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

NCT01496118 | Completed Phase 1 Results

• 1 other identifier: SCRI MM 27
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 13

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.

Conditions

Multiple Myeloma

Keywords

Relapsed/Refractory Multiple Myeloma; carfilzomib; panobinostat

Outcome Measures

Primary Outcomes (2)

• Number of Phase I Patients (Dose Level 1-6) Experiencing a Dose-Limiting Toxicity (DLT) to Determine the Optimal Dosage

  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.

  28 days from the start of study treatment

• Phase II: Overall Response Rate

  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.

  up to 6 years

Secondary Outcomes (3)

• Time-to-progression (TTP)

  up to 6 years

• Progression-free-survival (PFS)

  up to 6 years

• Overall-survival (OS)

  up to 6 years

Study Arms (1)

Carfilzomib and Panobinostat

EXPERIMENTAL

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; Drug: carfilzomib

Interventions

panobinostat DRUG

Specified dose on specified days

Also known as: LBH589 (Panobinostat)

Carfilzomib and Panobinostat

carfilzomib DRUG

Specified dose on specified days

Also known as: PX-171-007

Carfilzomib and Panobinostat

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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.

Sponsors & Collaborators

• SCRI Development Innovations, LLC: lead
• Onyx Therapeutics, Inc.: collaborator
• Novartis: collaborator

Study Sites (13)

Colorado Blood Cancer Institute

Denver, Colorado, 80218, United States

Location

Florida Cancer Specialists South

Fort Myers, Florida, 33916, United States

Location

Woodlands Medical Specialists

Pensacola, Florida, 32503, United States

Location

Florida Cancer Specialists North

St. Petersburg, Florida, 33705, United States

Location

Providence Medical Group

Terre Haute, Indiana, 47802, United States

Location

RHHP/Hope Cancer Center

Terre Haute, Indiana, 47802, United States

Location

Research Medical Center

Kansas City, Missouri, 64132, United States

Location

Hematology-Oncology Associates - Northern NJ

Morristown, New Jersey, 07962, United States

Location

Oncology Hematology Care, Inc.

Cincinnati, Ohio, 45242, United States

Location

Cancer Centers of Southwest Oklahoma

Lawton, Oklahoma, 73505, United States

Location

Tennessee Oncology-Chattanooga

Chattanooga, Tennessee, 37404, United States

Location

Tennessee Oncology

Nashville, Tennessee, 37205, United States

Location

The Center for Cancer and Blood Disorders

Fort Worth, Texas, 76104, United States

Location

Related Publications (2)

• Berdeja JG, Gregory TK, Faber EA, Hart LL, Mace JR, Arrowsmith ER, Flinn IW, Matous JV. A phase I/II study of the combination of panobinostat and carfilzomib in patients with relapsed or relapsed/refractory multiple myeloma: Final analysis of second dose-expansion cohort. Am J Hematol. 2021 Apr 1;96(4):428-435. doi: 10.1002/ajh.26088. Epub 2021 Jan 28.

  PMID: 33421178 DERIVED

• 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.

  PMID: 25710456 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Panobinostat; carfilzomib

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Hydroxamic Acids; Hydroxylamines; Amines; Organic Chemicals; Hydroxy Acids; Carboxylic Acids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Jesus Berdeja
• Organization: Sarah Cannon Development Innovations, LLC

CANN.InnovationsMedical@sarahcannon.com

844-710-6157

Study Officials

• Jesus Berdeja, MD

  SCRI Development Innovations, LLC

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 15, 2011
• First Posted: December 21, 2011
• Study Start: December 1, 2011
• Primary Completion: December 1, 2020
• Study Completion: December 1, 2020
• Last Updated: February 2, 2022
• Results First Posted: February 2, 2022

Record last verified: 2022-01

Locations

US (13)