Multiple Myeloma
Conditions
Keywords
Drug Therapy
Brief summary
The purpose of this Phase 1 study is to characterize the pharmacokinetic (PK) and tolerability of oral ixazomib (MLN9708) when administered in combination with lenalidomide and dexamethasone in adult Asian participants with relapsed and/or refractory multiple myeloma.
Detailed description
The drug being tested in this study was ixazomib. Ixazomib was tested to treat adult Asian people who had relapsed and/or refractory multiple myeloma. The study enrolled 43 patients. Participants were enrolled to receive: * Ixazomib 4 mg + Lenalidomide 25 mg + Dexamethasone 40 mg. All participants were asked to take ixazomib capsules orally on Days 1, 8, and 15; lenalidomide capsules, orally, on Days 1 through 21; and dexamethasone tablets, orally, on Days 1, 8, 15, and 22 of a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity (up to 20 cycles). This multi-center trial was conducted in Singapore, Hong Kong and South Korea. The overall time to participate in this study was up to 577 days. Participants made multiple visits to the clinic, and were contacted 30 days after last dose of study drug for a follow-up assessment.
Interventions
DRUGIxazomib
Ixazomib capsules
DRUGLenalidomide
Lenalidomide capsules
DRUGDexamethasone
Dexamethasone tablets
Sponsors
Millennium Pharmaceuticals, Inc.
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
* Male or female East Asian participants 18 years or older * Diagnosed Multiple Myeloma according to standard criteria * Measurable disease as specified in study protocol * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 * Participants with relapsed and/or refractory Multiple Myeloma who have received 1 to 3 prior therapies * Meet the clinical laboratories criteria as specified in the protocol * Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to abstain from heterosexual intercourse; must also adhere to the guidelines of the lenalidomide pregnancy prevention program * Male participants who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse and must adhere to the guidelines of the lenalidomide pregnancy prevention program * Must be able to take concurrent aspirin 325 mg daily * Voluntary written consent
Exclusion criteria
* Female participants who are lactating or pregnant * Major surgery or radiotherapy within 14 days before enrollment * Infection requiring systematic antibiotics within 14 days before study enrollment * Central nervous system involvement * Failure to have fully recovered from the effects of prior chemotherapy regardless of the interval since last treatment * Systemic treatment with strong inhibitors of cytochrome P450 1A2 (CYP1A2), strong inhibitors of CYP3A, or strong CYP3A inducers, or use of Ginko biloba or St. John's wort within 14 days before study enrollment * Diagnosis of Waldenstrom's macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome * Evidence of current uncontrolled cardiovascular conditions * Serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to the protocol * Known allergy to any of the study medications * Known gastrointestinal condition or procedure that could interfere with swallowing or the oral absorption of tolerance of ixazomib * Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease with the exception of nonmelanoma skin cancer or any completely resected carcinoma in situ * Ongoing or active systemic infection, active hepatitis B virus infect, active hepatitis C infection, or known human immunodeficiency virus (HIV) positive
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax: Maximum Observed Plasma Concentration for Ixazomib | Cycle 1, Day 1 pre-dose and multiple time-points (up to 168 hours) post-dose | — |
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Cycle 1, Day 1 pre-dose and multiple time-points (up to 168 hours) post-dose | — |
| AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for Ixazomib | Cycle 1, Day 1 pre-dose and multiple time-points (up to 168 hours) post-dose | — |
| Number of Participants With Dose Limiting Toxicities (DLTs) | Cycle 1 (up to Day 28) | DLT was defined as any of the following AEs that were considered by investigator to be possibly related to therapy: 1. Grade 4 neutropenia lasting at least 7 consecutive days; 2. Grade 3 neutropenia with fever and/or infection; 3. Grade 4 thrombocytopenia at least 7 consecutive days; 4. Grade 3 thrombocytopenia with clinically significant bleeding; 5. Platelet count \<10,000/mm\^3; 6. Grade 2 peripheral neuropathy with pain or ≥Grade 3 peripheral neuropathy; 7. Grade 3 or greater nausea and / or emesis despite the use of optimal anti-emetic prophylaxis; 8. Grade 3 or greater diarrhea that occurred despite maximal supportive therapy; 9. Any other Grade 3 or greater nonhematologic toxicity with the following exceptions: Grade 3 arthralgia/myalgia, \<1 week Grade 3 fatigue; 10. A delay of \>2 weeks in the subsequent cycle of treatment; 11. Other combination study drug-related nonhematologic toxicities ≥Grade 2 that, in the opinion of the investigator, required discontinuation of study drug. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From the first dose of study drug through 30 days after the last dose of study drug (up to 577 days) | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A SAE is defined as any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or was a medically important event. |
| Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity | From the first dose of study drug through 30 days after the last dose of study drug (up to 577 days) | Clinically significant laboratory abnormalities were defined as any test results which were observed beyond the clinically acceptable limits as per the discretion of investigator. Clinical laboratory tests included chemistry, hematology and urinalysis tests. |
| Number of Participants With Clinically Significant Vital Signs Reported as Adverse Events | From the first dose of study drug through 30 days after the last dose of study drug (up to 577 days) | The number of participants who meet markedly abnormal criteria for vital signs, included diastolic and systolic blood pressure, heart rate, oral temperature, respiratory rate, and body weight. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Confirmed Best Response Category | From Cycle 1, Day 1 to Cycle 3, Day 1 until disease progression (approximately 20 months) | Percentage of participants who achieve or maintain any best response category during the treatment period were reported. Best response includes complete response (CR), very good partial response (VGPR), and partial response (PR). Response was assessed according to IMWG criteria. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in bone marrow; PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg per 24 hours. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level \<100 mg per 24 hour. |
| Duration of Response (DOR) | From date of documentation of a confirmed response to date of progressive disease, (approximately 20 months) | DOR was defined as the length of time between the date of first documented response (PR, VGPR, or CR) and the date of first documented progressive disease (PD). According to IMWG criteria: CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in bone marrow; PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg per 24 hours. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level \<100 mg per 24 hour. |
Countries
Hong Kong, Singapore, South Korea
Participant flow
Recruitment details
Participants took part in the study at 8 investigative sites in Singapore, Hong Kong and South Korea from 17 December 2012 to 11 April 2017. Data cut-off for the analysis was 14 July 2014.
Pre-assignment details
Asian participants with a diagnosis of relapsed and/or refractory multiple myeloma were enrolled and received a combination of ixazomib, lenalidomide and dexamethasone.
Participants by arm
| Arm | Count |
|---|---|
| Ixazomib+Lenalidomide+Dexamethasone Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15; lenalidomide 25 mg, capsules, orally, once on Days 1 through 21; and dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15, and 22 of a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity (up to 20 cycles) | 43 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 4 |
| Overall Study | Participants Ongoing on Study Treatment | 22 |
| Overall Study | Progressive Disease | 12 |
| Overall Study | Reason not Defined | 1 |
| Overall Study | Unsatisfactory Therapeutic Response | 2 |
| Overall Study | Withdrawal by Participant | 2 |
Baseline characteristics
| Characteristic | Ixazomib+Lenalidomide+Dexamethasone |
|---|---|
| Age, Continuous | 61.5 years STANDARD_DEVIATION 9.84 |
| Height at Baseline | 160.2 cm STANDARD_DEVIATION 7.8 |
| Race/Ethnicity, Customized Asian | 43 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 43 Participants |
| Region of Enrollment Hong Kong | 6 Participants |
| Region of Enrollment Korea, Republic Of | 16 Participants |
| Region of Enrollment Singapore | 21 Participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 27 Participants |
| Weight at Baseline | 60.6 kg STANDARD_DEVIATION 10.47 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 43 |
| other Total, other adverse events | 43 / 43 |
| serious Total, serious adverse events | 18 / 43 |
Outcome results
Primary
AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for Ixazomib
Time frame: Cycle 1, Day 15 pre-dose and multiple time-points (up to 336 hours) post-dose
Population: PK-evaluable population included all participants who received protocol-specified dosing during Cycle 1, did not receive any excluded concomitant medications and had sufficient concentration-time data to permit reliable estimation of PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ixazomib+Lenalidomide+Dexamethasone | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for Ixazomib | 1746.0 hr*ng/mL | Standard Deviation 798.6 |
Primary
AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for Ixazomib
Time frame: Cycle 1, Day 1 pre-dose and multiple time-points (up to 168 hours) post-dose
Population: Participants from the PK-evaluable population, all participants who received protocol-specified dosing during Cycle 1, did not receive any excluded concomitant medications and had sufficient concentration-time data to permit reliable estimation of PK parameters, with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ixazomib+Lenalidomide+Dexamethasone | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for Ixazomib | 685.9 hr*ng/mL | Standard Deviation 246.35 |
Primary
Cmax: Maximum Observed Plasma Concentration for Ixazomib
Time frame: Cycle 1, Day 15 pre-dose and multiple time-points (up to 336 hours) post-dose
Population: PK-evaluable population included all participants who received protocol-specified dosing during Cycle 1, did not receive any excluded concomitant medications and had sufficient concentration-time data to permit reliable estimation of PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ixazomib+Lenalidomide+Dexamethasone | Cmax: Maximum Observed Plasma Concentration for Ixazomib | 57.57 ng/mL | Standard Deviation 38.507 |
Primary
Cmax: Maximum Observed Plasma Concentration for Ixazomib
Time frame: Cycle 1, Day 1 pre-dose and multiple time-points (up to 168 hours) post-dose
Population: Participants from the Pharmacokinetic (PK)-evaluable population, all participants who received protocol-specified dosing during Cycle 1, did not receive any excluded concomitant medications and had sufficient concentration-time data to permit reliable estimation of PK parameters, with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ixazomib+Lenalidomide+Dexamethasone | Cmax: Maximum Observed Plasma Concentration for Ixazomib | 37.57 ng/mL | Standard Deviation 31.701 |
Primary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A SAE is defined as any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or was a medically important event.
Time frame: From the first dose of study drug through 30 days after the last dose of study drug (up to 577 days)
Population: Safety population was defined as all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixazomib+Lenalidomide+Dexamethasone | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 43 participants |
| Ixazomib+Lenalidomide+Dexamethasone | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 18 participants |
Primary
Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity
Clinically significant laboratory abnormalities were defined as any test results which were observed beyond the clinically acceptable limits as per the discretion of investigator. Clinical laboratory tests included chemistry, hematology and urinalysis tests.
Time frame: From the first dose of study drug through 30 days after the last dose of study drug (up to 577 days)
Population: Safety population was defined as all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixazomib+Lenalidomide+Dexamethasone | Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity | Alanine Aminotransferase Increased | 2 participants |
| Ixazomib+Lenalidomide+Dexamethasone | Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity | Aspartate Aminotransferase Increased | 1 participants |
| Ixazomib+Lenalidomide+Dexamethasone | Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity | Blood Creatinine Increased | 1 participants |
| Ixazomib+Lenalidomide+Dexamethasone | Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity | Haemoglobin Decreased | 1 participants |
| Ixazomib+Lenalidomide+Dexamethasone | Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity | Neutrophil Count Decreased | 2 participants |
| Ixazomib+Lenalidomide+Dexamethasone | Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity | Platelet Count Decreased | 4 participants |
| Ixazomib+Lenalidomide+Dexamethasone | Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity | Anaemia | 6 participants |
| Ixazomib+Lenalidomide+Dexamethasone | Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity | Febrile Neutropenia | 1 participants |
| Ixazomib+Lenalidomide+Dexamethasone | Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity | Neutropenia | 12 participants |
| Ixazomib+Lenalidomide+Dexamethasone | Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity | Thrombocytopenia | 8 participants |
| Ixazomib+Lenalidomide+Dexamethasone | Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity | Hyperglycaemia | 1 participants |
| Ixazomib+Lenalidomide+Dexamethasone | Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity | Hypocalcaemia | 3 participants |
| Ixazomib+Lenalidomide+Dexamethasone | Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity | Hypokalaemia | 5 participants |
| Ixazomib+Lenalidomide+Dexamethasone | Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity | Hypomagnesaemia | 1 participants |
| Ixazomib+Lenalidomide+Dexamethasone | Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity | Hyponatraemia | 1 participants |
| Ixazomib+Lenalidomide+Dexamethasone | Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Adverse Events of ≥Grade 3 Intensity | Hypophosphataemia | 2 participants |
Primary
Number of Participants With Clinically Significant Vital Signs Reported as Adverse Events
The number of participants who meet markedly abnormal criteria for vital signs, included diastolic and systolic blood pressure, heart rate, oral temperature, respiratory rate, and body weight.
Time frame: From the first dose of study drug through 30 days after the last dose of study drug (up to 577 days)
Population: Safety population was defined as all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixazomib+Lenalidomide+Dexamethasone | Number of Participants With Clinically Significant Vital Signs Reported as Adverse Events | Grade 1 or 2 Hypertension | 4 participants |
| Ixazomib+Lenalidomide+Dexamethasone | Number of Participants With Clinically Significant Vital Signs Reported as Adverse Events | Grade 2 Hypotension | 1 participants |
Primary
Number of Participants With Dose Limiting Toxicities (DLTs)
DLT was defined as any of the following AEs that were considered by investigator to be possibly related to therapy: 1. Grade 4 neutropenia lasting at least 7 consecutive days; 2. Grade 3 neutropenia with fever and/or infection; 3. Grade 4 thrombocytopenia at least 7 consecutive days; 4. Grade 3 thrombocytopenia with clinically significant bleeding; 5. Platelet count \<10,000/mm\^3; 6. Grade 2 peripheral neuropathy with pain or ≥Grade 3 peripheral neuropathy; 7. Grade 3 or greater nausea and / or emesis despite the use of optimal anti-emetic prophylaxis; 8. Grade 3 or greater diarrhea that occurred despite maximal supportive therapy; 9. Any other Grade 3 or greater nonhematologic toxicity with the following exceptions: Grade 3 arthralgia/myalgia, \<1 week Grade 3 fatigue; 10. A delay of \>2 weeks in the subsequent cycle of treatment; 11. Other combination study drug-related nonhematologic toxicities ≥Grade 2 that, in the opinion of the investigator, required discontinuation of study drug.
Time frame: Cycle 1 (up to Day 28)
Population: DLT-evaluable population consisted of participants who either had a DLT during Cycle 1 or received all scheduled doses and completed all study procedures in Cycle 1 without having a DLT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ixazomib+Lenalidomide+Dexamethasone | Number of Participants With Dose Limiting Toxicities (DLTs) | 2 participants |
Primary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib
Time frame: Cycle 1, Day 15 pre-dose and multiple time-points (up to 336 hours) post-dose
Population: PK-evaluable population included all participants who received protocol-specified dosing during Cycle 1, did not receive any excluded concomitant medications and had sufficient concentration-time data to permit reliable estimation of PK parameters.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixazomib+Lenalidomide+Dexamethasone | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | 2.0 hours |
Primary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib
Time frame: Cycle 1, Day 1 pre-dose and multiple time-points (up to 168 hours) post-dose
Population: Participants from the PK-evaluable population, all participants who received protocol-specified dosing during Cycle 1, did not receive any excluded concomitant medications and had sufficient concentration-time data to permit reliable estimation of PK parameters, with data available for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixazomib+Lenalidomide+Dexamethasone | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | 1.5 hours |
Secondary
Duration of Response (DOR)
DOR was defined as the length of time between the date of first documented response (PR, VGPR, or CR) and the date of first documented progressive disease (PD). According to IMWG criteria: CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in bone marrow; PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg per 24 hours. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level \<100 mg per 24 hour.
Time frame: From date of documentation of a confirmed response to date of progressive disease, (approximately 20 months)
Population: Safety population was defined as all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixazomib+Lenalidomide+Dexamethasone | Duration of Response (DOR) | 12.9 months |
Secondary
Percentage of Participants With Confirmed Best Response Category
Percentage of participants who achieve or maintain any best response category during the treatment period were reported. Best response includes complete response (CR), very good partial response (VGPR), and partial response (PR). Response was assessed according to IMWG criteria. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in bone marrow; PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg per 24 hours. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level \<100 mg per 24 hour.
Time frame: From Cycle 1, Day 1 to Cycle 3, Day 1 until disease progression (approximately 20 months)
Population: Safety population was defined as all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ixazomib+Lenalidomide+Dexamethasone | Percentage of Participants With Confirmed Best Response Category | 53.5 percentage of participants |