Selinexor in Initial or Refractory and/or Relapsed Richter's Transformation

Richter's Transformation Clinical Trial

— SIRRT  

Official title:

A Phase 2 Study of the Safety and Anti-tumor Activity of the Oral Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330) in Patients With Initial or Refractory and/or Relapsed Richter's Transformation (RT)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02138786
• Other study ID #: KCP-330-010
• Status: Terminated
• Phase: Phase 2
• Start date: November 14, 2014
• Est. completion date: August 31, 2016

Study information

• Verified date: January 2023
• Source: Karyopharm Therapeutics Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 27
• Est. completion date: August 31, 2016
• Est. primary completion date: August 31, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Richter's Transformation

Intervention

Drug:
• selinexor
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).

Locations

Country	Name	City	State
Germany	University Hospital of Cologne	Koeln
Germany	University of Ulm	Ulm	Baden-Württemberg
Poland	Malopolskie Centrum Medyczne	Kraków
Poland	Copernicus Memorial Hospital, Department of Hematology	Lodz
Poland	Maria Sklodowska-Curie Institue of Oncology	Warszawa
Spain	Hospital Vall Hebron	Barcelona
Spain	Institut Català d'Oncologia Av.	Barcelona
Spain	Instituto Clinico Navarra, Pamplona	Pamplona	Navarra
United Kingdom	Churchill Hospital: Cancer and Haematology Centre	Oxford
United Kingdom	The Royal Marsden NHS Foundation Trust	Sutton	Surrey
United States	Winship Cancer Institute / Emory University	Atlanta	Georgia
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	City of Hope National Medical Center	Duarte	California
United States	Weill Cornell Medical College	New York	New York
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	University of California-Los Angeles	Santa Monica	California
United States	University of Arizona Cancer Center	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Karyopharm Therapeutics Inc

Countries where clinical trial is conducted

United States,  Germany,  Poland,  Spain,  United Kingdom, 

References & Publications (1)

Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M, Diehl V; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007 Feb 10;25(5):579-86. doi: 10.1200/JCO.2006.09.2403. Epub 2007 Jan 22. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	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.
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.	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.
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.	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.
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.	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.
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.	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.
Primary	Number of Participants With Not Evaluable (NE) Response	Number of patients who could not be assessed quantitatively for disease response for any reason.	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.
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.	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.
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.; .	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.