scores: "Disease related symptoms - physical," "Disease related symptoms - emotional," "Treatment side effects," and "Function and wellbeing." The Treatment Side-Effects subscale score ranges from 0 to 12, where higher scores indicate better health-related quality of life (HRQoL).
Time frame: Baseline and Weeks 4, 12, and 24
Part 2: Change From Baseline in European Quality of Life 5 Dimension (EQ-5D) Visual Analog Scale (VAS) Score
The EQ-5D VAS measures participants' self-rated health status on a scale from 0 to 100, with 100 = 'the best health you can imagine' and 0 = 'the worst health you can imagine'. Higher scores on VAS indicate higher health status.
Time frame: Baseline and Weeks 4, 12, and 24
Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events Leading to Treatment Discontinuation
An adverse event is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study drug, whether considered related to study drug or not. A serious adverse event is any untoward medical occurrence that, at any dose: * Resulted in death * Was life-threatening * Required hospitalization or prolongation of existing hospitalization. * Resulted in disability/incapacity. * Was a congenital anomaly/birth defect. * Was considered a significant medical adverse event by the investigator or sponsor based on medical judgment.
Time frame: From first dose of study drug up to 30 days after last dose or the data cut-off date, whichever occurred earlier; maximum duration of treatment in Part 2 was 24.8 months.