This phase II trial studies how well sotrastaurin acetate works in treating patients with chronic lymphocytic leukemia, small lymphocytic leukemia, prolymphocytic leukemia, or Richter's transformation that has returned or that does not respond to treatment. Sotrastaurin acetate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVES: I. To determine the objective clinical response rate of AEB071 (sotrastaurin acetate) treatment in patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL)/prolymphocytic leukemia (PLL)/Richter's transformation (RT). SECONDARY OBJECTIVES: I. To determine the feasibility and tolerability of long-term administration of a fixed dose of AEB071 in patients with relapsed or refractory CLL/SLL/PLL. II. To examine select downstream pharmacodynamic effects in this population of patients after receiving AEB071 including assessment of the wingless-type MMTV integration site family (WNT) signaling pathway. III. To determine the feasibility and tolerability of AEB071 treatment in patients with relapsed or refractory mantle cell lymphoma (MCL) as well as to gain preliminary data regarding efficacy in this patient population. TERTIARY OBJECTIVES: I. Determine the proportion of patients with select germline and somatic deoxyribonucleic acid (DNA) alterations, including in the B-cell receptor (BCR) pathway. II. Determine how mutational and transcriptional status in key genes affects response to this therapy and may have affected response to prior therapies. OUTLINE: Patients receive sotrastaurin acetate orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then at least every 3 months thereafter.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Given PO
Correlative studies
Correlative studies
Proportion of CLL/SLL/PLL/RT patients who achieve an objective clinical response, estimated by the number of complete, partial, or partial responses with lymphocytosis divided by the total number of evaluable patients
Categories of response for CLL and PLL patients defined according to criteria published by the International Workshop on CLL. Response for SLL/RT patients will be according to revised response criteria for malignant lymphoma. The objective response rate for all evaluable patients in the phase II study will be calculated with an exact 95% binomial confidence interval (assuming that the number of patients who respond is binomially distributed).
Time frame: Up to 9 months
Response duration
For CLL and PLL patients, defined according to the criteria published by the International Workshop on CLL with the modification outlined by Cheson et al. For SLL/RT patients, responses will be according to revised response criteria for malignant lymphoma. Summarized using standard Kaplan-Meier methods.
Time frame: From the time at which criteria for CR, PR, or PR with lymphocytosis is first assessed until the date at which recurrent or progressive disease or death due to disease is documented, assessed up to 3 years
Progression free survival (PFS)
For CLL and PLL patients, defined according to the criteria published by the International Workshop on CLL with the modification outlined by Cheson et al. For SLL/RT patients, responses will be according to revised response criteria for malignant lymphoma. Summarized using standard Kaplan-Meier methods.
Time frame: Time from the first dose of the study drug until disease progression or death from any cause, assessed up to 3 years
Overall survival (OS)
For CLL and PLL patients, defined according to the criteria published by the International Workshop on CLL with the modification outlined by Cheson et al. For SLL/RT patients, responses will be according to revised response criteria for malignant lymphoma. Summarized using standard Kaplan-Meier methods.
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Time frame: Time from the first dose of the study drug until death, assessed up to 3 years
Rate of objective clinical response (CR, PR) (optional PLCG2 enriched cohort, if activated)
For CLL and PLL patients, defined according to the criteria published by the International Workshop on CLL with the modification outlined by Cheson et al. For SLL/RT patients, responses will be according to revised response criteria for malignant lymphoma. Summarized using standard Kaplan-Meier methods.
Time frame: Up to 3 years
Response duration (optional PLCG2 enriched cohort, if activated)
For CLL and PLL patients, defined according to the criteria published by the International Workshop on CLL with the modification outlined by Cheson et al. For SLL/RT patients, responses will be according to revised response criteria for malignant lymphoma. Summarized using standard Kaplan-Meier methods.
Time frame: From the time at which criteria for CR, PR, or PR with lymphocytosis is first assessed until the date at which recurrent or progressive disease or death due to disease is documented, assessed up to 3 years
PFS (optional PLCG2 enriched cohort, if activated)
For CLL and PLL patients, defined according to the criteria published by the International Workshop on CLL with the modification outlined by Cheson et al. For SLL/RT patients, responses will be according to revised response criteria for malignant lymphoma. Summarized using standard Kaplan-Meier methods.
Time frame: Time from the first dose of the study drug until disease progression or death from any cause, assessed up to 3 years
OS (optional PLCG2 enriched cohort, if activated)
For CLL and PLL patients, defined according to the criteria published by the International Workshop on CLL with the modification outlined by Cheson et al. For SLL/RT patients, responses will be according to revised response criteria for malignant lymphoma. Summarized using standard Kaplan-Meier methods.
Time frame: Time from the first dose of the study drug until death, assessed up to 3 years
Rate of objective clinical response (CR, PR) (MCL cohort)
Responses are defined according the revised response criteria for malignant lymphoma. Summarized using standard Kaplan-Meier methods.
Time frame: Up to 3 years
Response duration (MCL cohort)
Responses are defined according the revised response criteria for malignant lymphoma. Summarized using standard Kaplan-Meier methods.
Time frame: From the time at which criteria for CR, PR, or PR with lymphocytosis is first assessed until the date at which recurrent or progressive disease or death due to disease is documented, assessed up to 3 years
PFS (MCL cohort)
Responses are defined according the revised response criteria for malignant lymphoma. Summarized using standard Kaplan-Meier methods.
Time frame: Time from the first dose of the study drug until disease progression or death from any cause, assessed up to 3 years
OS (MCL cohort)
Responses are defined according the revised response criteria for malignant lymphoma. Summarized using standard Kaplan-Meier methods.
Time frame: Time from the first dose of the study drug until death, assessed up to 3 years
Incidence of adverse events (AEs), assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 criteria
For each disease group, frequency and severity of adverse events will be collected and summarized by descriptive statistics.
Time frame: Up to 30 days post-treatment
Frequency of AEs requiring dose reduction or drug discontinuation
Number of patients who require dose modifications and/or dose delays will be assessed.
Time frame: Up to 30 days post-treatment
Number of courses completed
Number of courses started/completed and the reasons for going off-treatment will be assessed.
Time frame: Up to 30 days post-treatment
Pharmacodynamic modulation of the downstream targets of the BCR (including LCP1) after sotrastaurin acetate treatment
Markers will be summarized univariately in a quantitative manner and also summarized by clinical outcome group graphically to assess potential patterns and relationships. Changes in BCR signaling over time may be evaluated quantitatively using repeated measures models and graphically with individual time plots or box plots.
Time frame: Baseline to up to course 1 day 29
Pharmacodynamic modulation of the downstream targets of nuclear transcription factor kappa-B after sotrastaurin acetate treatment
Markers will be summarized univariately in a quantitative manner and also summarized by clinical outcome group graphically to assess potential patterns and relationships.
Time frame: Baseline to up to course 1 day 29
Pharmacodynamic modulation of downstream targets of WNT/beta-catenin pathway
Markers will be summarized univariately in a quantitative manner and also summarized by clinical outcome group graphically to assess potential patterns and relationships.
Time frame: Baseline to up to course 1 day 29
Genomic features associated with response by deep sequencing panel targeted at recurrent mutations in CLL
Markers will be summarized univariately in a quantitative manner and also summarized by clinical outcome group graphically to assess potential patterns and relationships.
Time frame: Up to course 1 day 29