Clinical trial NCT01496118: Study of the Combination of Panobinostat and Carfilzomib in Patients With Relapsed/Refractory Multiple Myeloma
Official title: Phase I/II Study of the Combination of Panobinostat and Carfilzomib in Patients With Relapsed/Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Multiple Myeloma
Keywords: Relapsed/Refractory Multiple Myeloma
carfilzomib
panobinostat
Lead sponsor: SCRI Development Innovations, LLC
Sponsor class: OTHER
Collaborators: name: Onyx Therapeutics, Inc.
name: Novartis
First posted: 2011-12-21
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

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.

Primary outcomes:
measure: Number of Phase I Patients (Dose Level 1-6) Experiencing a Dose-Limiting Toxicity (DLT) to Determine the Optimal Dosage
timeFrame: 28 days from the start of study treatment
measure: Phase II: Overall Response Rate
timeFrame: up to 6 years
Secondary outcomes:
measure: Time-to-progression (TTP)
timeFrame: up to 6 years
measure: Progression-free-survival (PFS)
timeFrame: up to 6 years
measure: Overall-survival (OS)
timeFrame: up to 6 years
Other outcomes:
Locations:
city: Denver
country: United States
facility: Colorado Blood Cancer Institute
state: Colorado
city: Fort Myers
country: United States
facility: Florida Cancer Specialists South
state: Florida
city: Pensacola
country: United States
facility: Woodlands Medical Specialists
state: Florida
city: Saint Petersburg
country: United States
facility: Florida Cancer Specialists North
state: Florida
city: Terre Haute
country: United States
facility: Providence Medical Group
state: Indiana
city: Terre Haute
country: United States
facility: RHHP/Hope Cancer Center
state: Indiana
city: Kansas City
country: United States
facility: Research Medical Center
state: Missouri
city: Morristown
country: United States
facility: Hematology-Oncology Associates - Northern NJ
state: New Jersey
city: Cincinnati
country: United States
facility: Oncology Hematology Care, Inc.
state: Ohio
city: Lawton
country: United States
facility: Cancer Centers of Southwest Oklahoma
state: Oklahoma
city: Chattanooga
country: United States
facility: Tennessee Oncology-Chattanooga
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Fort Worth
country: United States
facility: The Center for Cancer and Blood Disorders
state: Texas
Study officials:
affiliation: SCRI Development Innovations, LLC
name: Jesus Berdeja, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.