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Panobinostat and Carfilzomib in Treating Participants With Relapsed or Refractory Multiple Myeloma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01301807
Recruitment Status : Active, not recruiting
First Posted : February 23, 2011
Last Update Posted : September 20, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Tracking Information
First Submitted Date  ICMJE February 21, 2011
First Posted Date  ICMJE February 23, 2011
Last Update Posted Date September 20, 2018
Actual Study Start Date  ICMJE July 28, 2011
Estimated Primary Completion Date August 31, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 18, 2018)
  • Maximum tolerated dose (MTD) of the drug combination [ Time Frame: At 28 days ]
  • Incidence of adverse events per Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 8 years ]
Original Primary Outcome Measures  ICMJE
 (submitted: February 22, 2011)
Maximum Tolerated Dose (MTD) [ Time Frame: 28 days ]
A full safety evaluation will be conducted when patients have completed one cycle (28 days) of combination therapy.
Change History Complete list of historical versions of study NCT01301807 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 18, 2018)
Time to progression [ Time Frame: 30 days after the last dose is given ]
Will use Kaplan-Meier methods appropriate for survival analysis.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Panobinostat and Carfilzomib in Treating Participants With Relapsed or Refractory Multiple Myeloma
Official Title  ICMJE Phase 1/1b Study of the Efficacy and Safety of the Combination of Panobinostat + Carfilzomib in Patients With Relapsed/Refractory Myeloma
Brief Summary This phase I/Ib trial studies the side effects and best dose of panobinostat and carfilzomib in treating participants with multiple myeloma that has come back or that isn't responding to treatment. Carfilzomib keeps cancer cells from repairing themselves. If the cancer cells cannot repair themselves, they may die. Panobinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving panobinostat and carfilzomib may work better in treating participants with multiple myeloma.
Detailed Description

PRIMARY OBJECTIVES:

I. To determine the maximum recommended dose (MRD) of the combination of carfilzomib and panobinostat in patients with relapsed/refractory multiple myeloma (RRMM). (Phase I) II. To determine the overall response rate (stable disease [SD], minimal response [MR], partial response [PR], very good partial response [VGPR], near complete response/complete response [nCR/CR] of the combination. (Phase Ib)

SECONDARY OBJECTIVES:

I. To determine the overall response rate (ORR), stable disease (SD), minimal response (MR), partial response (PR), very good partial response (VGPR), near complete response/complete response (nCR/CR). (Phase I) II. To determine the time to progression (TTP). (Phase I and Ib) III. To determine the progression free survival (PFS). (Phase I and Ib) IV. To determine the time to best response. (Phase I and Ib) V. To determine time to next therapy. (Phase I and Ib) VI. To determine duration of response. (Phase I and Ib) VII. To determine the overall response rate (SD, MR, PR, VGPR, nCR/CR) of the combination. (Phase Ib) VIII. To assess the safety of the combination. (Phase Ib)

OUTLINE: This is a phase I and Ib dose escalation study.

Participants receive carfilzomib intravenously (IV) over 30 minutes on days 1, 2, 8, 9, 15, and 16 and panobinostat orally (PO) once daily (QD) on days 1, 3, 5, 8, 10, and 12 of each course. Courses repeat every 28 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. After 8 courses, participants may continue carfilzomib IV on days 1, 2, 15, and 16, and panobinostat PO on days 1, 3, 5, 8, 10, and 12 of each course. If the disease becomes worse, participants can receive carfilzomib on the original dosing schedule (days 1, 2, 8, 9, 15, and 16 of each course).

After completion of study treatment, participants are followed up at 30 days.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Non-Secretory Plasma Cell Myeloma
  • Plasmacytosis
  • Recurrent Plasma Cell Myeloma
  • Refractory Plasma Cell Myeloma
Intervention  ICMJE
  • Drug: Carfilzomib
    Given IV
    Other Names:
    • Kyprolis
    • PR-171
  • Drug: Panobinostat
    Given PO
    Other Names:
    • Faridak
    • Farydak
    • LBH589
Study Arms  ICMJE Experimental: Treatment (carfilzomib, panobinostat)
Participants receive carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16 and panobinostat PO QD on days 1, 3, 5, 8, 10, and 12 of each course. Courses repeat every 28 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. After 8 courses, participants may continue carfilzomib IV on days 1, 2, 15, and 16, and panobinostat PO on days 1, 3, 5, 8, 10, and 12 of each course. If the disease becomes worse, participants can receive carfilzomib on the original dosing schedule (days 1, 2, 8, 9, 15, and 16 of each course).
Interventions:
  • Drug: Carfilzomib
  • Drug: Panobinostat
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: September 18, 2018)
46
Original Estimated Enrollment  ICMJE
 (submitted: February 22, 2011)
58
Estimated Study Completion Date  ICMJE August 31, 2019
Estimated Primary Completion Date August 31, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Relapsed/refractory MM with failure to at least two lines of MM treatment which must include at least one immunomodulatory imide drugs (IMiD) (thalidomide, lenalidomide) and proteasome inhibitor (bortezomib) and measurable levels of myeloma paraprotein in serum (>= 0.5 g/dl), urine (>= 0.2 g excreted in a 24-hour collection sample), or abnormal free light chain (FLC) ratio. Oligo or non secretory myeloma patients may be included, if there is measurable plasmacytosis in the bone marrow biopsy or measurable extramedullary disease.
  • Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed.
  • Absolute neutrophil count (ANC) >= 1.0 x 10^9/L within 28 days of starting therapy.
  • Hemoglobin >= 8 g/dl (transfusions are permitted) within 28 days of starting therapy.
  • Platelet count > 70,000 cells/mm^3 for patients with < 50% of bone marrow plasma cells or platelet count > 25,000 cells/mm^3 for patients in whom > 50% of the bone marrow nucleated cells were plasma cells within 28 days of starting therapy.
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) within 28 days of starting therapy.
  • Serum bilirubin =< 2 x ULN within 28 days of starting therapy.
  • Eastern Cooperative Oncology Group (ECOG) performance status of =< 2.
  • Creatinine clearance (CrCl) >= 30 mL/minute within 28 days prior to registration, either measured or calculated using a standard formula (e.g., Cockcroft and Gault).
  • Multiple gated acquisition (MUGA) or echocardiogram (ECHO) must demonstrate left ventricular ejection fraction (LVEF) >= 45%.
  • Female patients who: are postmenopausal for at least 1 year before the screening visit, OR are surgically sterile, OR if they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study drug, or agree to completely abstain from heterosexual intercourse. Male patients, even if surgically sterilized (i.e., status post vasectomy), who: agree to practice effective barrier contraception during the entire study treatment period and through 30 days after the last dose of study drug, OR agree to completely abstain from heterosexual intercourse.

Exclusion Criteria:

  • Valproic acid for the treatment of cancer.
  • 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. (Patients with a history of atrial arrhythmia are eligible)
    • Any history of ventricular fibrillation or torsade de pointes
    • Bradycardia defined as heart rate (HR) < 50 bpm. Patients with pacemakers are eligible if HR >= 50 bpm.
    • Screening electrocardiogram (ECG) with a corrected QT interval (QTc) or 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 [NYHA] 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) grade 2.
  • 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.
  • Patients who have received chemotherapy within =< 2 weeks by time of cycle 1 day 1 of therapy on trial; or radiation therapy to > 30% of marrow-bearing bone within 2 weeks prior to starting study treatment; or who have not yet recovered from side effects of such therapies.
  • Female patients who are lactating or have a positive serum or urine pregnancy test during the screening period.
  • Patients 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.
  • Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01301807
Other Study ID Numbers  ICMJE 2010-0733
NCI-2018-01845 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2010-0733 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party M.D. Anderson Cancer Center
Study Sponsor  ICMJE M.D. Anderson Cancer Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Robert Orlowski M.D. Anderson Cancer Center
PRS Account M.D. Anderson Cancer Center
Verification Date September 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP