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

• ClinicalTrials.gov Identifier: NCT02138786
• Recruitment Status: Terminated
• First Posted: May 15, 2014
• Results First Posted: February 11, 2020
• Last Update Posted: January 26, 2023
• Sponsor: Karyopharm Therapeutics Inc
• Information provided by (Responsible Party): Karyopharm Therapeutics Inc

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Richter's Transformation	Drug: selinexor	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 27 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: November 14, 2014
• Actual Primary Completion Date: August 31, 2016
• Actual Study Completion Date: August 31, 2016

Arms and Interventions

Arm

Intervention/treatment

Experimental: selinexor; oral tablets; 10 mg & 25 mg (bottled); or; 20 mg (blister pack)

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).; Other Name: KPT-330

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Overall Response (Overall Response Rate) [ 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. ]
   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.
2. Number of Participants With Complete Response (CR) [ 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. ]
   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.
3. Number of Participants With Partial Response (PR) [ 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. ]
   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.
4. Number of Participants With Stable Disease (SD) [ 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. ]
   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.
5. Number of Participants With Progressive Disease (PD) [ 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. ]
   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.
6. Number of Participants With Not Evaluable (NE) Response [ 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. ]
   Number of patients who could not be assessed quantitatively for disease response for any reason.

Secondary Outcome Measures :

1. Percentage of Participants With Disease Control (Disease Control Rate) [ 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. ]
   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.
2. Duration of Progression Free Survival (PFS) [ 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. ]

   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.

   .

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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).

Contacts and Locations

Locations

United States, Arizona

University of Arizona Cancer Center

Tucson, Arizona, United States, 85724

United States, California

City of Hope National Medical Center

Duarte, California, United States, 91010

University of California-Los Angeles

Santa Monica, California, United States, 90404

United States, Georgia

Winship Cancer Institute / Emory University

Atlanta, Georgia, United States, 30322

United States, New York

Weill Cornell Medical College

New York, New York, United States, 10065

United States, Ohio

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States, 43202

United States, Utah

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, United States, 84112

Germany

University of Ulm

Ulm, Baden-Württemberg, Germany, 89081

University Hospital of Cologne

Koeln, Germany, 50937

Poland

Malopolskie Centrum Medyczne

Kraków, Poland, 30-510

Copernicus Memorial Hospital, Department of Hematology

Lodz, Poland, 93-513

Maria Skłodowska-Curie Institue of Oncology

Warszawa, Poland, 02-034

Spain

Instituto Clinico Navarra, Pamplona

Pamplona, Navarra, Spain, 31008

Institut Català d'Oncologia Av.

Barcelona, Spain, 08010

Hospital Vall Hebron

Barcelona, Spain, 08035

United Kingdom

The Royal Marsden NHS Foundation Trust

Sutton, Surrey, United Kingdom, SM2 5PT

Churchill Hospital: Cancer and Haematology Centre

Oxford, United Kingdom, OX3 8JL

Sponsors and Collaborators

Karyopharm Therapeutics Inc

More Information

Publications:

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.

• Responsible Party: Karyopharm Therapeutics Inc
• ClinicalTrials.gov Identifier: NCT02138786
• Other Study ID Numbers: KCP-330-010
• First Posted: May 15, 2014
• Results First Posted: February 11, 2020
• Last Update Posted: January 26, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Karyopharm Therapeutics Inc:

Richter's Transformation; Richter's Syndrome; Karyopharm; selinexor; KPT-330; SIRRT; CLL