Clinical trial NCT00530816: Phase 2 Study of Carfilzomib in Relapsed Multiple Myeloma
Official title: An Open-label, Single-arm, Phase 2 Study of Carfilzomib in Patients With Relapsed or Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Myeloma
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2007-09-18
Enrollment: 164
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: To evaluate the best overall response rate, safety and tolerability of carfilzomib in patients with relapsed or refractory multiple myeloma.

Detailed description: Two groups of patients with multiple myeloma were initially studied: bortezomib-naïve and bortezomib-treated. Following Amendment 2, only bortezomib-naïve patients were enrolled. Study results were reported in 2 parts, depending on whether a patient received prior bortezomib.

Eligibility criteria: Inclusion Criteria:

Disease Related

* Multiple myeloma
* Subjects must have measurable disease, defined as one or more of the following:

  * Serum M-protein ≥ 1 g/dL
  * Urine M-protein ≥ 200 mg/24 hours
* Subjects must have been responsive (i.e., achieve a minimal response \[MR\] or better) to standard, first line therapy
* Relapsed and/or refractory or progressive disease after at least one, but no more than three, prior therapeutic treatments or regimens for multiple myeloma. Refractory disease is defined as ≤ 25% response or progression during therapy or within 60 days after completion of therapy. Induction therapy and stem cell transplant will be considered as one regimen

Demographic

* Males and females ≥18 years of age
* Life expectancy of more than three months
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2

Laboratory

* 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
* Uric acid, if elevated, must be corrected to within laboratory normal range prior to dosing
* Total white blood cell (WBC) count ≥ 2,000/mm³, absolute neutrophil count \> 1,000/mm³, hemoglobin ≥ 8.0 g/dL, and platelet count \> 50,000/mm³
* Subjects should be platelet transfusion independent
* Screening absolute neutrophil count (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 may receive red blood cell (RBC) transfusion or receive supportive care such as erythropoietin and darbepoetin in accordance with institutional guidelines
* Calculated or measured creatinine clearance of ≥ 30 mL/minute, calculated using the formula of Cockcroft and Gault \[(140 - Age) X Mass (kg) / (72 X Creatinine mg/dL)\]. Multiply result by 0.85 if female.
* Serum creatinine ≤ 2 mg/dL

Ethical / Other

* Written informed consent in accordance with federal, local, and institutional guidelines
* Female subjects of child-bearing potential must have a negative serum pregnancy test within seven days of the first dose and agree to use dual methods of contraception during and for 3 months following last dose of drug. Post menopausal females (\> 45 years old and without menses for \> 1 year) and surgically sterilized females are exempt from a pregnancy test. Male subjects must use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with a female of child-bearing potential.
* Subjects must be able to receive outpatient treatment and laboratory monitoring at the institute that administers agent.

Exclusion Criteria:

Disease Related

* Multiple Myeloma Immunoglobulin M (IgM)
* Subjects previously treated with any proteasome inhibitor (for Part 2 Proteasome Inhibitor - Naïve only, criteria added at Amendment 2)
* Subjects must not be primary refractory to standard first-line therapy
* Subjects with non-secretory multiple myeloma, defined as \< 1 g/dL M-protein in serum, \< 200 mg/24 hour M-protein in urine
* Subjects with disease measurable only by serum free light chain (SFLC) analysis
* Glucocorticoid therapy (prednisone \>10 mg/day orally or equivalent) within the last three weeks
* POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
* Plasma cell leukemia
* Chemotherapy with approved or investigative anticancer therapeutics, including steroid therapy, within the three weeks prior to first dose
* Radiation therapy or immunotherapy in the previous four weeks; localized radiation therapy within 1 week prior to first dose
* Participation in an investigational therapeutic study within three weeks or within five drug half-lives (t1/2) prior to first dose, whichever time is greater
* Prior treatment with carfilzomib

Concurrent Conditions

* Major surgery within three weeks before Day 1
* Congestive heart failure (New York Heart Association class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction in the previous six months
* Acute active infection requiring systemic antibiotics, antivirals or antifungals within 2 weeks prior to first dose
* Known or suspected human immunodeficiency (HIV) infection or subjects who are HIV seropositive
* Active hepatitis A, B, or C infection
* 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 \< Gleason Grade 6 with stable prostate-specific antigen (PSA)
* Subjects with treatment related myelodysplastic syndrome
* Significant neuropathy (Grade 3, 4 or Grade 2 with pain) at the time of study initiation
* Subjects with known contraindication 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
* Any clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent

Ethical / Other

* Female subjects who are pregnant or lactating
* Serious psychiatric or medical conditions that could interfere with treatment

Primary outcomes:
measure: Best Overall Response Rate (ORR) in the Response Evaluable Subset Population
timeFrame: Disease response was assessed on Day 15 of Cycle 1, Day 1 of Cycles 2 through 12, and at End of Study, 30 days after last dose. Median duration of treatment was 100 days for Part 1 and 170 days for Part 2 participants.
Secondary outcomes:
measure: Best Overall Response Rate (ORR) in the Response Evaluable Population
timeFrame: Disease response was assessed on Day 15 of Cycle 1, Day 1 of Cycles 2 through 12, End of Study, 30 days after last dose; median duration of treatment was 100 days for Part 1 and 170 days for Part 2 participants.
measure: Clinical Benefit Rate (CBR)
timeFrame: Disease response was assessed on Day 15 of Cycle 1, Day 1 of Cycles 2 through 12, and at End of Study, 30 days after last dose. Median duration of treatment was 100 days for Part 1 and 170 days for Part 2 participants.
measure: Duration of Response (DOR)
timeFrame: Patients were followed for up to 2 years after study discontinuation. The data cutoff for the analysis is 30 November 2010 for Part 1 and 22 April 2011 for Part 2.
measure: Time to Progression (TTP)
timeFrame: Patients were followed for up to 2 years after study discontinuation. The data cutoff for the analysis is 30 November 2010 for Part 1 and 22 April 2011 for Part 2. Median follow-up time was 13.4 months for Part 1 and 11.5 months in Part 2.
measure: Progression-free Survival (PFS)
timeFrame: Patients were followed for up to 2 years after study discontinuation. The data cutoff for the analysis is 30 November 2010 for Part 1 and 22 April 2011 for Part 2. Median follow-up time was 13.4 months for Part 1 and 11.5 months in Part 2.
measure: Overall Survival (OS)
timeFrame: Patients were followed for up to 2 years after study discontinuation. The data cutoff for the analysis is 19 November 2012 for Part 1 and 07 January 2013 for Part 2. Median follow-up time was 19.1 months for Part 1 and 35.9 months in Part 2.
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic Scottsdale
state: Arizona
city: Beverly Hills
country: United States
facility: Tower Cancer Research Foundation
state: California
city: Laguna Hills
country: United States
facility: Therapeutic Research Institute of Orange County
state: California
city: Denver
country: United States
facility: Rocky Mountain Blood and Marrow Transplant Program
state: Colorado
city: Tamarac
country: United States
facility: Oncology & Hematology Assoc. of W. Broward
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center & Research Institute
state: Florida
city: Atlanta
country: United States
facility: Emory University Winship Cancer Institute
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Skokie
country: United States
facility: Orchard Research
state: Illinois
city: Lexington
country: United States
facility: University of Kentucky College of Medicine
state: Kentucky
city: Mount Sterling
country: United States
facility: Montgomery Cancer Center
state: Kentucky
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Hattiesburg
country: United States
facility: Hattiesburg Clinic
state: Mississippi
city: Jackson
country: United States
facility: Jackson Oncology Associates
state: Mississippi
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: St. Vincent's Comprehensive Cancer Center
state: New York
city: Akron
country: United States
facility: Summa Health System
state: Ohio
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Dayton
country: United States
facility: Dayton Clinical Oncology Program
state: Ohio
city: Middletown
country: United States
facility: Signal Point Clinical Research Center, LLC
state: Ohio
city: Amarillo
country: United States
facility: Harrington Cancer Center
state: Texas
city: Austin
country: United States
facility: Texas Oncology Cancer Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Cross Cancer Institute
state: Alberta
city: Toronto
country: Canada
facility: University of Toronto Princess Margaret Hospital
state: Ontario
city: Montreal
country: Canada
facility: Royal Victoria Hospital
state: Quebec
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: Vij R, Wang M, Kaufman JL, Lonial S, Jakubowiak AJ, Stewart AK, Kukreti V, Jagannath S, McDonagh KT, Alsina M, Bahlis NJ, Reu FJ, Gabrail NY, Belch A, Matous JV, Lee P, Rosen P, Sebag M, Vesole DH, Kunkel LA, Wear SM, Wong AF, Orlowski RZ, Siegel DS. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood. 2012 Jun 14;119(24):5661-70. doi: 10.1182/blood-2012-03-414359. Epub 2012 May 3.