Study of the Combination of Panobinostat and Carfilzomib in Patients With Relapsed/Refractory Multiple Myeloma
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ClinicalTrials.gov Identifier: NCT01496118 |
Recruitment Status :
Completed
First Posted : December 21, 2011
Results First Posted : February 2, 2022
Last Update Posted : February 2, 2022
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Condition or disease | Intervention/treatment | Phase |
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Multiple Myeloma | Drug: panobinostat Drug: carfilzomib | Phase 1 Phase 2 |
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 Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 80 participants |
Allocation: | N/A |
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 |
Actual Primary Completion Date : | December 2020 |
Actual Study Completion Date : | December 2020 |

Arm | Intervention/treatment |
---|---|
Experimental: Carfilzomib and Panobinostat
Phase I: Carfilzomib: cycle 1 - Dose is 20 mg/m^2 IV on day 1; 27 or 36 or 45 or 56 mg/m^2 IV on Days 8, 9, 15, 16 cycle 2 to progression - 27 or 36 or 45 or 56 mg/m^2 IV on days 1, 2, 8, 9, 15, 16 Panobinostat: cycle 1 and cycle 2 to progression - 20 mg or 30 mg on days 1, 3, 5, 15, 17, 19 Phase II: Carfilzomib and Panobinostat: Dose is optimal dose determined in Phase I |
Drug: panobinostat
Specified dose on specified days
Other Name: LBH589 (Panobinostat) Drug: carfilzomib Specified dose on specified days
Other Name: PX-171-007 |
- Number of Phase I Patients (Dose Level 1-6) Experiencing a Dose-Limiting Toxicity (DLT) to Determine the Optimal Dosage [ Time Frame: 28 days from the start of study treatment ]
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 (DLT) assessed by NCI CTCAE v4.0. DLT is defined as any of the following that are determined to be related to study treatment during Cycle 1:
Grade 4 neutropenia for >7 days, Febrile neutropenia, Grade 3 thrombocytopenia with ≥ Grade 2 bleeding, Grade 4 thrombocytopenia > 7 days, ≥ Grade 2 neuropathy with uncontrolled pain, ≥ Grade 3 non-hematologic drug-related toxicity (excluding alopecia), despite optimal supportive care lasting >72 hours or requiring a dose reduction in the first cycle and Patients who are unable to receive 75% of the required doses of both agents secondary to toxicity. Number of Participants With such Dose Limiting Toxicities (DLT) at each level are reported here.
- Phase II: Overall Response Rate [ Time Frame: up to 6 years ]Defined as the percentage 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.
- Time-to-progression (TTP) [ Time Frame: up to 6 years ]Measured from date of first treatment until date of first documented progression as per International Myeloma Working Group Uniform Response Criteria. Progressive disease id defined as an increase of ≥ 25% from the nadir in at least one of the following criteria: serum M-protein (absolute increase must be ≥0.5 g/dL); urine M-protein (absolute increase must be ≥200 mg/24h) ; only in patients with non-measurable serum and urine M-protein levels: difference in involved and uninvolved FLC levels (absolute increase must be >10 mg/dL); only in patients with non-measurable serum and urine M-protein levels and non-measurable disease by FLC levels, bone marrow plasma cell percentage (absolute % must be ≥10%) OR Definite development of new bone lesions or soft tissue plasmacytomas OR definite increase in the size of existing bone lesions or soft tissue plasmacytomas OR Development of hypercalcemia (corrected serum Ca >11.5mg/dL) for patients without hypercalcemia at baseline
- Progression-free-survival (PFS) [ Time Frame: up to 6 years ]Measured from date of first protocol treatment until date of tumor progression or death as per International Myeloma Working Group Uniform Response Criteria. Progressive disease id defined as an increase of ≥ 25% from the nadir in at least one of the following criteria: serum M-protein (absolute increase must be ≥0.5 g/dL); urine M-protein (absolute increase must be ≥200 mg/24h) ; only in patients with non-measurable serum and urine M-protein levels: difference in involved and uninvolved FLC levels (absolute increase must be >10 mg/dL); only in patients with non-measurable serum and urine M-protein levels and non-measurable disease by FLC levels, bone marrow plasma cell percentage (absolute % must be ≥10%) OR Definite development of new bone lesions or soft tissue plasmacytomas OR definite increase in the size of existing bone lesions or soft tissue plasmacytomas OR Development of hypercalcemia (corrected serum Ca >11.5mg/dL) for patients without hypercalcemia at baseline
- Overall-survival (OS) [ Time Frame: up to 6 years ]Measured from time of first study treatment until date of death or date last known alive.

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Eligible participants must have multiple myeloma using standard criteria.
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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
- 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.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
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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.)
- Ability to swallow oral medications.
- Baseline MUGA or ECHO must demonstrate left ventricular ejection fraction (LVEF) ≥ the lower limit of the institutional limits of normal.
- Male or females ≥ 18 years of age.
- Female patients must not be of child-bearing potential or must agree to use adequate contraceptive measures.
- Male patients willing to use adequate contraceptive measures.
- Willingness and ability to comply with the trial and follow-up procedures.
- Ability to understand the nature of this trial and give written informed consent.
Exclusion Criteria:
- 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.
- Previous treatment with HDAC, DAC, HSP90 or valproic acid for treatment of cancer.
- Requires valproic acid for any medical condition during the study ≤5 days prior to first panobinostat treatment.
- Patient has not recovered from all therapy-related toxicities associated with prior treatments to < Grade 2 CTCAE.
- Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib).
- Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis ≤14 days prior to study entry.
- 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.
- Patients with > grade 2 diarrhea.
- Patients with impaired cardiac function.
- Infection requiring IV antibiotics.
- Patients with > grade 2 peripheral neuropathy or with uncontrolled pain.
- Women who are pregnant or lactating.
- Any concurrent medical illness that may impair the ability of the patient to tolerate study treatment and comply with the requirements of the study.
- Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study.
- 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.
- 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.

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01496118
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 |
Study Chair: | Jesus Berdeja, MD | SCRI Development Innovations, LLC |
Documents provided by SCRI Development Innovations, LLC:
Responsible Party: | SCRI Development Innovations, LLC |
ClinicalTrials.gov Identifier: | NCT01496118 |
Other Study ID Numbers: |
SCRI MM 27 |
First Posted: | December 21, 2011 Key Record Dates |
Results First Posted: | February 2, 2022 |
Last Update Posted: | February 2, 2022 |
Last Verified: | January 2022 |
Relapsed/Refractory Multiple Myeloma carfilzomib panobinostat |
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 |