Clinical trial NCT00511238: Phase 2 Study of Carfilzomib in Relapsed and Refractory Multiple Myeloma
Official title: An Open-label, Single-arm, Phase 2 Study of Carfilzomib in Patients With Relapsed and Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: Onyx
PR171
carfilzomib
multiple myeloma
relapsed
refractory
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2007-08-03
Enrollment: 312
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Patients must have received prior treatment with bortezomib and either thalidomide or lenalidomide and be refractory to their last treatment.


Eligibility criteria: Inclusion Criteria:

* Disease Related

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

    * Serum M-protein ≥ 1 g/dL
    * Urine M-protein ≥ 200 mg/24 hours
    * Serum FLC ≥ 10 mg/dL with abnormal ratio (A0 Only)
    * Quantitative immunoglobulin levels using nephelometry or turbidometry (only if protein electrophoresis was felt to be unreliable for M-protein measurement) (A0 Only)
  * Subjects must have been responsive (i.e., achieved an MR or better) to first-line, standard of care therapy
  * Refractory to the most recently received therapy. Refractory disease is defined as ≤ 25% response or progression during therapy or within 60 days after completion of therapy.
  * Subjects must have received ≥ 2 prior regimens for relapsed disease. Induction therapy and stem cell transplant will be considered as one regimen (A1 Only)
  * Subjects must have received prior treatment with bortezomib, and either thalidomide or lenalidomide
  * Subjects must have received an alkylating agent either alone or in combination with other myeloma treatments (history of stem cell transplant is acceptable) (A1 Only)
  * Subjects must have received an anthracycline either alone or in combination with other myeloma treatments, unless not clinically indicated (A1 Only)
* 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 less than 2.0 times the upper limit of normal, and AST and ALT of less than 3.0 times the upper limit of normal
  * Uric acid within normal range (A0 Only)
  * Total white blood cell (WBC) count ≥ 2.0 × 109/L, absolute neutrophil count (ANC) ≥ 1.0 × 109/L, hemoglobin ≥ 8.0 g/dL, and platelet count ≥ 50.0 × 109/L (A0 Only)
  * Absolute neutrophil count \> 1,000/mm3, hemoglobin \> 8.0 g/dL, and platelet count \> 50,000/mm3 (A1 Only)

    * Subjects should be platelet transfusion independent
    * Screening ANC should be independent of G-CSF or GM-CSF support for ≥ 1 week and of pegylated G-CSF for ≥ 2 weeks
    * Subjects may receive red blood cell (RBC) or platelet transfusions or receive supportive care such as erythropoietin and darbepoetin in accordance with institutional guidelines
  * Calculated and 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.
* 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.

Exclusion Criteria:

* Disease Related

  * Multiple Myeloma IgM (A1 Only)
  * Subjects who failed to achieve at least a confirmed MR(≥ 25% reduction in M-protein for ≥ 6 weeks) (A1 Only)
  * Subjects with non-secretory multiple myeloma, defined as \< 1 g/dL M-protein in serum and \< 200 mg/24 hr M-protein in urine
  * Subjects with disease measurable only by serum free light chain (SFLC) analysis (A1 Only)
  * 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 Day 1, 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 cardiac ischemia, cardiomyopathy, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction in the previous six months, LVEF \< 40
  * Acute active infection requiring systemic antibiotics, antivirals or antifungals within 2 weeks prior to first dose
  * Known or suspected 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 PSA
  * Subjects with treatment related myelodysplastic syndrome
  * Significant neuropathy (Grade 3, 4 or Grade 2 with pain) at the time of study initiation
  * 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 (A1 Only)
  * Subjects with known or suspected amyloidosis (A1 Only)
  * Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis (A1 Only)
  * 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 (A1 Only)
* 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)
timeFrame: A0: Subjects evaluated for disease response on Day 24 of Cycles 2, 4, 6, 9, and 12. Onset of response measured on Day 15 of Cycle 1. A1: Subjects evaluated for disease response on Day 15 of Cycle 1, Day 1 of Cycles 2 through 12 and at End of Study.
Secondary outcomes:
measure: Clinical Benefit Response (CBR) (A0 Only)
timeFrame: Response assessments same as described in primary outcome measure
measure: Clinical Benefit Response (CBR) (A1 Only)
timeFrame: Response assessments same as described in primary outcome measure
measure: Duration of Response (A0 Only)
timeFrame: Response assessments same as described in primary outcome measure
measure: Duration of Response (A1 Only)
timeFrame: Response assessments same as described in primary outcome measure
measure: Time to Progression (A0 Only)
timeFrame: Response assessments same as described in primary outcome measure
measure: Time to Progression (A1 Only)
timeFrame: Response assessments same as described in primary outcome measure
measure: Progression-free Survival (A0 Only)
timeFrame: Response assessments same as described in primary outcome measure
measure: Progression-free Survival (A1 Only)
timeFrame: Response assessments same as described in primary outcome measure
measure: Overall Survival (A1 Only)
timeFrame: Patients were to be followed by telephone contact for disease progression and OS every 3 months after study discontinuation for the first year and every 6 months thereafter for up to 2 years
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Southern Cancer Center
state: Alabama
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: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: La Jolla
country: United States
facility: Scripps Clinic
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Fort Myers
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Atlanta
country: United States
facility: Emory University Winship Cancer Institute
state: Georgia
city: Chicago
country: United States
facility: Northwestern Universtiy
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
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: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: St. Vincent Catholic Medical Center
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest University
state: North Carolina
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Cincinnati
country: United States
facility: Oncology & Hematology Care
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: Northwest Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta, Cross Cancer Institute
state: Alberta
city: Vancouver
country: Canada
facility: Leukemia/BMT Program of BC
state: British Columbia
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Montreal
country: Canada
facility: Royal Victoria Hospital
state: Quebec
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, Trudel S, Kukreti V, Bahlis N, Alsina M, Chanan-Khan A, Buadi F, Reu FJ, Somlo G, Zonder J, Song K, Stewart AK, Stadtmauer E, Kunkel L, Wear S, Wong AF, Orlowski RZ, Jagannath S. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012 Oct 4;120(14):2817-25. doi: 10.1182/blood-2012-05-425934. Epub 2012 Jul 25.