Recruitment

Recruitment Status
Completed
Estimated Enrollment
28

Inclusion Criterias

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
Age ≥ 18 years at the time of signing informed consent.
...
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
Age ≥ 18 years at the time of signing informed consent.
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.
urine M-protein ≥ 200 mg/24 h, and/or
serum M-protein ≥ 0.5 g/dl,
serum FLC assay: involved FLC level ≥ 10 mg/dl with abnormal serum FLC ratio.
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.
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.
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).
Participants must have a previous diagnosis of Multiple Myeloma, according to International Myeloma Foundation 2003 Diagnostic Criteria
ECOG performance status <2 (Karnofsky >60%)
This includes: 1) non-responding, non-progressing; and 2) progressive; primary refractory, progressive disease where patients meet criteria for true progressive disease (Durie 2006).

Exclusion Criterias

Any condition, including laboratory abnormalities, that in the opinion of the investigator places the subject at unacceptable risk if he/she were to participate in the study.
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.
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).
...
Any condition, including laboratory abnormalities, that in the opinion of the investigator places the subject at unacceptable risk if he/she were to participate in the study.
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.
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).
Participants receiving any other investigational agents.
Known intolerance to steroid therapy
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.
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.)
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.
Any history of ventricular fibrillation or torsade de pointes
QTcF interval ≥ 450 milliseconds on screening ECG;
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
Participants who have had prior allogeneic stem cell transplantation with evidence of active graft-versus-host disease requiring immunosuppressive therapy
POEMS syndrome or AL Amyloidoses
Participants with any significant history of non-compliance to medical regimens or unwilling or unable to comply with the instructions given to him/her by the study staff.
Impairment of GI function or GI disease that may significantly alter the absorption of panobinostat.
Poor tolerability or known allergy to any of the study drugs or compounds of similar chemical or biologic composition to lenalidomide, bortezomib, panobinostat and/or dexamethasone.
Female participants pregnant or breast-feeding.
Right bundle branch block + left anterior hemiblock (bifascicular block)
Participants with myocardial infarction or unstable angina ≤ 6 months prior to starting study drug.
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.
Participants with primary refractory disease
Other clinically significant heart disease (e.g. CHF NY Heart Association class III or IV, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
Participant has ≥ Grade 2 peripheral neuropathy on clinical examination within 21 days before initiation of protocol therapy.
Known hypersensitivity to acyclovir or similar anti-viral drug
Prior malignancy (within the last 5 years) except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer
Serious, intercurrent illness including, but not limited to, clinically relevant active infection, known active hepatitis B or C viral infection, known HIV infection, uncontrolled diabetes mellitus, or serious co-morbid medical conditions such as chronic restrictive pulmonary disease, and cirrhosis.
Participants who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of the surgery.
Known significant cardiac abnormalities, including:
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.
Bradycardia defined as HR < 50 bpm. Participants with pacemakers are eligible if HR ≥ 50 bpm
Participants who have a history of prior MM treatment with panobinostat, or an alternative HDAC-inhibitor.
Participants with diarrhea > CTCAE grade 2
Participants who exhibit any of the following conditions at screening will not be eligible:
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
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.
Participants with known brain metastases.

Summary

Conditions
Multiple Myeloma in Relapse
Type
Interventional
Phase
Phase 1
Design
  • Allocation: N/A
  • Intervention Model: Single Group Assignment
  • Masking: None (Open Label)
  • Primary Purpose: Treatment

Participation Requirements

Age
Between 18 years and 125 years
Gender
Both males and females

Description

In this research study, the participant will be given a study drug-dosing diary for each treatment cycle. Each treatment cycle lasts 21 days (3 weeks) . The diary will also include special instructions for taking the study drug(s). The investigator are looking for the highest dose of the study drug ...

In this research study, the participant will be given a study drug-dosing diary for each treatment cycle. Each treatment cycle lasts 21 days (3 weeks) . The diary will also include special instructions for taking the study drug(s). The investigator are looking for the highest dose of the study drug that can be administered safely without severe or unmanageable side effects in participants that have multiple myeloma, not everyone who participates in this research study will receive the same dose of the study drug. The dose each participant will get will depend on the number of participants who have been enrolled in the study before each participant and how well they have tolerated their doses. Each treatment cycle will be 21 days long. The participant will have to come to the clinic on days 1, 4, 5, 8, 10 and 11 in Cycle 1 and on days 1, 4, 8 and 11 in Cycles 2 and beyond. Days 1 and 5 of Cycle 1 will take about 8 hours. Every other visit should take about 1-4 hours, however there is always the possibility that it could take longer. Study Drugs: Panobinostat is a capsule that the participant will take three times a week for the first two the weeks of each cycle. Then participant will have one week off study medication. Bortezomib will be administered in clinic as a subcutaneous injection twice a week during the first two weeks of each 21 day cycle. Lenalidomide will be taken orally once daily on days 1-14 of each cycle. Dexamethasone will be taken orally on the days of and after bortezomib administration during Cycles 1-8, and on days 1, 8 and 15 for Cycles 9 and beyond. Planned Follow-up: The investigators would like to monitor the participant's medical condition even after the participants are no longer participating in the study. The investigators would like to do this by calling the participants on the telephone once every 6 months to see how the participant is doing. Keeping in touch with the participant and checking on their condition helps the investigator look at the long-term effects of the research study.

Inclusion Criterias

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
Age ≥ 18 years at the time of signing informed consent.
...
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
Age ≥ 18 years at the time of signing informed consent.
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.
urine M-protein ≥ 200 mg/24 h, and/or
serum M-protein ≥ 0.5 g/dl,
serum FLC assay: involved FLC level ≥ 10 mg/dl with abnormal serum FLC ratio.
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.
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.
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).
Participants must have a previous diagnosis of Multiple Myeloma, according to International Myeloma Foundation 2003 Diagnostic Criteria
ECOG performance status <2 (Karnofsky >60%)
This includes: 1) non-responding, non-progressing; and 2) progressive; primary refractory, progressive disease where patients meet criteria for true progressive disease (Durie 2006).

Exclusion Criterias

Any condition, including laboratory abnormalities, that in the opinion of the investigator places the subject at unacceptable risk if he/she were to participate in the study.
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.
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).
...
Any condition, including laboratory abnormalities, that in the opinion of the investigator places the subject at unacceptable risk if he/she were to participate in the study.
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.
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).
Participants receiving any other investigational agents.
Known intolerance to steroid therapy
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.
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.)
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.
Any history of ventricular fibrillation or torsade de pointes
QTcF interval ≥ 450 milliseconds on screening ECG;
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
Participants who have had prior allogeneic stem cell transplantation with evidence of active graft-versus-host disease requiring immunosuppressive therapy
POEMS syndrome or AL Amyloidoses
Participants with any significant history of non-compliance to medical regimens or unwilling or unable to comply with the instructions given to him/her by the study staff.
Impairment of GI function or GI disease that may significantly alter the absorption of panobinostat.
Poor tolerability or known allergy to any of the study drugs or compounds of similar chemical or biologic composition to lenalidomide, bortezomib, panobinostat and/or dexamethasone.
Female participants pregnant or breast-feeding.
Right bundle branch block + left anterior hemiblock (bifascicular block)
Participants with myocardial infarction or unstable angina ≤ 6 months prior to starting study drug.
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.
Participants with primary refractory disease
Other clinically significant heart disease (e.g. CHF NY Heart Association class III or IV, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
Participant has ≥ Grade 2 peripheral neuropathy on clinical examination within 21 days before initiation of protocol therapy.
Known hypersensitivity to acyclovir or similar anti-viral drug
Prior malignancy (within the last 5 years) except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer
Serious, intercurrent illness including, but not limited to, clinically relevant active infection, known active hepatitis B or C viral infection, known HIV infection, uncontrolled diabetes mellitus, or serious co-morbid medical conditions such as chronic restrictive pulmonary disease, and cirrhosis.
Participants who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of the surgery.
Known significant cardiac abnormalities, including:
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.
Bradycardia defined as HR < 50 bpm. Participants with pacemakers are eligible if HR ≥ 50 bpm
Participants who have a history of prior MM treatment with panobinostat, or an alternative HDAC-inhibitor.
Participants with diarrhea > CTCAE grade 2
Participants who exhibit any of the following conditions at screening will not be eligible:
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
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.
Participants with known brain metastases.

Locations

Boston, Massachusetts, 02215
Durham, North Carolina, 27710
Boston, Massachusetts, 02115
Boston, Massachusetts, 02215
...
Boston, Massachusetts, 02215
Durham, North Carolina, 27710
Boston, Massachusetts, 02115
Boston, Massachusetts, 02215

Tracking Information

NCT #
NCT01965353
Collaborators
Novartis
Investigators
  • Principal Investigator: Jacob Laubach, MD Dana-Farber Cancer Institute
  • Jacob Laubach, MD Dana-Farber Cancer Institute