Acute Myeloid Leukemia
Conditions
Brief summary
Selinexor has shown single-agent activity in a current phase I study enrolling patients with relapsed/refractory AML with durable complete remissions (CR), complete remissions with incomplete hematologic recovery (CRi), partial remissions (PR), and stable disease (SD) observed. Furthermore, common toxicities included nausea, fatigue, and anorexia and were manageable with supportive care agents. Additionally, CLAG chemotherapy has proven activity in relapsed and refractory AML, and has been shown to be a relatively well tolerated regimen without significant non-hematologic toxicity. Given the established role of CLAG chemotherapy, the single agent activity of selinexor, and their non-overlapping toxicities, the investigators propose a phase I/II open label study of selinexor in combination with CLAG for the treatment of patients with relapsed/refractory AML.
Interventions
DRUGSelinexor
DRUGCladribine
DRUGG-CSF
DRUGCytarabine
PROCEDUREBone marrow biopsy
Sponsors
Karyopharm Therapeutics Inc
Washington University School of Medicine
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed AML (defined using WHO criteria) with one of the following: * Primary refractory disease following ≤ 2 cycles of induction chemotherapy, or * First relapse with no prior unsuccessful salvage chemotherapy, or * Relapsed or refractory to hypomethylating agent, defined as a lack of response, disease progression, loss of response, or intolerance as deemed by the study investigator * Age between 18 and 70 years old. * ECOG performance status ≤ 3 * Adequate organ function as defined below: * AST(SGOT), ALT(SGPT), total bilirubin ≤ 2 x IULN except when in the opinion of treating physician is due to direct involvement of leukemia (eg. hepatic infiltration or biliary obstruction due to leukemia) or Gilbert's disease * Creatinine clearance \>50 ml/min, calculated using the formula of Cockroft and Gault: (140-Age) x Mass (kg) / (72 x Creatinine mg/dL); multiply by 0.85 if female. * Left ventricular ejection fraction of ≥ 40% by MUGA scan or echocardiogram * To ensure that no patient will receive a dose of selinexor \>70mg/m\^2, body surface area (BSA) calculated by Dubois method must be \>1.43 m\^2 * Patients should not become pregnant or father a baby while on this study because the drugs in this study can affect an unborn baby. Women should not breastfeed a baby while on this study. It is important patients understand the need to use birth control while on this study. It is not anticipated that female patients enrolling in this study will be able to conceive. However, in the rare event that this is possible, female patients of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening, and male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing potential. Acceptable methods of contraception are condoms with contraceptive foam, oral, implantable or injectable contraceptives, contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or post-menopausal. For both male and female patients, effective methods of contraception must be used throughout the study and for three months following the last dose. * Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).
Exclusion criteria
* Acute promyelocytic leukemia (AML with t(15;17)(q22;q11) and variants). * Previous treatment with CLAG or other chemotherapy regimen containing both cladribine and cytarabine. * Colony stimulating factors within 2 weeks of study. * Active graft versus host disease (GVHD) after allogeneic stem cell transplantation. At least 2 months must have elapsed since completion of an allogeneic stem cell transplantation. * Less than 2 weeks from the completion of any previous cytotoxic chemotherapy (with the exception of hydroxyurea). * Concurrent active malignancy under treatment except prostate or breast cancer undergoing treatment with hormonal therapy. * Treatment with any investigational agent within three weeks prior to first dose in this study. * Active CNS involvement with leukemia. * Unstable cardiovascular function: * symptomatic ischemia, or * uncontrolled clinically significant conduction abnormalities (i.e. ventricular tachycardia on antiarrhythmics are excluded and 1st degree AV block or asymptomatic LAFB/RBBB will not be excluded), or * congestive heart failure (CHF) of NYHA class ≥3, or * myocardial infarction (MI) within 3 months * A history of allergic reactions attributed to compounds of similar chemical or biologic composition to KPT-330 or other agents used in the study. * Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose. Infections controlled on concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional guidelines is acceptable. * Any medical condition which, in the investigator's opinion, could compromise the patient's safety. * Pregnant and/or breastfeeding. Patient must have a negative urine pregnancy test within 5 days of study entry. * Unable to swallow tablets, or diagnosed malabsorption syndrome, or any other disease significantly affecting gastrointestinal function. * Known active hepatitis B virus (HBV) or C virus (HCV) infection; or known to be positive for HCV ribonucleic acid (RNA) or HBsAg (HBV surface antigen). * Known human immunodeficiency virus (HIV) infection. * Serious psychiatric or medical conditions that could interfere with treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | From start of treatment until 30 days following last day of study treatment or until the start of a subsequent treatment for AML, whichever came first (41 days) | -All adverse events will be classified using the descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0 |
| Complete Remission Rate (CR + CRi) | Median follow-up of 34 days | * Morphologic complete remission (CR): neutrophil count \> 1.0 x 109 /L, platelet count ≥ 100 x 109/L, \< 5% bone marrow blasts by morphologic review, no Auer rods, no evidence of extramedullary disease. (No requirements for marrow cellularity, hemoglobin concentration). * Morphologic complete remission with incomplete blood count recovery (CRi): same as CR but ANC may be \<1000/mcl or platelet count \<100,000/mcl * Participants in the phase I portion of the study, treated at the MTD will count towards the phase II accrual goal for evaluation of the primary endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Platelet Engraftment | 56 days | -Time to platelet engraftment: Defined as the date of the first dose of study drug to the date that the platelet count is \>100,000/mm\^3 in the absence of platelet transfusions. |
| Time to Neutrophil Engraftment | Up to 2 years | -Time to neutrophil engraftment: Defined as the date of the first dose of study drug to the date that the absolute neutrophil count is \>1,000/mm3 |
| Event-free Survival | Up to 2 years (median follow-up of 307 days) | Event-free survival (EFS): Defined as the interval from the date of first dose of study drug to date of treatment failure including progressive disease, recurrence, or discontinuation for any reason (including toxicity, patient preference, initiation of new treatment without documented progression, or death due to any cause). |
| Duration of Remission | Up to 2 years | -Duration of remission (DOR): Defined as the interval from the date complete remission is documented to the date of recurrence. |
| Relapse-free Survival | Median follow-up of 307 days | Relapse-free survival (RFS): For patients achieving a complete remission, defined as the interval from the date of first documentation of a leukemia free state to date of recurrence or death due to any cause. |
| Overall Survival | Up to 2 years (median follow-up of 307 days) | Overall survival (OS): Defined as the date of first dose of study drug to the date of death from any cause. OS will be evaluated at 3 month intervals for at least 12 months and up to a maximum of 2 years. |
| Number of Participants Who Were Able to Undergo Hematopoietic Stem Cell Transplantation | Up to 2 years (median follow-up of 307 days) | Allogeneic stem cell transplant utilization: the number of patients proceeding to allogeneic transplant within 2 months following end of study without any additional salvage therapy following study treatment. |
Countries
United States
Participant flow
Recruitment details
The study was opened to allow participant enrollment on 06/16/2015 and the study was closed to participant enrollment on 01/22/2018.
Pre-assignment details
* Principal Investigator decided not to escalate to Schedule B dosing in the interest of generating additional safety data * Maintenance Phase patients are patients who were enrolled & treated in Phase I Schedule A or Phase II but met certain criteria to receive maintenance selinexor. Their data will only be included in adverse event results.
Participants by arm
| Arm | Count |
|---|---|
| Phase I Schedule A (Selinexor) * Selinexor will be dosed on Days 1, 5, 10, and 12 of the 28-day cycle. All doses will be 60 mg each PO.
* Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
* Cladribine will be given 5 mg/m\^2/day IV once daily on Days 4-8.
* G-CSF will be given 300 mcg SC once daily on Days 3-8.
* Cytarabine will be given 2000 mg/m\^2/day IV once daily on Days 4-8.
* Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response. | 6 |
| Phase I Schedule B (Selinexor) * Selinexor will be dosed on Days 1, 5, 10, 12, 17, and 19 of the 28-day cycle. All doses will be 60 mg each PO.
* Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
* Cladribine will be given 5 mg/m\^2/day IV once daily on Days 4-8.
* G-CSF will be given 300 mcg SC once daily on Days 3-8.
* Cytarabine will be given 2000 mg/m\^2/day IV once daily on Days 4-8.
* Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response. | 0 |
| Phase II (Selinexor) * Selinexor will be given at the schedule as determined in Phase 1.
* Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
* Cladribine will be given 5 mg/m\^2/day IV once daily on Days 4-8.
* G-CSF will be given 300 mcg SC once daily on Days 3-8.
* Cytarabine will be given 2000 mg/m\^2/day IV once daily on Days 4-8.
* Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response. | 34 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Dose Escalation Phase | Adverse Event | 0 | 0 | 3 | 0 |
| Dose Escalation Phase | Withdrawal by Subject | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Phase I Schedule A (Selinexor) | Total | Phase II (Selinexor) |
|---|---|---|---|
| Age, Continuous | 63.5 years | 55.5 years | 55 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 40 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 38 Participants | 32 Participants |
| Region of Enrollment United States | 6 participants | 40 participants | 34 participants |
| Sex: Female, Male Female | 2 Participants | 15 Participants | 13 Participants |
| Sex: Female, Male Male | 4 Participants | 25 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 6 | 0 / 0 | 25 / 34 | 2 / 2 |
| other Total, other adverse events | 6 / 6 | 0 / 0 | 34 / 34 | 2 / 2 |
| serious Total, serious adverse events | 4 / 6 | 0 / 0 | 14 / 34 | 1 / 2 |
Outcome results
Primary
Complete Remission Rate (CR + CRi)
* Morphologic complete remission (CR): neutrophil count \> 1.0 x 109 /L, platelet count ≥ 100 x 109/L, \< 5% bone marrow blasts by morphologic review, no Auer rods, no evidence of extramedullary disease. (No requirements for marrow cellularity, hemoglobin concentration). * Morphologic complete remission with incomplete blood count recovery (CRi): same as CR but ANC may be \<1000/mcl or platelet count \<100,000/mcl * Participants in the phase I portion of the study, treated at the MTD will count towards the phase II accrual goal for evaluation of the primary endpoint.
Time frame: Median follow-up of 34 days
Population: -Phase I Schedule A Arm and Phase II Arm data was combined as all participants received the same dose and schedule of the study regimen.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I Schedule A and Phase II | Complete Remission Rate (CR + CRi) | 18 Participants |
Primary
Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants
-All adverse events will be classified using the descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0
Time frame: From start of treatment until 30 days following last day of study treatment or until the start of a subsequent treatment for AML, whichever came first (41 days)
Population: -Phase I Schedule A Arm and Phase II Arm data was combined as all participants received the same dose and schedule of the study regimen.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | Lymphocyte count decreased | 32 Participants |
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | White blood cell decreased | 28 Participants |
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | Hypophosphatemia | 26 Participants |
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | Platelet count decreased | 22 Participants |
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | Hyponatremia | 18 Participants |
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | Anemia | 14 Participants |
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | Sepsis | 8 Participants |
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | Hypokalemia | 8 Participants |
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | Hypoxia | 4 Participants |
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | Hypertension | 4 Participants |
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | Nausea | 3 Participants |
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | Edema limbs | 3 Participants |
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | Respiratory failure | 3 Participants |
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | Neutrophil count decreased | 21 Participants |
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | Hyperglycemia | 11 Participants |
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | Skin infection | 10 Participants |
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | Febrile neutropenia | 8 Participants |
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | Lung infection | 7 Participants |
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | Alanine aminotransferase increased | 5 Participants |
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | Oral thrush | 4 Participants |
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | Diarrhea | 3 Participants |
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | Catheter-related infection | 3 Participants |
| Phase I Schedule A and Phase II | Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | Hematuria | 3 Participants |
Secondary
Duration of Remission
-Duration of remission (DOR): Defined as the interval from the date complete remission is documented to the date of recurrence.
Time frame: Up to 2 years
Population: -Phase I Schedule A Arm and Phase II Arm data was combined as all participants received the same dose and schedule of the study regimen.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Schedule A and Phase II | Duration of Remission | 9.1 months |
Secondary
Event-free Survival
Event-free survival (EFS): Defined as the interval from the date of first dose of study drug to date of treatment failure including progressive disease, recurrence, or discontinuation for any reason (including toxicity, patient preference, initiation of new treatment without documented progression, or death due to any cause).
Time frame: Up to 2 years (median follow-up of 307 days)
Population: -Phase I Schedule A Arm and Phase II Arm data was combined as all participants received the same dose and schedule of the study regimen.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Schedule A and Phase II | Event-free Survival | 6.1 months |
Secondary
Number of Participants Who Were Able to Undergo Hematopoietic Stem Cell Transplantation
Allogeneic stem cell transplant utilization: the number of patients proceeding to allogeneic transplant within 2 months following end of study without any additional salvage therapy following study treatment.
Time frame: Up to 2 years (median follow-up of 307 days)
Population: -Phase I Schedule A Arm and Phase II Arm data was combined as all participants received the same dose and schedule of the study regimen.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I Schedule A and Phase II | Number of Participants Who Were Able to Undergo Hematopoietic Stem Cell Transplantation | 24 Participants |
Secondary
Overall Survival
Overall survival (OS): Defined as the date of first dose of study drug to the date of death from any cause. OS will be evaluated at 3 month intervals for at least 12 months and up to a maximum of 2 years.
Time frame: Up to 2 years (median follow-up of 307 days)
Population: -Phase I Schedule A Arm and Phase II Arm data was combined as all participants received the same dose and schedule of the study regimen.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Schedule A and Phase II | Overall Survival | 7.8 months |
Secondary
Relapse-free Survival
Relapse-free survival (RFS): For patients achieving a complete remission, defined as the interval from the date of first documentation of a leukemia free state to date of recurrence or death due to any cause.
Time frame: Median follow-up of 307 days
Population: -Phase I Schedule A Arm and Phase II Arm data was combined as all participants received the same dose and schedule of the study regimen.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Schedule A and Phase II | Relapse-free Survival | 152 days |
Secondary
Time to Neutrophil Engraftment
-Time to neutrophil engraftment: Defined as the date of the first dose of study drug to the date that the absolute neutrophil count is \>1,000/mm3
Time frame: Up to 2 years
Population: -Phase I Schedule A Arm and Phase II Arm data was combined as all participants received the same dose and schedule of the study regimen.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Schedule A and Phase II | Time to Neutrophil Engraftment | 28 days |
Secondary
Time to Platelet Engraftment
-Time to platelet engraftment: Defined as the date of the first dose of study drug to the date that the platelet count is \>100,000/mm\^3 in the absence of platelet transfusions.
Time frame: 56 days
Population: -Phase I Schedule A Arm and Phase II Arm data was combined as all participants received the same dose and schedule of the study regimen.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Schedule A and Phase II | Time to Platelet Engraftment | 38 days |