Phase 3 Study With Carfilzomib and Dexamethasone Versus Bortezomib and Dexamethasone for Relapsed Multiple Myeloma Patients (ENDEAVOR)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Onyx Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT01568866
First received: March 28, 2012
Last updated: December 14, 2015
Last verified: December 2015
  Purpose
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.

Condition Intervention Phase
Multiple Myeloma
Drug: Carfilzomib
Drug: Bortezomib
Drug: Dexamethasone
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized, Open-label, Phase 3 Study of Carfilzomib Plus Dexamethasone vs. Bortezomib Plus Dexamethasone in Patients With Relapsed Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by Onyx Pharmaceuticals:

Primary Outcome Measures:
  • Progression Free Survival [ Time Frame: 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 ] [ Designated as safety issue: No ]

    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.



Secondary Outcome Measures:
  • Overall Survival [ Time Frame: From randomization until the data cut-off date of 10 November 2014; median follow-up time for OS was 11.9 and 12.5 months for each treatment group respectively. ] [ Designated as safety issue: No ]

    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.


  • Overall Response [ Time Frame: 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. ] [ Designated as safety issue: No ]

    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.


  • Duration of Response [ Time Frame: 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. ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With ≥ Grade 2 Peripheral Neuropathy [ Time Frame: 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. ] [ Designated as safety issue: No ]

    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.


  • Percentage of Participants With a Significant Reduction in Left Ventricular Ejection Fraction (LVEF) [ Time Frame: Baseline and 24 weeks ] [ Designated as safety issue: No ]

    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%.


  • Change From Baseline in Right Ventricular Fractional Area Change (FAC) [ Time Frame: 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). ] [ Designated as safety issue: No ]
    Right ventricular function was assessed by measuring fractional area change (FAC) on echocardiogram.

  • Change From Baseline in Pulmonary Artery Systolic Pressure (PASP) [ Time Frame: 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). ] [ Designated as safety issue: No ]
    Pulmonary artery pressure was measured using transthoracic echocardiogram.


Enrollment: 929
Study Start Date: June 2012
Estimated Study Completion Date: December 2018
Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: Carfilzomib
Carfilzomib is administered over 30 minutes as an infusion.
Other Names:
  • PR-171
  • Krypolis
Drug: 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.
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.
Drug: Bortezomib
Bortezomib is administered as a 3-5 second bolus IV injection or SC injection (in accordance with regulatory approval)
Other Name: Velcade
Drug: 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01568866

  Show 241 Study Locations
Sponsors and Collaborators
Onyx Pharmaceuticals
Investigators
Principal Investigator: Hartmut Goldschmidt, MD Universitätsklinik Heidelberg, Heidelberg, Germany
Principal Investigator: Douglas Joshua, BSc, MBBS, DPhil (Oxon), FRACP Royal Prince Alfred Hospital, Camperdown, Australia
Principal Investigator: Philippe Moreau, MD Hôpital Hôtel-Dieu, NANTES Cedex 01, France
Principal Investigator: Robert Orlowski, PhD, MD UT M.D. Anderson Cancer Center, MD Anderson Cancer Center, Houston, Texas
  More Information

Responsible Party: Onyx Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01568866     History of Changes
Other Study ID Numbers: 2011-003  2012-000128-16 
Study First Received: March 28, 2012
Results First Received: November 6, 2015
Last Updated: December 14, 2015
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration
Canada: Health Canada
Austria : Federal Ministry for Labour, Health, and Social Affairs
Austria: Ethikkommission
Australia: Department of Health and Ageing Therapeutic Goods Administration
Australia: Human Research Ethics Committee
Belgium: Ethics Committee
Belgium: Federal Agency for Medicinal Products and Health Products
Brazil: Ethics Committee
Brazil: Ministry of Health
Bulgaria: Ethics committee
Bulgaria: Ministry of Health
Czech Republic: Ethics Committee
Czech Republic: State Institute for Drug Control
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
France: Institutional Ethical Committee
Germany: Ministry of Health
Germany: Ethics Commission
Greece: Ethics Committee
Greece: Ministry of Health and Welfare
Hungary: Institutional Ethics Committee
Hungary: National Institute for Quality and Organizational Development in Healthcare and Medicines
Israel: Ethics Commission
Italy: Ethics Committee
Italy: Ministry of Health
Japan: Institutional Review Board
Japan: Ministry of Health, Labor and Welfare
New Zealand: Ethics Committee
New Zealand: Medsafe
Poland: Ethics Committee
Poland: Ministry of Health
Romania: State Institute for Drug Control
Romania: Ethics Committee
Russia: Ethics Committee
Russia: Ministry of Health of the Russian Federation
Singapore: Health Sciences Authority
Singapore: Institutional Review Board
Slovakia: State Institute for Drug Control
Slovak Republic: Ethics Committee
South Korea: Institutional Review Board
South Korea: Korea Food and Drug Administration (KFDA)
Spain: Spanish Agency of Medicines
Spain: Ethics Committee
Taiwan: Department of Health
Taiwan: Research Ethics Committee
Thailand: Food and Drug Administration
Thailand: Institutional Review Board
Ukraine: Ministry of Health
Ukraine: Ethics Committee
United Kingdom: Medicines and Healthcare Products Regulatory Agency
United Kingdom: Research Ethics Committee

Keywords provided by Onyx Pharmaceuticals:
multiple myeloma
relapsed multiple myeloma

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Blood Protein Disorders
Cardiovascular Diseases
Hematologic Diseases
Hemorrhagic Disorders
Hemostatic Disorders
Immune System Diseases
Immunoproliferative Disorders
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Paraproteinemias
Vascular Diseases
BB 1101
Bortezomib
Dexamethasone
Dexamethasone 21-phosphate
Dexamethasone acetate
Anti-Inflammatory Agents
Antiemetics
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Autonomic Agents
Central Nervous System Agents
Enzyme Inhibitors
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists

ClinicalTrials.gov processed this record on April 27, 2016