Multiple Myeloma
Conditions
Keywords
Relapsed, Refractory, Myeloma
Brief summary
The main purpose of this study is to determine the recommended doses of selinexor in combination with liposomal doxorubicin and dexamethasone for patients with relapsed and refractory myeloma. In addition, the study will assess whether this combination with effective for patients with multiple myeloma.
Interventions
DRUGSelinexor
Selinexor orally as outlined in the study treatment arm.
DRUGLiposomal doxorubicin
Pegylated liposomal doxorubicin at a starting dose of 20 mb/m² as outlined in the treatment arm.
DRUGDexamethasone
Participants will be instructed to take Dexamethasone 40 mg (10 tablets) orally once weekly with meals (ideally with breakfast to minimize insomnia). Participants older than 75 years and patients previously intolerant to 40 mg dosage will be allowed to receive 20 mg (5 tablets) once a week.
Sponsors
Karyopharm Therapeutics Inc
H. Lee Moffitt Cancer Center and Research Institute
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
* Patients with relapsed and refractory multiple myeloma who have received at least 2 prior therapies which must include lenalidomide and a proteasome inhibitor. Patients must have disease refractory to the most recent therapy. Refractory myeloma is defined as progressive disease during or within 60 days of last therapy. Patients must have previously received or be ineligible for (or refused) autologous stem cell transplant. * Must have measurable myeloma paraprotein levels in serum (≥ 0.5 g/dL) or urine (≥ 0.2 g excreted in a 24-hour urine collection sample) or by free light chain (involved free light chain greater than 100 mg/L). * Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. ECOG 2 allowed if due to bone disease * Must have an echocardiogram or multigated acquisition (MUGA) scan indicating left ventricular ejection fraction (LVEF) ≥ 50% within 42 days prior to first dose of study drug * Adequate hematological function * Adequate hepatic function within 14 days prior to loading phase (day -14) * Adequate renal function within 14 days prior to loading: estimated creatinine clearance of ≥ 30 mL/min, (Cockcroft and Gault) * Female patients of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening. Male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing potential. For both male and female patients, effective methods of contraception must be used throughout the study and for three months following the last dose.
Exclusion criteria
* Women who are pregnant or lactating * Radiation, chemotherapy, or immunotherapy or any other approved anticancer therapy ≤2 weeks prior to day -7 (beginning of loading phase) * Major surgery within four weeks before Day -7 * Myocardial infarct within 6 months before enrollment, New York Heart Association (NYHA) Class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalities * Prior cumulative exposure to doxorubicin (including liposomal preparation) \> 350mg/m\^2 * Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; patients with controlled infection or on prophylactic antibiotics are permitted in the study * Known to be HIV seropositive * Known active hepatitis A, B, or C infection; or known to be positive for hepatitis C virus (HCV) RNA or HBsAg (HBV surface antigen) * Any underlying condition that would significantly interfere with the absorption of an oral medication * Grade \>2 peripheral neuropathy at baseline (within 14 days prior to loading phase (day -7)) * Serious psychiatric or medical conditions that could interfere with treatment * Participation in an investigational anti-cancer study within 3 weeks prior to day -7(beginning of loading phase) * Concurrent therapy with approved or investigational anticancer therapeutic * Coagulation problems and active bleeding in the last month * Previous allogeneic transplant within 6 months and have evidence of clinically significant graft versus host disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) | Up to 12 months | Determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D): Selinexor on Days 1, 8 and 15 when given in combination with Lipodox 20 mg/m\^2 and Dexamethasone 40 mg. Dose level 1: 40 mg in combination with Lipodox and Dexamethasone. Dose level 2: 80 mg (D1,8,15) in combination with Lipodox and Dexamethasone. Dose level 2m: 80 mg (D1,8,15) in combination with Lipodox and Dexamethasone. Dose level 3m: 80 mg (D1,3,8,10) in combination with Lipodox and Dexamethasone. |
| Overall Response Rate (ORR) - All Participants | Up to 24 months | ORR per the modified uniform response criteria of the International Myeloma Working Group (IMWG), partial response and better. Partial Remission (PR): \>/= 50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by \>/= 90% or to \< 200 mg per 24 hours; Very Good Partial Remission (VGPR): Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \<100 mg per 24 hours; Complete Remission (CR): Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \</= 5% plasma cells in bone marrow. Stable Disease: Not meeting criteria for CR, VGPR, PR, or progressive disease. Minimal response: Less than 50% decrease in M protein. Not evaluable: Cannot be measured because enough information has not been collected. |
| Overall Response Rate (ORR) -All Participants Treated at Recommended Phase 2 Dose | Up to 24 months | Determine the overall response rate per the modified uniform response criteria of the International Myeloma Working Group (IMWG), partial response and better. Partial Remission (PR): \>/= 50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by \>/= 90% or to \< 200 mg per 24 hours; Very Good Partial Remission (VGPR): Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \<100 mg per 24 hours; Complete Remission (CR): Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \</= 5% plasma cells in bone marrow. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited at Moffitt Cancer Center and Karmanos Cancer Center September 2014 through May 2017.
Pre-assignment details
6 of the 14 participants treated at RP2D moved on from Dose 2m arm in the dose escalation portion of study.
Participants by arm
| Arm | Count |
|---|---|
| Selinexor, Liposomal Doxorubicin and Dexamethasone Combination Therapy: Phase I Dose Escalation followed by Phase 2 treatment at Recommended Phase 2 Dose (RP2D) | 27 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Dose Escalation | Death | 0 | 0 | 0 | 1 | 0 | 0 |
| Treatment at RP2D | Died prior to treatment | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Selinexor, Liposomal Doxorubicin and Dexamethasone |
|---|---|
| Age, Continuous | 60 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 21 Participants |
| Region of Enrollment United States | 27 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 6 | 1 / 3 | 0 / 0 | 1 / 7 | 0 / 4 | 1 / 8 |
| other Total, other adverse events | 5 / 6 | 3 / 3 | 0 / 0 | 7 / 7 | 4 / 4 | 6 / 7 |
| serious Total, serious adverse events | 4 / 6 | 1 / 1 | 0 / 0 | 6 / 7 | 0 / 4 | 0 / 7 |
Outcome results
Primary
Maximum Tolerated Dose (MTD)
Determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D): Selinexor on Days 1, 8 and 15 when given in combination with Lipodox 20 mg/m\^2 and Dexamethasone 40 mg. Dose level 1: 40 mg in combination with Lipodox and Dexamethasone. Dose level 2: 80 mg (D1,8,15) in combination with Lipodox and Dexamethasone. Dose level 2m: 80 mg (D1,8,15) in combination with Lipodox and Dexamethasone. Dose level 3m: 80 mg (D1,3,8,10) in combination with Lipodox and Dexamethasone.
Time frame: Up to 12 months
Population: All participants treated during dose escalation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Selinexor, Liposomal Doxorubicin and Dexamethasone | Maximum Tolerated Dose (MTD) | 80 mg |
Primary
Overall Response Rate (ORR) - All Participants
ORR per the modified uniform response criteria of the International Myeloma Working Group (IMWG), partial response and better. Partial Remission (PR): \>/= 50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by \>/= 90% or to \< 200 mg per 24 hours; Very Good Partial Remission (VGPR): Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \<100 mg per 24 hours; Complete Remission (CR): Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \</= 5% plasma cells in bone marrow. Stable Disease: Not meeting criteria for CR, VGPR, PR, or progressive disease. Minimal response: Less than 50% decrease in M protein. Not evaluable: Cannot be measured because enough information has not been collected.
Time frame: Up to 24 months
Population: All participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Selinexor, Liposomal Doxorubicin and Dexamethasone | Overall Response Rate (ORR) - All Participants | >/= Very Good Partial Response | 2 Participants |
| Selinexor, Liposomal Doxorubicin and Dexamethasone | Overall Response Rate (ORR) - All Participants | >/= Partial Response | 4 Participants |
| Selinexor, Liposomal Doxorubicin and Dexamethasone | Overall Response Rate (ORR) - All Participants | >/= Minimal Response | 9 Participants |
| Selinexor, Liposomal Doxorubicin and Dexamethasone | Overall Response Rate (ORR) - All Participants | Stable Disease | 8 Participants |
| Selinexor, Liposomal Doxorubicin and Dexamethasone | Overall Response Rate (ORR) - All Participants | Not Evaluable | 4 Participants |
Primary
Overall Response Rate (ORR) -All Participants Treated at Recommended Phase 2 Dose
Determine the overall response rate per the modified uniform response criteria of the International Myeloma Working Group (IMWG), partial response and better. Partial Remission (PR): \>/= 50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by \>/= 90% or to \< 200 mg per 24 hours; Very Good Partial Remission (VGPR): Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \<100 mg per 24 hours; Complete Remission (CR): Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \</= 5% plasma cells in bone marrow.
Time frame: Up to 24 months
Population: All participants treated at recommended phase 2 dose, regardless of when they joined the study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Selinexor, Liposomal Doxorubicin and Dexamethasone | Overall Response Rate (ORR) -All Participants Treated at Recommended Phase 2 Dose | >/= Very Good Partial Response | 0 Participants |
| Selinexor, Liposomal Doxorubicin and Dexamethasone | Overall Response Rate (ORR) -All Participants Treated at Recommended Phase 2 Dose | >/= Partial Response | 1 Participants |
| Selinexor, Liposomal Doxorubicin and Dexamethasone | Overall Response Rate (ORR) -All Participants Treated at Recommended Phase 2 Dose | >/= Minimal Response | 2 Participants |
| Selinexor, Liposomal Doxorubicin and Dexamethasone | Overall Response Rate (ORR) -All Participants Treated at Recommended Phase 2 Dose | Stable Disease | 4 Participants |
| Selinexor, Liposomal Doxorubicin and Dexamethasone | Overall Response Rate (ORR) -All Participants Treated at Recommended Phase 2 Dose | Not Evaluable | 1 Participants |