Phase 1b/2 Study of Carfilzomib in Relapsed Solid Tumors, Multiple Myeloma, or Lymphoma

Phase 1

Completed

Conditions: Renal Cancer
Lymphoma
Non-small Cell Lung Cancer
Solid Tumors
Ovarian Cancer
Small Cell Lung Cancer
Multiple Myeloma

Interventions: Drug: Carfilzomib
Drug: Dexamethasone

Registration Number: NCT00531284

Lead Sponsor: Amgen

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 184

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase 1B Solid Tumors: Carfilzomib 20 mg/m² Bolus	Carfilzomib	Participants received carfilzomib 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.
Phase 1b MM: Carfilzomib 20/56 mg/m² + Dexamethasone	Carfilzomib	Participants 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.
Phase 1B Solid Tumors: Carfilzomib 45 mg/m²	Carfilzomib	Participants 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.
Phase 1B Solid Tumors: Carfilzomib 20/27 mg/m² Bolus	Carfilzomib	Participants 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.
Phase 1B Solid Tumors: Carfilzomib 20/36 mg/m² Bolus	Carfilzomib	Participants 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.
Phase 2 Solid Tumors: Carfilzomib 20/36 mg/m² Bolus	Carfilzomib	Participants 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.
Phase 1B Solid Tumors: Carfilzomib 36 mg/m²	Carfilzomib	Participants 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.
Phase 1B Solid Tumors: Carfilzomib 20/45 mg/m²	Carfilzomib	Participants 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.
Phase 1B Solid Tumors: Carfilzomib 20/56 mg/m²	Carfilzomib	Participants 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.
Phase 1B Solid Tumors: Carfilzomib 20/70 mg/m²	Carfilzomib	Participants 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.
Phase 1b Multiple Myeloma: Carfilzomib 20/36 mg/m²	Carfilzomib	Participants 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.
Phase 1b Multiple Myeloma: Carfilzomib 20/45 mg/m²	Carfilzomib	Participants 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.
Phase 1b Multiple Myeloma: Carfilzomib 20/56 mg/m²	Carfilzomib	Participants 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.
Phase 1b Multiple Myeloma: Carfilzomib 20/70 mg/m²	Carfilzomib	Participants 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.
Phase 1b Lymphoma: Carfilzomib 20/56 mg/m²	Carfilzomib	Participants 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.
Phase 1b Lymphoma: Carfilzomib 20/70 mg/m²	Carfilzomib	Participants 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.
Phase 1b MM: Carfilzomib 20/45 mg/m² + Dexamethasone	Carfilzomib	Participants 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.
Phase 1b MM: Carfilzomib 20/45 mg/m² + Dexamethasone	Dexamethasone	Participants 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.
Phase 1b MM: Carfilzomib 20/56 mg/m² + Dexamethasone	Dexamethasone	Participants 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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Trial Locations

Locations (7): Northwestern University
🇺🇸
Chicago, Illinois, United States
Tower Cancer Research Foundation
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Beverly Hills, California, United States
University of Maryland Greenebaum Cancer Center
🇺🇸
Baltimore, Maryland, United States
South Texas Accelerated Research Therapeutics (START)
🇺🇸
San Antonio, Texas, United States
The Sarah Cannon Research Institute
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Nashville, Tennessee, United States
Hackensack University Medical Center
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Hackensack, New Jersey, United States
Pinnacle Oncology
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Scottsdale, Arizona, United States