Renal cell cancer, the most common type of kidney cancer, develops in the lining of the kidney tubules. Several drugs are being studied to treat the cancer as a single agent or in combination with other anti-tumor drugs. Now, a phase I trial has reported the safety and efficacy of the combination treatment involving temsirolimus (TEM) and bryostatin (BRYO) for metastatic renal cell carcinoma (RCC). Findings of the study were presented at the annual meeting of the American Society of Clinical Oncology, held at Orlando, Florida, during May 29-June 2, 2009.
Elizabeth R Plimack, Medical Oncologist and Attending Physician at the Fox Chase Cancer Center, Philadelphia, and colleagues, conducted the phase I trial in 23 patients, 18 with RCC and the remaining 5 non-RCC patients with sarcoma or paraganglioma. The subjects were divided into four cohorts of 3-6 patients each, to receive 20 μg/m2 BRYO, weekly, across 28-day cycles, in combination with TEM in either of the doses: 10, 15, 25, or 37.5 mg. A median of two prior therapies, including immunotherapy, tyrosine kinase inhibitors, bevacizumab, were carried out in 15 patients, while the remaining had no prior treatment. First cycle toxicity of ≥grade 3 was considered as the dose-limiting toxicity (DLT).
Up to three treatment cycles were conducted on the 5 non-RCC patients, of whom two had prior cytotoxic therapy-developed DLT (grade 3 neutropenia and hypophosphatemia) at 15 mg dosage. Following this, prior cytotoxic therapy patients were eliminated from the study. Median progression-free survival of 7.8 months and 5.7 months were reported in all patients and previously treated patients, respectively. One patient from the RCC group withdrew before receiving treatment. Among the remaining 17 RCC patients receiving treatment, stable disease (SD) was noted in 9 and partial responses (PRs) in three patients. For more than two years after the treatment withdrawal, partial response was seen in one treatment naïve patient who received 15 mg TEM. First cycle DLTs were not reported in RCC patients. However, major toxicities such as grade 3/4 thrombosis, grade 4 thrombus/left ventricle dysfunction and grade 3 dyspnea/pneumonitis were observed at 37.5 mg, 15 mg, and 10 mg doses of TEM, respectively, during the later cycles. Of the patients receiving 37.5 mg TEM, one showed grade 4 hypercholesterolemia, and another developed grade 4 triglyceride elevation; both were reversed on treatment.
The study findings demonstrated that full doses of both agents in the TEM-BRYO combination were effective and provided long-lasting PR and SD in patients with refractory RCC, when scheduled in multiple cycles, on a weekly basis.
Earlier, Haas et al (Clinical Cancer Research, 2003) carried out a phase II trial to assess the induction of cytokines, response rate, time to progression, and toxicity of bryostatin-1, in advanced RCC. The study comprised of 32 patients receiving intravenous bryostatin-1 at dose 35-40 μg/m2, for over an hour, on the 1st, 8th, and 15th day of every 4-week cycle.
The common toxicities included fatigue, myalgias, dyspnea, ataxia, fatigue and cardiac events (4 cases) such as arrhythmias, congestive heart failure and fatal cardiac arrests. Fifteen patients showed stable disease, with six demonstrating disease stability for ≥6 months. Partial responses of six months were observed in two patients. An increase of plasma interleukin-6 levels to two or more times from the baseline were noted in 5patients, with no association to response or toxicity. The researchers noted that with lower objective responses, prolonged disease stability or partial remission in approximately 25% of cases in the study, bryostatin-1 at 35-40 μg/m2, could be a potential anti-tumor agent against renal cell carcinoma, possibly in combination with other drugs.
Bryostatin, a macrolide lactone isolated from the bryozoan, Bugula neritina, is a neoplastic agent that is currently under investigation for its therapeutic applications in oncology, Alzheimer disease and stroke. Temsirolimus (Torisel® | Wyeth, Inc.) was approved by the US FDA in May 2007, for the treatment of metastatic renal cell carcinoma.
According to the American Cancer Society, approximately 57,760 new cases and 12,980 deaths owing to cancer of the renal cell and renal pelvis are estimated for the year 2009 in the US. Currently employed treatment options include radiation therapy, arterial embolization, nephrectomy, which depend on the stage of the disease, age and general health of the patient.
The positive phase I results on the safety and efficacy of the combination therapy, paves the way for the initiation of further investigation into the development of a new treatment paradigm involving temsirolimus, an mTOR inhibitor, and bryostatin, a protein kinase C inhibitor, against renal cell cancer.
References
1. Plimack ER, Wong Y, Mehren MV, et al. A phase I study of temsirolimus (TEM) and bryostatin (BRYO) in patients with metastatic renal cell carcinoma (RCC). J Clin Oncol. 2009;27(suppl; abstr 5111):15s.
2. Two-Drug Combination Appears Safe and Active in Metastatic Kidney Cancer. Press Release. Fox Chase Cancer Center. Last Accessed June 5, 2009.
3. Haas NB, Smith M, Lewis N, et al. Weekly bryostatin-1 in metastatic renal cell carcinoma: a phase II study. Clin Cancer Res. 2003 Jan;9(1):109-14.
