Panobinostat and Everolimus in Treating Patients With Relapsed or Refractory Lymphoma or Multiple Myeloma

Lymphoma Clinical Trial

Official title:

A Phase I Study Evaluating the Combination of the Deacetylase Inhibitor, LBH589 Plus the mTOR Inhibitor RAD001, in Relapsed and Refractory Adult Patients With Lymphoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00962507
• Other study ID #: 08099
• Secondary ID: P30CA033572CHNMC
• Status: Completed
• Phase: Phase 1
• First received: August 19, 2009
• Last updated: February 13, 2013
• Start date: July 2009
• Est. completion date: January 2013

Study information

• Verified date: February 2013
• Source: City of Hope Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Panobinostat and everolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer. Giving panobinostat together with everolimus may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of panobinostat when given together with everolimus in treating patients with relapsed or refractory lymphoma or multiple myeloma.

Description:

OBJECTIVES:

Primary

• To evaluate the safety and feasibility of combining panobinostat with everolimus in patients with recurrent or refractory lymphoma or multiple myeloma.

• To define the maximum tolerated dose of panobinostat in combination with everolimus in these patients.

Secondary

• To obtain preliminary data for response to this treatment regimen in these patients.

• To perform correlative studies relevant to this treatment regimen.

OUTLINE: This is a dose-escalation study of panobinostat.

Patients receive oral panobinostat 3 days a week and oral everolimus once every other day for 4 weeks Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Blood and bone marrow samples may be collected for pharmacokinetic and correlative laboratory studies.

After completion of study treatment, patients are followed up for ≥ 4 weeks.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 11
• Est. completion date: January 2013
• Est. primary completion date: January 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of one of the following:

• Hodgkin or non-Hodgkin lymphoma (including small lymphocytic lymphoma [SLL])

• Any histology, including B, T, or NK/T cell allowed

• Multiple myeloma (MM)

• Relapsed or refractory disease

• Patients with lymphoma must have relapsed after or be refractory to an upfront regimen (e.g., CHOP or ABVD) and a salvage regimen (e.g., ICE or ESHAP)

• Patients with SLL should have relapsed after a fludarabine-containing regimen

• Patients with MM must have progressed within 100 days after receiving a regimen containing bortezomib and either thalidomide or lenalidomide AND have a 25% increase in serum paraproteins, urinary light chains, or plasma cell number in the bone marrow

• No active CNS disease

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2

• ANC = 1,500/mm³

• Platelet count = 75,000/mm³ (transfusion allowed in patients with biopsy-proven bone marrow involvement)

• AST and ALT = 2.5 times upper limit of normal (ULN) (= 5.0 times ULN if elevation due to leukemic involvement)

• Serum bilirubin = 1.5 times ULN

• Serum creatinine = 1.5 times ULN OR creatinine clearance = 50 mL/min

• Serum potassium normal

• Serum phosphorous normal

• Serum total calcium (corrected for serum albumin) or serum ionized calcium normal

• Serum magnesium normal

• TSH and free T4 normal (thyroid hormone replacement allowed)

• Fasting serum cholesterol = 300 mg/dL (or = 7.75 mmol/L) AND fasting triglycerides = 2.5 times ULN (elevated levels allowed provided an appropriate lipid-lowering medication has been initiated)

• LVEF normal by MUGA or ECHO

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective double-method (including barrier method) contraception during and for 3 months after completion of study treatment

• No impaired cardiac function, including any of the following:

• QTc > 450 msec by screening ECG

• Congenital long QT syndrome

• History of sustained ventricular tachycardia

• History of ventricular fibrillation or torsades de pointes

• Bradycardia, defined as heart rate (HR) < 50 beats/min (pacemaker allowed provided HR = 50 beats/min)

• Myocardial infarction or unstable angina within the past 6 months

• NYHA class III-IV congestive heart failure

• Right bundle branch block and left anterior hemiblock (bifascicular block)

• No uncontrolled hypertension

• No unresolved diarrhea > CTCAE grade 1

• No impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral agents (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)

• No other concurrent severe or uncontrolled medical condition

• No other primary malignancy within the past 5 years other than curatively treated carcinoma in situ of the cervix or basal cell or squamous cell carcinoma of the skin

• No known HIV or hepatitis C positivity

• No significant history of non-compliance to medical regimens

• No known hypersensitivity to everolimus, other rapamycins (e.g., sirolimus or temsirolimus), or their excipients

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• Prior autologous or allogeneic stem cell transplantation allowed

• More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) or radiotherapy and recovered

• More than 1 week since prior and no concurrent immunization with live attenuated vaccines

• More than 4 weeks since prior valproic acid

• No other prior histone deacetylase inhibitors

• No concurrent chronic systemic corticosteroids or another immunosuppressive agent, other than for control of itching (as in cutaneous T-cell lymphoma)

• Concurrent corticosteroids allowed provided patient has been on a stable dosage regimen for = 2 weeks before study entry

• Topical or inhaled corticosteroids allowed

• No concurrent drugs that may induce torsades de pointes

• No concurrent CYP3A4 inhibitors

• No concurrent radiotherapy or other anticancer therapy

• No concurrent grapefruit, grapefruit juice, or seville (sour) oranges

• No concurrent medications that may cause QTc prolongation

• No other concurrent investigational therapy

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Lymphoma
• Multiple Myeloma
• Multiple Myeloma and Plasma Cell Neoplasm
• Neoplasms, Plasma Cell
• Plasmacytoma

Intervention

Drug:
• everolimus
Beginning with 5 mg every other day Monday, Wednesday or Friday for a 28 day cycle. Dose escalation will be determined by the toxicities associated with treatment.
• panobinostat
10 mg every Monday and Thursday of a 28 day cycle. Dose escalation will be determined by the toxicities associated with treatment.

Other:
• laboratory biomarker analysis
Pre-study, day 1 and day 26 samples to evaluation how the study drugs work in vitro (in a test tube).
• pharmacological study
Pre-study, day 1 and day 26

Locations

Country	Name	City	State
United States	City of Hope Medical Center	Duarte	California
United States	City of Hope Medical Group	Pasadena	California

Sponsors (2)

Lead Sponsor	Collaborator
City of Hope Medical Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated dose		90 days post treatment start	Yes
Primary	Toxicity		90 days post treatment start	Yes
Secondary	Pharmacokinetic and correlative studies		Day 1 and Day 26 of the first cycle of treament	No