Pegylated Liposomal Doxorubicin, Bortezomib, Dexamethasone and Lenalidomide for Relapsed/Refractory Multiple Myeloma

This study has been completed.
Sponsor:
Collaborator:
Celgene Corporation
Information provided by (Responsible Party):
Oncotherapeutics
ClinicalTrials.gov Identifier:
NCT01160484
First received: July 7, 2010
Last updated: March 24, 2014
Last verified: March 2014
  Purpose

This is a phase II, multicenter, open label, nonrandomized study to evaluate the efficacy and safety of lenalidomide at a dose of 10 mg/dose in combination with bortezomib at 1.0 mg/m2/dose, pegylated liposomal doxorubicin (PLD) at 4.0 mg/m2/dose, and intravenous (IV) dexamethasone at 40 mg/dose in adult patients with relapsed/refractory multiple myeloma (MM). The study consists of a screening period, followed by up to eight 28 day open label treatment cycles, a final assessment to occur 28 days after the end of the last treatment cycle, and a follow-up period.


Condition Intervention Phase
Multiple Myeloma
Drug: DVD-R
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Pegylated Liposomal Doxorubicin, Bortezomib, Dexamethasone and Lenalidomide (DVD-R) for Patients With Relapsed/Refractory Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by Oncotherapeutics:

Primary Outcome Measures:
  • International Myeloma Working Group (IMWG) Response Criteria [ Time Frame: Up to 7.5 months (eight 28-day cycles) ] [ Designated as safety issue: No ]
    The investigator will evaluate each patient for response to therapy according to criteria augmented from those developed by Bladé et al., 1998 presented below (Table 7-1). Assessment of disease response will be performed prior to drug administration on Day 1 of Cycles 2 8 and at the End of Study Treatment visit. If a patient is determined to have complete response (CR), very good partial response (VGPR), partial response (PR), or minor response (MR), then assessment of disease response is to be performed 4 weeks later to confirm the response.


Secondary Outcome Measures:
  • Time to First Response [ Time Frame: Up to 7.5 months (eight 28-day cycles) ] [ Designated as safety issue: No ]
  • Time to Best Response [ Time Frame: Up to 7.5 months (eight 28-day cycles) ] [ Designated as safety issue: No ]
  • Duration of Response [ Time Frame: First evidence of PR or better (for overall response) and MR or better (for clinical benefit response) to start of disease progression or death. ] [ Designated as safety issue: No ]
  • Time to Progression [ Time Frame: Time from the start of treatment to progressive disease ] [ Designated as safety issue: No ]
  • Progression-free Survival [ Time Frame: Time from the start of treatment to progressive disease or until death ] [ Designated as safety issue: No ]
  • Follow-up Time [ Time Frame: Follow-up visits for disease progression and overall survival every 3 months after study discontinuation. After progression, follow-up visits for survival status every 6 months or until alternate therapy needs to be started or death intervenes ] [ Designated as safety issue: No ]
    time that patients were monitored for disease progression and overall survival


Enrollment: 40
Study Start Date: September 2009
Study Completion Date: February 2012
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: DVD-R single arm

Dose schematic of Dexamethasone + Bortezomib + Pegylated Liposomal Doxorubicin + Lenalidomide (DVD-R) Therapy:

Dexamethasone*- 40 mg IV Bortezomib**- 1.0 mg/m2 IV Push Pegylated Liposomal Doxorubicin*- 4.0 mg/m2 IV Lenalidomide***- 10 mg PO

Per 28 Day Cycle

  • Intravenous infusion (IV) Days 1, 4, 8 and 11 ** Intravenous push (IVP) Days 1, 4, 8 and 11 *** Per Orem (PO) Days 1-14
Drug: DVD-R
40 mg dexamethasone will be administered IV on Days 1, 4, 8, and 11 of each cycle. 1.0 mg/m2 Bortezomib will be administered IV over 3 to 5 seconds followed by a standard saline flush, on Days 1, 4, 8, and 11 immediately following the dexamethasone infusion. 4.0 mg/m2 PLD will be given as a 90 minute infusion on Day 1 of Cycle 1 and subsequent doses may be administered over 30 to 60 minutes on Days 4, 8 and 11 of Cycle 1 and on Days 1, 4, 8, and 11 of each subsequent cycle, following the bortezomib administration. 10 mg/day lenalidomide will be administered PO on days 1-14 of a 28-day treatment cycle, followed by a 14-day rest period, following the PLD administration.
Other Name: Decadron, Velcade, Doxil, Revlimid

Detailed Description:

Studies have shown that combinations of PLD and bortezomib have striking synergy in preclinical studies and impressive response rates (73 & 89%) in early clinical trials for MM patients with relapsed/refractory disease as well as first-line therapy. In addition, the efficacy of PLD with bortezomib in anthracycline-insensitive patients has been greater than single-agent bortezomib when comparing across studies. The immunomodulatory drugs, thalidomide and lenalidomide, target the tumor cell microenvironment, are antiangiogenic, have an immune activation effect and also exert a direct cytotoxic effect on myeloma cells. A phase 1 clinical study by our group also demonstrated that low dose PLD, administered at a more frequent dosing schedule, in combination with bortezomib, and dexamethasone (DVD regimen) is well tolerated and associated with high response rates and durable responses. In this phase II prospective trial, we will evaluate this regimen and show that this change enhances the DVD-R regimen's safety and efficacy for patients with relapsed/refractory MM.

  Eligibility

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

Inclusion Criteria:

  1. Has a diagnosis of multiple myeloma (MM) based on standard criteria (Durie 1986)
  2. Currently has MM with measurable disease (serum m protein > 1.0g/dl and/or 24 hr urine m protein > 200mg/24 hr)
  3. Currently has progressive MM that has relapsed or is refractory
  4. Voluntarily signed an informed consent
  5. Age 18 years
  6. Eastern Cooperative Oncology Group (ECOG) performance < 2
  7. Life-expectancy > 3 months
  8. Laboratory test results within these ranges:

    • Absolute neutrophil count (ANC) 1.5 x 109/L; if the bone marrow is extensively infiltrated (> 70% plasma cells) then 1.0 x 109/L
    • Platelet count 75 x 109/L; if the bone marrow is extensively infiltrated (> 70% plasma cells) then 50 x 109/L
    • Hg > 8 g/dL
    • Calculated or measured creatinine clearance > 30 mL/minute.
    • Total bilirubin 2.0 x upper limit of normal (ULN)
    • Aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) 3 x ULN or 5 x ULN if hepatic metastases are present
    • Serum potassium within the normal range
  9. Disease free of prior malignancies for 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast
  10. Registered into the mandatory RevAssist® program, willing and able to comply with the requirements of RevAssist®.
  11. Females of childbearing potential must have a negative serum or urine pregnancy test and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control.
  12. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to acetylsalicylic acid (ASA) may use warfarin or low molecular weight heparin)

Exclusion Criteria:

  1. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes syndrome
  2. Plasma cell leukemia
  3. Grade 2 peripheral neuropathy within 14 days before enrollment
  4. Impaired cardiac function or clinically significant cardiac diseases, including myocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) Class II or greater heart failure, Uncontrolled angina, clinically significant pericardial disease, severe uncontrolled ventricular arrhythmias, echocardiogram or Multigated acquisition(MUGA) scan evidence of left ventricular ejection fraction (LVEF) below institutional normal within 28 days prior to enrollment, electrocardiographic (ECG) evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.
  5. Severe hypercalcemia, i.e., serum calcium 12 mg/dL (3.0 mmol/L) corrected for albumin
  6. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form
  7. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
  8. Undergone major surgery within 28 days prior enrollment or has not recovered from side effects of such therapy (Kyphoplasty is not considered to be a major surgery; however, the investigator is to discuss enrollment of a patient with a recent history of kyphoplasty with the medical monitor).
  9. Pregnant or breast feeding females. (Lactating females must agree not to breast feed while taking lenalidomide)
  10. Received the following prior therapy:

    • Chemotherapy within 3 weeks of enrollment (6 wks for nitrosoureas)
    • Corticosteroids (>10 mg/day prednisone or equivalent) within 3 weeks of enrollment
    • Immunotherapy or antibody therapy as well as thalidomide, lenalidomide, arsenic trioxide or bortezomib within 21 days before enrollment
    • Radiation therapy within 28 days before enrollment, except localized radiation therapy
    • Use of any other experimental drug or therapy within 28 days of enrollment
  11. Known hypersensitivity to compounds of similar to thalidomide, doxorubicin, bortezomib, boron or mannitol.
  12. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs
  13. Concurrent use of other anti-cancer agents or treatments
  14. Known positivity for human immunodeficiency virus (HIV) or hepatitis B or C; baseline testing for HIV and hepatitis B or C is not required
  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: NCT01160484

Locations
United States, California
Comprehensive Blood and Cancer Center
Bakersfield, California, United States, 93309
Hematology-Oncology Medical Group of Fresno, Inc.
Fresno, California, United States, 93720
Loma Linda University
Loma Linda, California, United States, 92354
Santa Barbara Hematology Oncology
Santa Barbara, California, United States, 93105
James R. Berenson, M.D., Inc.
West Hollywood, California, United States, 90069
United States, Florida
Watson Clinic, LLP, Center for Care and Research
Lakeland, Florida, United States, 33805
United States, New York
Bassett Cancer Institute
Cooperstown, New York, United States, 13326
Broome Oncology
Johnson City, New York, United States, 13790
Sponsors and Collaborators
Oncotherapeutics
Celgene Corporation
Investigators
Principal Investigator: James R. Berenson, MD James R. Berenson, MD, Inc.
  More Information

Publications:
Responsible Party: Oncotherapeutics
ClinicalTrials.gov Identifier: NCT01160484     History of Changes
Other Study ID Numbers: RV-MM-PI-0533
Study First Received: July 7, 2010
Results First Received: January 10, 2014
Last Updated: March 24, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Oncotherapeutics:
multiple myeloma
refractory
relapsed
bortezomib
doxil

Additional relevant MeSH terms:
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
Bortezomib
Lenalidomide
Doxorubicin
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

ClinicalTrials.gov processed this record on July 23, 2014