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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Onyx Therapeutics, Inc.
Novartis
Information provided by (Responsible Party):
SCRI Development Innovations, LLC
ClinicalTrials.gov Identifier:
NCT01496118
First received: December 15, 2011
Last updated: January 3, 2017
Last verified: January 2017

December 15, 2011
January 3, 2017
December 2011
December 2016   (final data collection date for primary outcome measure)
  • Phase 1: Maximum Tolerated Dose (MTD) of panobinostat+carfilzomib [ Time Frame: every 4 weeks, projected 6 months ] [ Designated as safety issue: Yes ]
    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.
  • Phase II: overall response rate [ Time Frame: every 4 weeks, projected 24 months ] [ Designated as safety issue: No ]
    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.
  • establish optimal doses of carfilzomib in mg/m^2 and panobinostat in mg in combination with each other (Phase I) [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    The Phase I study will determine the maximum tolerated dose (MTD) of the combination of carfilzomib and panobinostat. The Phase I portion will follow a standard dose escalation design, beginning with 3 patients on dose level 1: carfilzomib 20 mg/m2 IV D1, 2 / 27 mg/m2 IV D8, 9, 15, 16 for cycle 1 and panobinostat 20 mg D 1, 3, 5, 15, 17, 19 for cycle 1; carfilzomib 27 mg/m2 IV D 1, 2, 8, 9, 15, 16 for cycle 2 and panobinostat 20 mg D 1, 3, 5, 15, 17, 19 for cycle 2. Patients will be assessed for dose-limiting toxicity (DLT) at each visit during Cycle 1 prior to receiving treatment.
  • evaluate overall response (Phase II) [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    To evaluate the overall response in patients with relapsed/refractory multiple myeloma treated with the combination of panobinostat and carfilzomib. (Phase II)The following restaging assessments will be done at baseline and every 2 cycles (8 weeks)to assess response: bone marrow aspiration/biopsy, skeletal survey, serum free light chain, serum immunoglobulin G, A, M, serum beta-2 microglobulin, SPEP & immunofixation, and UPEP & immunofixation.
Complete list of historical versions of study NCT01496118 on ClinicalTrials.gov Archive Site
  • time-to-progression (TTP) [ Time Frame: At baseline and every 2 cycles (8 weeks), projected 24 months ] [ Designated as safety issue: No ]
    Measured from date of first protocol treatment until date of first document progression.
  • progression-free-survival (PFS) [ Time Frame: At baseline and every 2 cycles (8 weeks), projected 24 months ] [ Designated as safety issue: No ]
    Measured from date of first protocol treatment until date of tumor progression or death.
  • overall-survival (OS) [ Time Frame: Every 8 weeks until progression then every 3 months thereafter, projected 24 months. ] [ Designated as safety issue: No ]
    Measured from time of first study treatment until date of death or date last known alive.
  • evaluate time-to-progression (TTP) [ Time Frame: 24 Months ] [ Designated as safety issue: No ]
    To evaluate time-to-progression (TTP)The following restaging assessments will be done at baseline and every 2 cycles (8 weeks)to assess if there is disease progression: bone marrow aspiration/biopsy, skeletal survey, serum free light chain, serum immunoglobulin G, A, M, serum beta-2 microglobulin, SPEP & immunofixation, and UPEP & immunofixation.
  • evaluate progression-free-survival (PFS) [ Time Frame: 24 Months ] [ Designated as safety issue: No ]
    To evaluate progression-free-survival (PFS)The following restaging assessments will be done at baseline and every 2 cycles (8 weeks)to evalute progression-free-survival: bone marrow aspiration/biopsy, skeletal survey, serum free light chain, serum immunoglobulin G, A, M, serum beta-2 microglobulin, SPEP & immunofixation, and UPEP & immunofixation.
  • evaluate overall-survival (OS) [ Time Frame: 24 Months ] [ Designated as safety issue: No ]
    To evaluate overall-survival (OS) After disease progression is documented, patients will be followed every 3 months for survival assessment.
  • evaluate safety by assessing toxicities [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    To evaluate safety by assessing possible toxicities of thrombocytopenia (platelets/mL), neutropenia (Absolute neutrophil/microL), febrile neutropenia (Absolute neutrophil count (ANC)/microL & temperature in degrees celcius), serum creatinine (Serum creatinine x ULN or calculated creatinine clearance ml/min), total bilirubin (Total bilirubin x the institutional ULN), diarrhea, vomiting, and average QTcF in msec from ECG's
Not Provided
Not Provided
 
Study of the Combination of Panobinostat and Carfilzomib in Patients With Relapsed/Refractory Multiple Myeloma
Phase I/II Study of the Combination of Panobinostat and Carfilzomib in Patients With Relapsed/Refractory Multiple Myeloma
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.

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).

Interventional
Phase 1
Phase 2
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Multiple Myeloma
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)
Experimental: Carfilzomib and Panobinostat
Intervention: Drug: carfilzomib and panobinostat
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
80
March 2017
December 2016   (final data collection date for primary outcome measure)

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.
All
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01496118
SCRI MM 27
No
Not Provided
Not Provided
SCRI Development Innovations, LLC
SCRI Development Innovations, LLC
  • Onyx Therapeutics, Inc.
  • Novartis
Study Chair: Jesus Berdeja, MD SCRI Development Innovations, LLC
SCRI Development Innovations, LLC
January 2017

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