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

NCT01440582 | Completed Phase 1 FDA Drug

• 2 other identifiers: 2011-0192NCI-2015-01566
• Study Type: interventional
• Target: 77
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Myeloma

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD) of Panobinostat with Bortezomib, Lenalidomide, and Dexamethasone

  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.

  First 21 days of study drug administration (continuous dosing)

Secondary Outcomes (1)

• Overall Response Rate

  After 8, 28 day cycles

Study Arms (1)

Panobinostat + Bortezomib + Lenalidomide + Dexamethasone

EXPERIMENTAL

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; Drug: Bortezomib; Drug: Lenalidomide; Drug: Dexamethasone; Behavioral: Symptom Questionnaire

Interventions

Panobinostat DRUG

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.

Also known as: LBH589B

Panobinostat + Bortezomib + Lenalidomide + Dexamethasone

Bortezomib DRUG

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.

Also known as: Velcade, LDP-341, MLN341, PS-341

Panobinostat + Bortezomib + Lenalidomide + Dexamethasone

Lenalidomide DRUG

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.

Also known as: CC-5013, Revlimid

Panobinostat + Bortezomib + Lenalidomide + Dexamethasone

Dexamethasone DRUG

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.

Also known as: Decadron

Panobinostat + Bortezomib + Lenalidomide + Dexamethasone

Symptom Questionnaire BEHAVIORAL

Completed on day 1 of each cycle.

Also known as: Survey

Panobinostat + Bortezomib + Lenalidomide + Dexamethasone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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. .
• 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.
• 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.
• Age \> / = 18 years at the time of signing Informed Consent.
• 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
• Baseline Multi Gated Acquisition Scan (MUGA) or echocardiogram (ECHO) must demonstrate LVEF \>/= 50%
• All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of \</= 2
• Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin).

You may not qualify if:

• Patient has \>/=Grade 2 peripheral neuropathy on clinical examination within 28 days of signing consent.
• Renal insufficiency Creatinine \> 2.5 mg/dl
• 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.
• Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first panobinostat treatment.
• 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)
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of panobinostat
• Patients with diarrhea \> Common Terminology Criteria for Adverse Events (CTCAE version 4) grade 2 at the time of signing consent
• 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
• 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
• Female subject is pregnant or breast-feeding.
• Hypersensitivity to acyclovir or similar anti-viral drug
• Hypersensitivity to boron or mannitol, or compounds containing these components

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• Novartis: collaborator

Study Sites (1)

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Manasanch EE, Shah JJ, Lee HC, Weber DM, Thomas SK, Amini B, Feng L, Berkova Z, Hildebrandt M, Orlowski RZ. Bortezomib, lenalidomide, and dexamethasone with panobinostat for front-line treatment of patients with multiple myeloma who are eligible for transplantation: a phase 1 trial. Lancet Haematol. 2018 Dec;5(12):e628-e640. doi: 10.1016/S2352-3026(18)30174-1.

  PMID: 30501870 DERIVED

Related Links

• University of Texas MD Anderson Cancer Center Website

MeSH Terms

Conditions

Neoplasms, Plasma Cell; Multiple Myeloma

Interventions

Panobinostat; Bortezomib; Lenalidomide; Dexamethasone; Calcium Dobesilate; Surveys and Questionnaires

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Hydroxamic Acids; Hydroxylamines; Amines; Organic Chemicals; Hydroxy Acids; Carboxylic Acids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Pyrazines; Heterocyclic Compounds, 1-Ring; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Piperidones; Piperidines; Isoindoles; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Data Collection; Epidemiologic Methods; Investigative Techniques; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health

Study Officials

• Elisabet E. Manasanch, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 22, 2011
• First Posted: September 26, 2011
• Study Start: February 18, 2013
• Primary Completion: February 28, 2019
• Study Completion: February 28, 2019
• Last Updated: March 4, 2019

Record last verified: 2019-03

Locations

US (1)