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Combination Therapy of Lenalidomide/Bortezomib/Dexamethasone and Panobinostat in Transplant Eligible New Diagnosed Multiple Myeloma (MM) Patients

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:
NCT01440582
First received: September 22, 2011
Last updated: November 23, 2016
Last verified: November 2016
  Purpose

The goal of this clinical research study is to find the highest tolerable dose of the drug panobinostat that can be given in combination with the drugs Velcade (bortezomib), Revlimid (lenalidomide), and Decadron (dexamethasone) to patients with MM. The safety of this drug combination will also be studied.

Panobinostat is designed to cause chemical changes in different groups of proteins that are attached to DNA (the genetic material of cells), which may slow the growth of cancer cells or cause the cancer cells to die.

Bortezomib is designed to block a protein that causes cells to grow. This may cause cancer cells to die.

Lenalidomide is designed to change the body's immune system. It may also interfere with the development of tiny blood vessels that help support tumor growth. This may slow the growth of cancer cells.

Dexamethasone is a corticosteroid that is similar to a natural hormone made by your body. Dexamethasone is often given to MM patients in combination with other chemotherapy to treat cancer.


Condition Intervention Phase
Myeloma
Drug: Panobinostat
Drug: Bortezomib
Drug: Lenalidomide
Drug: Dexamethasone
Behavioral: Symptom Questionnaire
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/Ib Trial of the Efficacy and Safety of Combination Therapy of Lenalidomide/Bortezomib/Dexamethasone and Panobinostat in Transplant Eligible Patients With Newly Diagnosed Multiple Myeloma (MM)

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) of Panobinostat with Bortezomib, Lenalidomide, and Dexamethasone [ Time Frame: First 21 days of study drug administration (continuous dosing) ] [ Designated as safety issue: Yes ]
    Maximum tolerated dose (MTD) defined as highest dose level in which 6 participants have less than 2 instances of dose limiting toxicities (DLT). Toxicities graded in severity according to guidelines outlined in NCI-CTCAE version 4.0. Hematologic and non-hematologic DLTs defined differently, and will be based on experiences that occur during the first cycle of study drug administration.


Secondary Outcome Measures:
  • Overall Response Rate [ Time Frame: After 8, 28 day cycles ] [ Designated as safety issue: No ]
    Response assessed according to the recently published International Uniform Response Criteria for multiple myeloma established by the International Myeloma Working Group (IMWG; Durie et al 2006).


Enrollment: 77
Study Start Date: February 2013
Estimated Primary Completion Date: February 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Panobinostat + Bortezomib + Lenalidomide + Dexamethasone

Induction Starting Doses: Lenalidomide 25 mg orally daily on days 1-14; Bortezomib 1.3 mg/m^2 intravenous (IV) daily on days 1, 4, 8 and 11; Dexamethasone 20 mg orally daily on days 1, 2, 4, 5, 8, 9, 11, 12 and Panobinostat orally 10 mg on days 1, 3, 5, 8, 10 and 12. Induction therapy consists of 21 day cycle in Part A and 28 day cycle in Part B.

Symptom Questionnaire completed on day 1 of each cycle.

Drug: Panobinostat

Induction Therapy (Part A, 21-day cycles): 10 mg by mouth on Days 1, 3, 5, 8, 10, and 12 for 2 weeks with 1 week of rest at the end of each cycle.

Induction Therapy (Part B, 28-day cycles): 10 mg by mouth on Days 1, 3, 5, 15, 17, and 19 of every cycle.

Maintenance dose (Part A, 28-day cycles): Maximum tolerated dose (MTD) from Induction phase on Days 1, 3, 5, 8, 10, and 12 of each cycle.

Maintenance dose (Part B, 28-day cycles): Maximum tolerated dose (MTD) from Induction phase on Days 1, 3, 5, 15, 17, 19 of each cycle.

Other Name: LBH589B
Drug: Bortezomib

Induction Therapy (Part A, 21-day cycles): 1.3 mg/m^2 by vein daily on days 1, 4, 8 and 11 of Cycles 1 - 8.

Induction Therapy (Part B, 28-day cycles): 1.3 mg/m^2 by vein daily on days 1, 8 and 15 of Cycles 1 - 8.

Other Names:
  • Velcade
  • LDP-341
  • MLN341
  • PS-341
Drug: Lenalidomide

Induction Therapy (Part A, 21-day cycles): 25 mg by mouth daily on days 1-14 of every cycle.

Induction Therapy (Part B, 28-day cycles): 25 mg by mouth daily on days 1-21 of every cycle.

Maintenance dose (Parts A and B, 28-day cycles): Last tolerated dose from Induction Phase on Days 1 - 21 of each cycle.

Other Names:
  • CC-5013
  • Revlimid
Drug: Dexamethasone

Induction Therapy (Part A, 21-day cycles): 20 mg by mouth daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 of Cycles 1 - 8.

Induction Therapy (Part B, 28-day cycles): 20 mg by mouth daily on Days 1, 2, 8, 9, 15 and 16 of Cycles 1-8.

Maintenance dose (Parts A and B, 28-day cycles): Last tolerated dose from Induction Phase on Days 1, 8, 15, 21 of each cycle.

Other Name: Decadron
Behavioral: Symptom Questionnaire
Completed on day 1 of each cycle.
Other Name: Survey

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Clonal bone marrow plasma cells >/=10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events: Myeloma defining events: Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: Hypercalcaemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL) Renal insufficiency: creatinine clearance <40 mL per min† or serum creatinine >177 μmol/L (>2 mg/dL)Anaemia: haemoglobin value of >20 g/L below the lower limit of normal, or a haemoglobin value <100 g/L Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT Any one or more of the following biomarkers of malignancy: Clonal bone marrow plasma cell percentage ≥60% Involved:uninvolved serum free light chain ratio§ ≥100>1 focal lesions on MRI studies.
  2. Continue of Inclusion Criteria 1: If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement. Patient must not have been previously treated with any prior systemic therapy for the treatment of active multiple myeloma. o Prior treatment of hypercalcemia or spinal cord compression with corticosteroids does not disqualify the patient (the dose should not exceed the equivalent of 320 mg of dexamethasone in a 2 week period). o Bisphosphonates are permitted. Prior Therapy for smoldering myeloma is permitted.
  3. Patients treated with local radiotherapy with or without concomitant exposure to steroids, for pain control or management of cord/nerve root compression, are eligible. One week must have lapsed since last date of radiotherapy, which is recommended to be a limited field and from start of protocol therapy. . Patients who require concurrent radiotherapy should have entry to the protocol deferred until the radiotherapy is completed and one week have passed since the last date of therapy and from start of protocol therapy. .
  4. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
  5. Females of childbearing potential (FCBP)† must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL 10-14 days prior to therapy and repeated again within 24 hours of starting lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy.
  6. Age > / = 18 years at the time of signing Informed Consent.
  7. Patients must meet the following laboratory criteria: absolute neutrophil count (ANC) >/= 1.5 x 10^9/L (growth factors not permitted to make eligible) , Hemoglobin >/= 9 g/dl (transfusion permitted) , Platelets >/= 100 x 10^9/L , Aspartate transaminase (AST) and Alanine transaminase (ALT) </= 2.5 x upper limits of normal (ULN) , Serum bilirubin </= 1.5 x ULN
  8. Baseline Multi Gated Acquisition Scan (MUGA) or echocardiogram (ECHO) must demonstrate LVEF >/= 50%
  9. All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®.
  10. Eastern Cooperative Oncology Group (ECOG) Performance Status of </= 2
  11. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin).

Exclusion Criteria:

  1. Patient has >/=Grade 2 peripheral neuropathy on clinical examination within 28 days of signing consent.
  2. Renal insufficiency Creatinine > 2.5 mg/dl
  3. Myocardial infarction within 6 months prior to signing consent or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any Electrocardiograph (ECG) abnormality at screening has to be documented by the investigator as not medically relevant.
  4. Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first panobinostat treatment.
  5. Impaired cardiac function or clinically significant cardiac diseases, including any one of the following: History or presence of sustained ventricular tachyarrhythmia; Any history of ventricular fibrillation or torsade de pointes; Bradycardia defined as HR< 50 bpm. Patients with pacemakers are eligible if heart rate (HR) >/= 50 bpm. Screening ECG with a QTcF > 450 msec, Right bundle branch block + left anterior hemiblock (bifascicular block) , Patients with myocardial infarction or unstable angina </= 6 months prior to starting study drug , Other clinically significant heart disease (e.g., congestive heart failure (CHF) New York Heart Association class III or IV , uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
  6. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of panobinostat
  7. Patients with diarrhea > Common Terminology Criteria for Adverse Events (CTCAE version 4) grade 2 at the time of signing consent
  8. Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes or active or uncontrolled infection) including abnormal laboratory values, that could cause unacceptable safety risks or compromise compliance with the protocol
  9. Patients using medications that have a relative risk of prolonging the QT interval or inducing torsade de pointes if treatment cannot be discontinued or switched to a different medication prior to starting study drug
  10. Female subject is pregnant or breast-feeding.
  11. Hypersensitivity to acyclovir or similar anti-viral drug
  12. Hypersensitivity to boron or mannitol, or compounds containing these components
  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: NCT01440582

Locations
United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Novartis
Investigators
Principal Investigator: Jatin J. Shah, MD M.D. Anderson Cancer Center
  More Information

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT01440582     History of Changes
Other Study ID Numbers: 2011-0192  NCI-2015-01566 
Study First Received: September 22, 2011
Last Updated: November 23, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by M.D. Anderson Cancer Center:
Myeloma
Multiple Myeloma
MM
Newly diagnosed
Transplant eligible
Panobinostat
LBH589B
Bortezomib
Velcade
LDP-341
MLN341
PS-341
Lenalidomide
CC-5013
Revlimid
Dexamethasone
Decadron
Symptom questionnaire
Survey

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
Lenalidomide
Panobinostat
Thalidomide
Bortezomib
BB 1101
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones

ClinicalTrials.gov processed this record on December 09, 2016