Multiple Myeloma
Conditions
Brief summary
The aim of this phase I/II trial is to determine the maximal tolerated dose (MTD) of carfilzomib together with pegylated liposomal doxorubicin hydrochloride (PLD) with or without dexamethasone, and then to establish the efficacy and safety of this novel combination in patients with relapsed or refractory multiple myeloma
Interventions
DRUGcarfilzomib
DRUGpegylated liposomal doxorubicin (PLD)
DRUGDexamethasone
Sponsors
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed diagnosis of multiple myeloma with a measurable disease parameter at time of screening; a measurable disease parameter is defined as one or more of the following: * Serum monoclonal protein \>= 0.5 g/dl * 24 hour urine monoclonal protein \>= 0.2 g/24 hour * Serum free light chain ratio \> 5 x normal ratio with an absolute difference of 10mg/dl between the involved and uninvolved free light chain * Soft tissue plasmacytoma \>= 2 cm measurable by either physical examination and/or applicable radiographs (e.g. magnetic resonance imaging \[MRI\], computed tomography \[CT\], etc) * Bone Marrow Plasma Cells \>= 30% * Documentation of at least one line of prior myeloma therapy now with relapsed or refractory disease requiring re-treatment * At least 18 years of age at the time of signing the informed consent. * Performance status of Eastern Cooperative Oncology Group (ECOG) =\< 2 or Karnofsky \>= 60%; participants with lower performance status based solely on bone pain secondary to multiple myeloma will be eligible * Required laboratory values * Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) and aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) \< 2.5 x the upper limit of the institutional normal value (ULN) * Total bilirubin =\< 1.5 x upper limit of normal (ULN) * Absolute neutrophil count (ANC) \>= 1,000 * Hemoglobin \>= 8 g/dl * Platelets \>= 50,000 * Creatinine clearance \> 15 ml/minute using Cockcroft-Gault formula * For those participants receiving warfarin (Coumadin), unfractionated heparin, or low-molecular weight heparin therapy, the applicable coagulation parameter that is being monitored must be within the accepted therapeutic ranges for those indications * Transfusions and/or growth factor dependent participants are not excluded if the above parameters can be achieved with such support * Females of childbearing potential (FCBP) must agree to refrain from becoming pregnant while on study drug and for 3 months after discontinuation from study drug, and must agree to use adequate contraception including hormonal contraception, (i.e. birth control pills, etc), barrier method contraception (i.e. condoms), or abstinence during that time frame; FCBP must agree to regular pregnancy testing during this timeframe; inclusion of FCBP requires two negative pregnancy tests prior to enrollment. All women, regardless of age, should be considered FCBP unless they are surgically sterile (post hysterectomy, post bilateral oophorectomy, etc) or have been naturally post menopausal for \>= 24 consecutive months * Men engaging in sexual intercourse with a FCBP must agree to use adequate contraception including hormonal contraception, (i.e. birth control pills, etc), barrier method contraception (i.e. condoms), or abstinence while on study drug and for 3 months after discontinuation from study drug * Ability to understand and willing to sign a written informed consent document
Exclusion criteria
* POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) * Plasma Cell Leukemia * Waldenstrom's macroglobulinemia * Pregnant or lactating females * Use of any anti-myeloma drug therapy within 14 days of initiation of study drug treatment excluding corticosteroids if given for an indication other than myeloma; bisphosphonates are not considered anti-myeloma drugs * Participation in an investigational therapeutic study within 14 days of initiation of study drug treatment * Radiotherapy to multiple sites or immunotherapy within 14 days of initiation of study drug treatment (localized radiotherapy to a single site at least 7 days before start is permissible) * Major surgery within 14 days of initiation of study drug treatment * Participants in whom the required program of oral (PO) and IV fluid hydration is contraindicated * Prior history of a hypersensitivity reaction to PLD, doxorubicin, bortezomib, carfilzomib, or liposomal drug formulations other than PLD; history of reactions to liposomal drug formulations other than PLD should be evaluated individually and if their reactions were felt to have been due to the encapsulated agent, rather than the liposomal component itself they should be excluded at the discretion of the investigators * Participants who are known to have active hepatitis A, B, or C viral infection may not participate in this study; active disease is defined as participants with a known viral hepatitis whose liver function tests are elevated * Known human immunodeficiency virus (HIV)-seropositive and are taking anti-retrovirals may not participate in this study; participants who are HIV-seropositive and not on anti-retroviral therapy and who otherwise meet the inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2 - Toxicity of Carfilzomib in Combination With PLD and Dexamethasone as Measured by Number of Participants Who Experience Grade 3/4 Toxicity | Through 30 days after completion of treatment (median number of cycles was 9.5 (range 1-34)) | — |
| Maximum Tolerated Dose (MTD) of Carfilzomib and PLD (Phase I - Part 2). | 28 days (completion of first cycle of all Phase I - Part 2 patients) | -MTD is the maximum tolerated dose level tested unless dose limiting toxicity (DLT) are observed during Cycle 1. If DLT is observed, MTD will be the next lower dose level. |
| Maximum Tolerated Dose (MTD) of Dexamethasone (Phase I - Part 2). | 28 days (completion of first cycle of all Phase I - Part 2 patients) | -MTD is the maximum tolerated dose level tested unless dose limiting toxicity (DLT) are observed during Cycle 1. If DLT is observed, MTD will be the next lower dose level. |
| Phase 2 - Efficacy of Carfilzomib in Combination With PLD and Dexamethasone as Measured by the Percentage of Participants With Confirmed Tumor Responses | Completion of treatment (median number of cycles was 9.5 (range 1-34)) | -A confirmed response is defined to be a complete response (CR), very good partial response (VGPR), or partial response (PR) per IMWG Criteria. |
| Maximum Tolerated Dose (MTD) of Carfilzomib and Pegylated Liposomal Doxorubicin (Phase I - Part 1). | 28 days (completion of first cycle of all Phase I - Part 1 patients) | * MTD is the maximum tolerated dose level tested unless dose limiting toxicity (DLT) are observed during Cycle 1. If DLT is observed, MTD will be the next lower dose level. * Please note that the maximum tolerated dose of carfilzomib and pegylated liposomal doxorubicin was not reached. The data below is the recommended dosage for further studies. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival Time (Phase 2 Only) | Through completion of follow-up (median follow-up was 23.3 months) | -Progression per IMWG Criteria |
| Median Duration of Overall Response | Through completion of follow-up (median follow-up was 23.3 months) | * For participants with confirmed tumor responses * A confirmed response is defined to be a complete response (CR), very good partial response (VGPR), or partial response (PR) per IMWG Criteria |
| Median Overall Survival | Completion of follow-up (median of 23.3 months) | — |
Countries
United States
Participant flow
Recruitment details
The study opened to participant enrollment on 05/14/2012 and closed to participant enrollment on 08/02/2016.
Participants by arm
| Arm | Count |
|---|---|
| Phase I - Part 1 Dose Level 0 (Carfilzomib 20/27 mg/m^2) Dose Level 0: Carfilzomib IV (20 mg/m2) D1&D2 of C1 and carfilzomib IV (27 mg/m2)D8, D9, D15, D16 of C1. Carfilzomib IV (27 mg/m2) D1, D2, D8, D9, D15, D16 C2-6. Carfilzomib IV (27 mg/m2)D1, D2, D8, D15, D22 C7+. PLD IV (30 mg/m2)D8 C1-6. | 3 |
| Phase I - Part 1 Dose Level 1 (Carfilzomib 20/36 mg/m^2) Dose Level 1: Carfilzomib IV (20 mg/m2) D1&D2 of C1 and carfilzomib IV (36 mg/m2)D8, D9, D15, D16 of C1. Carfilzomib IV (36 mg/m2) D1, D2, D8, D9, D15, D16 C2-6. Carfilzomib IV (36 mg/m2)D1, D2, D8, D15, D22 C7+. PLD IV (30 mg/m2)D8 C1-6. | 4 |
| Phase I - Part 1 Dose Level 2 (Carfilzomib 20/45 mg/m^2) Dose Level 2: Carfilzomib IV (20 mg/m2) D1&D2 of C1 and carfilzomib IV (45 mg/m2)D8, D9, D15, D16 of C1. Carfilzomib IV (45 mg/m2) D1, D2, D8, D9, D15, D16 C2-6. Carfilzomib IV (45 mg/m2)D1, D2, D8, D15, D22 C7+. PLD IV (30 mg/m2)D8 C1-6. | 4 |
| Phase I - Part 1 Dose Level 3 (Carfilzomib 20/56 mg/^2) Dose Level 3: Carfilzomib IV (20 mg/m2) D1&D2 of C1 and carfilzomib IV (56 mg/m2)D8, D9, D15, D16 of C1. Carfilzomib IV (56 mg/m2) D1, D2, D8, D9, D15, D16 C2-6. Carfilzomib IV (56 mg/m2)D1, D2, D8, D15, D22 C7+. PLD IV (30 mg/m2)D8 C1-6. | 5 |
| Phase I-Part 2 Cohort 0 (Carfilzomib 56 mg/m^2+Dexamethasone) Cohort 0: Carfilzomib IV (56 mg/\^2 - Phase 1 Part 1) D1, D2, D8, D9, D15, D16 C1-6. Carfilzomib IV (56 mg/m\^2 - Phase 1 Part 1) D1, D8, D15, D22 C7 and subsequent cycles. PLD IV (30 mg/m\^2 - Phase 1 Part 1) D8 of each cycle. Dexamethasone 20 mg IV or PO same schedule as carfilzomib. | 7 |
| Phase 2 (Carfilzomib 56 mg/m^2+ Dexamethasone) Carfilzomib IV (56 mg/\^2 - Phase 1 Part 1) D1, D2, D8, D9, D15, D16 C1-6. Carfilzomib IV (56 mg/m\^2 - Phase 1 Part 1) D1, D8, D15, D22 C7 and subsequent cycles. PLD IV (30 mg/m\^2 - Phase 1 Part 1) D8 of each cycle. Dexamethasone 20 mg IV or PO same schedule as carfilzomib. | 17 |
| Total | 40 |
Baseline characteristics
| Characteristic | Phase I - Part 1 Dose Level 0 (Carfilzomib 20/27 mg/m^2) | Total | Phase 2 (Carfilzomib 56 mg/m^2+ Dexamethasone) | Phase I-Part 2 Cohort 0 (Carfilzomib 56 mg/m^2+Dexamethasone) | Phase I - Part 1 Dose Level 3 (Carfilzomib 20/56 mg/^2) | Phase I - Part 1 Dose Level 2 (Carfilzomib 20/45 mg/m^2) | Phase I - Part 1 Dose Level 1 (Carfilzomib 20/36 mg/m^2) |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 65 years | 65 years | 65 years | 63 years | 57 years | 72 years | 66.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 37 Participants | 17 Participants | 7 Participants | 4 Participants | 4 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 9 Participants | 5 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 30 Participants | 11 Participants | 7 Participants | 4 Participants | 3 Participants | 3 Participants |
| Region of Enrollment United States | 3 Participants | 40 Participants | 17 Participants | 7 Participants | 5 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Female | 2 Participants | 23 Participants | 7 Participants | 5 Participants | 5 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 1 Participants | 17 Participants | 10 Participants | 2 Participants | 0 Participants | 2 Participants | 2 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 | 0 / 3 | 0 / 4 | 2 / 4 | 0 / 5 | 0 / 7 | 1 / 17 |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 4 / 4 | 5 / 5 | 7 / 7 | 17 / 17 |
| serious Total, serious adverse events | 2 / 3 | 3 / 4 | 4 / 4 | 3 / 5 | 2 / 7 | 10 / 17 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of Carfilzomib and Pegylated Liposomal Doxorubicin (Phase I - Part 1).
* MTD is the maximum tolerated dose level tested unless dose limiting toxicity (DLT) are observed during Cycle 1. If DLT is observed, MTD will be the next lower dose level. * Please note that the maximum tolerated dose of carfilzomib and pegylated liposomal doxorubicin was not reached. The data below is the recommended dosage for further studies.
Time frame: 28 days (completion of first cycle of all Phase I - Part 1 patients)
Population: Participants enrolled in the Phase I - Part 1 portion of this study were the only evaluable participants for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I - Part 1 | Maximum Tolerated Dose (MTD) of Carfilzomib and Pegylated Liposomal Doxorubicin (Phase I - Part 1). | Carfilzomib Recommended Dose | 56 mg/m^2 |
| Phase I - Part 1 | Maximum Tolerated Dose (MTD) of Carfilzomib and Pegylated Liposomal Doxorubicin (Phase I - Part 1). | Pegylated liposomal doxorubicin recommended dose | 30 mg/m^2 |
Primary
Maximum Tolerated Dose (MTD) of Carfilzomib and PLD (Phase I - Part 2).
-MTD is the maximum tolerated dose level tested unless dose limiting toxicity (DLT) are observed during Cycle 1. If DLT is observed, MTD will be the next lower dose level.
Time frame: 28 days (completion of first cycle of all Phase I - Part 2 patients)
Population: Participants enrolled in the Phase I - Part 2 portion of this study were the only evaluable participants for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I - Part 2 | Maximum Tolerated Dose (MTD) of Carfilzomib and PLD (Phase I - Part 2). | Carfilzomib dose | 56 mg/m^2 |
| Phase I - Part 2 | Maximum Tolerated Dose (MTD) of Carfilzomib and PLD (Phase I - Part 2). | Pegylated liposomal doxorubicin dose | 30 mg/m^2 |
Primary
Maximum Tolerated Dose (MTD) of Dexamethasone (Phase I - Part 2).
-MTD is the maximum tolerated dose level tested unless dose limiting toxicity (DLT) are observed during Cycle 1. If DLT is observed, MTD will be the next lower dose level.
Time frame: 28 days (completion of first cycle of all Phase I - Part 2 patients)
Population: Participants enrolled in the Phase I - Part 2 portion of this study were the only evaluable participants for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I - Part 2 | Maximum Tolerated Dose (MTD) of Dexamethasone (Phase I - Part 2). | 20 mg |
Primary
Phase 2 - Efficacy of Carfilzomib in Combination With PLD and Dexamethasone as Measured by the Percentage of Participants With Confirmed Tumor Responses
-A confirmed response is defined to be a complete response (CR), very good partial response (VGPR), or partial response (PR) per IMWG Criteria.
Time frame: Completion of treatment (median number of cycles was 9.5 (range 1-34))
Population: For this outcome measure the Phase I - Part 1 Dose Level 3 and Phase I - Part 2 participants were combined with the Phase 2 participants as they received the same dosing of carfilzomib. The remaining Phase I - Part 1 participants were not evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I - Part 2 | Phase 2 - Efficacy of Carfilzomib in Combination With PLD and Dexamethasone as Measured by the Percentage of Participants With Confirmed Tumor Responses | 20 Participants |
Primary
Phase 2 - Toxicity of Carfilzomib in Combination With PLD and Dexamethasone as Measured by Number of Participants Who Experience Grade 3/4 Toxicity
Time frame: Through 30 days after completion of treatment (median number of cycles was 9.5 (range 1-34))
Population: For this outcome measure the Phase I - Part 2 participants were combined with the Phase 2 participants as they received the same dosing regimen. Phase I - Part 1 participants were not evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I - Part 2 | Phase 2 - Toxicity of Carfilzomib in Combination With PLD and Dexamethasone as Measured by Number of Participants Who Experience Grade 3/4 Toxicity | 22 Participants |
Secondary
Median Duration of Overall Response
* For participants with confirmed tumor responses * A confirmed response is defined to be a complete response (CR), very good partial response (VGPR), or partial response (PR) per IMWG Criteria
Time frame: Through completion of follow-up (median follow-up was 23.3 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I - Part 1 | Median Duration of Overall Response | 6.090 months |
| Phase I - Part 2 | Median Duration of Overall Response | 6.840 months |
| Phase 2 | Median Duration of Overall Response | 3.420 months |
| Phase I - Part 1 Dose Level 3 (Carfilzomib 20/56 mg/^2) | Median Duration of Overall Response | 13.130 months |
| Phase I-Part 2 Cohort 0 (Carfilzomib 56 mg/m^2+Dexamethasone) | Median Duration of Overall Response | 9.440 months |
| Phase 2 (Carfilzomib 56 mg/m^2+ Dexamethasone) | Median Duration of Overall Response | 23.950 months |
Secondary
Median Overall Survival
Time frame: Completion of follow-up (median of 23.3 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I - Part 1 | Median Overall Survival | 25.490 months |
| Phase I - Part 2 | Median Overall Survival | 18.780 months |
| Phase 2 | Median Overall Survival | 11.610 months |
| Phase I - Part 1 Dose Level 3 (Carfilzomib 20/56 mg/^2) | Median Overall Survival | 32.340 months |
| Phase I-Part 2 Cohort 0 (Carfilzomib 56 mg/m^2+Dexamethasone) | Median Overall Survival | 18.720 months |
| Phase 2 (Carfilzomib 56 mg/m^2+ Dexamethasone) | Median Overall Survival | NA months |
Secondary
Progression-free Survival Time (Phase 2 Only)
-Progression per IMWG Criteria
Time frame: Through completion of follow-up (median follow-up was 23.3 months)
Population: This outcome measure is for Phase 2 (including Phase I Part 2) participants only. Phase I Part 2 and Phase 2 participants who began alternative anti-multiple myeloma treatment prior to progression were censored.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I - Part 2 | Progression-free Survival Time (Phase 2 Only) | 13.4 months |