Lymphoma, Multiple Myeloma, Non-small Cell Lung Cancer, Ovarian Cancer, Renal Cancer, Small Cell Lung Cancer, Solid Tumors
Conditions
Keywords
Non-small cell lung carcinoma, Small-cell lung carcinoma, Ovarian Cancer, Renal Cancer, Other solid tumors, multiple myeloma, lymphoma
Brief summary
The primary objectives of this Phase 1b/2 study were as follows: * Phase 1b (Bolus and Infusion): To evaluate the safety and tolerability of carfilzomib in patients with relapsed solid tumors and in patients with relapsed and/or refractory multiple myeloma and in patients with refractory lymphoma. * Phase 2 (Bolus): To evaluate the overall response rate (ORR) after 4 cycles of carfilzomib in patients with relapsed solid tumors.
Interventions
DRUGCarfilzomib
Administered by intravenous (IV) bolus (2-10 minute) infusion or 30 minute infusion
DRUGDexamethasone
Administered orally or by IV infusion prior to carfilzomib
Sponsors
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Disease related Phase 1 Subjects (Bolus and Infusion): Solid Tumor: * Histologically confirmed advanced solid tumor * 1 to 3 prior treatment regimens * At least one site of radiographically measurable disease of ≥ 2 cm in the largest dimension by traditional computed tomography (CT) scanning technique or ≥ 1 cm in the largest dimension by spiral CT scanning (per Response Evaluation Criteria in Solid Tumors \[RECIST\] criteria); or if, in the Principal Investigator's opinion, evaluable disease can be reliably and consistently followed, the subject may be eligible upon approval by the Medical Monitor Multiple Myeloma (MM): * Relapsed and/or refractory multiple myeloma following 2 or more prior treatment regimens. * Measurable disease as indicated by one or more of the following: * Serum M-protein ≥ 1 g/dL * Urine M-protein ≥ 200 mg/24 hr * Serum Free Light Chain: Involved free light chain (FLC) level ≥ 10 mg/dL provided serum FLC ratio is abnormal Lymphoma: * Histologically or cytologically confirmed lymphoma. * Patients must have had an initial diagnosis of indolent non-Hodgkin lymphoma (NHL) (including follicular, small lymphocytic, lymphoplasmacytoid, and marginal zone lymphoma), indolent disease that transformed to a more aggressive subtype, as previously described or patients may have mantle cell lymphoma. * Patients are required to have received prior rituximab (alone or combined with other treatment) and are considered refractory to (defined as no response, or progression within 6 months of completing therapy) or intolerant of continued rituximab. * Patients may have received up to a maximum of four prior unique chemotherapy regimens, including if not contra-indicated autologous stem-cell transplantation (ASCT). * For patients to enroll in the expanded dose group for lymphoma, patients must have measurable disease Phase 2 Bolus Subjects: -Histologically confirmed advanced solid tumor diagnosis and: * Non-small cell lung cancer (NSCLC): Failed at least 1 prior platinum-based chemotherapy regimen but not more than 3 prior therapies for metastatic disease * Small cell lung cancer (SCLC): Failed 1 to 3 prior chemotherapy regimens * Ovarian: Failed at least 1 prior platinum-based chemotherapy regimen but not more than 4 therapies for metastatic disease * Renal: Failed at least 2 prior chemotherapy regimens for metastatic disease * Other solid tumor types: Failed at least 1 prior chemotherapy regimen for metastatic or relapsed disease and for which standard of care therapy is no longer effective or does not exist * At least one site of radiographically measurable disease of ≥ 2 cm in the largest dimension by traditional CT scanning technique or ≥ 1 cm in the largest dimension by spiral CT scanning (per RECIST criteria); or if, in the Principal Investigator's opinion, evaluable disease can be reliably and consistently followed, the subject may be eligible upon approval by the Medical Monitor Demographic * Males and females ≥ 18 years of age * Life expectancy of more than 3 months * Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 Laboratory * Adequate hepatic function, with bilirubin 1.5 times the upper limit of normal (ULN), and alanine aminotransferase (ALT) 3 times ULN * Absolute neutrophil count (ANC) \> 1000/mm³, hemoglobin ≥ 8 gm/dL for solid tumors or 7.0 gm/dL for MM, and platelet count ≥ 100,000/mm³ for solid tumors or ≥ 30,000/mm³ for MM. * Subjects should not have received platelet transfusions for at least 1 week prior to screening * Screening ANC should be independent of granulocyte- and granulocyte/macrophage colony stimulating factor (G-CSF and GM-CSF) support for at least 1 week and of pegylated G-CSF for ≥ 2 weeks * Subjects may receive red blood cell (RBC) transfusions or receive supportive care with erythropoietin or darbepoetin in accordance with institutional guidelines * Calculated or measured creatinine clearance (CrCl) of ≥ 20 mL/minute calculated using the formula of Cockcroft and Gault. Subjects with calculated CrCl \< 20 mL/min may be allowed, only with prior approval by the Medical Monitor. Ethical/Other * Written informed consent in accordance with federal, local, and institutional guidelines * Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 3 days of the first dose and agree to use dual methods of contraception during the study and for 3 months following the last dose of study drug. Post-menopausal females (\> 45 years old and without menses for \> 1 year) and surgically sterilized females are exempt from these requirements. Male subjects must use an effective barrier method of contraception during the study and for 3 months following the last dose if sexually active with a female of childbearing potential.
Exclusion criteria
Disease Related * Chemotherapy with approved or investigational anticancer therapeutics, including steroid therapy, within 3 weeks prior to first dose or 6 weeks for antibody therapy * Radiation therapy or immunotherapy within 3 weeks prior to first dose (except for antibody therapy, where 6 weeks is required); localized radiation therapy within 1 week prior to first dose * Subjects with prior brain metastases are permitted, but must have completed treatment and have no evidence of active central nervous system (CNS) disease for at least 4 weeks prior to first dose * For lymphoma patients; patients with prior stem cell transplant therapy (autologous SCT within the prior 8 weeks; allogeneic SCT within the prior 16 weeks). Patients with prior allogeneic SCT should not have evidence of moderate-to-severe graft-versus-host disease (GVHD) * Evidence of CNS lymphoma * Participation in an investigational therapeutic study within 3 weeks prior to first dose * Prior treatment with carfilzomib Concurrent Conditions * Major surgery within 3 weeks prior to first dose * Congestive heart failure (New York Heart Association class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within 3 months prior to first dose * Acute active infection requiring systemic antibiotics, antivirals, or antifungals within 2 weeks prior to first dose * Known or suspected human immunodeficiency virus (HIV) infection or subjects who are HIV seropositive * Active hepatitis A, B, or C infection * Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of the first dose * Subjects with pleural effusions requiring routine thoracentesis or ascites requiring routine paracentesis * Subjects at risk\* in whom the required program of oral and intravenous fluid hydration is contraindicated, e.g., due to pre-existing pulmonary, cardiac, or renal impairment * High risk for Tumor Lysis Syndrome. Ethical / Other * Female subjects who are pregnant or lactating * Any clinically significant psychiatric or medical condition that in the opinion of the Investigator could interfere with protocol adherence or a subject's ability to give informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Number of Participants With Dose-limiting Toxicities (DLT) | 28 days | Participants were evaluated for dose-limiting toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute (NCI) version 3.0. A DLT was defined as treatment-related ≥ Grade 2 neuropathy with pain, ≥ Grade 3 non-hematologic toxicity, Grade 4 neutropenia or thrombocytopenia lasting 7 or more days, or thrombocytopenia with bleeding. The maximum tolerated dose (MTD) for each of the 3 populations (solid tumor, multiple myeloma, and lymphoma) was defined as the dose level at which \< 33% of participants experienced a dose-limiting toxicity during the first 28-day cycle. |
| Phase 2: Percentage of Participants With an Overall Response After 4 Treatment Cycles | 4 months | Overall response is defined as participants with a best overall response of complete response (CR), partial response (PR) or stable disease (SD) after 4 cycles, assessed by the Investigator using tumor measurement and according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target and non-target lesions and no new lesions; PR: Disappearance of all target lesions, persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits and no lesions, or, at least a 30% decrease in the size of target lesions and no progression of existing non-target lesions or any new lesions. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest size since the treatment started, and no progression of existing non-target lesions or any new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With an Overall Response Throughout the Study | Tumor assessments occurred at the end of Cycle 2, 4, 6, 9, and 12 and continued every 3 cycles thereafter up to 6 months after last dose. Analysis includes data up to the data cut-off date of 07 October 2014; maximum duration of treatment was 35 months. | Solid tumor participants were evaluated for disease response according to RECIST, Version 1.1. Multiple myeloma participants were evaluated using the International Myeloma Working Group (IMWG) Uniform Response Criteria with the addition of minimal response (MR) based on the European Group for Blood and Marrow Transplant Group (EBMT). Non-Hodgkin lymphoma (NHL) participants were evaluated using the International Workshop NHL criteria. Waldenström macroglobulinemia (WM) participants were evaluated using Criteria from the Sixth International Workshop for WM. Overall response is defined in Outcome Measure 2 for participants with solid tumors. For NHL, overall response is defined as a best overall response of CR or PR. For multiple myeloma and WM, overall response is defined as participants with a best overall response of stringent complete response (sCR), CR, very good partial response (VGPR) or PR. |
| Duration of Response | Tumor assessments occurred at the end of Cycle 2, 4, 6, 9, and 12 and continued every 3 cycles thereafter up to 6 months after last dose. Analysis includes data up to the data cut-off date of 07 October 2014; maximum duration of treatment was 35 months. | Duration of response is defined as the time from first evidence of a partial response or better (the first observation of PR before confirmation) to disease progression, with deaths owing to causes other than progression censored. |
| Progression-Free Survival | Tumor assessments occurred at the end of Cycle 2, 4, 6, 9, and 12 and continued every 3 cycles thereafter up to 6 months after last dose. Analysis includes data up to the data cut-off date of 07 October 2014; maximum duration of treatment was 35 months. | Progression-free survival (PFS) is the time from start of treatment to disease progression or death (due to any cause), whichever occurred first. |
| Time to Progression | Tumor assessments occurred at the end of Cycle 2, 4, 6, 9, and 12 and continued every 3 cycles thereafter up to 6 months after last dose. Analysis includes data up to the data cut-off date of 07 October 2014; maximum duration of treatment was 35 months. | Time to Progression (TTP) is defined as number of months between start of treatment and first evidence/documentation of disease progression. |
| Maximum Observed Plasma Concentration of Carfilzomib | Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion. | Plasma concentrations of carfilzomib were determined by a validated liquid chromatography tandem mass spectrometry method. Concentration values that were below the lower limit of quantification of 0.1 ng/mL were set to zero. Treatment groups receiving the same dose (e.g. 20 mg/m²) were combined for Day 1 analyses. |
| Time to Maximum Observed Plasma Concentration (Tmax) of Carfilzomib | Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion. | — |
| Area Under the Plasma Concentration-time Curve From Time Zero to the Last Concentration Measured (AUC0-last) for Carfilzomib | Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion. | — |
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) for Carfilzomib | Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion. | — |
| Elimination Half-life (t½) of Carfilzomib | Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion. | — |
| Clearance (CL) of Carfilzomib | Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion. | — |
| Volume of Distribution at Steady State (Vss) of Carfilzomib | Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion. | — |
| Mean Residence Time (MRT) Extrapolated to Infinity for Carfilzomib | Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion. | — |
Countries
United States
Participant flow
Recruitment details
Patients with relapsed solid tumors (non-small and small cell lung, ovarian, renal, any other solid tumor type), multiple myeloma or lymphoma were enrolled at 7 sites in the US. Under the original protocol patients received a bolus intravenous (IV) infusion of carfilzomib; patients enrolled under Amendments 2 to 4 received a 30-minute IV infusion.
Pre-assignment details
Phase 1b followed a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD). For Phase 2 (bolus), a Simon 2-stage design was planned using the MTD from phase 1b. The first stage of the Simon's 2-stage design was carried out; however, the study did not progress to the second stage.
Participants by arm
| Arm | Count |
|---|---|
| P1B ST: CFZ 20 mg/m² Bolus Participants with solid tumors (ST) received carfilzomib (CFZ) 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. | 3 |
| P1B ST: CFZ 20/27 mg/m² Bolus Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 27 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. | 4 |
| P1B ST: CFZ 20/36 mg/m² Bolus Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. | 7 |
| P2 ST: CFZ 20/36 mg/m² Bolus Participants with solid tumors received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. | 65 |
| P1B ST: CFZ 36 mg/m² Participants with solid tumors received carfilzomib 36 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. | 6 |
| P1B ST: CFZ 45 mg/m² Participants with solid tumors received carfilzomib 45 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. | 7 |
| P1B ST: CFZ 20/45 mg/m² Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. | 6 |
| P1B ST: CFZ 20/56 mg/m² Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. | 10 |
| P1B ST: CFZ 20/70 mg/m² Participants with solid tumors received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. | 11 |
| P1B MM: CFZ 20/36 mg/m² Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. | 4 |
| P1B MM: CFZ 20/45 mg/m² Participants with multiple myeloma (MM) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. | 3 |
| P1b MM: CFZ 20/56 mg/m² Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. | 24 |
| P1B MM: CFZ 20/70 mg/m² Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. | 2 |
| P1B LYM: CFZ 20/56 mg/m² Participants with lymphoma (LYM) received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. | 3 |
| P1B LYM: CFZ 20/70 mg/m² Participants with lymphoma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. | 7 |
| P1B MM: CFZ 20/45 mg/m² + Dex Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment plus dexamethasone 40 mg weekly. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. | 14 |
| P1B MM: CFZ 20/56 mg/m² + Dex Participants with multiple myeloma received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment plus dexamethasone 40 mg weekly. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. | 8 |
| Total | 184 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 | FG016 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 1 | 7 | 0 | 2 | 3 | 2 | 3 | 0 | 0 | 5 | 0 | 1 | 1 | 0 | 2 |
| Overall Study | Other | 1 | 0 | 0 | 10 | 2 | 1 | 0 | 0 | 2 | 1 | 0 | 2 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Progressive Disease | 1 | 3 | 5 | 42 | 4 | 4 | 3 | 8 | 6 | 3 | 3 | 14 | 2 | 1 | 2 | 11 | 5 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 4 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 0 | 1 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | P1B ST: CFZ 20 mg/m² Bolus | P1B ST: CFZ 20/27 mg/m² Bolus | P1B ST: CFZ 20/36 mg/m² Bolus | P2 ST: CFZ 20/36 mg/m² Bolus | P1B ST: CFZ 36 mg/m² | P1B ST: CFZ 45 mg/m² | P1B ST: CFZ 20/45 mg/m² | P1B ST: CFZ 20/56 mg/m² | P1B ST: CFZ 20/70 mg/m² | P1B MM: CFZ 20/36 mg/m² | P1B MM: CFZ 20/45 mg/m² | P1b MM: CFZ 20/56 mg/m² | P1B MM: CFZ 20/70 mg/m² | P1B LYM: CFZ 20/56 mg/m² | P1B LYM: CFZ 20/70 mg/m² | P1B MM: CFZ 20/45 mg/m² + Dex | P1B MM: CFZ 20/56 mg/m² + Dex | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous 30-minute Infusion Groups | NA years | NA years | NA years | NA years | 60.0 years STANDARD_DEVIATION 5.18 | 69.9 years STANDARD_DEVIATION 11.1 | 61.2 years STANDARD_DEVIATION 10.38 | 61.4 years STANDARD_DEVIATION 7.4 | 61.6 years STANDARD_DEVIATION 11.58 | 63.3 years STANDARD_DEVIATION 3.77 | 72.0 years STANDARD_DEVIATION 5.57 | 62.7 years STANDARD_DEVIATION 9.88 | 69.5 years STANDARD_DEVIATION 12.02 | 58.7 years STANDARD_DEVIATION 10.69 | 65.4 years STANDARD_DEVIATION 10.31 | 58.6 years STANDARD_DEVIATION 9.54 | 58.3 years STANDARD_DEVIATION 6.14 | 62.3 years STANDARD_DEVIATION 9.47 |
| Age, Continuous Bolus Groups | 47.3 years STANDARD_DEVIATION 14.74 | 60.8 years STANDARD_DEVIATION 8.81 | 60.0 years STANDARD_DEVIATION 11.72 | 62.0 years STANDARD_DEVIATION 9.97 | NA years | NA years | NA years | NA years | NA years | NA years | NA years | NA years | NA years | NA years | NA years | NA years | NA years | 62.20 years STANDARD_DEVIATION 10.43 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 | 1 participants | 3 participants | 4 participants | 27 participants | 2 participants | 1 participants | 0 participants | 2 participants | 4 participants | 4 participants | 0 participants | 8 participants | 0 participants | 2 participants | 3 participants | 7 participants | 5 participants | 73 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 | 2 participants | 1 participants | 3 participants | 35 participants | 4 participants | 4 participants | 6 participants | 7 participants | 7 participants | 0 participants | 2 participants | 15 participants | 1 participants | 0 participants | 3 participants | 6 participants | 3 participants | 99 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2 | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 2 participants | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants | 1 participants | 1 participants | 1 participants | 1 participants | 1 participants | 0 participants | 9 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Missing | 0 participants | 0 participants | 0 participants | 3 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 3 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 4 Participants | 38 Participants | 0 Participants | 4 Participants | 3 Participants | 5 Participants | 4 Participants | 2 Participants | 1 Participants | 7 Participants | 1 Participants | 1 Participants | 3 Participants | 4 Participants | 1 Participants | 80 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 3 Participants | 27 Participants | 6 Participants | 3 Participants | 3 Participants | 5 Participants | 7 Participants | 2 Participants | 2 Participants | 17 Participants | 1 Participants | 2 Participants | 4 Participants | 10 Participants | 7 Participants | 104 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 | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 7 / 7 | 65 / 65 | 6 / 6 | 7 / 7 | 6 / 6 | 10 / 10 | 11 / 11 | 4 / 4 | 3 / 3 | 24 / 24 | 2 / 2 | 3 / 3 | 7 / 7 | 14 / 14 | 8 / 8 |
| serious Total, serious adverse events | 1 / 3 | 1 / 4 | 4 / 7 | 27 / 65 | 2 / 6 | 4 / 7 | 5 / 6 | 5 / 10 | 6 / 11 | 2 / 4 | 0 / 3 | 11 / 24 | 2 / 2 | 1 / 3 | 5 / 7 | 5 / 14 | 3 / 8 |
Outcome results
Primary
Phase 1b: Number of Participants With Dose-limiting Toxicities (DLT)
Participants were evaluated for dose-limiting toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute (NCI) version 3.0. A DLT was defined as treatment-related ≥ Grade 2 neuropathy with pain, ≥ Grade 3 non-hematologic toxicity, Grade 4 neutropenia or thrombocytopenia lasting 7 or more days, or thrombocytopenia with bleeding. The maximum tolerated dose (MTD) for each of the 3 populations (solid tumor, multiple myeloma, and lymphoma) was defined as the dose level at which \< 33% of participants experienced a dose-limiting toxicity during the first 28-day cycle.
Time frame: 28 days
Population: Dose-limiting toxicity analysis was based on subsets of the safety population including participants exposed to carfilzomib in Cycle 1 who experienced a DLT or completed 28 days of evaluation after the first dose of carfilzomib. Participants enrolled into the expansion cohorts (MTD dose expansion, carfilzomib + DEX) were not evaluated for DLT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| P1B ST: CFZ 20 mg/m² Bolus | Phase 1b: Number of Participants With Dose-limiting Toxicities (DLT) | 0 participants |
| P1B ST: CFZ 20/27 mg/m² Bolus | Phase 1b: Number of Participants With Dose-limiting Toxicities (DLT) | 0 participants |
| P1B ST: CFZ 20/36 mg/m² Bolus | Phase 1b: Number of Participants With Dose-limiting Toxicities (DLT) | 1 participants |
| P1B ST: CFZ 36 mg/m² | Phase 1b: Number of Participants With Dose-limiting Toxicities (DLT) | 0 participants |
| P1B ST: CFZ 45 mg/m² | Phase 1b: Number of Participants With Dose-limiting Toxicities (DLT) | 2 participants |
| P1B ST: CFZ 20/45 mg/m² | Phase 1b: Number of Participants With Dose-limiting Toxicities (DLT) | 0 participants |
| P1B ST: CFZ 20/56 mg/m² | Phase 1b: Number of Participants With Dose-limiting Toxicities (DLT) | 0 participants |
| P1B ST: CFZ 20/70 mg/m² | Phase 1b: Number of Participants With Dose-limiting Toxicities (DLT) | 1 participants |
| P1B MM: CFZ 20/36 mg/m² | Phase 1b: Number of Participants With Dose-limiting Toxicities (DLT) | 0 participants |
| P1B MM: CFZ 20/45 mg/m² | Phase 1b: Number of Participants With Dose-limiting Toxicities (DLT) | 0 participants |
| P1b MM: CFZ 20/56 mg/m² | Phase 1b: Number of Participants With Dose-limiting Toxicities (DLT) | 1 participants |
| P1B MM: CFZ 20/70 mg/m² | Phase 1b: Number of Participants With Dose-limiting Toxicities (DLT) | 2 participants |
| P1B LYM: CFZ 20/56 mg/m² | Phase 1b: Number of Participants With Dose-limiting Toxicities (DLT) | 0 participants |
| P1B LYM: CFZ 20/70 mg/m² | Phase 1b: Number of Participants With Dose-limiting Toxicities (DLT) | 1 participants |
Primary
Phase 2: Percentage of Participants With an Overall Response After 4 Treatment Cycles
Overall response is defined as participants with a best overall response of complete response (CR), partial response (PR) or stable disease (SD) after 4 cycles, assessed by the Investigator using tumor measurement and according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target and non-target lesions and no new lesions; PR: Disappearance of all target lesions, persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits and no lesions, or, at least a 30% decrease in the size of target lesions and no progression of existing non-target lesions or any new lesions. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest size since the treatment started, and no progression of existing non-target lesions or any new lesions.
Time frame: 4 months
Population: Phase 2 Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| P1B ST: CFZ 20 mg/m² Bolus | Phase 2: Percentage of Participants With an Overall Response After 4 Treatment Cycles | 15.4 percentage of participants |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) for Carfilzomib
Time frame: Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.
Population: Safety population with available pharmacokinetic (PK) data. PK analyses were conducted in solid tumor and multiple myeloma groups only and were not conducted for lymphoma or participants enrolled under Amendment 4 (CFX + dexamethasone).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| P1B ST: CFZ 20 mg/m² Bolus | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) for Carfilzomib | 223 h*ng/mL | Geometric Coefficient of Variation 104 |
| P1B ST: CFZ 20/27 mg/m² Bolus | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) for Carfilzomib | 324 h*ng/mL | Geometric Coefficient of Variation 52.8 |
| P1B ST: CFZ 20/36 mg/m² Bolus | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) for Carfilzomib | 426 h*ng/mL | Geometric Coefficient of Variation 70.1 |
| P1B ST: CFZ 36 mg/m² | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) for Carfilzomib | 538 h*ng/mL | Geometric Coefficient of Variation 150.1 |
| P1B ST: CFZ 45 mg/m² | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) for Carfilzomib | 273 h*ng/mL | Geometric Coefficient of Variation 55.3 |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to the Last Concentration Measured (AUC0-last) for Carfilzomib
Time frame: Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.
Population: Safety population with available pharmacokinetic (PK) data. PK analyses were conducted in solid tumor and multiple myeloma groups only and were not conducted for lymphoma or participants enrolled under Amendment 4 (CFX + dexamethasone).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| P1B ST: CFZ 20 mg/m² Bolus | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Concentration Measured (AUC0-last) for Carfilzomib | 251 h*ng/mL | Geometric Coefficient of Variation 92 |
| P1B ST: CFZ 20/27 mg/m² Bolus | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Concentration Measured (AUC0-last) for Carfilzomib | 346 h*ng/mL | Geometric Coefficient of Variation 57.4 |
| P1B ST: CFZ 20/36 mg/m² Bolus | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Concentration Measured (AUC0-last) for Carfilzomib | 426 h*ng/mL | Geometric Coefficient of Variation 70.1 |
| P1B ST: CFZ 36 mg/m² | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Concentration Measured (AUC0-last) for Carfilzomib | 536 h*ng/mL | Geometric Coefficient of Variation 150.4 |
| P1B ST: CFZ 45 mg/m² | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Concentration Measured (AUC0-last) for Carfilzomib | 269 h*ng/mL | Geometric Coefficient of Variation 54.3 |
Secondary
Clearance (CL) of Carfilzomib
Time frame: Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.
Population: Safety population with available pharmacokinetic (PK) data. PK analyses were conducted in solid tumor and multiple myeloma groups only and were not conducted for lymphoma or participants enrolled under Amendment 4 (CFX + dexamethasone).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| P1B ST: CFZ 20 mg/m² Bolus | Clearance (CL) of Carfilzomib | 263 liters/hour | Standard Deviation 398 |
| P1B ST: CFZ 20/27 mg/m² Bolus | Clearance (CL) of Carfilzomib | 139 liters/hour | Standard Deviation 70.1 |
| P1B ST: CFZ 20/36 mg/m² Bolus | Clearance (CL) of Carfilzomib | 182 liters/hour | Standard Deviation 88.8 |
| P1B ST: CFZ 36 mg/m² | Clearance (CL) of Carfilzomib | 302 liters/hour | Standard Deviation 438 |
| P1B ST: CFZ 45 mg/m² | Clearance (CL) of Carfilzomib | 164 liters/hour | Standard Deviation 89.6 |
Secondary
Duration of Response
Duration of response is defined as the time from first evidence of a partial response or better (the first observation of PR before confirmation) to disease progression, with deaths owing to causes other than progression censored.
Time frame: Tumor assessments occurred at the end of Cycle 2, 4, 6, 9, and 12 and continued every 3 cycles thereafter up to 6 months after last dose. Analysis includes data up to the data cut-off date of 07 October 2014; maximum duration of treatment was 35 months.
Population: Safety Population with a partial response or better
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| P1B ST: CFZ 20/36 mg/m² Bolus | Duration of Response | 6.2 months |
| P1B MM: CFZ 20/45 mg/m² | Duration of Response | 9.3 months |
| P1b MM: CFZ 20/56 mg/m² | Duration of Response | 5.5 months |
| P1B MM: CFZ 20/70 mg/m² | Duration of Response | 8.0 months |
| P1B LYM: CFZ 20/56 mg/m² | Duration of Response | 14.8 months |
| P1B WM: CFZ 20/56 mg/m² | Duration of Response | NA months |
| P1B WM: CFZ 20/70 mg/m² | Duration of Response | NA months |
| P1B MM: CFZ 20/45 mg/m² + Dex | Duration of Response | 9.0 months |
| P1B MM: CFZ 20/56 mg/m² + Dex | Duration of Response | 22.6 months |
Secondary
Elimination Half-life (t½) of Carfilzomib
Time frame: Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.
Population: Safety population with available pharmacokinetic (PK) data. PK analyses were conducted in solid tumor and multiple myeloma groups only and were not conducted for lymphoma or participants enrolled under Amendment 4 (CFX + dexamethasone).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| P1B ST: CFZ 20 mg/m² Bolus | Elimination Half-life (t½) of Carfilzomib | 0.444 hours |
| P1B ST: CFZ 20/27 mg/m² Bolus | Elimination Half-life (t½) of Carfilzomib | 0.888 hours |
| P1B ST: CFZ 20/36 mg/m² Bolus | Elimination Half-life (t½) of Carfilzomib | 0.917 hours |
| P1B ST: CFZ 36 mg/m² | Elimination Half-life (t½) of Carfilzomib | 0.952 hours |
| P1B ST: CFZ 45 mg/m² | Elimination Half-life (t½) of Carfilzomib | 0.888 hours |
Secondary
Maximum Observed Plasma Concentration of Carfilzomib
Plasma concentrations of carfilzomib were determined by a validated liquid chromatography tandem mass spectrometry method. Concentration values that were below the lower limit of quantification of 0.1 ng/mL were set to zero. Treatment groups receiving the same dose (e.g. 20 mg/m²) were combined for Day 1 analyses.
Time frame: Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.
Population: Safety population with available pharmacokinetic (PK) data. PK analyses were conducted in solid tumor and multiple myeloma groups only and were not conducted for lymphoma or participants enrolled under Amendment 4 (CFX + dexamethasone).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| P1B ST: CFZ 20 mg/m² Bolus | Maximum Observed Plasma Concentration of Carfilzomib | 2390 ng/mL | Geometric Coefficient of Variation 104 |
| P1B ST: CFZ 20/27 mg/m² Bolus | Maximum Observed Plasma Concentration of Carfilzomib | 914 ng/mL | Geometric Coefficient of Variation 58.2 |
| P1B ST: CFZ 20/36 mg/m² Bolus | Maximum Observed Plasma Concentration of Carfilzomib | 1061 ng/mL | Geometric Coefficient of Variation 50.7 |
| P1B ST: CFZ 36 mg/m² | Maximum Observed Plasma Concentration of Carfilzomib | 1193 ng/mL | Geometric Coefficient of Variation 197.3 |
| P1B ST: CFZ 45 mg/m² | Maximum Observed Plasma Concentration of Carfilzomib | 722 ng/mL | Geometric Coefficient of Variation 62.1 |
Secondary
Mean Residence Time (MRT) Extrapolated to Infinity for Carfilzomib
Time frame: Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.
Population: Safety population with available pharmacokinetic (PK) data. PK analyses were conducted in solid tumor and multiple myeloma groups only and were not conducted for lymphoma or participants enrolled under Amendment 4 (CFX + dexamethasone).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| P1B ST: CFZ 20 mg/m² Bolus | Mean Residence Time (MRT) Extrapolated to Infinity for Carfilzomib | 0.0902 hours | Standard Deviation 0.0319 |
| P1B ST: CFZ 20/27 mg/m² Bolus | Mean Residence Time (MRT) Extrapolated to Infinity for Carfilzomib | 0.227 hours | Standard Deviation 0.15 |
| P1B ST: CFZ 20/36 mg/m² Bolus | Mean Residence Time (MRT) Extrapolated to Infinity for Carfilzomib | 0.116 hours | Standard Deviation 0.0828 |
| P1B ST: CFZ 36 mg/m² | Mean Residence Time (MRT) Extrapolated to Infinity for Carfilzomib | 0.205 hours | Standard Deviation 0.156 |
| P1B ST: CFZ 45 mg/m² | Mean Residence Time (MRT) Extrapolated to Infinity for Carfilzomib | 0.117 hours | Standard Deviation 0.0799 |
Secondary
Percentage of Participants With an Overall Response Throughout the Study
Solid tumor participants were evaluated for disease response according to RECIST, Version 1.1. Multiple myeloma participants were evaluated using the International Myeloma Working Group (IMWG) Uniform Response Criteria with the addition of minimal response (MR) based on the European Group for Blood and Marrow Transplant Group (EBMT). Non-Hodgkin lymphoma (NHL) participants were evaluated using the International Workshop NHL criteria. Waldenström macroglobulinemia (WM) participants were evaluated using Criteria from the Sixth International Workshop for WM. Overall response is defined in Outcome Measure 2 for participants with solid tumors. For NHL, overall response is defined as a best overall response of CR or PR. For multiple myeloma and WM, overall response is defined as participants with a best overall response of stringent complete response (sCR), CR, very good partial response (VGPR) or PR.
Time frame: Tumor assessments occurred at the end of Cycle 2, 4, 6, 9, and 12 and continued every 3 cycles thereafter up to 6 months after last dose. Analysis includes data up to the data cut-off date of 07 October 2014; maximum duration of treatment was 35 months.
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| P1B ST: CFZ 20 mg/m² Bolus | Percentage of Participants With an Overall Response Throughout the Study | 100.0 percentage of participants |
| P1B ST: CFZ 20/27 mg/m² Bolus | Percentage of Participants With an Overall Response Throughout the Study | 0.0 percentage of participants |
| P1B ST: CFZ 20/36 mg/m² Bolus | Percentage of Participants With an Overall Response Throughout the Study | 42.9 percentage of participants |
| P1B ST: CFZ 36 mg/m² | Percentage of Participants With an Overall Response Throughout the Study | 38.5 percentage of participants |
| P1B ST: CFZ 45 mg/m² | Percentage of Participants With an Overall Response Throughout the Study | 33.3 percentage of participants |
| P1B ST: CFZ 20/45 mg/m² | Percentage of Participants With an Overall Response Throughout the Study | 28.6 percentage of participants |
| P1B ST: CFZ 20/56 mg/m² | Percentage of Participants With an Overall Response Throughout the Study | 50.0 percentage of participants |
| P1B ST: CFZ 20/70 mg/m² | Percentage of Participants With an Overall Response Throughout the Study | 10.0 percentage of participants |
| P1B MM: CFZ 20/36 mg/m² | Percentage of Participants With an Overall Response Throughout the Study | 36.4 percentage of participants |
| P1B MM: CFZ 20/45 mg/m² | Percentage of Participants With an Overall Response Throughout the Study | 50.0 percentage of participants |
| P1b MM: CFZ 20/56 mg/m² | Percentage of Participants With an Overall Response Throughout the Study | 33.3 percentage of participants |
| P1B MM: CFZ 20/70 mg/m² | Percentage of Participants With an Overall Response Throughout the Study | 50.0 percentage of participants |
| P1B LYM: CFZ 20/56 mg/m² | Percentage of Participants With an Overall Response Throughout the Study | 50.0 percentage of participants |
| P1B LYM: CFZ 20/70 mg/m² | Percentage of Participants With an Overall Response Throughout the Study | 0.0 percentage of participants |
| P1B NHL: CFZ 20/70 mg/m² | Percentage of Participants With an Overall Response Throughout the Study | 0.0 percentage of participants |
| P1B WM: CFZ 20/56 mg/m² | Percentage of Participants With an Overall Response Throughout the Study | 100.0 percentage of participants |
| P1B WM: CFZ 20/70 mg/m² | Percentage of Participants With an Overall Response Throughout the Study | 100.0 percentage of participants |
| P1B MM: CFZ 20/45 mg/m² + Dex | Percentage of Participants With an Overall Response Throughout the Study | 64.3 percentage of participants |
| P1B MM: CFZ 20/56 mg/m² + Dex | Percentage of Participants With an Overall Response Throughout the Study | 37.5 percentage of participants |
Secondary
Progression-Free Survival
Progression-free survival (PFS) is the time from start of treatment to disease progression or death (due to any cause), whichever occurred first.
Time frame: Tumor assessments occurred at the end of Cycle 2, 4, 6, 9, and 12 and continued every 3 cycles thereafter up to 6 months after last dose. Analysis includes data up to the data cut-off date of 07 October 2014; maximum duration of treatment was 35 months.
Population: Safety population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| P1B ST: CFZ 20 mg/m² Bolus | Progression-Free Survival | 5.1 months |
| P1B ST: CFZ 20/27 mg/m² Bolus | Progression-Free Survival | 1.8 months |
| P1B ST: CFZ 20/36 mg/m² Bolus | Progression-Free Survival | 1.8 months |
| P1B ST: CFZ 36 mg/m² | Progression-Free Survival | 1.8 months |
| P1B ST: CFZ 45 mg/m² | Progression-Free Survival | 1.7 months |
| P1B ST: CFZ 20/45 mg/m² | Progression-Free Survival | 2.9 months |
| P1B ST: CFZ 20/56 mg/m² | Progression-Free Survival | 1.4 months |
| P1B ST: CFZ 20/70 mg/m² | Progression-Free Survival | 1.5 months |
| P1B MM: CFZ 20/36 mg/m² | Progression-Free Survival | 1.6 months |
| P1B MM: CFZ 20/45 mg/m² | Progression-Free Survival | 5.2 months |
| P1b MM: CFZ 20/56 mg/m² | Progression-Free Survival | 4.6 months |
| P1B MM: CFZ 20/70 mg/m² | Progression-Free Survival | 6.9 months |
| P1B LYM: CFZ 20/56 mg/m² | Progression-Free Survival | 9.4 months |
| P1B LYM: CFZ 20/70 mg/m² | Progression-Free Survival | NA months |
| P1B NHL: CFZ 20/70 mg/m² | Progression-Free Survival | 1.0 months |
| P1B WM: CFZ 20/56 mg/m² | Progression-Free Survival | NA months |
| P1B WM: CFZ 20/70 mg/m² | Progression-Free Survival | NA months |
| P1B MM: CFZ 20/45 mg/m² + Dex | Progression-Free Survival | 4.6 months |
| P1B MM: CFZ 20/56 mg/m² + Dex | Progression-Free Survival | 11.5 months |
Secondary
Time to Maximum Observed Plasma Concentration (Tmax) of Carfilzomib
Time frame: Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.
Population: Safety population with available pharmacokinetic (PK) data. PK analyses were conducted in solid tumor and multiple myeloma groups only and were not conducted for lymphoma or participants enrolled under Amendment 4 (CFX + dexamethasone).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| P1B ST: CFZ 20 mg/m² Bolus | Time to Maximum Observed Plasma Concentration (Tmax) of Carfilzomib | 0.0500 hours |
| P1B ST: CFZ 20/27 mg/m² Bolus | Time to Maximum Observed Plasma Concentration (Tmax) of Carfilzomib | 0.500 hours |
| P1B ST: CFZ 20/36 mg/m² Bolus | Time to Maximum Observed Plasma Concentration (Tmax) of Carfilzomib | 0.258 hours |
| P1B ST: CFZ 36 mg/m² | Time to Maximum Observed Plasma Concentration (Tmax) of Carfilzomib | 0.275 hours |
| P1B ST: CFZ 45 mg/m² | Time to Maximum Observed Plasma Concentration (Tmax) of Carfilzomib | 0.250 hours |
Secondary
Time to Progression
Time to Progression (TTP) is defined as number of months between start of treatment and first evidence/documentation of disease progression.
Time frame: Tumor assessments occurred at the end of Cycle 2, 4, 6, 9, and 12 and continued every 3 cycles thereafter up to 6 months after last dose. Analysis includes data up to the data cut-off date of 07 October 2014; maximum duration of treatment was 35 months.
Population: Safety population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| P1B ST: CFZ 20 mg/m² Bolus | Time to Progression | 5.1 months |
| P1B ST: CFZ 20/27 mg/m² Bolus | Time to Progression | 1.8 months |
| P1B ST: CFZ 20/36 mg/m² Bolus | Time to Progression | 1.8 months |
| P1B ST: CFZ 36 mg/m² | Time to Progression | 1.8 months |
| P1B ST: CFZ 45 mg/m² | Time to Progression | 1.7 months |
| P1B ST: CFZ 20/45 mg/m² | Time to Progression | 1.6 months |
| P1B ST: CFZ 20/56 mg/m² | Time to Progression | 1.6 months |
| P1B ST: CFZ 20/70 mg/m² | Time to Progression | 1.6 months |
| P1B MM: CFZ 20/36 mg/m² | Time to Progression | 1.6 months |
| P1B MM: CFZ 20/45 mg/m² | Time to Progression | 5.2 months |
| P1b MM: CFZ 20/56 mg/m² | Time to Progression | 4.6 months |
| P1B MM: CFZ 20/70 mg/m² | Time to Progression | 6.9 months |
| P1B LYM: CFZ 20/56 mg/m² | Time to Progression | 9.4 months |
| P1B LYM: CFZ 20/70 mg/m² | Time to Progression | NA months |
| P1B NHL: CFZ 20/70 mg/m² | Time to Progression | 1.0 months |
| P1B WM: CFZ 20/56 mg/m² | Time to Progression | NA months |
| P1B WM: CFZ 20/70 mg/m² | Time to Progression | NA months |
| P1B MM: CFZ 20/45 mg/m² + Dex | Time to Progression | 4.6 months |
| P1B MM: CFZ 20/56 mg/m² + Dex | Time to Progression | 11.5 months |
Secondary
Volume of Distribution at Steady State (Vss) of Carfilzomib
Time frame: Cycle 1, Day 1, predose and at 5 minutes and 15 minutes post start of infusion (for 30-minute infusion groups only), and at the end of infusion, 5, 15, and 30 minutes; and 1, 2, and 4 hours after the end of the infusion.
Population: Safety population with available pharmacokinetic (PK) data. PK analyses were conducted in solid tumor and multiple myeloma groups only and were not conducted for lymphoma or participants enrolled under Amendment 4 (CFX + dexamethasone).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| P1B ST: CFZ 20 mg/m² Bolus | Volume of Distribution at Steady State (Vss) of Carfilzomib | 27.7 liters | Standard Deviation 48.6 |
| P1B ST: CFZ 20/27 mg/m² Bolus | Volume of Distribution at Steady State (Vss) of Carfilzomib | 31.0 liters | Standard Deviation 21.9 |
| P1B ST: CFZ 20/36 mg/m² Bolus | Volume of Distribution at Steady State (Vss) of Carfilzomib | 22.7 liters | Standard Deviation 24.2 |
| P1B ST: CFZ 36 mg/m² | Volume of Distribution at Steady State (Vss) of Carfilzomib | 113 liters | Standard Deviation 230 |
| P1B ST: CFZ 45 mg/m² | Volume of Distribution at Steady State (Vss) of Carfilzomib | 21.8 liters | Standard Deviation 24.6 |