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

NCT ID: NCT01496118

Last Updated: 2022-02-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 80 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-12-31
• Study Completion Date: 2020-12-31

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.

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).

Conditions

Multiple Myeloma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

panobinostat

Intervention Type: DRUG

Specified dose on specified days

carfilzomib

Intervention Type: DRUG

Specified dose on specified days

Interventions

panobinostat

Specified dose on specified days

Intervention Type: DRUG

carfilzomib

Specified dose on specified days

Intervention Type: DRUG

Other Intervention Names

LBH589 (Panobinostat); PX-171-007

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Onyx Therapeutics, Inc.

INDUSTRY

Sponsor Role: collaborator

Novartis

INDUSTRY

Sponsor Role: collaborator

SCRI Development Innovations, LLC

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jesus Berdeja, MD

Role: STUDY_CHAIR

SCRI Development Innovations, LLC

Locations

Colorado Blood Cancer Institute

Denver, Colorado, United States

Florida Cancer Specialists South

Fort Myers, Florida, United States

Woodlands Medical Specialists

Pensacola, Florida, United States

Florida Cancer Specialists North

St. Petersburg, Florida, United States

Providence Medical Group

Terre Haute, Indiana, United States

RHHP/Hope Cancer Center

Terre Haute, Indiana, United States

Research Medical Center

Kansas City, Missouri, United States

Hematology-Oncology Associates - Northern NJ

Morristown, New Jersey, United States

Oncology Hematology Care, Inc.

Cincinnati, Ohio, United States

Cancer Centers of Southwest Oklahoma

Lawton, Oklahoma, United States

Tennessee Oncology-Chattanooga

Chattanooga, Tennessee, United States

Tennessee Oncology

Nashville, Tennessee, United States

The Center for Cancer and Blood Disorders

Fort Worth, Texas, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 33421178 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25710456 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

SCRI MM 27

Identifier Type: -

Identifier Source: org_study_id