Renal Cell Carcinoma
Conditions
Keywords
Renal Cell Carcinoma, Refractory, LBH589
Brief summary
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.
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.
Interventions
DRUGLBH589
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.
Sponsors
Novartis
SCRI Development Innovations, LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | 18 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing ≥Grade 2 Adverse Events | 18 months | 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. |
| Number of Participants With Overall Response | 18 months | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Treatment |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 11 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 15 / 20 |
| serious Total, serious adverse events | 6 / 20 |
Outcome results
Primary
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.
Time frame: 18 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment | Progression-free Survival | 1.7 months |
Secondary
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.
Time frame: 18 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Number of Participants Experiencing ≥Grade 2 Adverse Events | 15 Participants |
Secondary
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
Time frame: 18 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Number of Participants With Overall Response | 0 Participants |