LBH589 Treatment for Refractory Clear Cell Renal Carcinoma
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
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 Design
Arms and Interventions
| 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:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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
Eligibility Criteria
Criteria
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,
- 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.
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Florida Cancer Specialists | Fort Myers | Florida | United States | 33901 |
| 2 | Northeast Georgia Medical Center | Gainesville | Georgia | United States | 30501 |
| 3 | Baton Rouge General Medical Center | Baton Rouge | Louisiana | United States | 70806 |
| 4 | Center for Cancer and Blood Disorders | Bethesda | Maryland | United States | 20817 |
| 5 | Methodist Cancer Center | Omaha | Nebraska | United States | 68114 |
| 6 | Hematology Oncology Associates of Northern NJ | Morristown | New Jersey | United States | 07960 |
| 7 | Oncology Hematology Care | Cincinnati | Ohio | United States | 45242 |
| 8 | Chattanooga Oncology Hematology Associates | Chattanooga | Tennessee | United States | 37404 |
| 9 | Tennessee Oncology, PLLC | Nashville | Tennessee | United States | 37023 |
| 10 | Peninsula Cancer Institute | Newport News | Virginia | United States | 23601 |
Sponsors and Collaborators
- SCRI Development Innovations, LLC
- Novartis
Investigators
- Study Chair: John D. Hainsworth, M.D., SCRI Development Innovations, LLC
Study Documents (Full-Text)
None provided.More Information
Publications
- SCRI GU 49
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Treatment |
|---|---|
| Arm/Group Description | 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. |
| Period Title: Overall Study | |
| STARTED | 20 |
| COMPLETED | 11 |
| NOT COMPLETED | 9 |
Baseline Characteristics
| Arm/Group Title | Treatment |
|---|---|
| Arm/Group Description | 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. |
| Overall Participants | 20 |
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
9
45%
|
| >=65 years |
11
55%
|
| Sex: Female, Male (Count of Participants) | |
| Female |
12
60%
|
| Male |
8
40%
|
| Region of Enrollment (participants) [Number] | |
| United States |
20
100%
|
Outcome Measures
| Title | Progression-free Survival |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Treatment |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 20 |
| Median (95% Confidence Interval) [months] |
1.7
|
| Title | Number of Participants Experiencing ≥Grade 2 Adverse Events |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Treatment |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 20 |
| Count of Participants [Participants] |
15
75%
|
| Title | Number of Participants With Overall Response |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Treatment |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 20 |
| Count of Participants [Participants] |
0
0%
|
Adverse Events
| Time Frame | ||
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Treatment | |
| Arm/Group Description | 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. | |
All Cause Mortality |
||
| Treatment | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Treatment | ||
| Affected / at Risk (%) | # Events | |
| Total | 6/20 (30%) | |
| Blood and lymphatic system disorders | ||
| Thrombocytopenia | 1/20 (5%) | 1 |
| Gastrointestinal disorders | ||
| Dehydration | 1/20 (5%) | 1 |
| Infections and infestations | ||
| Infection - Other | 1/20 (5%) | 1 |
| Nervous system disorders | ||
| Pain | 1/20 (5%) | 1 |
| Renal and urinary disorders | ||
| Cystitis | 1/20 (5%) | 1 |
| Renal Failure | 1/20 (5%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| Treatment | ||
| Affected / at Risk (%) | # Events | |
| Total | 15/20 (75%) | |
| Blood and lymphatic system disorders | ||
| Neutropenia | 1/20 (5%) | 1 |
| Thrombocytopenia | 8/20 (40%) | 8 |
| Anemia | 6/20 (30%) | 6 |
| Gastrointestinal disorders | ||
| Nausea/Vomiting | 3/20 (15%) | 3 |
| Dehydration | 3/20 (15%) | 3 |
| General disorders | ||
| Fatigue | 7/20 (35%) | 7 |
| Musculoskeletal and connective tissue disorders | ||
| Weakness | 2/20 (10%) | 2 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The sponsor can review/embargo results communications prior to public release for a period that is >60 days but ≤180 days from date submitted to sponsor, who may require changes to the communication in order to remove specifically identified confidential information (other than study data) and/or delay the proposed publication to enable the sponsor to seek patent protection for inventions. The PI may not publish its results until 18 mos. after the trial has been completed at all sites.
Results Point of Contact
| Name/Title | John D. Hainsworth, MD |
|---|---|
| Organization | Sarah Cannon Research Institute |
| Phone | 615-329-7274 |
| jhainsworth@tnonc.com |
- SCRI GU 49