Hodgkin's Disease, Multiple Myeloma, Non-Hodgkin's Lymphoma, Waldenstrom's Macroglobulinemia
Conditions
Keywords
Hematological, Proteasome, Myeloma, Lymphoma
Brief summary
The purpose of this study is to test the safety and tolerability of carfilzomib at different dose levels on hematological cancers such as multiple myeloma, non-Hodgkin's lymphoma, Hodgkin's disease, or Waldenstrom's macroglobulinemia. Carfilzomib is a proteasome inhibitor, an enzyme responsible for degrading a wide variety of cellular proteins.
Interventions
DRUGCarfilzomib
Administered as an IV bolus dose
DRUGDexamethasone
Administered orally prior to carfilzomib
Sponsors
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written informed consent in accordance with federal, local, and institutional guidelines 2. Males and females ≥18 years of age 3. Histologically confirmed diagnosis of one of the hematologic malignancies below: * Multiple myeloma (MM) * Non-Hodgkin's lymphoma (NHL) * Waldenström's Macroglobulinemia (WM) * Hodgkin's disease (HD) 4. Subjects who are refractory or relapsed following at least two prior therapies 5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 6. Adequate cardiovascular function without symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction in the previous six months 7. Adequate hepatic function, with bilirubin \< 2.0 times the upper limit of normal, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of \< 3.0 times the upper limit of normal 8. Total white blood cell (WBC) count ≥ 2,000/mm³, absolute neutrophil count (ANC) ≥ 1000/mm³, hemoglobin ≥ 8.0 g/dL, and platelet count ≥ 50,000/mm³ * Screening ANC should be independent of granulocyte colony stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) support for ≥ 1 week and of pegylated G-CSF for ≥ 2 weeks) * Subjects receiving supportive care including erythropoietin, darbepoetin and/or bisphosphonates can continue to do so, but must be transfusion independent; subjects receiving erythropoietic support must remain on the same dose for the first 28 days of study participation 9. An estimated creatinine clearance of ≥ 30 mL/min, calculated using the formula of Cockroft and Gault 10. Serum creatinine ≤ 2.0 mg/dL 11. Uric acid, if elevated, must be corrected to within laboratory normal range prior to dosing 12. Female subjects of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test. Male subjects must use an effective barrier method of contraception throughout the study and for three months following the last dose if sexually active with a female of child-bearing potential.
Exclusion criteria
1. Female subjects who are pregnant or lactating 2. Subjects who are transfusion dependent 3. Subjects with NHL or HL who have received steroid therapy in the previous seven days 4. Subjects with MM or Waldenström's Macroglobulinemia who have received steroid therapy in the previous three weeks, except for MM subjects in the Carfilzomib + DEX Expansion Cohort, where previous treatment with dexamethasone will be allowed. The dose and schedule of administration of dexamethasone will be adjusted to that used in the protocol 5. Radiation, chemotherapy, or immunotherapy in the previous four weeks, or subjects who, in the judgment of the Investigator, have not recovered from the effects of previous therapy 6. For the Dose Escalation period, subjects who have received prior radioimmunotherapy with anti-cluster of differentiation (CD)20 monoclonal antibodies such as Bexxar® or Zevalin®; subjects treated with these products will be allowed in the Dose Expansion period 7. Subjects who have received allogeneic stem cell transplant therapy 8. Subjects with NHL or HL who have received autologous stem cell transplant therapy and have relapsed within 100 days of therapy 9. Rituxan therapy within three months before Day 1 unless there is evidence of disease progression 10. Major surgery within three weeks before Day 1 11. Congestive heart failure (CHF) (New York Heart Association class III to IV) 12. Acute active infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose 13. Subjects who are known or suspected of having human immunodeficiency virus (HIV) infection or who are HIV seropositive 14. Active hepatitis A, B, or C infection; or positive for Hepatitis C ribonucleic acid (RNA) or hepatitis B antigen 15. Non-hematologic malignancy within the past three years except a) adequately treated basal cell or squamous cell skin cancer, b) carcinoma in situ of the cervix, or c) prostate cancer with stable prostate specific antigen (PSA) levels for three years 16. Subjects with treatment-related myelodysplastic disorder 17. Subjects with known brain metastasis (active central nervous system \[CNS\] disease only) 18. Serious psychiatric or medical conditions that could interfere with treatment 19. Participation in an investigational therapeutic study within one month prior to Day 1 20. Significant neurotoxicity (Grade 2 or higher with pain) at the time of study initiation 21. Concurrent therapy with approved or investigative anticancer therapeutics 22. Subjects with previous hypersensitivity to bortezomib injection 23. Subjects with contraindications to receiving allopurinol 24. Subjects in whom the required program of oral and intravenous fluid hydration is contraindicated, e.g., due to pre-existing pulmonary, cardiac, or renal impairment 25. Subjects with known or suspected amyloidosis 26. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve to Last Measureable Timepoint (AUClast) for Carfilzomib | Cycle 1, Day 1 at predose, 5, 15, and 30 minutes, and 1, 2, 4, and 24 hours post dose. | — |
| Area Under the Concentration-time Curve Extrapolated to Infinity (AUCinf) for Carfilzomib | Cycle 1, Day 1 at predose, 5, 15, and 30 minutes, and 1, 2, 4, and 24 hours post dose. | — |
| Number of Participants With Dose-limiting Toxicities (DLTs) | 28 days | A DLT was defined as any of the following occurring in the first 28 days of study participation: Nonhematologic: * \> Grade 2 neuropathy with pain * ≥ Grade 3 nonhematologic toxicity (excluding nausea, vomiting, or diarrhea) * ≥ Grade 3 nausea, vomiting, or diarrhea uncontrolled by maximal antiemetic/antidiarrheal therapy Hematologic: * Grade 4 neutropenia (absolute neutrophil count \[ANC\] \< 0.5 × 10ˆ9/L) lasting ≥ 14 days without hematopoietic growth factor support * Febrile neutropenia (ANC \< 1.0 × 10ˆ9/L with a fever ≥ 38.3°C) * Grade 4 thrombocytopenia (platelets \< 25.0 × 10ˆ9/L) or thrombocytopenia associated with bleeding. Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute (NCI) version 3.0. |
| Maximum Observed Plasma Concentration of Carfilzomib (Cmax) | Cycle 1, Day 1 at predose, 5, 15, and 30 minutes, and 1, 2, 4, and 24 hours post dose. | — |
| Time to Maximum Observed Plasma Concentration of Carfilzomib (Tmax) | Cycle 1, Day 1 at predose, 5, 15, and 30 minutes, and 1, 2, 4, and 24 hours post dose. | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | From the first dose of study drug until 30 days after the last dose. Median duration of treatment was 6.3 weeks in the dose escalation phase and 6.4 weeks in the dose expansion phase. | Duration of objective response is defined as the time from the date of first documented assessment of clinical response (confirmed or unconfirmed complete response, partial response, or minimal response) to the date of documented assessment of progressive disease or death, whichever comes first, plus one day. Participants without tumor progression or death were censored at the date of their last valid clinical response assessment. Median duration of response was calculated using the Kaplan-Meier method. |
| Time to Progression | From the first dose of study drug until 30 days after the last dose. Median duration of treatment was 6.3 weeks in the dose escalation phase and 6.4 weeks in the dose expansion phase. | Time to progressive disease is defined as the time from the date of Cycle 1, Day 1 of treatment to the date of documented assessment of progressive disease, plus one day. Participants without tumor progression were censored at the date of their last clinical response assessment. Median time to progression was calculated using the Kaplan-Meier method. |
| Progression-free Survival | From the first dose of study drug until 30 days after the last dose. Median duration of treatment was 6.3 weeks in the dose escalation phase and 6.4 weeks in the dose expansion phase. | Progression-free survival is defined as the time from the date of Cycle 1, Day 1 of treatment to the date of documented assessment of progressive disease or death, whichever comes first, plus one day. Participants without tumor progression or death were censored at the date of their last valid clinical response assessment. Median progression-free survival was calculated using the Kaplan-Meier method. |
| Best Clinical Response to Treatment | From the first dose of study drug until 30 days after the last dose. Median duration of treatment was 6.3 weeks in the dose escalation phase and 6.4 weeks in the dose expansion phase. | Disease response criteria for NHL were according to the International Working Group Criteria for Non-Hodgkin's Lymphoma. Disease response criteria for Multiple Myeloma were according to the European Group for Blood and Marrow Transplantation (EBMT). Disease response criteria for WM were according to the consensus panel recommendations from the Second International Workshop on Waldenström's Macroglobulinemia. The disease response criteria for Hodgkin's Lymphoma are defined as follows: * Complete response: total resolution of measurable disease parameters. * Partial response: a ≥ 50% resolution without the appearance of new disease. * Stable disease: between \< 50% resolution and ≤ 25% increases in measurable disease parameters without appearance of new disease. * Progressive disease: an increase of \> 25% in measurable disease parameters. Best clinical response is the best response observed from the start of study treatment until disease progression or death. |
Countries
United States
Participant flow
Recruitment details
Adults with with multiple myeloma (MM)-both secretory and nonsecretory, non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD), or Waldenström's macroglobulinemia (WM) were eligible for enrollment in this study.
Pre-assignment details
The study was divided into a sequential Dose Escalation phase (Part 1; Arms 1-9), followed by a Dose Expansion phase (Part 2; Arms 10-11) consisting of a carfilzomib-only cohort and a carfilzomib-plus dexamethasone cohort.
Participants by arm
| Arm | Count |
|---|---|
| CFZ 1.2 mg/m² Participants received carfilzomib (CFZ) 1.2 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. | 3 |
| CFZ 2.4 mg/m² Participants received carfilzomib 2.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. | 3 |
| CFZ 4.0 mg/m² Participants received carfilzomib 4.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. | 4 |
| CFZ 6.0 mg/m² Participants received carfilzomib 6.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. | 3 |
| CFZ 8.4 mg/m² Participants received carfilzomib 8.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. | 3 |
| CFZ 11.0 mg/m² Participants received carfilzomib 11.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. | 4 |
| CFZ 15.0 mg/m² Participants received carfilzomib 15.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. | 3 |
| CFZ 20.0 mg/m² Participants received carfilzomib 20.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. | 8 |
| CFZ 27.0 mg/m² Participants received carfilzomib 27.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. | 6 |
| CFZ 20/27 mg/m² Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. | 7 |
| CFZ 20/27 mg/m² + DEX Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. Participants also received 20 mg dexamethasone (DEX) administered before each dose of carfilzomib (i.e. 40 mg weekly). | 4 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 2 | 0 | 1 | 0 |
| Overall Study | Death | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Disease Progression or Relapse | 3 | 1 | 2 | 1 | 2 | 2 | 3 | 5 | 5 | 3 | 2 |
| Overall Study | Other | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 | 0 | 1 | 2 | 0 | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | CFZ 1.2 mg/m² | CFZ 2.4 mg/m² | CFZ 4.0 mg/m² | CFZ 6.0 mg/m² | CFZ 8.4 mg/m² | CFZ 11.0 mg/m² | CFZ 15.0 mg/m² | CFZ 20.0 mg/m² | CFZ 27.0 mg/m² | CFZ 20/27 mg/m² | CFZ 20/27 mg/m² + DEX | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous Dose Escalation (Part 1) | 62.5 years STANDARD_DEVIATION 17.47 | 69.6 years STANDARD_DEVIATION 4.8 | 55.3 years STANDARD_DEVIATION 21.71 | 51.7 years STANDARD_DEVIATION 6.2 | 61.6 years STANDARD_DEVIATION 9.15 | 61.3 years STANDARD_DEVIATION 3.76 | 50.3 years STANDARD_DEVIATION 12.99 | 60.6 years STANDARD_DEVIATION 11.99 | 67.6 years STANDARD_DEVIATION 9.82 | NA years | NA years | 60.6 years STANDARD_DEVIATION 12.25 |
| Age, Continuous Dose Expansion (Part 2) | NA years | NA years | NA years | NA years | NA years | NA years | NA years | NA years | NA years | 66.3 years STANDARD_DEVIATION 9.21 | 54.3 years STANDARD_DEVIATION 13.57 | 61.9 years STANDARD_DEVIATION 11.96 |
| Disease Diagnosis Hodgkin's Disease | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Disease Diagnosis Multiple Myeloma | 0 participants | 3 participants | 0 participants | 2 participants | 1 participants | 2 participants | 2 participants | 6 participants | 5 participants | 3 participants | 4 participants | 28 participants |
| Disease Diagnosis Non-Hodgkin's Lymphoma | 3 participants | 0 participants | 3 participants | 1 participants | 2 participants | 2 participants | 1 participants | 2 participants | 1 participants | 2 participants | 0 participants | 17 participants |
| Disease Diagnosis Waldenstrom's Macroglobulinemia | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized African American | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Caucasian | 3 participants | 2 participants | 3 participants | 3 participants | 2 participants | 4 participants | 3 participants | 7 participants | 6 participants | 6 participants | 3 participants | 42 participants |
| Race/Ethnicity, Customized Hispanic | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Native American | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 2 participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 3 Participants | 2 Participants | 1 Participants | 4 Participants | 1 Participants | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 22 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 2 Participants | 6 Participants | 4 Participants | 5 Participants | 1 Participants | 26 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 | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 4 / 4 | 3 / 3 | 3 / 3 | 4 / 4 | 3 / 3 | 8 / 8 | 6 / 6 | 7 / 7 | 4 / 4 |
| serious Total, serious adverse events | 2 / 3 | 1 / 3 | 3 / 4 | 2 / 3 | 2 / 3 | 2 / 4 | 1 / 3 | 3 / 8 | 4 / 6 | 3 / 7 | 2 / 4 |
Outcome results
Primary
Area Under the Concentration-time Curve Extrapolated to Infinity (AUCinf) for Carfilzomib
Time frame: Cycle 1, Day 1 at predose, 5, 15, and 30 minutes, and 1, 2, 4, and 24 hours post dose.
Population: Participants with available pharmacokinetic (PK) data. AUCinf was only determined for cohorts receiving carfilzomib ≥ 11 mg/m². For cohorts with carfilzomib dose at 1.2-8.4 mg/m², carfilzomib was measurable at too few time points to allow a good estimation. Participants in the two Dose Expansion cohorts (20/27 mg/m²) were combined for PK analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CFZ 11.0 mg/m² | Area Under the Concentration-time Curve Extrapolated to Infinity (AUCinf) for Carfilzomib | 4056 ng*minute/mL | Standard Deviation 3698 |
| CFZ 15.0 mg/m² | Area Under the Concentration-time Curve Extrapolated to Infinity (AUCinf) for Carfilzomib | 1420 ng*minute/mL | Standard Deviation 922 |
| CFZ 20.0 mg/m² | Area Under the Concentration-time Curve Extrapolated to Infinity (AUCinf) for Carfilzomib | 4942 ng*minute/mL | Standard Deviation 3497 |
| CFZ 27.0 mg/m² | Area Under the Concentration-time Curve Extrapolated to Infinity (AUCinf) for Carfilzomib | 3417 ng*minute/mL | Standard Deviation 3962 |
| CFZ 20/27 mg/m² | Area Under the Concentration-time Curve Extrapolated to Infinity (AUCinf) for Carfilzomib | 4997 ng*minute/mL | Standard Deviation 5812 |
Primary
Area Under the Concentration-time Curve to Last Measureable Timepoint (AUClast) for Carfilzomib
Time frame: Cycle 1, Day 1 at predose, 5, 15, and 30 minutes, and 1, 2, 4, and 24 hours post dose.
Population: Participants with available pharmacokinetic (PK) data. AUClast was only determined for cohorts receiving carfilzomib ≥ 11 mg/m². For cohorts with carfilzomib dose at 1.2-8.4 mg/m², carfilzomib was measurable at too few time points to allow a good estimation. Participants in the two Dose Expansion cohorts (20/27 mg/m²) were combined for PK analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CFZ 11.0 mg/m² | Area Under the Concentration-time Curve to Last Measureable Timepoint (AUClast) for Carfilzomib | 4049 ng*minute/mL | Standard Deviation 3695 |
| CFZ 15.0 mg/m² | Area Under the Concentration-time Curve to Last Measureable Timepoint (AUClast) for Carfilzomib | 1414 ng*minute/mL | Standard Deviation 919 |
| CFZ 20.0 mg/m² | Area Under the Concentration-time Curve to Last Measureable Timepoint (AUClast) for Carfilzomib | 4911 ng*minute/mL | Standard Deviation 3495 |
| CFZ 27.0 mg/m² | Area Under the Concentration-time Curve to Last Measureable Timepoint (AUClast) for Carfilzomib | 3409 ng*minute/mL | Standard Deviation 3964 |
| CFZ 20/27 mg/m² | Area Under the Concentration-time Curve to Last Measureable Timepoint (AUClast) for Carfilzomib | 4970 ng*minute/mL | Standard Deviation 5817 |
Primary
Maximum Observed Plasma Concentration of Carfilzomib (Cmax)
Time frame: Cycle 1, Day 1 at predose, 5, 15, and 30 minutes, and 1, 2, 4, and 24 hours post dose.
Population: Participants with available pharmacokinetic (PK) data. Cmax was only determined for cohorts receiving carfilzomib ≥ 11 mg/m². For cohorts with carfilzomib dose at 1.2-8.4 mg/m², carfilzomib was measurable at too few time points to allow a good estimation. Participants in the two Dose Expansion cohorts (20/27 mg/m²) were combined for PK analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CFZ 11.0 mg/m² | Maximum Observed Plasma Concentration of Carfilzomib (Cmax) | 505.17 ng/mL | Standard Deviation 485.12 |
| CFZ 15.0 mg/m² | Maximum Observed Plasma Concentration of Carfilzomib (Cmax) | 142.67 ng/mL | Standard Deviation 97.22 |
| CFZ 20.0 mg/m² | Maximum Observed Plasma Concentration of Carfilzomib (Cmax) | 527.50 ng/mL | Standard Deviation 405.59 |
| CFZ 27.0 mg/m² | Maximum Observed Plasma Concentration of Carfilzomib (Cmax) | 406.08 ng/mL | Standard Deviation 517.29 |
| CFZ 20/27 mg/m² | Maximum Observed Plasma Concentration of Carfilzomib (Cmax) | 390.66 ng/mL | Standard Deviation 492.92 |
Primary
Number of Participants With Dose-limiting Toxicities (DLTs)
A DLT was defined as any of the following occurring in the first 28 days of study participation: Nonhematologic: * \> Grade 2 neuropathy with pain * ≥ Grade 3 nonhematologic toxicity (excluding nausea, vomiting, or diarrhea) * ≥ Grade 3 nausea, vomiting, or diarrhea uncontrolled by maximal antiemetic/antidiarrheal therapy Hematologic: * Grade 4 neutropenia (absolute neutrophil count \[ANC\] \< 0.5 × 10ˆ9/L) lasting ≥ 14 days without hematopoietic growth factor support * Febrile neutropenia (ANC \< 1.0 × 10ˆ9/L with a fever ≥ 38.3°C) * Grade 4 thrombocytopenia (platelets \< 25.0 × 10ˆ9/L) or thrombocytopenia associated with bleeding. Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute (NCI) version 3.0.
Time frame: 28 days
Population: Safety-evaluable: All participants who were enrolled and received at least 1 dose of carfilzomib
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CFZ 1.2 mg/m² | Number of Participants With Dose-limiting Toxicities (DLTs) | 1 participants |
| CFZ 2.4 mg/m² | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| CFZ 4.0 mg/m² | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| CFZ 6.0 mg/m² | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| CFZ 8.4 mg/m² | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| CFZ 11.0 mg/m² | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| CFZ 15.0 mg/m² | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| CFZ 20.0 mg/m² | Number of Participants With Dose-limiting Toxicities (DLTs) | 1 participants |
| CFZ 27.0 mg/m² | Number of Participants With Dose-limiting Toxicities (DLTs) | 1 participants |
| CFZ 20/27 mg/m² | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| CFZ 20/27 mg/m² + DEX | Number of Participants With Dose-limiting Toxicities (DLTs) | 1 participants |
Primary
Time to Maximum Observed Plasma Concentration of Carfilzomib (Tmax)
Time frame: Cycle 1, Day 1 at predose, 5, 15, and 30 minutes, and 1, 2, 4, and 24 hours post dose.
Population: Participants with available pharmacokinetic (PK) data. Tmax was only determined for cohorts receiving carfilzomib ≥ 11 mg/m². For cohorts with carfilzomib dose at 1.2-8.4 mg/m², carfilzomib was measurable at too few time points to allow a good estimation. Participants in the two Dose Expansion cohorts (20/27 mg/m²) were combined for PK analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CFZ 11.0 mg/m² | Time to Maximum Observed Plasma Concentration of Carfilzomib (Tmax) | 5 minutes | Standard Deviation 0 |
| CFZ 15.0 mg/m² | Time to Maximum Observed Plasma Concentration of Carfilzomib (Tmax) | 6 minutes | Standard Deviation 1 |
| CFZ 20.0 mg/m² | Time to Maximum Observed Plasma Concentration of Carfilzomib (Tmax) | 7 minutes | Standard Deviation 2 |
| CFZ 27.0 mg/m² | Time to Maximum Observed Plasma Concentration of Carfilzomib (Tmax) | 6 minutes | Standard Deviation 2 |
| CFZ 20/27 mg/m² | Time to Maximum Observed Plasma Concentration of Carfilzomib (Tmax) | 16 minutes | Standard Deviation 11 |
Secondary
Best Clinical Response to Treatment
Disease response criteria for NHL were according to the International Working Group Criteria for Non-Hodgkin's Lymphoma. Disease response criteria for Multiple Myeloma were according to the European Group for Blood and Marrow Transplantation (EBMT). Disease response criteria for WM were according to the consensus panel recommendations from the Second International Workshop on Waldenström's Macroglobulinemia. The disease response criteria for Hodgkin's Lymphoma are defined as follows: * Complete response: total resolution of measurable disease parameters. * Partial response: a ≥ 50% resolution without the appearance of new disease. * Stable disease: between \< 50% resolution and ≤ 25% increases in measurable disease parameters without appearance of new disease. * Progressive disease: an increase of \> 25% in measurable disease parameters. Best clinical response is the best response observed from the start of study treatment until disease progression or death.
Time frame: From the first dose of study drug until 30 days after the last dose. Median duration of treatment was 6.3 weeks in the dose escalation phase and 6.4 weeks in the dose expansion phase.
Population: Biologic response-evaluable: All participants who received at least 1 cycle of carfilzomib and had both baseline and at least 1 post-baseline disease assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CFZ 1.2 mg/m² | Best Clinical Response to Treatment | Complete Response | 0 participants |
| CFZ 1.2 mg/m² | Best Clinical Response to Treatment | Progressive Disease | 1 participants |
| CFZ 1.2 mg/m² | Best Clinical Response to Treatment | Unknown | 0 participants |
| CFZ 1.2 mg/m² | Best Clinical Response to Treatment | Stable Disease/No Change | 0 participants |
| CFZ 1.2 mg/m² | Best Clinical Response to Treatment | Partial Response | 0 participants |
| CFZ 1.2 mg/m² | Best Clinical Response to Treatment | Minimal Response | 0 participants |
| CFZ 2.4 mg/m² | Best Clinical Response to Treatment | Partial Response | 0 participants |
| CFZ 2.4 mg/m² | Best Clinical Response to Treatment | Stable Disease/No Change | 1 participants |
| CFZ 2.4 mg/m² | Best Clinical Response to Treatment | Minimal Response | 0 participants |
| CFZ 2.4 mg/m² | Best Clinical Response to Treatment | Progressive Disease | 1 participants |
| CFZ 2.4 mg/m² | Best Clinical Response to Treatment | Complete Response | 0 participants |
| CFZ 2.4 mg/m² | Best Clinical Response to Treatment | Unknown | 0 participants |
| CFZ 4.0 mg/m² | Best Clinical Response to Treatment | Stable Disease/No Change | 1 participants |
| CFZ 4.0 mg/m² | Best Clinical Response to Treatment | Complete Response | 0 participants |
| CFZ 4.0 mg/m² | Best Clinical Response to Treatment | Unknown | 1 participants |
| CFZ 4.0 mg/m² | Best Clinical Response to Treatment | Partial Response | 0 participants |
| CFZ 4.0 mg/m² | Best Clinical Response to Treatment | Progressive Disease | 1 participants |
| CFZ 4.0 mg/m² | Best Clinical Response to Treatment | Minimal Response | 0 participants |
| CFZ 6.0 mg/m² | Best Clinical Response to Treatment | Partial Response | 0 participants |
| CFZ 6.0 mg/m² | Best Clinical Response to Treatment | Progressive Disease | 0 participants |
| CFZ 6.0 mg/m² | Best Clinical Response to Treatment | Unknown | 0 participants |
| CFZ 6.0 mg/m² | Best Clinical Response to Treatment | Complete Response | 0 participants |
| CFZ 6.0 mg/m² | Best Clinical Response to Treatment | Stable Disease/No Change | 2 participants |
| CFZ 6.0 mg/m² | Best Clinical Response to Treatment | Minimal Response | 0 participants |
| CFZ 8.4 mg/m² | Best Clinical Response to Treatment | Partial Response | 0 participants |
| CFZ 8.4 mg/m² | Best Clinical Response to Treatment | Minimal Response | 0 participants |
| CFZ 8.4 mg/m² | Best Clinical Response to Treatment | Stable Disease/No Change | 1 participants |
| CFZ 8.4 mg/m² | Best Clinical Response to Treatment | Progressive Disease | 2 participants |
| CFZ 8.4 mg/m² | Best Clinical Response to Treatment | Unknown | 0 participants |
| CFZ 8.4 mg/m² | Best Clinical Response to Treatment | Complete Response | 0 participants |
| CFZ 11.0 mg/m² | Best Clinical Response to Treatment | Progressive Disease | 2 participants |
| CFZ 11.0 mg/m² | Best Clinical Response to Treatment | Complete Response | 0 participants |
| CFZ 11.0 mg/m² | Best Clinical Response to Treatment | Partial Response | 0 participants |
| CFZ 11.0 mg/m² | Best Clinical Response to Treatment | Stable Disease/No Change | 1 participants |
| CFZ 11.0 mg/m² | Best Clinical Response to Treatment | Minimal Response | 0 participants |
| CFZ 11.0 mg/m² | Best Clinical Response to Treatment | Unknown | 0 participants |
| CFZ 15.0 mg/m² | Best Clinical Response to Treatment | Progressive Disease | 1 participants |
| CFZ 15.0 mg/m² | Best Clinical Response to Treatment | Partial Response | 1 participants |
| CFZ 15.0 mg/m² | Best Clinical Response to Treatment | Unknown | 0 participants |
| CFZ 15.0 mg/m² | Best Clinical Response to Treatment | Stable Disease/No Change | 0 participants |
| CFZ 15.0 mg/m² | Best Clinical Response to Treatment | Minimal Response | 0 participants |
| CFZ 15.0 mg/m² | Best Clinical Response to Treatment | Complete Response | 0 participants |
| CFZ 20.0 mg/m² | Best Clinical Response to Treatment | Minimal Response | 0 participants |
| CFZ 20.0 mg/m² | Best Clinical Response to Treatment | Stable Disease/No Change | 2 participants |
| CFZ 20.0 mg/m² | Best Clinical Response to Treatment | Partial Response | 1 participants |
| CFZ 20.0 mg/m² | Best Clinical Response to Treatment | Progressive Disease | 3 participants |
| CFZ 20.0 mg/m² | Best Clinical Response to Treatment | Complete Response | 0 participants |
| CFZ 20.0 mg/m² | Best Clinical Response to Treatment | Unknown | 0 participants |
| CFZ 27.0 mg/m² | Best Clinical Response to Treatment | Minimal Response | 1 participants |
| CFZ 27.0 mg/m² | Best Clinical Response to Treatment | Progressive Disease | 1 participants |
| CFZ 27.0 mg/m² | Best Clinical Response to Treatment | Complete Response | 0 participants |
| CFZ 27.0 mg/m² | Best Clinical Response to Treatment | Stable Disease/No Change | 1 participants |
| CFZ 27.0 mg/m² | Best Clinical Response to Treatment | Unknown | 0 participants |
| CFZ 27.0 mg/m² | Best Clinical Response to Treatment | Partial Response | 2 participants |
| CFZ 20/27 mg/m² | Best Clinical Response to Treatment | Complete Response | 0 participants |
| CFZ 20/27 mg/m² | Best Clinical Response to Treatment | Unknown | 0 participants |
| CFZ 20/27 mg/m² | Best Clinical Response to Treatment | Stable Disease/No Change | 2 participants |
| CFZ 20/27 mg/m² | Best Clinical Response to Treatment | Minimal Response | 0 participants |
| CFZ 20/27 mg/m² | Best Clinical Response to Treatment | Partial Response | 2 participants |
| CFZ 20/27 mg/m² | Best Clinical Response to Treatment | Progressive Disease | 2 participants |
| CFZ 20/27 mg/m² + DEX | Best Clinical Response to Treatment | Unknown | 0 participants |
| CFZ 20/27 mg/m² + DEX | Best Clinical Response to Treatment | Complete Response | 0 participants |
| CFZ 20/27 mg/m² + DEX | Best Clinical Response to Treatment | Partial Response | 0 participants |
| CFZ 20/27 mg/m² + DEX | Best Clinical Response to Treatment | Progressive Disease | 2 participants |
| CFZ 20/27 mg/m² + DEX | Best Clinical Response to Treatment | Minimal Response | 1 participants |
| CFZ 20/27 mg/m² + DEX | Best Clinical Response to Treatment | Stable Disease/No Change | 0 participants |
Secondary
Duration of Response
Duration of objective response is defined as the time from the date of first documented assessment of clinical response (confirmed or unconfirmed complete response, partial response, or minimal response) to the date of documented assessment of progressive disease or death, whichever comes first, plus one day. Participants without tumor progression or death were censored at the date of their last valid clinical response assessment. Median duration of response was calculated using the Kaplan-Meier method.
Time frame: From the first dose of study drug until 30 days after the last dose. Median duration of treatment was 6.3 weeks in the dose escalation phase and 6.4 weeks in the dose expansion phase.
Population: Biologic response-evaluable participants with an objective response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CFZ 15.0 mg/m² | Duration of Response | 308.0 days |
| CFZ 20.0 mg/m² | Duration of Response | 176.0 days |
| CFZ 27.0 mg/m² | Duration of Response | 225.0 days |
| CFZ 20/27 mg/m² | Duration of Response | NA days |
| CFZ 20/27 mg/m² + DEX | Duration of Response | NA days |
Secondary
Progression-free Survival
Progression-free survival is defined as the time from the date of Cycle 1, Day 1 of treatment to the date of documented assessment of progressive disease or death, whichever comes first, plus one day. Participants without tumor progression or death were censored at the date of their last valid clinical response assessment. Median progression-free survival was calculated using the Kaplan-Meier method.
Time frame: From the first dose of study drug until 30 days after the last dose. Median duration of treatment was 6.3 weeks in the dose escalation phase and 6.4 weeks in the dose expansion phase.
Population: Biologic response-evaluable population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CFZ 1.2 mg/m² | Progression-free Survival | 114.0 days |
| CFZ 2.4 mg/m² | Progression-free Survival | 232.0 days |
| CFZ 4.0 mg/m² | Progression-free Survival | NA days |
| CFZ 6.0 mg/m² | Progression-free Survival | NA days |
| CFZ 8.4 mg/m² | Progression-free Survival | 55.0 days |
| CFZ 11.0 mg/m² | Progression-free Survival | 48.0 days |
| CFZ 15.0 mg/m² | Progression-free Survival | 186.0 days |
| CFZ 20.0 mg/m² | Progression-free Survival | 110.5 days |
| CFZ 27.0 mg/m² | Progression-free Survival | 225.0 days |
| CFZ 20/27 mg/m² | Progression-free Survival | NA days |
| CFZ 20/27 mg/m² + DEX | Progression-free Survival | 49.0 days |
Secondary
Time to Progression
Time to progressive disease is defined as the time from the date of Cycle 1, Day 1 of treatment to the date of documented assessment of progressive disease, plus one day. Participants without tumor progression were censored at the date of their last clinical response assessment. Median time to progression was calculated using the Kaplan-Meier method.
Time frame: From the first dose of study drug until 30 days after the last dose. Median duration of treatment was 6.3 weeks in the dose escalation phase and 6.4 weeks in the dose expansion phase.
Population: Biologic response-evaluable population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CFZ 1.2 mg/m² | Time to Progression | 114.0 days |
| CFZ 2.4 mg/m² | Time to Progression | 232.0 days |
| CFZ 4.0 mg/m² | Time to Progression | NA days |
| CFZ 6.0 mg/m² | Time to Progression | NA days |
| CFZ 8.4 mg/m² | Time to Progression | 55.0 days |
| CFZ 11.0 mg/m² | Time to Progression | 48.0 days |
| CFZ 15.0 mg/m² | Time to Progression | 186.0 days |
| CFZ 20.0 mg/m² | Time to Progression | 110.5 days |
| CFZ 27.0 mg/m² | Time to Progression | 225.0 days |
| CFZ 20/27 mg/m² | Time to Progression | NA days |
| CFZ 20/27 mg/m² + DEX | Time to Progression | 49.0 days |