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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01568866




Registration number
NCT01568866
Ethics application status
Date submitted
28/03/2012
Date registered
2/04/2012
Date last updated
10/04/2019

Titles & IDs
Public title
Phase 3 Study With Carfilzomib and Dexamethasone Versus Bortezomib and Dexamethasone for Relapsed Multiple Myeloma Patients
Scientific title
A Randomized, Open-label, Phase 3 Study of Carfilzomib Plus Dexamethasone vs. Bortezomib Plus Dexamethasone in Patients With Relapsed Multiple Myeloma
Secondary ID [1] 0 0
2012-000128-16
Secondary ID [2] 0 0
2011-003
Universal Trial Number (UTN)
Trial acronym
ENDEAVOR
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Myeloma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Carfilzomib
Treatment: Drugs - Bortezomib
Treatment: Drugs - Dexamethasone

Experimental: Carfilzomib plus Dexamethasone - Participants received 20 mg/m² carfilzomib administered by intravenous (IV) infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.

Active Comparator: Bortezomib plus Dexamethasone - Participants received bortezomib 1.3 mg/m² administered IV or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.


Treatment: Drugs: Carfilzomib
Carfilzomib is administered over 30 minutes as an infusion.

Treatment: Drugs: Bortezomib
Bortezomib is administered as a 3-5 second bolus IV injection or SC injection (in accordance with regulatory approval)

Treatment: Drugs: Dexamethasone
Tablet for oral administration; On days when carfilzomib or bortezomib was administered, the dexamethasone was to be given 30 minutes to 4 hours prior to the carfilzomib or bortezomib dose.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Progression-free Survival - Progression-free survival (PFS) was defined as the time from randomization to the earlier of disease progression or death due to any cause. Participants were evaluated for disease response and progression according to the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC) as assessed by an Independent Review Committee (IRC).
Median PFS was estimated using the Kaplan-Meier method. Participants with no baseline disease assessments, starting a new anticancer therapy before documentation of disease progression or death, death or disease progression immediately after more than 1 consecutively missed disease assessment visit, or alive without documentation of disease progression before the data cut-off date were censored.
Timepoint [1] 0 0
From randomization until the data cut-off date of 10 November 2014; median follow-up time for PFS was 11.1.and 11.9 months in the bortezomib and carfilzomib arms respectively
Secondary outcome [1] 0 0
Overall Survival - Overall survival (OS) is defined as the time from randomization to the date of death (whatever the cause). Participants who were alive or lost to follow-up as of the data analysis cut-off date were censored at the patient's date of last contact (last known to be alive).
Median overall survival was estimated using the Kaplan-Meier method.
Timepoint [1] 0 0
From randomization until the data cut-off date of 03 January 2017; median follow-up time for OS was 36.9 and 37.5 months for each treatment group respectively.
Secondary outcome [2] 0 0
Overall Response - Disease response was evaluated according to the IMWG-URC by the IRC. Overall response was defined as the percentage of participants with a best overall response of partial response (PR), very good PR (VGPR), complete response (CR) or stringent CR (sCR).
sCR: As for CR, normal serum free light chain (SFLC) ratio and no clonal cells in bone marrow (BM).
CR: No immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and < 5% plasma cells in BM biopsy; VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or = 90% reduction in serum M-protein with urine M-protein <100 mg/24 hours. A = 50% reduction in the size of soft tissue plasmacytomas if present at baseline.
PR: = 50% reduction of serum M-protein and reduction in urine M-protein by = 90% or to < 200 mg/24 hours. A = 50% reduction in the size of soft tissue plasmacytomas if present at baseline.
Timepoint [2] 0 0
Disease response was assessed every 28 days until end of treatment or the data cut-off date of 10 November 2014; median duration of treatment was 27 weeks in the bortezomib group and 40 weeks in the carfilzomib treatment group.
Secondary outcome [3] 0 0
Duration of Response - Duration of response (DOR) was calculated for participants who achieved an sCR, CR, VGPR, or PR. Duration of response is defined as the time from first evidence of PR or better to confirmation of disease progression or death due to any cause. Median duration of response was estimated using the Kaplan-Meier method. Participants with no baseline disease assessments, starting a new anticancer therapy before documentation of disease progression or death, death or disease progression immediately after more than 1 consecutively missed disease assessment visit, or alive without documentation of disease progression before the data cut-off date were censored.
Timepoint [3] 0 0
From randomization until the data cut-off date of 10 November 2014; median follow-up time for DOR was 9.4 and 10.4 months for each treatment group respectively.
Secondary outcome [4] 0 0
Percentage of Participants With = Grade 2 Peripheral Neuropathy - Neuropathy events were defined as Grade 2 or higher peripheral neuropathy as specified by peripheral neuropathy Standardised Medical Dictionary for Regulatory Activities (MedDRA) Query, narrow (scope) (SMQN) terms.
Peripheral neuropathy was assessed by neurologic exam and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03:
Grade 1: Asymptomatic; Grade 2: Moderate symptoms, limiting instrumental activities of daily living (ADL) Grade 3: Severe symptoms; limiting self-care ADL; Grade 4: Life-threatening consequences, urgent intervention indicated; Grade 5: Death.
Timepoint [4] 0 0
From the first dose of study drug up to 30 days after the last dose of study drug as of the data cut-off date of 10 November 2014; median duration of treatment was 27 weeks in the bortezomib group and 40 weeks in the carfilzomib treatment group.
Secondary outcome [5] 0 0
Percentage of Participants With a Significant Reduction in Left Ventricular Ejection Fraction (LVEF) - A significant reduction in LVEF was defined as a = 10% decrease (absolute change) from baseline in participants whose baseline LVEF is = 55%.
For participants with LVEF > 55% at baseline, a significant change was defined as a decrease in LVEF to < 45%.
Timepoint [5] 0 0
Baseline and 24 weeks
Secondary outcome [6] 0 0
Change From Baseline in Right Ventricular Fractional Area Change (FAC) - Right ventricular function was assessed by measuring fractional area change (FAC) on echocardiogram.
Timepoint [6] 0 0
Baseline and Weeks 12, 24 and 36 and at end of treatment (median duration of treatment was 27 weeks in the bortezomib group and 40 weeks in the carfilzomib treatment group).
Secondary outcome [7] 0 0
Change From Baseline in Pulmonary Artery Systolic Pressure (PASP) - Pulmonary artery pressure was measured using transthoracic echocardiogram.
Timepoint [7] 0 0
Baseline and Weeks 12, 24 and 36 and at end of treatment (median duration of treatment was 27 weeks in the bortezomib group and 40 weeks in the carfilzomib treatment group).

Eligibility
Key inclusion criteria
1. Multiple myeloma with relapsing or progressing disease at study entry.

2. Patients must have evaluable multiple myeloma with, at least one of the following
(assessed within 21 days prior to randomization):

- Serum M-protein = 0.5 g/dL, or

- Urine M-protein = 200 mg/24 hour, or

- In patients without detectable serum or urine M-protein, serum free light chain
(SFLC) > 100 mg/L (involved light chain) and an abnormal serum kappa/lamda ratio,
or

- For immunoglobulin (Ig) A patients whose disease can only be reliably measured by
serum quantitative immunoglobulin (qIgA) = 750 mg/dL (0.75 g/dL).

3. Patients must have documented at least partial response (PR) to at least 1 line of
prior therapy. PR documentation can be based on Investigator assessment.

4. Received 1, but no more than 3 prior treatment regimens or lines of therapy for
multiple myeloma. (Induction therapy followed by stem cell transplant and
consolidation/maintenance therapy will be considered as one line of therapy).

5. Prior therapy with Velcade is allowed as long as the patient had at least a PR to
prior Velcade therapy, was not removed from Velcade therapy due to toxicity, and will
have at least a 6 month Velcade treatment-free interval from last dose received until
first study treatment. (Patients may receive maintenance therapy with drugs that are
not in the proteasome inhibitor class during this 6 month Velcade treatment-free
interval).

6. Prior therapy with carfilzomib is allowed as long as the patient had at least a PR to
prior carfilzomib therapy, was not removed from carfilzomib therapy due to toxicity,
and had at least a 6-month carfilzomib treatment-free interval from last dose received
until first study treatment. (Patients may receive maintenance therapy with drugs that
are not in the proteasome inhibitor class during this 6 month carfilzomib
treatment-free interval). The exception to this is patients randomized or previously
randomized in any other Onyx-Sponsored Phase 3 trial.

7. Males and females = 18 years of age.

8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2.

9. Adequate hepatic function within 21 days prior to randomization, with bilirubin < 1.5
times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and
alanine aminotransferase (ALT) < 3 times the ULN.

10. Left ventricular ejection fraction (LVEF) = 40%.

11. Absolute neutrophil count (ANC) = 1000/mm³ within 21 days prior to randomization.
Screening ANC should be independent of growth factor support for = 1 week.

12. Hemoglobin = 8.0 g/dL within 21 days prior to randomization. Use of erythropoietic
stimulating factors and red blood cell (RBC) transfusions per institutional guidelines
is allowed, however most recent RBC transfusion may not have been done within 7 days
prior to obtaining screening hemoglobin.

13. Platelet count = 50,000/mm³ (= 30,000/mm³ if myeloma involvement in the bone marrow is
> 50%) within 21 days prior to randomization. Patients should not have received
platelet transfusions for at least 1 week prior to obtaining the screening platelet
count.

14. Calculated or measured creatinine clearance (CrCl) of = 15 mL/min within 21 days prior
to randomization. Calculation should be based on standard formula such as the
Cockcroft and Gault:

[(140 - Age) x Mass (kg) / (72 x Creatinine mg/dL)]; multiply result by 0.85 if
female.

15. Written informed consent in accordance with federal, local, and institutional
guidelines.

16. Female patients of child-bearing potential (FCBP) must have a negative serum pregnancy
test within 21 days prior to randomization and agree to use an effective method of
contraception during and for 3 months following last dose of drug (more frequent
pregnancy tests may be conducted if required per local regulations). FCBP is defined
as a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral
oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer
therapy does not rule out childbearing potential) for at least 12 consecutive months
(i.e., has had menses at any time in the preceding 12 consecutive months).

17. Male patients must use an effective barrier method of contraception during study and
for 3 months following the last dose if sexually active with a FCBP.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Multiple Myeloma of IgM subtype.

2. Glucocorticoid therapy (prednisone > 30 mg/day or equivalent) within 14 days prior to
randomization.

3. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and
skin changes).

4. Plasma cell leukemia or circulating plasma cells = 2 × 10^9/L.

5. Waldenstrom's Macroglobulinemia.

6. Patients with known amyloidosis.

7. Chemotherapy with approved or investigational anticancer therapeutics within 21 days
prior to randomization.

8. Patients randomized or previously randomized in any other Onyx-Sponsored Phase 3
trial.

9. Focal radiation therapy within 7 days prior to randomization. Radiation therapy to an
extended field involving a significant volume of bone marrow within 21 days prior to
randomization (i.e., prior radiation must have been to less than 30% of the bone
marrow).

10. Immunotherapy within 21 days prior to randomization.

11. Major surgery (excluding kyphoplasty) within 28 days prior to randomization.

12. Active congestive heart failure (New York Heart Association [NYHA] Class III to IV),
symptomatic ischemia, or conduction abnormalities uncontrolled by conventional
intervention. Myocardial infarction within four months prior to randomization.

13. Acute active infection requiring systemic antibiotics, antiviral (except antiviral
therapy directed at hepatitis B) or antifungal agents within 14 days prior to
randomization.

14. Known human immunodeficiency (HIV) seropositive, hepatitis C infection, and/or
hepatitis B (except for patients with hepatitis B surface antigen [SAg] or core
antibody receiving and responding to antiviral therapy directed at hepatitis B: these
patients are allowed).

15. Patients with known cirrhosis.

16. Second malignancy within the past 3 years except:

- adequately treated basal cell or squamous cell skin cancer

- carcinoma in situ of the cervix

- prostate cancer < Gleason score 6 with stable prostate-specific antigen (PSA)
over 12 months

- breast carcinoma in situ with full surgical resection

- treated medullary or papillary thyroid cancer

17. Patients with myelodysplastic syndrome.

18. Significant neuropathy (Grades 3 to 4, or Grade 2 with pain) within 14 days prior to
randomization.

19. Female patients who are pregnant or lactating.

20. Known history of allergy to Captisol(a cyclodextrin derivative used to solubilize
carfilzomib).

21. Patients with hypersensitivity to carfilzomib, Velcade, boron, or mannitol.

22. Patients with contraindication to dexamethasone.

23. Contraindication to any of the required concomitant drugs or supportive treatments,
including hypersensitivity to antiviral drugs, or intolerance to hydration due to
preexisting pulmonary or cardiac impairment.

24. Ongoing graft-vs-host disease.

25. Patients with pleural effusions requiring thoracentesis or ascites requiring
paracentesis within 14 days prior to randomization.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC,WA
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Westmead Hospital - Westmead
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Royal Brisbane and Women's Hospital - Herston
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Haematology & Oncology Clinics of Australia - South Brisbane
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Haematology and Oncology Clinics of Australia at Chermside - South Brisbane
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Haematology and Oncology Clinics of Australia at Wesley - South Brisbane
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Royal Adelaide Hospital - Adelaide
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The Queen Elizabeth Hospital - Woodville
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Box Hill Hospital - Box Hill
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Monash Medical Centre - Clayton
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Saint Vincent's Hospital - East Melbourne
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Western Hospital - Footscray
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The Alfred Hospital - Melbourne
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- Perth
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Lubelskie
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Slaskie
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Poland
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Bucuresti
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Brasov
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England

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Amgen
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The primary objective of this study was to compare progression-free survival in patients with
multiple myeloma who relapsed after 1 to 3 prior therapies treated with carfilzomib plus
dexamethasone or bortezomib plus dexamethasone.
Trial website
https://clinicaltrials.gov/show/NCT01568866
Trial related presentations / publications
Moreau P, Joshua D, Chng WJ, Palumbo A, Goldschmidt H, Hájek R, Facon T, Ludwig H, Pour L, Niesvizky R, Oriol A, Rosiñol L, Suvorov A, Gaidano G, Pika T, Weisel K, Goranova-Marinova V, Gillenwater HH, Mohamed N, Aggarwal S, Feng S, Dimopoulos MA. Impact of prior treatment on patients with relapsed multiple myeloma treated with carfilzomib and dexamethasone vs bortezomib and dexamethasone in the phase 3 ENDEAVOR study. Leukemia. 2017 Jan;31(1):115-122. doi: 10.1038/leu.2016.186. Epub 2016 Jul 4.
Chng WJ, Goldschmidt H, Dimopoulos MA, Moreau P, Joshua D, Palumbo A, Facon T, Ludwig H, Pour L, Niesvizky R, Oriol A, Rosiñol L, Suvorov A, Gaidano G, Pika T, Weisel K, Goranova-Marinova V, Gillenwater HH, Mohamed N, Feng S, Aggarwal S, Hájek R. Carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR. Leukemia. 2017 Jun;31(6):1368-1374. doi: 10.1038/leu.2016.390. Epub 2016 Dec 27.
Dimopoulos MA, Goldschmidt H, Niesvizky R, Joshua D, Chng WJ, Oriol A, Orlowski RZ, Ludwig H, Facon T, Hajek R, Weisel K, Hungria V, Minuk L, Feng S, Zahlten-Kumeli A, Kimball AS, Moreau P. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1327-1337. doi: 10.1016/S1470-2045(17)30578-8. Epub 2017 Aug 23. Erratum in: Lancet Oncol. 2017 Oct;18(10):e562.
Ludwig H, Dimopoulos MA, Moreau P, Chng WJ, Goldschmidt H, Hájek R, Facon T, Pour L, Niesvizky R, Oriol A, Rosiñol L, Suvorov A, Gaidano G, Pika T, Weisel K, Goranova-Marinova V, Palumbo A, Gillenwater HH, Mohamed N, Aggarwal S, Feng S, Joshua D. Carfilzomib and dexamethasone vs bortezomib and dexamethasone in patients with relapsed multiple myeloma: results of the phase 3 study ENDEAVOR (NCT01568866) according to age subgroup. Leuk Lymphoma. 2017 Oct;58(10):2501-2504. doi: 10.1080/10428194.2017.1298755. Epub 2017 Mar 17.
Hari P, Mateos MV, Abonour R, Knop S, Bensinger W, Ludwig H, Song K, Hajek R, Moreau P, Siegel DS, Feng S, Obreja M, Aggarwal SK, Iskander K, Goldschmidt H. Efficacy and safety of carfilzomib regimens in multiple myeloma patients relapsing after autologous stem cell transplant: ASPIRE and ENDEAVOR outcomes. Leukemia. 2017 Dec;31(12):2630-2641. doi: 10.1038/leu.2017.122. Epub 2017 Apr 25.
Mateos MV, Goldschmidt H, San-Miguel J, Mikhael J, DeCosta L, Zhou L, Obreja M, Blaedel J, Szabo Z, Leleu X. Carfilzomib in relapsed or refractory multiple myeloma patients with early or late relapse following prior therapy: A subgroup analysis of the randomized phase 3 ASPIRE and ENDEAVOR trials. Hematol Oncol. 2018 Apr;36(2):463-470. doi: 10.1002/hon.2499. Epub 2018 Feb 15.
Chari A, Stewart AK, Russell SD, Moreau P, Herrmann J, Banchs J, Hajek R, Groarke J, Lyon AR, Batty GN, Ro S, Huang M, Iskander KS, Lenihan D. Analysis of carfilzomib cardiovascular safety profile across relapsed and/or refractory multiple myeloma clinical trials. Blood Adv. 2018 Jul 10;2(13):1633-1644. doi: 10.1182/bloodadvances.2017015545. Review.
Ludwig H, Moreau P, Dimopoulos MA, Mateos MV, Kaiser M, Hajek R, Feng S, Cocks K, Buchanan J, Weisel K. Health-related quality of life in the ENDEAVOR study: carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed/refractory multiple myeloma. Blood Cancer J. 2019 Feb 22;9(3):23. doi: 10.1038/s41408-019-0181-0.
Dimopoulos M, Siegel D, White DJ, Boccia R, Iskander KS, Yang Z, Kimball AS, Mezzi K, Ludwig H, Niesvizky R. Carfilzomib vs bortezomib in patients with multiple myeloma and renal failure: a subgroup analysis of ENDEAVOR. Blood. 2019 Jan 10;133(2):147-155. doi: 10.1182/blood-2018-06-860015. Epub 2018 Nov 26.
Public notes

Contacts
Principal investigator
Name 0 0
MD
Address 0 0
Amgen
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications