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

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Waldenstrom's Macroglobulinemia; Non-Hodgkin's Lymphoma; Hodgkin's Disease; Multiple Myeloma	Drug: Carfilzomib; Drug: Dexamethasone	Phase 1

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	48 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase I Study of the Safety and Pharmacokinetics of Escalating Intravenous Doses of the Proteasome Inhibitor PR-171 in Patients With Hematological Malignancies
Study Start Date :	September 2005
Actual Primary Completion Date :	October 2009
Actual Study Completion Date :	October 2009

Arms and Interventions

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Arm	Intervention/treatment
Experimental: 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.	Drug: Carfilzomib; Administered as an IV bolus dose; Other Names: PR-171; Kyprolis
Experimental: 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.	Drug: Carfilzomib; Administered as an IV bolus dose; Other Names: PR-171; Kyprolis
Experimental: 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.	Drug: Carfilzomib; Administered as an IV bolus dose; Other Names: PR-171; Kyprolis
Experimental: 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.	Drug: Carfilzomib; Administered as an IV bolus dose; Other Names: PR-171; Kyprolis
Experimental: 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.	Drug: Carfilzomib; Administered as an IV bolus dose; Other Names: PR-171; Kyprolis
Experimental: 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.	Drug: Carfilzomib; Administered as an IV bolus dose; Other Names: PR-171; Kyprolis
Experimental: CFZ 15.0 mg/m²; 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; Administered as an IV bolus dose; Other Names: PR-171; Kyprolis
Experimental: 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.	Drug: Carfilzomib; Administered as an IV bolus dose; Other Names: PR-171; Kyprolis
Experimental: 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.	Drug: Carfilzomib; Administered as an IV bolus dose; Other Names: PR-171; Kyprolis
Experimental: 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.	Drug: Carfilzomib; Administered as an IV bolus dose; Other Names: PR-171; Kyprolis
Experimental: 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).	Drug: Carfilzomib; Administered as an IV bolus dose; Other Names: PR-171; Kyprolis Drug: Dexamethasone; Administered orally prior to carfilzomib

Outcome Measures

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Primary Outcome Measures :

1. Number of Participants With Dose-limiting Toxicities (DLTs) [ Time Frame: 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.

2. 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. ]
3. 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. ]
4. 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. ]
5. 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. ]

Secondary Outcome Measures :

1. Best Clinical Response to Treatment [ 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. ]

   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.

2. Duration of Response [ 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. ]

   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.

3. Time to Progression [ 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. ]

   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.

4. Progression-free Survival [ 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. ]
   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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Locations

United States, California
Tower Cancer Research Foundation
Beverly Hills, California, United States, 90211-1850
United States, Florida
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, United States, 33612
United States, New York
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10021
Weil Medical College of Cornell University
New York, New York, United States, 10021
Herbert Irving Comprehensive Cancer Center, Columbia University
New York, New York, United States, 10032

Sponsors and Collaborators

Amgen

Investigators

Study Director:	MD	Amgen

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Amgen
ClinicalTrials.gov Identifier:	NCT00150462 History of Changes
Other Study ID Numbers:	PX-171-002
First Posted:	September 8, 2005
Results First Posted:	December 3, 2015
Last Update Posted:	May 2, 2017
Last Verified:	April 2017

Keywords provided by Amgen:

Hematological; Proteasome; Myeloma; Lymphoma

Additional relevant MeSH terms:

Multiple Myeloma; Lymphoma, Non-Hodgkin; Waldenstrom Macroglobulinemia; Hodgkin Disease; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders	Immunoproliferative Disorders; Immune System Diseases; Lymphoma; Lymphatic Diseases; Dexamethasone acetate; Dexamethasone; BB 1101; Proteasome Inhibitors; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids