Back to resultsA Phase II Study of Selinexor Plus Cytarabine and Idarubicin in Patients With Relapsed/Refractory Acute Myeloid Leukemia (AML)
Primary Purpose
Acute Myeloid Leukemia (Relapsed/Refractory)
Status
Completed
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
Selinexor
Idarubicin
Cytarabine
Sponsored by
About this trial
This is an interventional treatment trial for Acute Myeloid Leukemia (Relapsed/Refractory)
Eligibility Criteria
Inclusion Criteria:
- Cytological or histological diagnosis of AML with the exception of promyelocytic leukemia (AML M3)
Patients must have relapsed/refractory disease (relapse after stem cell transplantation is permitted) as defined as:
- patients with <PR after first cycle of induction chemotherapy, or
- patients with <CR(i) after second cycle of induction chemotherapy, or
- patients who relapse after conventional chemotherapy or
- patients who have undergone a single stem cell transplantation and who have relapse of their AML.
- Men and women aged ≥18 years and eligible for standard dose of chemotherapy (7+3);
- A period of at least 3 weeks needs to have elapsed since last treatment (with the exception of hydroxyurea) before participating in this study. Hydroxyurea induction therapy to reduce peripheral blast counts is permitted prior to initiation of treatment on protocol. Treatment may begin in <3 weeks from last treatment if deemed in the best interest of the patient after discussion with the PI of the study;
- ECOG performance status ≤ 2
- Serum biochemical values with the following limits unless considered due to leukemia: creatinine ≤2 mg/dl; total bilirubin ≤2x ULN, unless increase is due to hemolysis or congenital disorder; transaminases (SGPT or SGOT) ≤2.5x ULN.
- Ability to swallow and retain oral medication;
- Ability to understand and provide signed informed consent;
- Cardiac ejection fraction must be >/=50% (by echocardiography).
- Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
Exclusion Criteria:
- Treatment with any investigational agent within four weeks.
- Cumulative anthracycline dose (daunorubicin or equivalent) >360 mg/m^2
- HIV infection
- Presence of any medical or psychiatric condition which may limit full compliance with the study, including but not limited to:
- Presence of CNS leukemia
- Unresolved toxicity from previous anti-cancer therapy or incomplete recovery from surgery.
For patients after SCT as part of prior treatment:
- Necessity of immunosuppressive drugs
- GvHD > grade 1
- Any of the following within the 12 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis, or other thromboembolic event.
- Ongoing cardiac dysrhythmias of NCI CTCAE >/= Grade 2.
- Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.
- Clinically significant bleeding within 1 month
Sites / Locations
- Universitätsklinikum Frankfurt
- Medizinische Hochschule Hannover
- Universitätsklinikum Hamburg-Eppendorf
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Cohort 1 / Selinexor 40 mg/m^2 in combination with cytarabine and idarubicin
Cohort 2 / Selinexor 60 mg flat dose in combination with cytarabine and idarubicin
Arm Description
All enrolled patients are treated with cytarabine at a dose of 100 mg/m² continuous infusion (day 1-7) and idarubicin at a dose of 10 mg/m^2 iv (day 1,3,5) every 4 weeks and selinexor for up to 2 induction cycles. If a second cycle is applied idarubicin is only given on day 1 and 3. Selinexor is administered at a dose of 40 mg/m^2 twice weekly orally starting on day 2 (total of 8 doses per induction cycle).
All enrolled patients are treated with cytarabine at a dose of 100 mg/m^2 continuous infusion (day 1-7) and idarubicin at a dose of 10 mg/m^2 iv (day 1,3,5) every 4 weeks and selinexor for up to 2 induction cycles. If a second cycle is applied idarubicin is only given on day 1 and 3. Selinexor is administered at a flat dose of 60 mg twice weekly orally in weeks 1-3 of a 4-week cycle starting on day 2 (total of 6 doses per induction cycle).
Outcomes
Primary Outcome Measures
Number of Participants With CR/CRi = Overall Reponse Rate
Efficacy of selinexor in combination with standard chemotherapy in patients with relapsed/refractory AML by determination of rate of complete response (CR) or morphologic complete response with incomplete blood count recovery (CRi), as defined by the recommendations on diagnosis and management of AML in adults from an international expert panel, on behalf of the European LeukemiaNet:
CR: Absolute Neutrophil count (ANC) >1.0x10^9/L, Platelet count >100x10^9/L, Bone marrow blasts <5%, no Auer rods, no evidence of extramedullary disease.
CRi: Same as CR, but ANC may be <1.0x10^9/L and/or Platelet count <100x10^9/L.
Patients with morphologic leukemia free-state (MLFS) were included in the group of responders. MLFS: Bone marrow blasts <5%, no Auer rods, no evidence of extramedullary disease.
The best response after Selinexor treatment was analyzed, thus the best response after the induction cycle(s).
Secondary Outcome Measures
Number of Participants With Partial Remission (PR) = Rate of PR
Efficacy of selinexor in combination with standard chemotherapy in patients with relapsed/refractory AML by determination of rate of partial remission(PR) as defined by the recommendations on diagnosis and management of AML in adults from an international expert panel, on behalf of the European LeukemiaNet:
PR: Absolute Neutrophil count (ANC) >1.0x10^9/L, Platelet count >100x10^9/L, at least a 50% decrease in the percentage of marrow aspirate blasts to 5-25%, or marrow blasts <5% with persistent Auer rods.
The best response after Selinexor treatment was analyzed, thus the best response after the induction cycle(s).
Percentage of Patients Transplanted After Induction Therapy (Stem Cell Transplantation)
Percentage of patients being transplanted after induction therapy (stem cell transplantation)
Early Death Rate
Early death was defined as death before the end of the first induction cycle.
Overall Survival
Overall survival (OS) was calculated from the date of informed consent to the date of death. Patients still alive at the end of follow-up were censored at the last date of follow-up.
Relapse-Free Survival
Relapse-free survival (RFS) was calculated from the date of CR/CRi until death or relapse, whichever occurred first. Patients were censored on the date of the last follow-up if they were alive without relapse.
Event-Free Survival
Event-free survival (EFS) was calculated from the time of informed consent until death, not achieving CR/CRi or relapse after CR/CRi.
Progression-Free Survival
Progression-free survival (PFS) was calculated from the time of informed consent to the date of recurrence or death, whichever occurred first. Patients were censored at the date of the last follow-up visit if they were alive without relapse.
Disease progression was defined as presence of >50% increase in bone marrow blasts to a level of at least 50% and/or a doubling of the percentage of peripheral blood blasts to a level of at least 50%.
Full Information
NCT ID
NCT02249091
First Posted
September 16, 2014
Last Updated
August 1, 2021
Sponsor
GSO Global Clinical Research BV
Collaborators
Karyopharm Therapeutics Inc
1. Study Identification
Unique Protocol Identification Number
NCT02249091
Brief Title
A Phase II Study of Selinexor Plus Cytarabine and Idarubicin in Patients With Relapsed/Refractory Acute Myeloid Leukemia (AML)
Official Title
An Investigator-Initiated Study To Evaluate Ara-C and Idarubicin in Combination With the Selective Inhibitor Of Nuclear Export (SINE) Selinexor (KPT-330) in Patients With Relapsed Or Refractory AML
Study Type
Interventional
2. Study Status
Record Verification Date
August 2021
Overall Recruitment Status
Completed
Study Start Date
September 2014 (undefined)
Primary Completion Date
July 31, 2018 (Actual)
Study Completion Date
July 31, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
GSO Global Clinical Research BV
Collaborators
Karyopharm Therapeutics Inc
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
Acute Myeloid Leukemia (AML) is currently treated with chemotherapy by combining several drugs with different ways of inhibiting the cell growth. In this trial, standard chemotherapeutics that have proven their effectiveness for years, Ara-C and Idarubicin, will be combined with a new drug called Selinexor.
Selinexor inhibits the growth of cancer cells by keeping certain proteins in the nucleus which control the cell growth.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia (Relapsed/Refractory)
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Sequential Assignment
Model Description
In the initial protocol, 25 patients are included in the clinical trial on the schedule described as cohort 1. After an amendment 15 further patients are included on the schedule described as cohort 2.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
42 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Cohort 1 / Selinexor 40 mg/m^2 in combination with cytarabine and idarubicin
Arm Type
Experimental
Arm Description
All enrolled patients are treated with cytarabine at a dose of 100 mg/m² continuous infusion (day 1-7) and idarubicin at a dose of 10 mg/m^2 iv (day 1,3,5) every 4 weeks and selinexor for up to 2 induction cycles. If a second cycle is applied idarubicin is only given on day 1 and 3.
Selinexor is administered at a dose of 40 mg/m^2 twice weekly orally starting on day 2 (total of 8 doses per induction cycle).
Arm Title
Cohort 2 / Selinexor 60 mg flat dose in combination with cytarabine and idarubicin
Arm Type
Experimental
Arm Description
All enrolled patients are treated with cytarabine at a dose of 100 mg/m^2 continuous infusion (day 1-7) and idarubicin at a dose of 10 mg/m^2 iv (day 1,3,5) every 4 weeks and selinexor for up to 2 induction cycles. If a second cycle is applied idarubicin is only given on day 1 and 3.
Selinexor is administered at a flat dose of 60 mg twice weekly orally in weeks 1-3 of a 4-week cycle starting on day 2 (total of 6 doses per induction cycle).
Intervention Type
Drug
Intervention Name(s)
Selinexor
Other Intervention Name(s)
KPT-330
Intervention Description
Patients receive Selinexor as specified in arm/group description (8 doses of 40 mg/m^2 or 6 doses of 60 mg per induction cycle).
Intervention Type
Drug
Intervention Name(s)
Idarubicin
Intervention Description
Infusion, iv, 10 mg/m^2, on days 1,3,5 in cycle 1, on days 1,3 in cycle 2
Intervention Type
Drug
Intervention Name(s)
Cytarabine
Other Intervention Name(s)
Ara-C
Intervention Description
Continuous infusion day 1 to 7, 100 mg/m^2, iv,
Primary Outcome Measure Information:
Title
Number of Participants With CR/CRi = Overall Reponse Rate
Description
Efficacy of selinexor in combination with standard chemotherapy in patients with relapsed/refractory AML by determination of rate of complete response (CR) or morphologic complete response with incomplete blood count recovery (CRi), as defined by the recommendations on diagnosis and management of AML in adults from an international expert panel, on behalf of the European LeukemiaNet:
CR: Absolute Neutrophil count (ANC) >1.0x10^9/L, Platelet count >100x10^9/L, Bone marrow blasts <5%, no Auer rods, no evidence of extramedullary disease.
CRi: Same as CR, but ANC may be <1.0x10^9/L and/or Platelet count <100x10^9/L.
Patients with morphologic leukemia free-state (MLFS) were included in the group of responders. MLFS: Bone marrow blasts <5%, no Auer rods, no evidence of extramedullary disease.
The best response after Selinexor treatment was analyzed, thus the best response after the induction cycle(s).
Time Frame
1-2 induction cycles (4 - 8 weeks)
Secondary Outcome Measure Information:
Title
Number of Participants With Partial Remission (PR) = Rate of PR
Description
Efficacy of selinexor in combination with standard chemotherapy in patients with relapsed/refractory AML by determination of rate of partial remission(PR) as defined by the recommendations on diagnosis and management of AML in adults from an international expert panel, on behalf of the European LeukemiaNet:
PR: Absolute Neutrophil count (ANC) >1.0x10^9/L, Platelet count >100x10^9/L, at least a 50% decrease in the percentage of marrow aspirate blasts to 5-25%, or marrow blasts <5% with persistent Auer rods.
The best response after Selinexor treatment was analyzed, thus the best response after the induction cycle(s).
Time Frame
1-2 induction cycles (4 - 8 weeks)
Title
Percentage of Patients Transplanted After Induction Therapy (Stem Cell Transplantation)
Description
Percentage of patients being transplanted after induction therapy (stem cell transplantation)
Time Frame
1-2 induction cycles (4 - 8 weeks)
Title
Early Death Rate
Description
Early death was defined as death before the end of the first induction cycle.
Time Frame
1 induction cycle (4 weeks)
Title
Overall Survival
Description
Overall survival (OS) was calculated from the date of informed consent to the date of death. Patients still alive at the end of follow-up were censored at the last date of follow-up.
Time Frame
Time from registration to event, max 2 years
Title
Relapse-Free Survival
Description
Relapse-free survival (RFS) was calculated from the date of CR/CRi until death or relapse, whichever occurred first. Patients were censored on the date of the last follow-up if they were alive without relapse.
Time Frame
Time from registration to event, max 2 years
Title
Event-Free Survival
Description
Event-free survival (EFS) was calculated from the time of informed consent until death, not achieving CR/CRi or relapse after CR/CRi.
Time Frame
Time from registration to event, max 2 years
Title
Progression-Free Survival
Description
Progression-free survival (PFS) was calculated from the time of informed consent to the date of recurrence or death, whichever occurred first. Patients were censored at the date of the last follow-up visit if they were alive without relapse.
Disease progression was defined as presence of >50% increase in bone marrow blasts to a level of at least 50% and/or a doubling of the percentage of peripheral blood blasts to a level of at least 50%.
Time Frame
Time from registration to event, max 2 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Cytological or histological diagnosis of AML with the exception of promyelocytic leukemia (AML M3)
Patients must have relapsed/refractory disease (relapse after stem cell transplantation is permitted) as defined as:
patients with <PR after first cycle of induction chemotherapy, or
patients with <CR(i) after second cycle of induction chemotherapy, or
patients who relapse after conventional chemotherapy or
patients who have undergone a single stem cell transplantation and who have relapse of their AML.
Men and women aged ≥18 years and eligible for standard dose of chemotherapy (7+3);
A period of at least 3 weeks needs to have elapsed since last treatment (with the exception of hydroxyurea) before participating in this study. Hydroxyurea induction therapy to reduce peripheral blast counts is permitted prior to initiation of treatment on protocol. Treatment may begin in <3 weeks from last treatment if deemed in the best interest of the patient after discussion with the PI of the study;
ECOG performance status ≤ 2
Serum biochemical values with the following limits unless considered due to leukemia: creatinine ≤2 mg/dl; total bilirubin ≤2x ULN, unless increase is due to hemolysis or congenital disorder; transaminases (SGPT or SGOT) ≤2.5x ULN.
Ability to swallow and retain oral medication;
Ability to understand and provide signed informed consent;
Cardiac ejection fraction must be >/=50% (by echocardiography).
Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
Exclusion Criteria:
Treatment with any investigational agent within four weeks.
Cumulative anthracycline dose (daunorubicin or equivalent) >360 mg/m^2
HIV infection
Presence of any medical or psychiatric condition which may limit full compliance with the study, including but not limited to:
Presence of CNS leukemia
Unresolved toxicity from previous anti-cancer therapy or incomplete recovery from surgery.
For patients after SCT as part of prior treatment:
Necessity of immunosuppressive drugs
GvHD > grade 1
Any of the following within the 12 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis, or other thromboembolic event.
Ongoing cardiac dysrhythmias of NCI CTCAE >/= Grade 2.
Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.
Clinically significant bleeding within 1 month
Facility Information:
Facility Name
Universitätsklinikum Frankfurt
City
Frankfurt am Main
State/Province
Hessen
ZIP/Postal Code
60590
Country
Germany
Facility Name
Medizinische Hochschule Hannover
City
Hannover
State/Province
Niedersachsen
ZIP/Postal Code
30625
Country
Germany
Facility Name
Universitätsklinikum Hamburg-Eppendorf
City
Hamburg
ZIP/Postal Code
20246
Country
Germany
12. IPD Sharing Statement
Learn more about this trial
A Phase II Study of Selinexor Plus Cytarabine and Idarubicin in Patients With Relapsed/Refractory Acute Myeloid Leukemia (AML)
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