Phase 3 Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (CRd) vs Lenalidomide and Dexamethasone (Rd) in Subjects With Relapsed Multiple Myeloma

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Onyx Pharmaceuticals ( Onyx Therapeutics, Inc. )
ClinicalTrials.gov Identifier:
NCT01080391
First received: March 2, 2010
Last updated: July 15, 2015
Last verified: July 2015

March 2, 2010
July 15, 2015
July 2010
June 2014   (final data collection date for primary outcome measure)
Progression-free Survival (PFS) [ Time Frame: From randomization through the data cutoff date of 16 June 2014. Median follow-up time was approximately 31 months. ] [ Designated as safety issue: No ]
Kaplan-Meier estimate of median time from randomization to progressive disease (PD) or all-cause death. PD was assessed using International Myeloma Working Group-Uniform Response Criteria (IMWG-URC). 1 or more conditions were required to meet PD: 2 consecutive rising serum or urine M-protein from central lab; documented new bone lesion(s) or soft tissue plasmacytoma(s) or increased size of existing bone lesion(s) or plasmacytoma(s); or confirmed hypercalcemia due solely to plasma cell proliferative disorder (local lab greater than 11.5 mg/dL on 2 separate occasions). Censoring conditions (censoring dates) were: no post-baseline disease assessment (DA) (randomization date); started non-protocol systemic anticancer treatment before PD or death (last DA date before such treatment); died or had PD after more than 1 missed DA (last DA date without PD before the first missed visit); or were alive and without documentation of PD, including lost to follow-up without PD (last DA date).
Progression-free survival (PFS) [ Time Frame: 18 months ] [ Designated as safety issue: No ]
The primary objective of this study is to compare PFS in subjects with relapsed multiple myeloma who are receiving CRd vs subjects receiving Rd alone in a randomized multicenter setting.
Complete list of historical versions of study NCT01080391 on ClinicalTrials.gov Archive Site
  • Overall Survival [ Time Frame: From randomization through the data cutoff date of 16 June 2014. Median follow up time was approximiately 32 months. ] [ Designated as safety issue: No ]
    Time elapsed between the randomization date and the date of death. Participants who were still alive were censored at the date when the subject was last known to be alive or the data cutoff date, whichever occurs earlier. The median and all but one of the 95% confidence limits were not estimable. Instead, the number of participants who died or were censored are reported.
  • Overall Response [ Time Frame: From randomization through the data cutoff date of 16 June 2014.Median follow-up time was approximately 31 months. ] [ Designated as safety issue: No ]
    Number of participants who achieved confirmed stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) as their best response based on the Independent Review Committee (IRC) assessed response outcome. Response was determined using the International Myeloma Working Group - Uniform Response Criteria (IMWG-URC).
  • Disease Control [ Time Frame: From randomization through the data cutoff date of 16 June 2014. Median follow-up time was approximately 31 months. ] [ Designated as safety issue: No ]
    Number of participants who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), or stable disease (SD) lasting ≥ 8 weeks according to International Myeloma Working Group - Uniform Response Criteria (IMWG-URC) (MR was determined using European Group for Blood and Marrow Transplantation criteria).
  • Duration of Response [ Time Frame: From randomization through the data cutoff date of 16 June 2014. Longest follow-up time was approximately 42 months. ] [ Designated as safety issue: No ]
    Duration of response (DOR) was calculated for subjects who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). Duration of response was defined as the time in months from the initial start of response (PR or better) to the earlier of documented Progressive disease (PD) or death due to any cause. Participants who had not progressed or died were censored according to the censoring rules defined previously for PFS.
  • Duration of Disease Control [ Time Frame: From randomization through the data cutoff date of 16 June 2014. Longest follow-up time was approximately 46 months. ] [ Designated as safety issue: No ]
    Duration of disease control (DDC) was calculated for participants who achieved disease control.DDC was defined as the time in months from randomization to the earlier of documented Progressive disease (PD) or death due to any cause. Participants who had not progressed or died were censored according to the censoring rules defined previously for PFS.
  • QLQ-C30 Global Health Status/Quality of Life Scores [ Time Frame: Day 1 of Cycles 3, 6, 12, 18 ] [ Designated as safety issue: No ]
    European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core Module QLQ-C30 (QLQ-C30 GHS/QoL) is a validated instrument in multiple myeloma patients. Scores range from 0 to 100, with higher scores indicating better health related quality of life. The minimal important difference for between group differences is 5 points.
Overall Survival, overall response rate (sCR+CR+VGPR+PR), duration of response (DOR), disease control rate (DCR), safety, time to progression (TTP), time to next treatment [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]

Investigating the effect of carfilzomib given with lenalidomide and dexamethasone on other standard efficacy variables including ORR (sCR + CR + VGPR + PR), disease control rate (DCR), duration of response (DOR), OS, time to progression (TTP), and time to next treatment.

Additionally, this study will examine the safety profile of CRd compared with Rd alone based on the incidence and severity of AEs and laboratory changes.

Not Provided
Not Provided
 
Phase 3 Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (CRd) vs Lenalidomide and Dexamethasone (Rd) in Subjects With Relapsed Multiple Myeloma
A Randomized, Multicenter, Phase 3 Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (CRd) vs Lenalidomide and Dexamethasone (Rd) in Subjects With Relapsed Multiple Myeloma

To compare progression-free survival in subjects with relapsed multiple myeloma who are receiving CRd vs subjects receiving Rd in a randomized multicenter setting.

This is a Phase 3, randomized, open-label, multicenter study comparing two treatment regimens for subjects with relapsed multiple myeloma. Eligible subjects will be randomized in a 1:1 ratio to receive either the control Rd or CRd. Randomization will be stratified by β2 microglobulin levels (< vs ≥ 2.5 mg/L), prior bortezomib (no vs yes), and prior lenalidomide (no vs yes). Subjects will receive the treatment determined by randomization in 28-day cycles until disease progression or unacceptable toxicity (whichever occurs first). The primary endpoint of this Phase 3 study is progression-free survival.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Relapsed Multiple Myeloma
  • Drug: Dexamethasone
    40 mg PO or IV on Days 1, 8, 15, 22
  • Drug: Lenalidomide
    25 mg PO on Days 1-21
    Other Name: Revlimid
  • Drug: Carfilzomib
    20 mg/m2, 27 mg/m2
    Other Name: PR-171
  • Active Comparator: Lenalidomide and Dexamethasone (Rd)
    Treatment was administered in cycles repeated every 28 days. Lenalidomide 25 mg was administered orally on Days 1 to 21 and Dexamethasone 40 mg was administered orally or IV on Days 1, 8, 15, and 22.
    Interventions:
    • Drug: Dexamethasone
    • Drug: Lenalidomide
  • Experimental: Carfilzomib, Lenalidomide, and Dexamethasone (CRd)
    Treatment was administered in cycles every 28 days. Carfilzomib 20 mg/m2 was administered intravenously (IV) on Days 1 and 2 of Cycle 1, escalating to 27 mg/m2 on Days 8, 9, 15, and 16 of Cycle 1 and continuing on Days 1, 2, 8, 9, 15, and 16 of Cycle 2 through Cycle 12 and then from Cycle 13 through Cycle 18, 27 mg/m2 on Days 1, 2, 15, and 16. Lenalidomide 25 mg was administered orally on Days 1 to 21 from Cycle 1 through Cycle 18 and from Cycle 19 and higher. Dexamethasone 40 mg was administered orally or IV on Days 1, 8, 15, and 22 from Cycle 1 through Cycle 18 and from Cycle 19 and higher.
    Interventions:
    • Drug: Dexamethasone
    • Drug: Lenalidomide
    • Drug: Carfilzomib
Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Špička I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Mihaylov GG, Goranova-Marinova V, Rajnics P, Suvorov A, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Wang M, Maisnar V, Minarik J, Bensinger WI, Mateos MV, Ben-Yehuda D, Kukreti V, Zojwalla N, Tonda ME, Yang X, Xing B, Moreau P, Palumbo A; ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015 Jan 8;372(2):142-52. doi: 10.1056/NEJMoa1411321. Epub 2014 Dec 6.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
792
March 2017
June 2014   (final data collection date for primary outcome measure)

Inclusion Criteria:

  1. Symptomatic multiple myeloma
  2. Measurable disease, as defined by one or more of the following (assessed within 21 days prior to randomization):

    • Serum M-protein ≥ 0.5 g/dL
    • Urine Bence-Jones protein ≥ 200 mg/24 hours
    • For IgA patients whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA) ≥ 750 mg/dL (0.75 g/dL)
  3. Prior treatment with at least one, but no more than three, regimens for multiple myeloma
  4. Documented relapse or progressive disease on or after any regimen
  5. Achieved a response to at least one prior regimen
  6. Age ≥ 18 years
  7. Life expectancy ≥ 3 months
  8. Eastern Cooperative Oncology Group performance status 0-2
  9. Adequate hepatic function, with serum ALT ≤ 3.5 times the upper limit of normal and serum direct bilirubin ≤ 2 mg/dL (34 µmol/L) within 21 days prior to randomization
  10. Absolute neutrophil count ≥ 1.0 × 10^9/L within 21 days prior to randomization
  11. Hemoglobin ≥ 8 g/dL (80 g/L) within 21 days prior to randomization
  12. Platelet count ≥ 50 × 10^9/L (≥ 30 × 10^9/L if myeloma involvement in the bone marrow is > 50%) within 21 days prior to randomization
  13. Creatinine clearance (CrCl) ≥ 50 mL/minute within 21 days prior to randomization
  14. Written informed consent in accordance with federal, local, and institutional guidelines
  15. Females of childbearing potential must agree to ongoing pregnancy testing and to practice contraception
  16. Male subjects must agree to practice contraception

Exclusion Criteria:

  1. If previously treated with bortezomib (alone or in combination), progression during treatment
  2. If previously treated with a lenalidomide and dexamethasone (len/dex) combination:

    • Progression during the first 3 months of initiating treatment
    • Any progression during treatment if the len/dex combination was the subject's most recent line of therapy
  3. Discontinuation of previous lenalidomide or dexamethasone due to intolerance; subjects intolerant to bortezomib are not excluded
  4. Prior carfilzomib treatment
  5. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
  6. Waldenström's macroglobulinemia or IgM myeloma
  7. Plasma cell leukemia (> 2.0 × 10^9/L circulating plasma cells by standard differential)
  8. Chemotherapy or investigational agent within 3 weeks prior to randomization or antibody therapy within 6 weeks prior to randomization
  9. Radiotherapy to multiple sites or immunotherapy/antibody therapy within 28 days prior to randomization; localized radiotherapy to a single site within 7 days prior to randomization
  10. Corticosteroid therapy at a dose equivalent to dexamethasone > 4 mg/day within 21 days prior to randomization
  11. Pregnant or lactating females
  12. Major surgery within 21 days prior to randomization
  13. Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to randomization
  14. Known human immunodeficiency virus infection
  15. Active hepatitis B or C infection
  16. Myocardial infarction within 4 months prior to randomization, NYHA Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker
  17. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to randomization
  18. Other malignancy, including MDS, within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas
  19. Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to randomization
  20. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib)
  21. Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment
  22. Ongoing graft-vs-host disease
  23. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to randomization
  24. Any other 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
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States,   Austria,   Belgium,   Bulgaria,   Canada,   Czech Republic,   France,   Germany,   Greece,   Hungary,   Israel,   Italy,   Netherlands,   Poland,   Romania,   Russian Federation,   Serbia,   Spain,   Sweden,   United Kingdom
 
NCT01080391
PX-171-009
Yes
Onyx Pharmaceuticals ( Onyx Therapeutics, Inc. )
Onyx Therapeutics, Inc.
Not Provided
Principal Investigator: A. Keith Stewart, MD Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona, USA
Principal Investigator: S. Vincent Rajkumar, MD Division of Hematology and Internal medicine, Mayo Clinic, Rochester, Minnesota, USA
Principal Investigator: Philippe Moreau, MD Department of Hematology, University Hospital, Nantes, France
Principal Investigator: Antonio Palumbo, MD Divisione di Ematologia dell'Universita' di Torino, Azienda Ospedaliera San Giovanni Battista, Torino, Italy
Onyx Pharmaceuticals
July 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP