Safety Study of the Proteasome Inhibitor PR-171 (Carfilzomib for Injection) in Patients With Hematological Malignancies

Study Overview
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Brief Summary
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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.

Official Title
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A Phase I Study of the Safety and Pharmacokinetics of Escalating Intravenous Doses of the Proteasome Inhibitor PR-171 in Patients With Hematological Malignancies

Conditions
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Waldenstrom's Macroglobulinemia, Non-Hodgkin's Lymphoma, Hodgkin's Disease, Multiple Myeloma

Intervention / Treatment
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* Drug: Carfilzomib
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent in accordance with federal, local, and institutional guidelines Males and females ≥18 years of age 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) Subjects who are refractory or relapsed following at least two prior therapies Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 Adequate cardiovascular function without symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction in the previous six months 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 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 An estimated creatinine clearance of ≥ 30 mL/min, calculated using the formula of Cockroft and Gault Serum creatinine ≤ 2.0 mg/dL Uric acid, if elevated, must be corrected to within laboratory normal range prior to dosing 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: Female subjects who are pregnant or lactating Subjects who are transfusion dependent Subjects with NHL or HL who have received steroid therapy in the previous seven days 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 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 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 Subjects who have received allogeneic stem cell transplant therapy Subjects with NHL or HL who have received autologous stem cell transplant therapy and have relapsed within 100 days of therapy Rituxan therapy within three months before Day 1 unless there is evidence of disease progression Major surgery within three weeks before Day 1 Congestive heart failure (CHF) (New York Heart Association class III to IV) Acute active infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose Subjects who are known or suspected of having human immunodeficiency virus (HIV) infection or who are HIV seropositive Active hepatitis A, B, or C infection; or positive for Hepatitis C ribonucleic acid (RNA) or hepatitis B antigen 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 Subjects with treatment-related myelodysplastic disorder Subjects with known brain metastasis (active central nervous system [CNS] disease only) Serious psychiatric or medical conditions that could interfere with treatment Participation in an investigational therapeutic study within one month prior to Day 1 Significant neurotoxicity (Grade 2 or higher with pain) at the time of study initiation Concurrent therapy with approved or investigative anticancer therapeutics Subjects with previous hypersensitivity to bortezomib injection Subjects with contraindications to receiving allopurinol 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 Subjects with known or suspected amyloidosis Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CFZ 1.2 mg/m²<br>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. | Drug: Carfilzomib<br>* Administered as an IV bolus dose<br>* Other names: Kyprolis;|
| Experimental: CFZ 2.4 mg/m²<br>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. | Drug: Carfilzomib<br>* Administered as an IV bolus dose<br>* Other names: Kyprolis;|
| Experimental: CFZ 4.0 mg/m²<br>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. | Drug: Carfilzomib<br>* Administered as an IV bolus dose<br>* Other names: Kyprolis;|
| Experimental: CFZ 6.0 mg/m²<br>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. | Drug: Carfilzomib<br>* Administered as an IV bolus dose<br>* Other names: Kyprolis;|
| Experimental: CFZ 8.4 mg/m²<br>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. | Drug: Carfilzomib<br>* Administered as an IV bolus dose<br>* Other names: Kyprolis;|
| Experimental: CFZ 11.0 mg/m²<br>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. | Drug: Carfilzomib<br>* Administered as an IV bolus dose<br>* Other names: Kyprolis;|
| Experimental: CFZ 15.0 mg/m²<br>Participants received carfilzomib 115.0 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. | Drug: Carfilzomib<br>* Administered as an IV bolus dose<br>* Other names: Kyprolis;|
| Experimental: CFZ 20.0 mg/m²<br>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. | Drug: Carfilzomib<br>* Administered as an IV bolus dose<br>* Other names: Kyprolis;|
| Experimental: CFZ 27.0 mg/m²<br>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. | Drug: Carfilzomib<br>* Administered as an IV bolus dose<br>* Other names: Kyprolis;|
| Experimental: CFZ 20/27 mg/m²<br>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. | Drug: Carfilzomib<br>* Administered as an IV bolus dose<br>* Other names: Kyprolis;|
| Experimental: CFZ 20/27 mg/m² + DEX<br>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). | Drug: Carfilzomib<br>* Administered as an IV bolus dose<br>* Other names: Kyprolis;Drug: Dexamethasone<br>* Administered orally prior to carfilzomib<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 28 days | 
| 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. | 
| 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 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. | 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 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. | 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 | 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. | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hematological, Proteasome, Myeloma, Lymphoma