A Phase I Study of Gemcitabine, Carboplatin and Lenalidomide (GCL) for Treatment of Patients With Advanced/Metastatic Urothelial Carcinoma (UC) and Other Solid Tumors
- Gemcitabine plus carboplatin is an accepted first-line therapy in patients unfit for
cisplatin chemotherapy with metastatic urothelial carcinoma or other solid tumor
- Both non-clinical and clinical data support targeting angiogenesis in urothelial
carcinoma and other solid tumors.
- Both non-clinical and clinical data support targeting the immune system in urothelial
carcinoma and other solid tumors.
- Lenalidomide has both anti-angiogenic and potent immunomodulatory properties.
- Lenalidomide has been safely coadministered with cytotoxic therapy in patients with
solid tumors and non-clinical studies demonstrate possible synergy with gemcitabine.
- To establish the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of
lenalidomide which can be safely combined with gemcitabine and carboplatin in patients with
advanced/metastatic UC and other solid tumors that are unfit for cisplatin.
- To preliminarily evaluate the progression free survival, response rate and overall
survival in patients with advanced/metastatic UC and other solid tumors treated with
the combination of lenalidomide, gemcitabine, and carboplatin.
- To determine the effects of treatment on a set of 4 laboratory parameters (including
Treg, sIL-2R, VEGF and CTC.) in the expansion cohort of patients with bladder cancer
treated at the MTD.
- Adult patients with histologic documentation of an advanced solid tumor with
unresectable or metastatic disease.
- Urothelial cancer patients should be ineligible for cisplatin based on one or more of
- Calculated creatinine clearance of < 60 mL/min (but greater than or equal to 30
- Solitary kidney
- Karnofsky Performance Status < 80%
- No prior combination systemic chemotherapy for metastatic disease allowed for patients
with UC, except single agent radiosensitizing chemotherapy (not considered prior
systemic therapy), or prior neoadjuvant or adjuvant systemic chemotherapy (including
cisplatin-based) is allowed provided if it was completed >= 6 months prior to diagnosis
of metastatic disease; or prior intravesical therapy is permitted. Up to 1 line of
chemotherapy in the metastatic setting is permitted for non UC patients.
- Laboratory evaluation must meet safety requirements, including a creatinine clearance
greater than 30 using the Cockroft-Gault formula; may not be pregnant or
- This is a single-institution phase I study of gemcitabine (1000 mg/m2 on days 1 and 8) and
(AUC 5 on day 1) plus escalating doses of lenalidomide (GCL) in patients with
advanced/metastatic UC and other solid tumors ineligible for cisplatin therapy. Lenalidomide
will be administered once daily on days 1 through 14 every 21 days at escalating dose. An
expansion cohort at the MTD of an additional 15 patients with urothelial carcinoma will be
enrolled in order to determine whether there are differences between pre-treatment and
post-treatment levels of the following parameters: Treg, sIL-2R, VEGF and CTC.
- Patients will receive a total of 6 cycles of gemcitabine and carboplatin in combination
with lenalidomide unless disease progression or unacceptable toxicity occurs. Patients
who achieve stable disease, a partial response, or a complete response after completion
of 6 cycles will be eligible to continue lenalidomide alone at the same dose and
schedule until disease progression. Restaging evaluations will occur after every 3
cycles of treatment (approximately 9 weeks).
- Based on a standard 3+3 design with 4 dose levels per cohort, a maximum of 24 patients,
with the potential for an additional 3 patients with CrCl> 60 mL/min, may need to be
evaluated to determine the dose limiting toxicities (DLTs) and maximum tolerated dose
(MTD) of lenalidomide in this combination therapy. With an expansion cohort of 15
patients at MTD, a total of 42 subjects may be enrolled over 1.5 -3 years.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To establish the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of lenalidomide which can be safely combined with gemcitabine and carboplatin in patients with advanced/metastatic UC and other solid tumors that are unfit for cispla...
Andrea B Apolo, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|