Multiple Myeloma
Conditions
Brief summary
To assess if amrubicin is safe and useful for patients with multiple myeloma requiring additional treatment.
Detailed description
PRIMARY OBJECTIVES * Establish the maximum tolerated dose (MTD) and toxicity profile for the combination of amrubicin with lenalidomide and dexamethasone in previously treated adult patients with multiple myeloma during Phase I * Determine the combined rate of complete response (CR) and very good partial response (VGPR) for this combination in this population as defined by the International Myeloma Working Group Uniform Response Criteria (IMWGURC) SECONDARY OBJECTIVES * Determine the overall response rate (CR, VGPR and PR) * Assess additional evidence of ant-tumor activity as measured by duration of response (DOR), progression-free survival (PFS), time to tumor progression (TTP), and overall survival (OS)
Interventions
DRUGAmrubicin
40, 60, or 80 mg/m2 intravenous (IV)
DRUGLenalidomide
15 mg daily by mouth
DRUGDexamethasone
40 mg weekly by mouth
DRUGAspirin
81 or 325 mg daily by mouth
DRUGPegfilgrastim
6 mg subcutaneous on Day 2
Sponsors
Celgene Corporation
Michaela Liedtke
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
* Relapsed or refractory multiple myeloma that has progressed following at least 1 prior therapy. * Measurable disease defined as one of the following: * Serum M-protein ≥ 1 g/dL * Urine M-protein ≥ 200 mg/24 hours * Received at least 1 prior line of systemic treatment that may have included lenalidomide and/or an anthracycline. * No cytotoxic chemotherapy within 4 weeks prior to first dose of amrubicin. This interval may be reduced to 14 days for thalidomide, lenalidomide, bortezomib or corticosteroids, provided other entry criteria are met. * Age ≥ 18 at the time of consent. * Life expectancy of more than ≥ 3 months. * No known central nervous system involvement by myeloma. * Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 at study registration during phase 1. Once safety is confirmed, ECOG performance status 0 to 2 at study registration during phase 2. * No poorly-controlled intercurrent illness. * Platelets \> 100 x 10\^9/L * Hemoglobin \> 8.0g/dL * Absolute neutrophil count (ANC) \>1.5 x 10\^9/L * Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x upper limit of normal (ULN) * Total bilirubin ≤ 1.5 x ULN * Calculated creatinine clearance ≥ 50 mL/min by Cockcroft-Gault formula. * Left ventricular ejection fraction (LVEF) ≥ 50% by Echocardiogram (ECHO) or multiple gate acquisition scan (MUGA) * All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the Requirements of RevAssist. * Disease-free of prior malignancies for ≥ 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast. * Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 U/mL within 10 to 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin 2 acceptable methods of birth control, one highly effective method and one additional effective method at the same time, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. * Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. * Ability to understand and the willingness to sign a written informed consent document. * Able to adhere to the study visit schedule and other protocol requirements. * Able to take aspirin (81 or ≥ 25 mg) daily as prophylactic anticoagulation. Patients intolerant to aspirin may use warfarin or low molecular weight heparin (LMWH). Patients with previous thromboembolic event on lenalidomide or thalidomide may be started on warfarin or LMWH. Patients already taking warfarin or LMWH do not require additional aspirin.. * Lactating females must agree not to breast-feed while taking lenalidomide
Exclusion criteria
* Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form. * Pregnant or breastfeeding females. * Any concurrent severe or uncontrolled medical disease which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. * Use of any other experimental drug or therapy within 28 days of first dose of amrubicin. * Known hypersensitivity to thalidomide or lenalidomide. * The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs. * LVEF ≤ 50%. * Concurrent use of other anti-cancer agents or treatments. * Known positive for HIV, or infectious hepatitis, type B or C. * Cranial radiotherapy ≤ 21 days prior to first dose of amrubicin; radiotherapy to all other areas ≤ 7 days prior to first dose of amrubicin.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rates After Amrubicin + Lenalidomide + Dexamethasone, Per International Myeloma Working Group Uniform Response Criteria | 12 weeks | Modified International Myeloma Working Group Uniform Response Criteria: Complete (CR)= * Negative for monoclonal protein (MP) in urine (U) and serum (S) + * No tissue plasmacytomas (PC) + * \<5% plasma cells (PCs) in marrow (M) Stringent CR (sCR)= CR with normal light chain ratio+ no PCs in M Near CR (nCR)= CR, except MP persists in U and S Partial (PR)= S MP ≤50%, + U MP ≤90% or \<200 mg/24 hours (hr) Very Good PR (VGPR)= in S MP ≤90%, + U MP \<100 mg/24 hr Minimal (MR)= * S MP ≤51-75%, + * If light chain is excreted, reduced 50-89%/24 hr that is also \>200 mg/24 hr, + * No increase in lytic bone lesions Progressive disease (PD)= any of: * S MP ≥125% and/or ≥+0.5 g/dL, * U MP ≥125% and/or ≥+200 mg/24 hr * New or increased bone lesions/PC * S calcium \>11.5 mg/dL (attributed to increased PCs) PD after CR/sCR= * Reappearance of S or U MP * ≥5% clonal PCs in M * New PC, lytic bone lesions, hypercalcemia Stable Disease (SD)= Not CR, VGPR, MR, PR, or PD |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | 140 days | — |
| Progression-free Survival (PFS) | 9 months | Progression-free survival (PFS) is alive and free from progression, per the modified International Myeloma Working Group Uniform Response Criteria, defined as any of: * Serum monoclonal protein ≥ 125% baseline and/or ≥ +0.5 g/dL from baseline, * Urine monoclonal protein ≥ 125% baseline and/or ≥ +200 mg/24 hour from baseline * New or increased bone lesions or plasmacytomas * Serum calcium \> 11.5 mg/dL (attributed to increased plasma cells) |
| Time-to-next Treatment | 9 months | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Amrubicin + Lenalidomide + Dexamethasone Amrubicin 40, 60, or 80 mg/m2 intravenous (IV) will be given intravenously on Day 1 of each 3-week cycle beginning with 40 mg/m2, for a maximum of 4 cycles.
Concurrent therapeutic medications:
* Lenalidomide: 10 or 15 mg daily by mouth, Days 1 to 14
* Dexamethasone: 40 mg weekly by mouth (Days 1, 8, and 15)
Other drugs:
* Aspirin: 81 or 325 mg daily oral
* Pegfilgrastim subcutaneous on Day 2 | 14 |
| Total | 14 |
Baseline characteristics
| Characteristic | Amrubicin + Lenalidomide + Dexamethasone |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Region of Enrollment United States | 14 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 12 / 14 |
| serious Total, serious adverse events | 3 / 14 |
Outcome results
Primary
Response Rates After Amrubicin + Lenalidomide + Dexamethasone, Per International Myeloma Working Group Uniform Response Criteria
Modified International Myeloma Working Group Uniform Response Criteria: Complete (CR)= * Negative for monoclonal protein (MP) in urine (U) and serum (S) + * No tissue plasmacytomas (PC) + * \<5% plasma cells (PCs) in marrow (M) Stringent CR (sCR)= CR with normal light chain ratio+ no PCs in M Near CR (nCR)= CR, except MP persists in U and S Partial (PR)= S MP ≤50%, + U MP ≤90% or \<200 mg/24 hours (hr) Very Good PR (VGPR)= in S MP ≤90%, + U MP \<100 mg/24 hr Minimal (MR)= * S MP ≤51-75%, + * If light chain is excreted, reduced 50-89%/24 hr that is also \>200 mg/24 hr, + * No increase in lytic bone lesions Progressive disease (PD)= any of: * S MP ≥125% and/or ≥+0.5 g/dL, * U MP ≥125% and/or ≥+200 mg/24 hr * New or increased bone lesions/PC * S calcium \>11.5 mg/dL (attributed to increased PCs) PD after CR/sCR= * Reappearance of S or U MP * ≥5% clonal PCs in M * New PC, lytic bone lesions, hypercalcemia Stable Disease (SD)= Not CR, VGPR, MR, PR, or PD
Time frame: 12 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amrubicin + Lenalidomide + Dexamethasone | Response Rates After Amrubicin + Lenalidomide + Dexamethasone, Per International Myeloma Working Group Uniform Response Criteria | Complete Response (CR) rate | 0 percentage of participants |
| Amrubicin + Lenalidomide + Dexamethasone | Response Rates After Amrubicin + Lenalidomide + Dexamethasone, Per International Myeloma Working Group Uniform Response Criteria | Very Good Partial Response (VGPR) Rate | 7.6 percentage of participants |
| Amrubicin + Lenalidomide + Dexamethasone | Response Rates After Amrubicin + Lenalidomide + Dexamethasone, Per International Myeloma Working Group Uniform Response Criteria | Total CR + VGPR | 7.6 percentage of participants |
| Amrubicin + Lenalidomide + Dexamethasone | Response Rates After Amrubicin + Lenalidomide + Dexamethasone, Per International Myeloma Working Group Uniform Response Criteria | Partial Response (PR) Rate | 15.4 percentage of participants |
| Amrubicin + Lenalidomide + Dexamethasone | Response Rates After Amrubicin + Lenalidomide + Dexamethasone, Per International Myeloma Working Group Uniform Response Criteria | Overall Response Rate (ORR = CR + VGPR + PR) | 23 percentage of participants |
Secondary
Duration of Response (DOR)
Time frame: 140 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Amrubicin + Lenalidomide + Dexamethasone | Duration of Response (DOR) | 133 days |
Secondary
Progression-free Survival (PFS)
Progression-free survival (PFS) is alive and free from progression, per the modified International Myeloma Working Group Uniform Response Criteria, defined as any of: * Serum monoclonal protein ≥ 125% baseline and/or ≥ +0.5 g/dL from baseline, * Urine monoclonal protein ≥ 125% baseline and/or ≥ +200 mg/24 hour from baseline * New or increased bone lesions or plasmacytomas * Serum calcium \> 11.5 mg/dL (attributed to increased plasma cells)
Time frame: 9 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Amrubicin + Lenalidomide + Dexamethasone | Progression-free Survival (PFS) | 96 days |
Secondary
Time-to-next Treatment
Time frame: 9 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Amrubicin + Lenalidomide + Dexamethasone | Time-to-next Treatment | 92 days |