LBH589 Treatment for Refractory Clear Cell Renal Carcinoma

A Phase II Study of LBH589 in the Treatment of Patients With Refractory Clear Cell Renal Carcinoma

Inhibition of histone deacetylase (HDAC) provides a novel approach for cancer treatment. LBH589, an oral HDAC inhibitor, has been well tolerated in phase I trials and has shown activity against several types of cancer. In this nonrandomized phase II trial, we are investigating the activity of LBH589 in the treatment of patients with refractory clear cell renal carcinoma.

Study Overview

• Status: Completed
• Conditions: Renal Cell Carcinoma
• Intervention / Treatment: Drug: LBH589

Detailed Description

Inhibition of histone deacetylase (HDAC) provides a potential target for cancer treatment. Histones are components of the core proteins of nucleosomes, and acetylation and deacetylation of these proteins play a role in the regulation of gene expression. HDAC activity is known to be increased in many types of malignant cells; HDAC inhibitors have been shown to induce differentiation, cell cycle arrest, and apoptosis in cultured tumor cells. Since this tumor-associated mechanism is common to many types of cancer, HDAC may have a broad role in cancer treatment.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists
  • Georgia
    • Gainesville, Georgia, United States, 30501
      • Northeast Georgia Medical Center
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70806
      • Baton Rouge General Medical Center
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • Center for Cancer and Blood Disorders
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Methodist Cancer Center
  • New Jersey
    • Morristown, New Jersey, United States, 07960
      • Hematology Oncology Associates of Northern NJ
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Oncology Hematology Care
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Chattanooga Oncology Hematology Associates
    • Nashville, Tennessee, United States, 37023
      • Tennessee Oncology, PLLC
  • Virginia
    • Newport News, Virginia, United States, 23601
      • Peninsula Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically documented metastatic or locally unresectable clear cell renal carcinoma. In patients with mixed histologies, the clear cell component must comprise > 75% of the cancer.
• Documented disease progression or intolerance while receiving treatment with: a) sunitinib, sorafenib, or both, and b) temsirolimus.
• Maximum of 4 prior systemic regimens allowed and may include other targeted agents, immunotherapy and chemotherapy.
• Measurable disease by RECIST criteria.
• ECOG PS 0 or 1.
• Laboratory values as follows: ANC >= 1500/μL, Hgb >= 9 g/dL, Platelets >= 100,000/uL, AST/SGOT and ALT/SGPT <= 2.5 x ULN or <= 5.0 x ULN in patients with liver metastases, Creatinine <= 2.0 mg/dL Or Calculated Creatinine Clearance >= 50 ml/min, Albumin >= 3 g/dL, Potassium >= lower limit normal (LLN),Phosphorous >= LLN, Calcium >= LLN, Magnesium > LLN
• Women of childbearing potential must have a negative serum or urine pregnancy test performed within 7 days prior to start of treatment.
• Life expectancy > 12 weeks.
• Accessible for treatment and follow-up.
• All patients must be able to understand the nature of the study and give written informed consent prior to study entry.

Exclusion Criteria:

• Age < 18 years of age.
• Prior treatment with an HDAC inhibitor.
• Impaired cardiac function
• Ongoing therapy with antiarrhythmics or other medications associated with QTc prolongation.
• Uncorrected hypokalemia or hypomagnesemia.
• Uncontrolled hypertension or cardiac arrhythmias.
• Active parenchymal brain metastases. Patients who have had brain metastases resected, or have received radiation therapy ending > 8 weeks prior to study entry are eligible if they meet all of the following criteria: 1) residual neurologic symptoms < grade 1, 2) no dexamethasone requirement, 3) follow-up MRI shows regression of lesions after treatment, with no new lesions appearing.
• Active meningeal metastases.
• Known diagnosis of human immunodeficiency virus (HIV) infection.
• Unresolved diarrhea > CTCAE grade 1.
• Concomitant requirement for medication classified as CYP3A4 inducers or inhibitors.
• Chemotherapy, investigational drug therapy, major surgery < 4 weeks prior to starting study drug or patients that have not recovered from side effects of previous therapy.
• Patient is < 5 years free of another primary malignancy except if the other primary malignancy is not currently clinically significant or requiring active intervention, or if other primary malignancy is a basal cell skin cancer or a cervical carcinoma in situ. Existence of any other malignant disease is not allowed.
• Concomitant use of any anti-cancer therapy or radiation therapy.
• Pregnant or breast feeding or female of reproductive potential not using 2 effective methods of birth control.
• Male patients whose sexual partners are women of childbearing potential not using effective birth control.
• Patients with gastrointestinal (GI) tract disease, causing the inability to take oral medication, malabsorption syndrome, a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease.
• Other concurrent severe, uncontrolled infection or intercurrent illness
• Abnormal thyroid function (TSH or free T4) detected at screening. Patients with known hypothyroidism who are stable on thyroid replacement are eligible.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Treatment; LBH589 will be administered orally at a dose of 45 mg (1 - 5 mg capsule and 2 - 20 mg capsules) on Monday and Thursday of each week (twice weekly). To enable patients to undergo cardiac monitoring, all patients must begin treatment on a Monday, and continue Monday/Thursday dosing during subsequent treatment cycles. Patients with objective response or stable disease after re-evaluation at week 8 will continue LBH589 at the same dose until disease progression, unacceptable toxicity and/or at the discretion of the investigator.

Drug: LBH589; LBHLBH589 will be administered orally at a dose of 45 mg (1 - 5 mg capsule and 2 - 20 mg capsules) on Monday and Thursday of each week (twice weekly). To enable patients to undergo cardiac monitoring (Section 3.5.2), all patients must begin treatment on a Monday, and continue Monday/Thursday dosing during subsequent treatment cycles.; Other Names: Panobinostat

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	Progression-free survival was defined as the interval from the date of first treatment with panobinostat until the date that disease progression or death occurred. Progressive disease (PD): 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing ≥Grade 2 Adverse Events	An adverse event (AE) is the development of an undesirable medical condition, or the deterioration of a preexisting medical condition (other than the condition that is being treated by the trial) following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. The number of participants experiencing such adverse events that are related to the study drug are reported here.	18 months
Number of Participants With Overall Response	Response was evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee. Overall response is defined as the proportion of participants whose disease either decreased (partial response- PR) or disappeared (Complete response - CR). Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD	18 months

Collaborators and Investigators

• Sponsor: SCRI Development Innovations, LLC
• Collaborators: Novartis
• Investigators: Study Chair: John D. Hainsworth, M.D., SCRI Development Innovations, LLC

Publications and helpful links

General Publications

• Hainsworth JD, Infante JR, Spigel DR, Arrowsmith ER, Boccia RV, Burris HA. A phase II trial of panobinostat, a histone deacetylase inhibitor, in the treatment of patients with refractory metastatic renal cell carcinoma. Cancer Invest. 2011 Aug;29(7):451-5. doi: 10.3109/07357907.2011.590568. Epub 2011 Jun 22.

Study record dates

Study Major Dates

• Study Start: January 1, 2008
• Primary Completion (Actual): March 1, 2010
• Study Completion (Actual): June 1, 2010

Study Registration Dates

• First Submitted: October 26, 2007
• First Submitted That Met QC Criteria: October 26, 2007
• First Posted (Estimate): October 29, 2007

Study Record Updates

• Last Update Posted (Actual): November 23, 2021
• Last Update Submitted That Met QC Criteria: October 26, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Refractory; LBH589; Renal Cell Carcinoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Carcinoma, Renal Cell; Carcinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Histone Deacetylase Inhibitors; Panobinostat
• Other Study ID Numbers: SCRI GU 49