Richter's Transformation
Conditions
Keywords
Richter's Transformation, Richter's Syndrome, Karyopharm, selinexor, KPT-330, SIRRT, CLL
Brief summary
This is a multi-center, phase 2, single arm, open-label study of oral selinexor monotherapy in patients with Richter's Transformation, arising in the setting of prior chronic lymphocytic leukemia (CLL), after at least one chemo-immunotherapy regimen for CLL.
Detailed description
Multi-center, phase 2, single arm, open-label study of oral selinexor monotherapy in patients with Richter's Transformation, arising in the setting of prior CLL, documented by histologically confirmed lymphoma, including diffuse large B-cell (DLBCL) and immunoblastic variants. Eligible patients must have had at least one prior regimen for CLL. Approximately 50 patients are anticipated to be treated in this study. Eligible patients following screening will receive selinexor orally twice weekly at a dose of 60 mg. The selinexor dose may be increased to 80 mg after Cycle 1 unless clinically contraindicated. Patients may continue in multiple treatment cycles at a given dose; there is no maximum treatment duration. Each cycle is 28 days. Dose adjustments will be made as appropriate by the investigator. Patients who were treated twice weekly for weeks 1-3 under a previous version of the protocol may, at the discretion of the investigator, have had the frequency of selinexor dosing increased to twice weekly for weeks 1-4. If there was no contraindicated toxicity, the selinexor dose may have been increased to 80 mg at Cycle 3.
Interventions
DRUGselinexor
* 60 mg dose twice weekly, on Days 1 and 3 of weeks 1-4 of each 4-week cycle; dose may be increased to 80 mg after Cycle 1 unless clinically contraindicated (Protocol V.5.0). * 60 mg dose twice weekly on Days 1 and 3 of weeks 1-3 of each 4-week cycle; dose may be increased to 80 mg at Cycle 3 Day 1 unless clinically contraindicated (Protocol V.4.0). * 60 mg/m² dose, based on BSA, twice weekly, on Days 1 and 3 of weeks 1-3 of each 4-week cycle (Protocol V. 3.0). * 60 mg/m² dose, based on BSA, twice weekly, on Days 1 and 3 of weeks 1-4 of each 4-week cycle (Protocol V. \< 3.0).
Sponsors
Karyopharm Therapeutics Inc
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Richter's Transformation, arising in the setting of prior CLL, documented by histologically confirmed lymphoma, including large B-cell and immunoblastic variants. * All patients must have received at least one prior regimen for CLL, including cytotoxic chemotherapy, anti-CD20 monoclonal antibodies, a BTK inhibitor, or a PI3K inhibitor. Patients may have received high dose chemotherapy/autologous stem cell transplant (HDT/ASCT) or allogeneic hematopoietic stem cell transplant (allo SCT). * One or more measurable (\> 1.5 cm in longest dimension) disease sites on CT (preferably PET/CT) or, if CT is contraindicated, MRI (preferably PET/MRI) scans. * Objective documented evidence of disease progression at study entry * Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2
Exclusion criteria
* Radiation, chemotherapy, or immunotherapy or any other anticancer therapy ≤ 2 weeks prior to Cycle 1 Day 1, except ibrutinib which may be continued until one day prior to initiation of selinexor; radio-immunotherapy 4 weeks prior to Cycle 1 Day 1. Patients must have recovered to Grade ≤ 1 from clinically significant adverse effects. * Prolymphocytic transformation * Less than 1 month since completion of autologous stem cell transplantation or less than 3 months since completion of allogeneic stem cell transplantation * Major surgery within 4 weeks of C1D1 * Impairment of GI function or GI disease that could interfere with the absorption of selinexor, including obstructed GI tract and uncontrolled vomiting or diarrhea. * Inability or unwillingness to take supportive medications including a centrally acting appetite stimulant (e.g., mirtazapine or olanzapine) and a peripherally acting appetite stimulant (e.g., low dose glucocorticoids or megesterol acetate).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Progressive Disease (PD) | Assessments were performed at Screening or Cycle 1/Day 1 prior to dosing and on Cycle 3/Day 1 and alternate cycles thereafter until disease progression, study drug intolerability had been reached, study withdrawal, or death. | Number of patients whose best overall response to study treatment was PD (any new lesion or increase by ≥ 50% of previously involved sites from nadir). Disease response was assessed using the International Working Group (IWG) Response Criteria for non-Hodgkin's lymphoma (Cheson 2007), including assessment of lymph node, spleen and liver lesions by PET (positron emission tomography) scan and assessment of bone marrow biopsies by morphologic, immunohistochemistry, and flow cytometry tests. |
| Number of Participants With Not Evaluable (NE) Response | Assessments were performed at Screening or Cycle 1/Day 1 prior to dosing and on Cycle 3/Day 1 and alternate cycles thereafter until disease progression, study drug intolerability had been reached, study withdrawal, or death. | Number of patients who could not be assessed quantitatively for disease response for any reason. |
| Number of Participants With Stable Disease (SD) | Assessments were performed at Screening or Cycle 1/Day 1 prior to dosing and on Cycle 3/Day 1 and alternate cycles thereafter until disease progression, study drug intolerability had been reached, study withdrawal, or death. | Number of patients whose best overall response to study treatment was SD (failure to attain criteria for CR or PR, or to meet criteria for PD). Disease response was assessed using the International Working Group (IWG) Response Criteria for non-Hodgkin's lymphoma (Cheson 2007), including assessment of lymph node, spleen and liver lesions by PET (positron emission tomography) scan and assessment of bone marrow biopsies by morphologic, immunohistochemistry, and flow cytometry tests. |
| Percentage of Participants With Overall Response (Overall Response Rate) | Assessments were performed at Screening or Cycle 1/Day 1 prior to dosing and on Cycle 3/Day 1 and alternate cycles thereafter until disease progression, study drug intolerability had been reached, study withdrawal, or death. | Overall Response Rate (ORR) is defined as the point estimate of the percentage of patients who have complete response (CR) or partial response (PR). Disease response was assessed using the International Working Group (IWG) Response Criteria for non-Hodgkin's lymphoma (Cheson 2007), including assessment of lymph node, spleen and liver lesions by PET (positron emission tomography) scan and assessment of bone marrow biopsies by morphologic, immunohistochemistry, and flow cytometry tests. CR was defined as disappearance of all evidence of disease, and PR was defined as ≥ 50% regression of measurable disease and no new sites. |
| Number of Participants With Complete Response (CR) | Assessments were performed at Screening or Cycle 1/Day 1 prior to dosing and on Cycle 3/Day 1 and alternate cycles thereafter until disease progression, study drug intolerability had been reached, study withdrawal, or death. | Number of patients who achieved CR (complete disappearance of all detectable evidence of disease). Disease response was assessed using the International Working Group (IWG) Response Criteria for non-Hodgkin's lymphoma (Cheson 2007), including assessment of lymph node, spleen and liver lesions by PET (positron emission tomography) scan and assessment of bone marrow biopsies by morphologic, immunohistochemistry, and flow cytometry tests. |
| Number of Participants With Partial Response (PR) | Assessments were performed at Screening or Cycle 1/Day 1 prior to dosing and on Cycle 3/Day 1 and alternate cycles thereafter until disease progression, study drug intolerability had been reached, study withdrawal, or death. | Number of patients whose best overall response to study treatment was PR (≥ 50% regression of measurable disease and no new sites). Disease response was assessed using the International Working Group (IWG) Response Criteria for non-Hodgkin's lymphoma (Cheson 2007), including assessment of lymph node, spleen and liver lesions by PET (positron emission tomography) scan and assessment of bone marrow biopsies by morphologic, immunohistochemistry, and flow cytometry tests. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Progression Free Survival (PFS) | Assessments were performed at Screening or Cycle 1/Day 1 prior to dosing and on Cycle 3/Day 1 and alternate cycles thereafter until disease progression, study drug intolerability had been reached, study withdrawal, or death. | Number of days calculated from date of start of study therapy to date of progression based on IWG criteria, or date of death if progression did not occur. Patients who dropped out prior to study end without evidence of disease progression were censored at the day they were last known to be alive. Patients without documented disease progression or recurrence were censored at the date of last disease assessment. Disease response was assessed using the International Working Group (IWG) Response Criteria for non-Hodgkin's lymphoma (Cheson 2007), including assessment of lymph node, spleen and liver lesions by PET (positron emission tomography) scan and assessment of bone marrow biopsies by morphologic, immunohistochemistry, and flow cytometry tests. . |
| Percentage of Participants With Disease Control (Disease Control Rate) | Assessments were performed at Screening or Cycle 1/Day 1 prior to dosing and on Cycle 3/Day 1 and alternate cycles thereafter until disease progression, study drug intolerability had been reached, study withdrawal, or death. | Disease Control Rate (DCR) is defined as the percentage of patients who achieved CR, PR, or SD lasting for at least 8 weeks. CR was defined as disappearance of all evidence of disease. PR was defined as ≥ 50% regression of measurable disease and no new sites. SD was defined as failure to attain criteria for CR or PR, or to meet criteria for PD. Disease response was assessed using the International Working Group (IWG) Response Criteria for non-Hodgkin's lymphoma (Cheson 2007), including assessment of lymph node, spleen and liver lesions by PET (positron emission tomography) scan and assessment of bone marrow biopsies by morphologic, immunohistochemistry, and flow cytometry tests. |
Countries
Germany, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
This multicenter study was conducted at 30 clinical investigative sites in the United States and Europe. Of the 30 investigative sites, 15 sites enrolled a total of 27 patients in the study. * Date first patient enrolled: 14 November 2014 * Date last patient completed: 31 August 2016
Pre-assignment details
Of the 35 total patients screened, 8 patients were screen-failures. Of the 27 enrolled patients, one patient withdrew from the study prior to receiving treatment. Therefore, a total of 26 patients comprised the Safety population.
Participants by arm
| Arm | Count |
|---|---|
| Selinexor 60 mg/m² (8 Doses/Cycle) 60 mg/m² oral dose twice weekly for Weeks 1-4 | 3 |
| Selinexor 60 mg (6 Doses/Cycle) 60 mg oral dose twice weekly for Weeks 1-3 | 15 |
| Selinexor 60 mg (8 Doses/Cycle) 60 mg oral dose twice weekly for Weeks 1-4 | 8 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 1 |
| Overall Study | Death | 1 | 7 | 2 |
| Overall Study | Disease Progression | 1 | 1 | 3 |
| Overall Study | Non-Compliance | 0 | 0 | 1 |
| Overall Study | Patient's Wish | 0 | 2 | 0 |
| Overall Study | Sponsor Terminated Study | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 0 |
Baseline characteristics
| Characteristic | Selinexor 60 mg (6 Doses/Cycle) | Total | Selinexor 60 mg/m² (8 Doses/Cycle) | Selinexor 60 mg (8 Doses/Cycle) |
|---|---|---|---|---|
| Age, Continuous | 68.0 years | 68.0 years | 68.0 years | 69.0 years |
| ECOG score Missing | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| ECOG score Score=0 | 5 Participants | 7 Participants | 0 Participants | 2 Participants |
| ECOG score Score=1 | 6 Participants | 13 Participants | 3 Participants | 4 Participants |
| ECOG score Score=2 | 4 Participants | 5 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 23 Participants | 1 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 26 Participants | 3 Participants | 8 Participants |
| Sex: Female, Male Female | 3 Participants | 9 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 12 Participants | 17 Participants | 1 Participants | 4 Participants |
| Weight | 76.5 kg | 74.40 kg | 56.5 kg | 73.05 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 8 / 15 | 2 / 8 |
| other Total, other adverse events | 3 / 3 | 15 / 15 | 7 / 8 |
| serious Total, serious adverse events | 3 / 3 | 9 / 15 | 5 / 8 |
Outcome results
Primary
Number of Participants With Complete Response (CR)
Number of patients who achieved CR (complete disappearance of all detectable evidence of disease). Disease response was assessed using the International Working Group (IWG) Response Criteria for non-Hodgkin's lymphoma (Cheson 2007), including assessment of lymph node, spleen and liver lesions by PET (positron emission tomography) scan and assessment of bone marrow biopsies by morphologic, immunohistochemistry, and flow cytometry tests.
Time frame: Assessments were performed at Screening or Cycle 1/Day 1 prior to dosing and on Cycle 3/Day 1 and alternate cycles thereafter until disease progression, study drug intolerability had been reached, study withdrawal, or death.
Population: Modified Intent to Treat (mITT) population, consisting of all patients who received at least one dose of selinexor and had at least one post-baseline efficacy evaluation. Patients without post-baseline efficacy follow-up information who discontinued the study due to toxicity, disease progression, or death were included in this population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Selinexor | Number of Participants With Complete Response (CR) | 0 Participants |
Primary
Number of Participants With Not Evaluable (NE) Response
Number of patients who could not be assessed quantitatively for disease response for any reason.
Time frame: Assessments were performed at Screening or Cycle 1/Day 1 prior to dosing and on Cycle 3/Day 1 and alternate cycles thereafter until disease progression, study drug intolerability had been reached, study withdrawal, or death.
Population: Modified Intent to Treat (mITT) population, consisting of all patients who received at least one dose of selinexor and had at least one post-baseline efficacy evaluation. Patients without post-baseline efficacy follow-up information who discontinued the study due to toxicity, disease progression, or death were included in this population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Selinexor | Number of Participants With Not Evaluable (NE) Response | 11 Participants |
Primary
Number of Participants With Partial Response (PR)
Number of patients whose best overall response to study treatment was PR (≥ 50% regression of measurable disease and no new sites). Disease response was assessed using the International Working Group (IWG) Response Criteria for non-Hodgkin's lymphoma (Cheson 2007), including assessment of lymph node, spleen and liver lesions by PET (positron emission tomography) scan and assessment of bone marrow biopsies by morphologic, immunohistochemistry, and flow cytometry tests.
Time frame: Assessments were performed at Screening or Cycle 1/Day 1 prior to dosing and on Cycle 3/Day 1 and alternate cycles thereafter until disease progression, study drug intolerability had been reached, study withdrawal, or death.
Population: Modified Intent to Treat (mITT) population, consisting of all patients who received at least one dose of selinexor and had at least one post-baseline efficacy evaluation. Patients without post-baseline efficacy follow-up information who discontinued the study due to toxicity, disease progression, or death were included in this population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Selinexor | Number of Participants With Partial Response (PR) | 1 Participants |
Primary
Number of Participants With Progressive Disease (PD)
Number of patients whose best overall response to study treatment was PD (any new lesion or increase by ≥ 50% of previously involved sites from nadir). Disease response was assessed using the International Working Group (IWG) Response Criteria for non-Hodgkin's lymphoma (Cheson 2007), including assessment of lymph node, spleen and liver lesions by PET (positron emission tomography) scan and assessment of bone marrow biopsies by morphologic, immunohistochemistry, and flow cytometry tests.
Time frame: Assessments were performed at Screening or Cycle 1/Day 1 prior to dosing and on Cycle 3/Day 1 and alternate cycles thereafter until disease progression, study drug intolerability had been reached, study withdrawal, or death.
Population: Modified Intent to Treat (mITT) population, consisting of all patients who received at least one dose of selinexor and had at least one post-baseline efficacy evaluation. Patients without post-baseline efficacy follow-up information who discontinued the study due to toxicity, disease progression, or death were included in this population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Selinexor | Number of Participants With Progressive Disease (PD) | 7 Participants |
Primary
Number of Participants With Stable Disease (SD)
Number of patients whose best overall response to study treatment was SD (failure to attain criteria for CR or PR, or to meet criteria for PD). Disease response was assessed using the International Working Group (IWG) Response Criteria for non-Hodgkin's lymphoma (Cheson 2007), including assessment of lymph node, spleen and liver lesions by PET (positron emission tomography) scan and assessment of bone marrow biopsies by morphologic, immunohistochemistry, and flow cytometry tests.
Time frame: Assessments were performed at Screening or Cycle 1/Day 1 prior to dosing and on Cycle 3/Day 1 and alternate cycles thereafter until disease progression, study drug intolerability had been reached, study withdrawal, or death.
Population: Modified Intent to Treat (mITT) population, consisting of all patients who received at least one dose of selinexor and had at least one post-baseline efficacy evaluation. Patients without post-baseline efficacy follow-up information who discontinued the study due to toxicity, disease progression, or death were included in this population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Selinexor | Number of Participants With Stable Disease (SD) | 6 Participants |
Primary
Percentage of Participants With Overall Response (Overall Response Rate)
Overall Response Rate (ORR) is defined as the point estimate of the percentage of patients who have complete response (CR) or partial response (PR). Disease response was assessed using the International Working Group (IWG) Response Criteria for non-Hodgkin's lymphoma (Cheson 2007), including assessment of lymph node, spleen and liver lesions by PET (positron emission tomography) scan and assessment of bone marrow biopsies by morphologic, immunohistochemistry, and flow cytometry tests. CR was defined as disappearance of all evidence of disease, and PR was defined as ≥ 50% regression of measurable disease and no new sites.
Time frame: Assessments were performed at Screening or Cycle 1/Day 1 prior to dosing and on Cycle 3/Day 1 and alternate cycles thereafter until disease progression, study drug intolerability had been reached, study withdrawal, or death.
Population: Modified Intent to Treat (mITT) population, consisting of all patients who received at least one dose of selinexor and had at least one post-baseline efficacy evaluation. Patients without post-baseline efficacy follow-up information who discontinued the study due to toxicity, disease progression, or death were included in this population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Selinexor | Percentage of Participants With Overall Response (Overall Response Rate) | 4 Percentage of participants |
Secondary
Duration of Progression Free Survival (PFS)
Number of days calculated from date of start of study therapy to date of progression based on IWG criteria, or date of death if progression did not occur. Patients who dropped out prior to study end without evidence of disease progression were censored at the day they were last known to be alive. Patients without documented disease progression or recurrence were censored at the date of last disease assessment. Disease response was assessed using the International Working Group (IWG) Response Criteria for non-Hodgkin's lymphoma (Cheson 2007), including assessment of lymph node, spleen and liver lesions by PET (positron emission tomography) scan and assessment of bone marrow biopsies by morphologic, immunohistochemistry, and flow cytometry tests. .
Time frame: Assessments were performed at Screening or Cycle 1/Day 1 prior to dosing and on Cycle 3/Day 1 and alternate cycles thereafter until disease progression, study drug intolerability had been reached, study withdrawal, or death.
Population: Modified Intent to Treat (mITT) population, consisting of all patients who received at least one dose of selinexor and had at least one post-baseline efficacy evaluation. Patients without post-baseline efficacy follow-up information who discontinued the study due to toxicity, disease progression, or death were included in this population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Selinexor | Duration of Progression Free Survival (PFS) | 38.0 Days |
Secondary
Percentage of Participants With Disease Control (Disease Control Rate)
Disease Control Rate (DCR) is defined as the percentage of patients who achieved CR, PR, or SD lasting for at least 8 weeks. CR was defined as disappearance of all evidence of disease. PR was defined as ≥ 50% regression of measurable disease and no new sites. SD was defined as failure to attain criteria for CR or PR, or to meet criteria for PD. Disease response was assessed using the International Working Group (IWG) Response Criteria for non-Hodgkin's lymphoma (Cheson 2007), including assessment of lymph node, spleen and liver lesions by PET (positron emission tomography) scan and assessment of bone marrow biopsies by morphologic, immunohistochemistry, and flow cytometry tests.
Time frame: Assessments were performed at Screening or Cycle 1/Day 1 prior to dosing and on Cycle 3/Day 1 and alternate cycles thereafter until disease progression, study drug intolerability had been reached, study withdrawal, or death.
Population: Modified Intent to Treat (mITT) population, consisting of all patients who received at least one dose of selinexor and had at least one post-baseline efficacy evaluation. Patients without post-baseline efficacy follow-up information who discontinued the study due to toxicity, disease progression, or death were included in this population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Selinexor | Percentage of Participants With Disease Control (Disease Control Rate) | 28.0 Percentage of participants |