Carfilzomib, Pegylated Liposomal Doxorubicin Hydrochloride, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma

This study is currently recruiting participants.
Verified April 2014 by Washington University School of Medicine
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT01246063
First received: November 15, 2010
Last updated: April 4, 2014
Last verified: April 2014
  Purpose

The aim of this phase I/II trial is to determine the maximal tolerated dose (MTD) of carfilzomib together with pegylated liposomal doxorubicin hydrochloride (PLD) with or without dexamethasone, and then to establish the efficacy and safety of this novel combination in patients with relapsed or refractory multiple myeloma


Condition Intervention Phase
Multiple Myeloma
Drug: carfilzomib
Drug: pegylated liposomal doxorubicin (PLD)
Drug: Dexamethasone
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Trial of Carfilzomib, Pegylated Liposomal Doxorubicin, and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • To determine the MTD of carfilzomib and PLD with and without dexamethasone (Phase I - Part 1). [ Time Frame: 28 days (completion of first cycle) ] [ Designated as safety issue: Yes ]
    MTD is the maximum dose level tested unless dose limiting toxicity (DLT) are observed during Cycle 1. If DLT is observed, MTD will be the next lower dose level.

  • Phase 2 - To evaluate the efficacy of carfilzomib in combination with PLD and dexamethasone [ Time Frame: Up to 12 cycles of treatment. ] [ Designated as safety issue: Yes ]
    Proportion of confirmed tumor responses. A confirmed response is defined to be a CR, VGPR, or PR.

  • To determine the MTD of carfilzomib and PLD with and without dexamethasone (Phase I - Part 2). [ Time Frame: 28 days (completion of first cycle) ] [ Designated as safety issue: Yes ]
    MTD is the maximum dose level tested unless dose limiting toxicity (DLT) are observed during Cycle 1. If DLT is observed, MTD will be the next lower dose level.

  • Phase 2 - To evaluate the toxicity of carfilzomib in combination with PLD and dexamethasone [ Time Frame: 30 days after completion of treatment ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Survival time [ Time Frame: 18 months after removal from study or until death, whichever occurs first ] [ Designated as safety issue: No ]
  • Progression-free survival time [ Time Frame: 18 months after removal from study or until death, whichever occurs first ] [ Designated as safety issue: No ]
  • Duration of overall response [ Time Frame: 18 months after removal from study or until death, whichever occurs first ] [ Designated as safety issue: No ]
    For participants with confirmed tumor responses.


Estimated Enrollment: 53
Study Start Date: May 2012
Estimated Study Completion Date: November 2015
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase I - Part 1

Dose Level 0: Carfilzomib IV (20 mg/m2) D1&D2 of C1 and carfilzomib IV (27 mg/m2)D8, D9, D15, D16 of C1. Carfilzomib IV (27 mg/m2) D1, D2, D8, D9, D15, D16 C2. Carfilzomib IV (27 mg/m2)D1, D2, D8, D15, D22 C3-6. PLD IV (30 mg/m2)D8 C1-6.

Dose Level 1: Carfilzomib IV (20 mg/m2) D1&D2 of C1 and carfilzomib IV (36 mg/m2)D8, D9, D15, D16 of C1. Carfilzomib IV (36 mg/m2) D1, D2, D8, D9, D15, D16 C2. Carfilzomib IV (36 mg/m2)D1, D2, D8, D15, D22 C3-6. PLD IV (30 mg/m2)D8 C1-6.

Dose Level 2: Carfilzomib IV (20 mg/m2) D1&D2 of C1 and carfilzomib IV (45 mg/m2)D8, D9, D15, D16 of C1. Carfilzomib IV (45 mg/m2) D1, D2, D8, D9, D15, D16 C2. Carfilzomib IV (45 mg/m2)D1, D2, D8, D15, D22 C3-6. PLD IV (30 mg/m2)D8 C1-6.

Dose Level 3: Carfilzomib IV (20 mg/m2) D1&D2 of C1 and carfilzomib IV (56 mg/m2)D8, D9, D15, D16 of C1. Carfilzomib IV (56 mg/m2) D1, D2, D8, D9, D15, D16 C2. Carfilzomib IV (56 mg/m2)D1, D2, D8, D15, D22 C3-6. PLD IV (30 mg/m2)D8 C1-6.

Drug: carfilzomib
Other Names:
  • Kyprolis
  • CFZ
Drug: pegylated liposomal doxorubicin (PLD)
Other Name: DOXIL
Experimental: Phase I - Part 2

Dose Level 0: Carfilzomib IV (MTD - Phase 1 Part 1) D1, D2, D8, D9, D15, D16 C1-6. Carfilzomib IV (MTD - Phase 1 Part 1) D1, D8, D15, D22 C7 and subsequent cycles. PLD IV (MTD - Phase 1 Part 1) D8 of each cycle. Dexamethasone 20 mg IV or PO same schedule as carfilzomib.

Dose Level 1: Carfilzomib IV (1 dose level above MTD) D1, D2, D8, D9, D15, D16 C1-6. Carfilzomib IV (1 dose level above MTD) D1, D8, D15, D22 C7 and subsequent cycles. PLD IV (1 dose level above MTD) D8 of each cycle. Dexamethasone 20 mg IV or PO same schedule as carfilzomib.

Dose Level 2: Carfilzomib IV (2 dose levels above MTD) D1, D2, D8, D9, D15, D16 C1-6. Carfilzomib IV (2 dose levels above MTD) D1, D8, D15, D22 C7 and subsequent cycles. PLD IV (2 dose levels above MTD) D8 of each cycle. Dexamethasone 20 mg IV or PO same schedule as carfilzomib.

Drug: carfilzomib
Other Names:
  • Kyprolis
  • CFZ
Drug: pegylated liposomal doxorubicin (PLD)
Other Name: DOXIL
Drug: Dexamethasone
Other Name: Decadron
Experimental: Phase 2
Carfilzomib IV (MTD - Phase 1 Part 2) D1, D2, D8, D9, D15, D16 C1-6. Carfilzomib IV (MTD - Phase 1 Part 2) D1, D8, D15, D22 C7 and subsequent cycles. PLD IV (MTD - Phase 1 Part 2) D8 of each cycle. Dexamethasone 20 mg IV or PO same schedule as carfilzomib.
Drug: carfilzomib
Other Names:
  • Kyprolis
  • CFZ
Drug: pegylated liposomal doxorubicin (PLD)
Other Name: DOXIL
Drug: Dexamethasone
Other Name: Decadron

Detailed Description:

Phase I dose-escalation study. Patients receive carfilzomib intravenously (IV) on Days 1, 2, 8, 9, 15, and 16 of Cycles 1-6, and on Days 1, 8, 15, and 22 beginning on Cycle 7 until disease progression or relapse. Participants treated prior to approval of Amendment 1 will have carfilzomib administered on Days 1, 2, 8, 9, 15, and 16 during Cycles 1 and 2 and on Days 1, 8, 15, and 22 beginning on Cycle 3. PLD will be administered on Day 8 during Cycles 1-6. Dexamethasone will be administered on the same schedule as carfilzomib (for patients treated in part 2 of phase 1 or phase 2). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Phase II will use the MTD from Phase I.

  Eligibility

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

Inclusion Criteria:

  • Histologically confirmed diagnosis of multiple myeloma with a measurable disease parameter at time of screening; a measurable disease parameter is defined as one or more of the following:

    • Serum monoclonal protein >= 0.5 g/dl
    • 24 hour urine monoclonal protein >= 0.2 g/24 hour
    • Serum free light chain ratio > 5 x normal ratio with an absolute difference of 10mg/dl between the involved and uninvolved free light chain
    • Soft tissue plasmacytoma >= 2 cm measurable by either physical examination and/or applicable radiographs (e.g. magnetic resonance imaging [MRI], computed tomography [CT], etc)
    • Bone Marrow Plasma Cells >= 30%
  • Documentation of at least one line of prior myeloma therapy now with relapsed or refractory disease requiring re-treatment
  • At least 18 years of age at the time of signing the informed consent.
  • Performance status of Eastern Cooperative Oncology Group (ECOG) =< 2 or Karnofsky >= 60%; participants with lower performance status based solely on bone pain secondary to multiple myeloma will be eligible
  • Required laboratory values

    • Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) and aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) < 2.5 x the upper limit of the institutional normal value (ULN)
    • Total bilirubin =< 1.5 x upper limit of normal (ULN)
    • Absolute neutrophil count (ANC) >= 1,000
    • Hemoglobin >= 8 g/dl
    • Platelets >= 50,000
    • Creatinine clearance > 15 ml/minute using Cockcroft-Gault formula
    • For those participants receiving warfarin (Coumadin), unfractionated heparin, or low-molecular weight heparin therapy, the applicable coagulation parameter that is being monitored must be within the accepted therapeutic ranges for those indications
    • Transfusions and/or growth factor dependent participants are not excluded if the above parameters can be achieved with such support
  • Females of childbearing potential (FCBP) must agree to refrain from becoming pregnant while on study drug and for 3 months after discontinuation from study drug, and must agree to use adequate contraception including hormonal contraception, (i.e. birth control pills, etc), barrier method contraception (i.e. condoms), or abstinence during that time frame; FCBP must agree to regular pregnancy testing during this timeframe; inclusion of FCBP requires two negative pregnancy tests prior to enrollment. All women, regardless of age, should be considered FCBP unless they are surgically sterile (post hysterectomy, post bilateral oophorectomy, etc) or have been naturally post menopausal for >= 24 consecutive months
  • Men engaging in sexual intercourse with a FCBP must agree to use adequate contraception including hormonal contraception, (i.e. birth control pills, etc), barrier method contraception (i.e. condoms), or abstinence while on study drug and for 3 months after discontinuation from study drug
  • Ability to understand and willing to sign a written informed consent document

Exclusion Criteria:

  • POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
  • Plasma Cell Leukemia
  • Waldenstrom's macroglobulinemia
  • Pregnant or lactating females
  • Use of any anti-myeloma drug therapy within 14 days of initiation of study drug treatment excluding corticosteroids if given for an indication other than myeloma; bisphosphonates are not considered anti-myeloma drugs
  • Participation in an investigational therapeutic study within 14 days or within 5 drug half-lives (t1/2) prior to first dose, whichever time is greater
  • Radiotherapy to multiple sites or immunotherapy within 14 days before start of protocol treatment (localized radiotherapy to a single site at least 7 days before start is permissible)
  • Major surgery within 14 days prior to first dose
  • Participants in whom the required program of oral (PO) and IV fluid hydration is contraindicated
  • Prior history of a hypersensitivity reaction to PLD, doxorubicin, bortezomib, carfilzomib, or liposomal drug formulations other than PLD; history of reactions to liposomal drug formulations other than PLD should be evaluated individually and if their reactions were felt to have been due to the encapsulated agent, rather than the liposomal component itself they should be excluded at the discretion of the investigators
  • Participants who are known to have active hepatitis A, B, or C viral infection may not participate in this study; active disease is defined as participants with a known viral hepatitis whose liver function tests are elevated
  • Known human immunodeficiency virus (HIV)-seropositive and are taking anti-retrovirals may not participate in this study; participants who are HIV-seropositive and not on anti-retroviral therapy and who otherwise meet the inclusion/exclusion criteria will be eligible for the study
  • Compromised cardiovascular function defined as any of the following:

    • Electrocardiogram (EKG) evidence of acute ischemia
    • EKG evidence of medically significant conduction system abnormalities
    • History of myocardial infarction within the last 6 months
    • Unstable angina pectoris or cardiac arrhythmia
    • History of Class 3 or Class 4 New York Heart Association Congestive Heart Failure within 6 months of enrollment on study
    • Left ventricular ejection fraction (LVEF) < 45% by either echocardiography or radionuclide-based multiple gated acquisition (Echo or MUGA)
  • Uncontrolled concurrent illness including: other hematologic or non-hematologic malignancy, active infection, or uncontrolled diabetes
  • Any significant psychological, medical, or surgical condition thought to compromise the participant, the study, or prevent informed consent
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01246063

Locations
United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Ravi Vij, M.D.    314-454-8304    rvij@dom.wustl.edu   
Principal Investigator: Ravi Vij, M.D.         
Sub-Investigator: Camille Abboud, M.D.         
Sub-Investigator: Amanda Cashen, M.D.         
Sub-Investigator: John DiPersio, M.D., Ph.D.         
Sub-Investigator: Timothy Graubert, M.D.         
Sub-Investigator: Keith Stockerl-Goldstein, M.D.         
Sub-Investigator: Michael Tomasson, M.D.         
Sub-Investigator: Geoffrey Uy, M.D         
Sub-Investigator: Matthew Walter, M.D.         
Sub-Investigator: Peter Westervelt, M.D., Ph.D.         
Sponsors and Collaborators
Washington University School of Medicine
Investigators
Principal Investigator: Ravi Vij, M.D. Washington University School of Medicine
  More Information

Additional Information:
No publications provided

Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT01246063     History of Changes
Other Study ID Numbers: 201102043, NCI-2011-00224
Study First Received: November 15, 2010
Last Updated: April 4, 2014
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Additional relevant MeSH terms:
Doxorubicin
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Dexamethasone
Dexamethasone 21-phosphate
BB 1101
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents
Gastrointestinal Agents
Glucocorticoids
Hormones

ClinicalTrials.gov processed this record on April 14, 2014