View Clinical Trial (Medical Research Study)
A Phase I/II Study of the HDAC Inhibitor LBH589 in Combination With the mTOR Inhibitor RAD001 in Metastatic Renal Cell Carcinoma
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Buffalo |
| State: |
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New York |
| Zip Code: |
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14263 |
| Conditions: |
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Renal Cell Carcinoma - Metastatic Renal Cell Carcinoma |
| Purpose: |
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This study will see how these two commonly used treatments (Everolimus and Panobinostat)
work together in treating kidney cancer. These two drugs have already progressed through the
earliest types of research trials, such as a dose finding trial. We will combine these drugs
at doses that were found to be safe when given alone, and will watch participants carefully
to determine how well this drug combination is working to control your kidney cancer.
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| Study Summary: |
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The tyrosine kinase inhibitors sunitinib and sorafenib which target the VEGF pathway are now
standard of care for renal cell carcinoma patients and are used as first-line agents.
mTOR inhibitors which have been shown to have direct antitumor effects against renal cell
carcinoma cells and also decrease angiogenesis by downregulation of HIF-1ά are another
promising class of agents in renal cell carcinoma. Recently, the mTOR inhibitor temsirolimus
was approved as a first-line agent for metastatic renal cell carcinoma in patients with
decreased performance status. An improvement in overall-survival was seen when compared to
the interferon alpha treatment group.
We have recently shown in preclinical studies that HDAC inhibitors induce HIF-1ά inhibition
by increased acetylation and polyubiquitination and subsequently increased degradation.
Furthermore, in preclinical models we have demonstrated the in vivo and in vivo
antiangiogenic activity for the single agent LBH589.
Based on these data, we hypothesized that the combination of a HDAC inhibitor and an mTOR
inhibitor may have greater antiangiogenic and antitumor activity than single agents in a
renal cell carcinoma model.
Taken together, these data suggests that the antiangiogenic activity of the HDAC inhibitor
LBH589 and its direct antitumor effect may increase the therapeutic effect of RAD001,
further delay disease progression and increase progression-free survival in patients with
metastatic renal cell carcinoma (RCC). With this clinical trial, we will test for the
efficacy of this particular combination as second line treatment in patients with metastatic
renal cell carcinoma progressing after prior cytokine and /or tyrosine kinase inhibitor
treatment.
This is a dose escalation study. The Phase II dose will be based upon Phase I findings.
Patients will be allowed to remain on therapy provided that they are tolerating therapy and
do not develop progressive disease.
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| Criteria: |
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Inclusion Criteria:
Patients must have histologically confirmed metastatic or unresectable renal cell
carcinoma. Predominant clear cell component is required. Pure papillary and chromophobe
renal cell carcinoma, collecting duct tumors and transitional cell carcinoma are not
eligible.
Patients must have at least one measurable site of disease according to RECIST criteria
that has not been previously irradiated. If the patient has had previous radiation to the
marker lesion(s), there must be evidence of progression since radiation.
Patients must have metastatic disease which has progressed on or within 6 months of
stopping treatment with VEGFR receptor tyrosine kinase inhibitors. Previous therapy with
bevacizumab, interleukin 2, or interferon alpha is also permitted.
Male or female patients ≥18 years old.
Ability to provide written informed consent obtained prior to participation in the study
and any related procedures being performed.
Patients must meet the following laboratory criteria:
- Serum albumin ≥3 g/dL
- AST/SGOT and ALT/SGPT ≤2.5 x upper limit of normal (ULN)
- Serum bilirubin ≤1.5 x ULN
- Serum creatinine ≤1.5 x ULN or 24 hour creatinine clearance ≥ 50 ml/min
- Serum potassium ≥LLN
- Serum phosphorus ≥LLN
- Serum total calcium (corrected for serum albumin) or serum ionized calcium ≥LLN
- Serum magnesium ≥LLN
- TSH and free T4 within normal limits (WNL) (patients may be on thyroid hormone
replacement)
- Adequate bone marrow function as shown by: ANC ≥1.5 x 10 to the 9th power/L,
Platelets ≥100 x 10 to the 9th power, Hb >9 g/dL
- INR <1.3
- Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤2.5 x
ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only
be included after initiation of appropriate lipid lowering medication.
Baseline MUGA or ECHO must demonstrate LVEF ≥ the lower limit of the institutional normal.
ECOG Performance Status of ≤2
Exclusion Criteria:
Prior treatment with an HDAC or mTOR inhibitor
Patients currently receiving anticancer therapy within 4 weeks of the study drug
(including chemotherapy, radiation therapy, antibody therapy, etc.)
Patients who have had major surgery or significant traumatic injury within 4 weeks of
start of study drug patients who have not recovered from the side effects of any major
surgery (defined as requiring general anesthesia) or patients that may require major
surgery during the course of the study
Prior treatment with any investigational drug within the preceding 4 weeks
Patients receiving chronic, systemic treatment with corticosteroids or another
immunosuppressive agent. Topical or inhaled corticosteroids are allowed
Patients should not receive immunization with attenuated live vaccines within one week of
study entry or during study period
Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticosteroids for brain or leptomeningeal metastases
Other malignancies within the past 3 years except for adequately treated carcinoma of the
cervix or basal or squamous cell carcinomas of the skin
Patients who have any severe and/or uncontrolled medical conditions or other conditions
that could affect their participation in the study such as:
- Symptomatic congestive heart failure of New York Heart Association Class III or IV)
- Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction
within 6 months of study drug, serious uncontrolled cardiac arrhythmia or any other
clinically significant heart disease
- Concomitant use of drugs with a risk of causing torsades de pointes
- Severly impaired lung function (O2 saturation 90% or less at rest on room air
- Uncontrolled diabetes as defined be fasting serum glucose >1.5 ULN
- Active (acute or chronic) or uncontrolled severe infections
- Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent
hepatitis
A know history of HIV seropositivity
Impairment of gastrointestinal (GI) function or GI disease that may significantly alter
the absorption of oral LBH589 or RAD001 (e.g., ulcerative disease, uncontrolled nausea,
vomiting, diarrhea, malabsorption syndrome or small bowel resection)
Patients with an active, bleeding diathesis
Female patients who are pregnant or breast feeding or adults of reproductive potential who
are not using effective birth control methods. If barrier contraceptives are used, these
must be continued throughout the trial by both sexes. Hormonal contraceptives are not
acceptable as a sole method of contraception. (Women of childbearing potential must have a
negative urine or serum pregnancy test within 7 days of the first administration of oral
LBH589 and RAD001)
Patients who have received prior treatments with an mTOR inhibitor (sirolimus,
temsirolimus, everolimus).
Patients with a know hypersensitivity to RAD001 (everolimus) or other rapamycins
(sirolimus, temsirolimus) or to its excipients
History of non-compliance to medical regimens
Patients unwilling to or unable to comply with the protocol
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| NCT ID: |
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NCT01037257 |
| Primary Contact: |
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Principal Investigator
Roberto Pili, MD
Roswell Park Cancer Institute
AskRPCI
Phone: 1-877-275-7724
Email: AskRPCI@roswellpark.org
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| Backup Contact: |
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N/A |
| Location Contact: |
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Buffalo, New York 14263
United States
There is no listed contact information for this specific location.
Site Status: Recruiting |
| Data Source: |
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ClinicalTrials.gov |
| Date Processed: |
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May 23, 2013 |
| Modifications to this listing: |
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