A Phase I Study Of Panobinostat/Lenalidomide/Bortezomib/Dex for Relapsed And Relapsed/Refractory Multiple Myeloma

NCT01965353 | Completed Phase 1 DMC

• 1 other identifier: 13-262
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 4

Brief Summary

This research study is evaluating an investigational drug called "panobinostat" (LBH589) in combination with the standard agents lenalidomide, bortezomib, and dexamethasone as a possible treatment for multiple myeloma.

Conditions

Multiple Myeloma in Relapse

Keywords

Relapsed Multiple Myeloma; Relapse-Refractory Multiple Myeloma

Outcome Measures

Primary Outcomes (2)

• MTD (Maximum Tolerated Dose) of panobinostat in combination with RVD

  2 Years

• Recommended dose of the combination for Phase 2 studies in participants with relapsed and relapsed/refractory multiple myeloma (MM) with SC bortezomib.

  2 Years

Secondary Outcomes (3)

• Response to pan-RVD (minimal response or better

  2 Years

• Progression-free survival (PFS)

  2 Years

• Duration of response

  2 Years

Study Arms (1)

Panobinostat

EXPERIMENTAL

Panobinostat - single oral dose on days 1, 3, 5, 8, 10 and 12 and followed by a 9-day rest period. * Bortezomib - subcutaneous injection twice a week during the first two weeks of each 21 day cycle. * Dexamethasone oral dose on the days of and after bortezomib administration during Cycles 1-8, and on days 1, 8 and 15 for Cycles 9 and beyond. * Lenalidomide - oral dose once daily on days 1-14 of each cycle. Accrual to the next higher dose level will not occur until the safety and tolerability of the prior dose level(s) has been determined at the end of the first cycle. Each cycle of treatment will consist of 21 days. Accrual to the next higher dose level will not occur until the safety and tolerability of the prior dose level(s) has been determined at the end of the first cycle

Drug: Panobinostat; Drug: Dexamethasone; Drug: Lenalidomide; Drug: Bortezomib

Interventions

Panobinostat DRUG

\- Panobinostat - single oral dose on days 1, 3, 5, 8, 10 and 12 and followed by a 9-day rest period.

Panobinostat

Dexamethasone DRUG

Dexamethasone - oral dose on Days 1, 2, 4, 5, 8, 9, 11 and 12 followed by a 9-day rest period

Panobinostat

Lenalidomide DRUG

Lenalidomide - daily oral dose on Days 1-14 followed by 7-day rest period

Also known as: Revlimid

Panobinostat

Bortezomib DRUG

Bortezomib - subcutaneous injection, on Days 1, 4, 8, and 11 followed by a 10-day rest period. At least 72 hours should elapse between bortezomib doses, but if needed an interval of 70 hours is permitted

Also known as: Velcade

Panobinostat

Eligibility Criteria

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

You may qualify if:

• Patients must meet the following criteria on screening examination. All laboratory assessments should be performed within 21 days of initiation of protocol therapy unless otherwise specified.
• Participants must have a previous diagnosis of Multiple Myeloma, according to International Myeloma Foundation 2003 Diagnostic Criteria
• Patients must have relapsed or relapsed and refractory disease after receiving 2 or more lines of therapy.
• Relapse is the occurrence of any of the following: 1) \>25% increase in M-protein from the baseline levels; 2) reappearance of M-protein that had disappeared; or 3) definite increase in the size and number of lytic bone lesions recognized on radiographs (compression fractures per se do not constitute a relapse).
• Subjects will be considered refractory to therapy, as defined by progression during treatment or within 60 days after the completion of salvage treatment. Subjects with primary refractory disease are excluded.
• This includes: 1) non-responding, non-progressing; and 2) progressive; primary refractory, progressive disease where patients meet criteria for true progressive disease (Durie 2006).
• Participants must have measurable myeloma, defined as one or more of the following:
• serum M-protein ≥ 0.5 g/dl,
• urine M-protein ≥ 200 mg/24 h, and/or
• serum FLC assay: involved FLC level ≥ 10 mg/dl with abnormal serum FLC ratio.
• Age ≥ 18 years at the time of signing informed consent.
• ECOG performance status \<2 (Karnofsky \>60%)
• Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mlU/mL 10 to14 days prior to therapy and repeated again within 24 hours of starting lenalidomide and must either commit to complete abstinence from heterosexual contact or begin TWO acceptable methods of birth control, one highly effective method and one additional effective (barrier) method, AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must practice complete abstinence or agree to use a condom during sexual contact with a FCBP even if they have had a successful vasectomy. All participants agree to enroll and comply with the RevAssist® program for the prevention of pregnancy.
• A female of childbearing potential is a sexually mature female 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 24 consecutive months
• Ability to understand and the willingness to sign a written informed consent document. Voluntary written informed consent must be obtained before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.

You may not qualify if:

• Participants who exhibit any of the following conditions at screening will not be eligible:
• Participants with primary refractory disease
• Participants who have a history of prior MM treatment with panobinostat, or an alternative HDAC-inhibitor.
• Participant has ≥ Grade 2 peripheral neuropathy on clinical examination within 21 days before initiation of protocol therapy.
• Renal insufficiency, defined as creatinine clearance \< 60 mL/min (either actual or calculated value), within 21 days of initiation of protocol therapy. The Cockcroft-Gault formula should be used for calculating creatinine clearance values: 140-age) x Body mass (kg) x 0.85 (female) or 1.0 (male)/serum creat. (mg/dL) x 72
• Platelet count \<75,000cells/mm3at time of screening evaluation. Transfusion may not be used to meet platelet eligibility criteria within 7 days of obtaining screening evaluation.
• Participants with an absolute neutrophil count (ANC) \< 1500 cells/mm3 at time of screening evaluation. Growth factor may not be used to meet ANC eligibility criteria within 7 days of obtaining screening evaluation.
• Participants with hemoglobin level \< 8.0 g/dL, at time of screening. Transfusion may not be used to meet eligibility criteria within 7 days of obtaining screening evaluation.
• Participants with hepatic impairment, defined as bilirubin \> 1.5 x institutional upper limit of normal (ULN) or AST (SGOT), ALT (SGPT), or alkaline phosphatase \> 2x institutional ULN, within 21 days of initiation of protocol therapy. Patients with benign hyperbilirubinemia (e.g., Gilbert's syndrome) are eligible
• Other ongoing anti-myeloma therapy. Patients may be receiving concomitant therapy with bisphosphonates and low dose corticosteroids (e.g., prednisone up to but no more than 10 mg p.o. q.d. or its equivalent) for symptom management and comorbid conditions. Doses of corticosteroid should be stable for at least 7 days prior to study treatment.)
• Concomitant use of drugs that may cause a prolongation of the QTcF or inducing torsade de pointes if treatment cannot be discontinued or switched to a different medication prior to starting study drug.
• Concomitant use of CYP3A4 inhibitors at time of screening. If use of CYP3A4 inhibitors becomes medically necessary during study, they must be used with caution.
• Anti-myeloma therapy, including radiotherapy, within 2 weeks or within 5 half-lives of the agent and active metabolites (whichever is longer) prior to Day 1 and who have not recovered from side effects (to ≤ Grade 1) of those therapies.
• Known significant cardiac abnormalities, including:
• History or presence of sustained ventricular tachyarrhythmia. (Participants with a history of atrial arrhythmia are eligible but should be discussed with the investigator prior to enrollment).

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Novartis: collaborator

Study Sites (4)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Panobinostat; Dexamethasone; Lenalidomide; Bortezomib

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; 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; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Isoindoles; Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Pyrazines

Study Officials

• Jacob Laubach, MD

  Dana-Farber Cancer Institute

  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: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: October 10, 2013
• First Posted: October 18, 2013
• Study Start: October 1, 2013
• Primary Completion: March 1, 2019
• Study Completion: September 1, 2021
• Last Updated: September 5, 2021

Record last verified: 2021-09

Locations

US (4)