Relapsed and/or Refractory Multiple Myeloma
Conditions
Brief summary
To confirm the maximum tolerated dose (MTD) from the BI 836909 trial of 400 mcg/d, given as 28-day continuous intravenous infusion in patients with relapsed and/or refractory multiple myeloma, to test the 600 mcg/d dose, given as a 28-day continuous iV infusion.
Detailed description
Cohort 1 will consist of 10 subjects dosed at 400 mcg/d. Cohort 2 will consist of 10 subjects dosed at 600 mcg/d. All doses will be given as a 28-day continuous IV infusion, followed by a 2 week treatment-free interval, until subject experiences disease progression as per International Myeloma Working Group (IMWG) criteria.
Interventions
DRUGAMG 420
28 day continuous Intravenous infusion of either 400 mcg/d or 600 mcg/d followed by 2 treatment free weeks
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 1b Primary objective Establish the safety and tolerability of AMG 420 at dose levels of 400 mcg/day and 600 mcg/day in subjects with relapsed and/or refractory multiple myeloma (RRMM) Phase 1b Key Secondary/Secondary objectives: Estimate overall response rate (ORR) and duration of response (DOR) Evaluate the rate of minimal residual disease (MRD)-negativity at the time of CR Establish the safety and tolerability of AMG 420 in subjects with extramedullary relapsed MM Characterize the PK of AMG 420 when administered as 4-week continuous IV infusion Evaluate other measures of anti-myeloma activity of AMG 420: Time to response, PFS, OS, TFI, BOR
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Subject has provided informed consent prior to initiation of any study specific activities/procedures 2. Multiple myeloma meeting the following criteria: 3. Pathologically-documented diagnosis of multiple myeloma that is relapsed or is refractory as defined by the following: Relapsed after 3 or more lines of prior therapy that must include a proteasome inhibitors (PI), an immunomodulators (IMiD), and a CD38-directed monoclonal antibody in any order during the course of treatment OR refractory to a PI, IMiD, and CD38-directed monoclonal antibody. -Measurable disease, defined by 1 or more of the following at time of screening: 1) serum M-protein \> 0.5 g/dL measured by serum protein electrophoresis (SPEP); 2) urinary M-protein excretion \> 200 mg/24 hours; 3) Involved serum free light chain (sFLC ) measurement \> 10 mg/dL, provided that the sFLC ratio is abnormal (\<0.26 or \>1.65) as per IMWG response criteria 4. . ECOG performance status of less than or equal to 2 5. Life expectancy of at least 3 months per PI judgement at screening 6. Hematological function without transfusion support (within 7 days from screening assessment) as follows: * ANC ≥ 1.0 x 10\^9/L (without growth factor support) * platelet count ≥ 25 x 10\^9/L (without transfusions) * hemoglobin ≥ 7.0 g/dL (transfusions permitted no later than 48 hours before screening) 7. Renal function as follows: calculated or measured creatinine clearance ≥30 mL/min using the Cockcroft-Gault equation or via 24-hour urine collection with plasma and urine creatinine concentrations, respectively 8. Hepatic function as follows: AST and ALT \< 3x upper limit of normal (ULN); TBIL \<1.5 x ULN (unless considered due to Gilbert's syndrome) Key
Exclusion criteria
1. Known central nervous system involvement by multiple myeloma 2. Evidence of primary or secondary plasma cell leukemia at the time of screening 3. Waldenstrom's macroglobulinemia 4. Unresolved toxicities from prior anticancer therapy, defined as not having resolved to CTCAE version 5.0 grade 1 or to levels dictated in the eligibility criteria with the exception of grade 2 peripheral neuropathy, alopecia, or toxicities from prior anticancer therapy that are considered irreversible (defined as having been present and stable for \> 4 weeks) which may be allowed if they are not otherwise described in the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-limiting Toxicities (DLTs) | Day 1 to Week 4 | DLTs were graded using Common Terminology Criteria for Adverse Events (CTCAE) v5.0, with the exception of cytokine release syndrome (CRS) and tumor lysis syndrome (TLS), which graded using the criteria referenced in the publication by Lee et al, 2014 and the Cairo Bishop criteria referenced in the publication by Coiffier et al, 2008 respectively. A participant was non-DLT evaluable if they dropped out before completion of the DLT-evaluable period for reasons other than a DLT. |
| Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Up to approximately 3 years | The severity of TEAEs were graded using the CTCAE version 5.0 with the exception of CRS and TLS, which graded using the criteria referenced in the publication by Lee et al, 2014 and the Cairo Bishop criteria referenced in the publication by Coiffier et al, 2008. Any clinically significant changes in vital signs, electrocardiograms (ECGs) and clinical laboratory tests were recorded as TEAEs. |
| Number of Participants Who Experienced a Treatment-related TEAE | Up to approximately 3 years | The severity of treatment-related TEAEs were graded using the CTCAE version 5.0 with the exception of CRS and TLS, which graded using the criteria referenced in the publication by Lee et al, 2014 and the Cairo Bishop criteria referenced in the publication by Coiffier et al, 2008. Treatment-related TEAEs were those that were considered related to the study treatment by the investigator. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Up to approximately 3 years | ORR was defined as the percentage of participants for whom the best overall response was a stringent complete response (CR), CR, very good partial response (PR), or partial response as determined by the IMWG Uniform Response Criteria. The ORR along with the associated 95% exact binomial confidence interval (Clopper Pearson Method) was determined. |
| Number of Participants With Minimal Residual Disease (MRD) Negativity Response at CR | Up to approximately 3 years | Number of participants with MRD negativity at CR or better assessed by using the IMWG criteria. |
| Duration of Response (DOR) | Up to approximately 3 years | DOR was defined as number of months between first objective response to progressive disease or death (due to any cause), whichever occurred first. Kaplan-Meier methods were used to estimate the distribution of DOR. The median and corresponding two-sided 95% confidence intervals were calculated. |
| Percentage of Participants With Minimal Residual Disease (MRD) Negativity Response at CR | Up to approximately 3 years | MRD negativity at CR or better assessed by using the IMWG criteria. Percentage of MRD negative responders at CR along with exact 2- sided 95% were provided by using the Clopper Pearson method. |
Countries
Australia, Belgium, Japan, Switzerland, United States
Participant flow
Recruitment details
This study was conducted at 10 centers in Australia, Belgium, Japan, Switzerland, and the United States from 04 March 2019 to 21 April 2022.
Pre-assignment details
23 participants were enrolled and all 23 of those participants received study drug.
Participants by arm
| Arm | Count |
|---|---|
| AMG 420 200 µg/Day 28 day continuous intravenous infusion of AMG 420 200 µg/day followed by a 2 week treatment-free interval, until progressive disease (PD) or relapse as defined by International Myeloma Working Group (IMWG) response criteria, unacceptable safety events, next anti-multiple myeloma treatment, or other reason for permanent treatment discontinuation | 1 |
| AMG 420 400 µg/Day 28 day continuous intravenous infusion of AMG 420 400 µg/day followed by a 2 week treatment-free interval, until PD or relapse as defined by IMWG response criteria, unacceptable safety events, next anti-multiple myeloma treatment, or other reason for permanent treatment discontinuation | 12 |
| AMG 420 600 µg/Day 28 day continuous intravenous infusion of AMG 420 600 µg/day followed by a 2 week treatment-free interval, until PD or relapse as defined by IMWG response criteria, unacceptable safety events, next anti-multiple myeloma treatment, or other reason for permanent treatment discontinuation | 10 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 1 | 6 | 4 |
| Overall Study | Decision by sponsor | 0 | 2 | 4 |
| Overall Study | Protocol-specified criteria | 0 | 2 | 1 |
| Overall Study | Withdrawal of consent from study | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | AMG 420 200 µg/Day | AMG 420 400 µg/Day | AMG 420 600 µg/Day | Total |
|---|---|---|---|---|
| Age, Continuous | 49.0 years | 64.7 years STANDARD_DEVIATION 6.7 | 60.8 years STANDARD_DEVIATION 11.7 | 62.3 years STANDARD_DEVIATION 9.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 12 Participants | 10 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 10 Participants | 7 Participants | 17 Participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 5 Participants | 9 Participants |
| Sex: Female, Male Male | 0 Participants | 9 Participants | 5 Participants | 14 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 | 1 / 1 | 6 / 12 | 4 / 10 | 11 / 23 |
| other Total, other adverse events | 1 / 1 | 12 / 12 | 10 / 10 | 23 / 23 |
| serious Total, serious adverse events | 1 / 1 | 10 / 12 | 8 / 10 | 19 / 23 |
Outcome results
Primary
Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)
The severity of TEAEs were graded using the CTCAE version 5.0 with the exception of CRS and TLS, which graded using the criteria referenced in the publication by Lee et al, 2014 and the Cairo Bishop criteria referenced in the publication by Coiffier et al, 2008. Any clinically significant changes in vital signs, electrocardiograms (ECGs) and clinical laboratory tests were recorded as TEAEs.
Time frame: Up to approximately 3 years
Population: Safety analysis set defined as all participants that are enrolled and receive at least 1 dose of AMG 420.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AMG 420 200 µg/Day | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | 1 Participants |
| AMG 420 400 µg/Day | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | 12 Participants |
| AMG 420 600 µg/Day | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | 10 Participants |
Primary
Number of Participants Who Experienced a Treatment-related TEAE
The severity of treatment-related TEAEs were graded using the CTCAE version 5.0 with the exception of CRS and TLS, which graded using the criteria referenced in the publication by Lee et al, 2014 and the Cairo Bishop criteria referenced in the publication by Coiffier et al, 2008. Treatment-related TEAEs were those that were considered related to the study treatment by the investigator.
Time frame: Up to approximately 3 years
Population: Safety analysis set defined as all participants that are enrolled and receive at least 1 dose of AMG 420.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AMG 420 200 µg/Day | Number of Participants Who Experienced a Treatment-related TEAE | 1 Participants |
| AMG 420 400 µg/Day | Number of Participants Who Experienced a Treatment-related TEAE | 12 Participants |
| AMG 420 600 µg/Day | Number of Participants Who Experienced a Treatment-related TEAE | 9 Participants |
Primary
Number of Participants With Dose-limiting Toxicities (DLTs)
DLTs were graded using Common Terminology Criteria for Adverse Events (CTCAE) v5.0, with the exception of cytokine release syndrome (CRS) and tumor lysis syndrome (TLS), which graded using the criteria referenced in the publication by Lee et al, 2014 and the Cairo Bishop criteria referenced in the publication by Coiffier et al, 2008 respectively. A participant was non-DLT evaluable if they dropped out before completion of the DLT-evaluable period for reasons other than a DLT.
Time frame: Day 1 to Week 4
Population: DLT evaluation analysis set includes participants who completed the DLT evaluable period or experienced a DLT any time during the DLT evaluable period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AMG 420 200 µg/Day | Number of Participants With Dose-limiting Toxicities (DLTs) | 1 Participants |
| AMG 420 400 µg/Day | Number of Participants With Dose-limiting Toxicities (DLTs) | 1 Participants |
| AMG 420 600 µg/Day | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
Secondary
Duration of Response (DOR)
DOR was defined as number of months between first objective response to progressive disease or death (due to any cause), whichever occurred first. Kaplan-Meier methods were used to estimate the distribution of DOR. The median and corresponding two-sided 95% confidence intervals were calculated.
Time frame: Up to approximately 3 years
Population: Safety analysis set includes all participants who enrolled and received at least 1 dose of AMG 420.~DOR was only calculated for participants who experienced a best overall response of partial response or better.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AMG 420 400 µg/Day | Duration of Response (DOR) | 5.49 Months |
| AMG 420 600 µg/Day | Duration of Response (DOR) | NA Months |
Secondary
Number of Participants With Minimal Residual Disease (MRD) Negativity Response at CR
Number of participants with MRD negativity at CR or better assessed by using the IMWG criteria.
Time frame: Up to approximately 3 years
Population: Safety analysis set includes all participants who enrolled and received at least 1 dose of AMG 420.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AMG 420 200 µg/Day | Number of Participants With Minimal Residual Disease (MRD) Negativity Response at CR | 0 Participants |
| AMG 420 400 µg/Day | Number of Participants With Minimal Residual Disease (MRD) Negativity Response at CR | 1 Participants |
| AMG 420 600 µg/Day | Number of Participants With Minimal Residual Disease (MRD) Negativity Response at CR | 1 Participants |
Secondary
Overall Response Rate (ORR)
ORR was defined as the percentage of participants for whom the best overall response was a stringent complete response (CR), CR, very good partial response (PR), or partial response as determined by the IMWG Uniform Response Criteria. The ORR along with the associated 95% exact binomial confidence interval (Clopper Pearson Method) was determined.
Time frame: Up to approximately 3 years
Population: Safety analysis set includes all participants who enrolled and received at least 1 dose of AMG 420.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AMG 420 200 µg/Day | Overall Response Rate (ORR) | 0 Percentage of participants |
| AMG 420 400 µg/Day | Overall Response Rate (ORR) | 41.7 Percentage of participants |
| AMG 420 600 µg/Day | Overall Response Rate (ORR) | 30.0 Percentage of participants |
Secondary
Percentage of Participants With Minimal Residual Disease (MRD) Negativity Response at CR
MRD negativity at CR or better assessed by using the IMWG criteria. Percentage of MRD negative responders at CR along with exact 2- sided 95% were provided by using the Clopper Pearson method.
Time frame: Up to approximately 3 years
Population: Safety analysis set includes all participants who enrolled and received at least 1 dose of AMG 420.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AMG 420 200 µg/Day | Percentage of Participants With Minimal Residual Disease (MRD) Negativity Response at CR | 0.0 Percentage of participants |
| AMG 420 400 µg/Day | Percentage of Participants With Minimal Residual Disease (MRD) Negativity Response at CR | 8.3 Percentage of participants |
| AMG 420 600 µg/Day | Percentage of Participants With Minimal Residual Disease (MRD) Negativity Response at CR | 10.0 Percentage of participants |