Study of the Combination of Panobinostat and Carfilzomib in Patients With Relapsed/Refractory Multiple Myeloma

Study Description

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Brief Summary:

Relapsed/refractory Multiple Myeloma (MM) is an incurable disorder with a poor prognosis. Carfilzomib is a novel proteasome inhibitor with activity in this setting. Panobinostat is a pan-deacetylase inhibitor which has shown synergistic cytotoxicity in vitro and in vivo with proteasome inhibitors. The combination should enhance the activity of both agents against myeloma cells. In Phase I, the optimal doses of the combination of carfilzomib and panobinostat will be determined. Assuming this combination is feasible, the Phase II portion will proceed using the doses determined in Phase I.

Condition or disease	Intervention/treatment	Phase
Multiple Myeloma	Drug: carfilzomib and panobinostat	Phase 1; Phase 2

Detailed Description:

In this open-label, non-randomized Phase I/II study, a maximum of 4 planned dose levels of carfilzomib and panobinostat were evaluated to determine the maximum tolerated dose (MTD) to administer. The MTD was not reached so patients in Phase II received treatment at dose level 4 to further assess efficacy. Response to treatment was evaluated after each 4-week cycle. Those having an objective response or stable disease are continuing treatment until disease progression or unacceptable toxicity occurs.

As the MTD in the 4 planned dose levels were not reached, a parallel Phase I study was initiated to examine additional dose levels using a traditional 3+3 design. If these dose levels are tolerable, then more patients will be recruited into an expansion cohort to assess efficacy at the new dose level(s).

Study Design

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	80 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase I/II Study of the Combination of Panobinostat and Carfilzomib in Patients With Relapsed/Refractory Multiple Myeloma
Study Start Date :	December 2011
Estimated Primary Completion Date :	December 2018
Estimated Study Completion Date :	December 2019

Arms and Interventions

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Arm

Intervention/treatment

Experimental: Carfilzomib and Panobinostat

Drug: carfilzomib and panobinostat; Cohort 1 (Dose Level 4): Carfilzomib Cycle 1: 20 mg/m2 IV D1, 2 / 45 mg/m2 IV D8, 9, 15, 16; Carfilzomib Cycle 2 to progression: 45 mg/m2 IV D 1, 2, 8, 9, 15, 16; Panobinostat cycle 1: 30 mg D 1, 3, 5, 15, 17, 19; Panobinostat cycle 2 to progression: 30 mg D 1, 3, 5, 15, 17, 19 Cohort 2 (Dose Level 6): Carfilzomib Cycle 1: 20 mg/m2 IV D1, 2 / 56 mg/m2 IV D8, 9, 15, 16; Carfilzomib Cycle 2: 56 mg/m2 IV D 1, 2, 8, 9, 15, 16; Panobinostat all cycles: 20 mg D 1, 3, 5, 15, 17, 19.; Other Name: LBH589 (Panobinostat)

Outcome Measures

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :

1. Phase 1: Maximum Tolerated Dose (MTD) of panobinostat+carfilzomib [ Time Frame: every 4 weeks, projected 6 months ]
   Using a traditional 3+3 dose escalation design, successive cohorts of subjects will receive a fixed dose level of the drug combination. The MTD is defined as the highest dose level at which ≤1 of 6 subjects experiences a dose-limiting toxicity assessed by NCI CTCAE v4.0.
2. Phase II: overall response rate [ Time Frame: every 4 weeks, projected 24 months ]
   Defined as the proportion of patients with confirmed complete response, very good partial response, or partial response (CR, VGPR, or PR) according to International Myeloma Working Group Uniform Response Criteria. CR=bone marrow contains ≤5% plasma cells; negative fixation on serum and urine; disappearance of soft tissue plasmacytomas. VGPR=≥90% reduction from baseline serum; urine M-protein level 100mg for 24h. PR=≥50% reduction from baseline in serum M-protein; disappearance of any soft tissue plasmacytomas.

Secondary Outcome Measures :

1. time-to-progression (TTP) [ Time Frame: At baseline and every 2 cycles (8 weeks), projected 24 months ]
   Measured from date of first protocol treatment until date of first document progression.
2. progression-free-survival (PFS) [ Time Frame: At baseline and every 2 cycles (8 weeks), projected 24 months ]
   Measured from date of first protocol treatment until date of tumor progression or death.
3. overall-survival (OS) [ Time Frame: Every 8 weeks until progression then every 3 months thereafter, projected 24 months. ]
   Measured from time of first study treatment until date of death or date last known alive.

Eligibility Criteria

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Eligible participants must have multiple myeloma using standard criteria.

2. Patients must have measurable disease requiring systemic therapy defined as at least one of the following:

   • Serum M-protein ≥1 g/dl (≥10 g/l)
   • Urine M-protein ≥200 mg/24 hrs
   • Serum free light chain assay: involved free light chain level ≥10 mg/dl (≥100 mg/l) provided the serum free light chain ratio is abnormal
3. Must have progressed during or after at least one previous bortezomib-containing treatment regimen. Patients who have received previous high-dose therapy/autologous stem cell transplantation are eligible.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

5. Must meet the following laboratory criteria:

   • Absolute neutrophil count (ANC) ≥1000/μL;
   • Platelets ≥70,000/microL;
   • AST or ALT and alkaline phosphatase (ALP) must be ≤ 2.5 x ULN, or ≤ 5 x ULN in patients with plasmacytomas of the liver;
   • Total bilirubin ≤ 1.5 x the institutional ULN;
   • Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 50 ml/min;
   • Serum potassium, calcium, magnesium WNL (These may be corrected prior to starting therapy, to make the patient eligible.)
6. Ability to swallow oral medications.
7. Baseline MUGA or ECHO must demonstrate left ventricular ejection fraction (LVEF) ≥ the lower limit of the institutional limits of normal.
8. Male or females ≥ 18 years of age.
9. Female patients must not be of child-bearing potential or must agree to use adequate contraceptive measures.
10. Male patients willing to use adequate contraceptive measures.
11. Willingness and ability to comply with the trial and follow-up procedures.
12. Ability to understand the nature of this trial and give written informed consent.

Exclusion Criteria:

1. Currently receiving or have received systemic cancer therapy (chemotherapy, biologic therapy) ≤ 21 days of initiating study therapy. For patients receiving small molecule targeted therapy, study treatment may begin >21 days after last dose or >5 half lives of previous treatment, whichever is shorter. Patients must have completed radiation therapy ≥7 days prior to starting study treatment. Patients must have recovered from or come to a new chronic stable baseline from all treatment-related toxicities. Dexamethasone or other high-dose steroid therapy must be stopped ≥ days prior to starting study treatment.
2. Previous treatment with HDAC, DAC, HSP90 or valproic acid for treatment of cancer.
3. Requires valproic acid for any medical condition during the study ≤5 days prior to first panobinostat treatment.
4. Patient has not recovered from all therapy-related toxicities associated with prior treatments to < Grade 2 CTCAE.
5. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib).
6. Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis ≤14 days prior to study entry.
7. Patients using medications that have a risk of prolonging the QT interval or inducing Torsade de Pointes if treatment cannot be discontinued or switched to a different medication prior to receiving study drug.
8. Patients with > grade 2 diarrhea.
9. Patients with impaired cardiac function.
10. Infection requiring IV antibiotics.
11. Patients with > grade 2 peripheral neuropathy or with uncontrolled pain.
12. Women who are pregnant or lactating.
13. Any concurrent medical illness that may impair the ability of the patient to tolerate study treatment and comply with the requirements of the study.
14. Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study.
15. Use of any non-approved or investigational agent ≤30 days prior to administration of the first dose of study drug. Patients may not receive any other investigational or anti-cancer treatments while participating in this study.
16. Presence of other active cancers, or history of treatment for invasive cancer ≤ 5 years. Patients with stage I cancer who have received definitive local treatment at least 3 years previously, and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (i.e. non-invasive) are eligible, as are patients with history of non-melanoma skin cancer.

Contacts and Locations

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, Colorado
Colorado Blood Cancer Institute
Denver, Colorado, United States, 80218
United States, Florida
Florida Cancer Specialists South
Fort Myers, Florida, United States, 33916
Woodlands Medical Specialists
Pensacola, Florida, United States, 32503
Florida Cancer Specialists North
Saint Petersburg, Florida, United States, 33705
United States, Indiana
Providence Medical Group
Terre Haute, Indiana, United States, 47802
RHHP/Hope Cancer Center
Terre Haute, Indiana, United States, 47802
United States, Missouri
Research Medical Center
Kansas City, Missouri, United States, 64132
United States, New Jersey
Hematology-Oncology Associates - Northern NJ
Morristown, New Jersey, United States, 07962
United States, Ohio
Oncology Hematology Care, Inc.
Cincinnati, Ohio, United States, 45242
United States, Oklahoma
Cancer Centers of Southwest Oklahoma
Lawton, Oklahoma, United States, 73505
United States, Tennessee
Tennessee Oncology-Chattanooga
Chattanooga, Tennessee, United States, 37404
Tennessee Oncology
Nashville, Tennessee, United States, 37205
United States, Texas
The Center for Cancer and Blood Disorders
Fort Worth, Texas, United States, 76104

Sponsors and Collaborators

SCRI Development Innovations, LLC

Onyx Therapeutics, Inc.

Novartis

Investigators

Study Chair:	Jesus Berdeja, MD	SCRI Development Innovations, LLC

More Information

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Berdeja JG, Hart LL, Mace JR, Arrowsmith ER, Essell JH, Owera RS, Hainsworth JD, Flinn IW. Phase I/II study of the combination of panobinostat and carfilzomib in patients with relapsed/refractory multiple myeloma. Haematologica. 2015 May;100(5):670-6. doi: 10.3324/haematol.2014.119735. Epub 2015 Feb 20.

Responsible Party:	SCRI Development Innovations, LLC
ClinicalTrials.gov Identifier:	NCT01496118 History of Changes
Other Study ID Numbers:	SCRI MM 27
First Posted:	December 21, 2011
Last Update Posted:	November 13, 2017
Last Verified:	November 2017

Keywords provided by SCRI Development Innovations, LLC:

Relapsed/Refractory Multiple Myeloma; carfilzomib; panobinostat

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; Panobinostat; Antineoplastic Agents; Histone Deacetylase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action