bryostatin-1 and Carcinoma--Renal-Cell

Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR) complex 1, is approved for the treatment of metastatic renal cell carcinoma (RCC). Bryostatin-1 inhibits protein kinase C, a downstream effector of mTOR complex 2. We observed antitumor effects with the combination of temsirolimus and bryostatin-1 in RCC cell lines. METHODS. Four cohorts of patients received weekly bryostatin-1 (20 μg/m²) with temsirolimus (10, 15, 25, or 37.5 mg) in 28-day cycles.. Thirty patients received a total of 138 cycles across four dose levels. Twenty-five patients had RCC (17 clear cell, 7 papillary, and 1 unclassified). Two sarcoma patients with prior cytotoxic therapy experienced dose-limiting toxicity at 15 mg of temsirolimus (grade 3 neutropenia and grade 3 hypophosphatemia). Subsequently, patients with prior cytotoxic therapy were excluded. Two additional dose-limiting toxicities were noted with 37.5 mg of temsirolimus (grade 3 neutropenia and grade 3 creatinine elevation). Consequently, the maximum tolerated dose was defined as temsirolimus at 25 mg and bryostatin-1 at 20 μg/m² every 28 days. Of the 25 RCC patients, 3 patients had partial responses that lasted for 14 months, 28 months, and ≥ 80 months, respectively. Partial responses were seen in both clear cell and papillary histology.. This combination of 37.5 mg of temsirolimus with 20 μg/m² of bryostatin-1 was reasonably safe and well tolerated. Durable responses were observed in 3 of 25 patients with RCC.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bryostatins; Carcinoma, Renal Cell; Drug Administration Schedule; Humans; Kidney Neoplasms; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; Protein Kinase C; Protein Kinase Inhibitors; Sarcoma; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Bryostatin-1 is a PKC modulator with direct anti-tumor activity and immunomodulatory properties. We combined different doses of Bryostatin-1 with IL-2 to determine effects on clinical response rate and T cell phenotype in patients with advanced kidney cancer.. IL-2 naïve patients were given 11 x 10(6) IU subcutaneously of IL-2 on days 1-4, 8-11, and 15-18 of every 28-day cycle. Twenty four patients were randomized to treatment cohorts of 5, 15 or 25 mcg/m2 of Bryostatin-1 on days 1, 8 and 15, starting in the second cycle. An additional nine, non-randomized patients were given 35 mcg/m2. Lymphocytes were analyzed for number, activation status, and production of IL-2, IL-4 and IFN-gamma. Response evaluation was performed every 3 cycles.. Common grade 3 toxicities included fatigue (5), nausea/vomiting (5), myopathy (3), dyspnea (3), and syncope (3). Four patients, in the two highest dose cohorts, demonstrated evidence of tumor shrinkage, although there was only 1 objective PR. The median time to progression was 104 days (95% CI 88-120) and the median survival was 452 days (95% CI = 424-480). There was no significant boosting effect of Bryostatin-1 on lymphocytes.. The addition of Bryostatin-1 to IL-2 was well tolerated, but the overall response rate was low (3.2%), indicating that further studies with this combination are not warranted.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bryostatins; Carcinoma, Renal Cell; Cytokines; Dose-Response Relationship, Drug; Female; Humans; Interleukin-2; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; T-Lymphocytes; Treatment Failure

We conducted a Phase II trial of bryostatin-1, an inhibitor of protein kinase C, in advanced renal cell carcinoma to measure toxicity, response rate, time to progression, and induction of cytokines.. A total of 32 patients (26 male and 6 female) received bryostatin-1 at 35-40 microg/m(2) i.v. over 1 h on days 1, 8, and 15 of each 4-week cycle. Plasma interleukin-6, tumor necrosis factor-alpha, and C-reactive protein levels were assayed pretreatment, 1 and 23 h after completion of bryostatin-1 infusion at weeks 1 and 5.. Cycles (102) of bryostatin-1 were given (median 2, range 1-8). The most common grade 1 or 2 toxicities were myalgias (46.8%), fatigue (59.3%), and dyspnea (18.8%). Grade 3-4 toxicity included myalgias (40.6%), ataxia (9.3%), and dyspnea (15.6%). Four (12%) patients experienced cardiac events while on study (cardiac arrhythmias and congestive heart failure occurred in 2 patients, and 2 patients had fatal cardiac arrests). Of 32 patients evaluable for response, 2 (6.3%) had partial responses lasting 9 with 6 months. A total of 15 patients (46.8%) had stable disease, and 6 (18.8%) patients had stable disease for >or=6 months. Plasma interleukin-6 increased >or=2-fold over baseline measurements in 5 of 17 patients (29.4%) but did not correlate with response or toxicity.. Although weekly bryostatin-1 at 35-40 microg/m(2) produced a low proportion of objective responses, prolonged (>6 months) stable disease or partial remission in 25% of patients suggests that this agent, or other inhibitors of protein kinase C, may have a role in the treatment of renal cell carcinoma, perhaps in combination with other agents.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bryostatins; C-Reactive Protein; Carcinoma, Renal Cell; Disease Progression; Enzyme Inhibitors; Female; Humans; Interleukin-6; Kidney Neoplasms; Lactones; Macrolides; Male; Middle Aged; Neoplasm Metastasis; Protein Kinase C; Time Factors; Tumor Necrosis Factor-alpha

Protein kinase C (PKC) has a critical role in several signal transduction pathways, and is involved in renal cancer pathogenesis. Bryostatin-1 modulates PKC activity and has antitumour effects in preclinical studies. We conducted a multicentre phase II clinical trial in patients with advanced renal cancer to determine the response rate, immunomodulatory activity and toxicity of bryostatin-1 given as a continuous 24 h infusion weekly for 3 out of 4 weeks at a dose of 25 mug m(-2). In all, 16 patients were recruited (11 males and five females). The median age was 59 years (range 44-68). Patients had been treated previously with nephrectomy (8) and/or interferon therapy (9) and/or hormone therapy (4) and/or radiotherapy (6). Eight, five and three patients had performance statuses of 0, 1 and 2, respectively. A total of 181 infusions were administered with a median of 12 infusions per patient (range 1-29). Disease response was evaluable in 13 patients. Three patients achieved stable disease lasting for 10.5, 8 and 5.5 months, respectively. No complete responses or partial responses were seen. Myalgia, fatigue, nausea, headache, vomiting, anorexia, anaemia and lymphopenia were the commonly reported side effects. Assessment of biological activity of bryostatin-1 was carried out using the whole-blood cytokine release assay in six patients, two of whom had a rise in IL-6 levels 24 h after initiating bryostatin-1 therapy compared to pretreatment values. However, the IL-6 level was found to be significantly lower at day 28 compared to the pretreatment level in all six patients analysed.

Topics: Adult; Aged; Antineoplastic Agents; Bryostatins; Carcinoma, Renal Cell; Female; Humans; Infusions, Intravenous; Interleukin-6; Kidney Neoplasms; Lactones; Macrolides; Male; Middle Aged; Treatment Outcome

Patients with metastatic renal cell carcinoma have a poor prognosis and no standard therapy is available. The authors performed a Phase II trial of the novel agent bryostatin-1 in this patient population.. In all, 30 patients with measurable, previously untreated metastatic renal cell carcinoma were studied. Patients had excellent physiologic reserve and preserved performance status. Bryostatin-1 (25 microg/m(2)) was given in the PET (polyethyleneglycol, ethanol, and Tween 80) formulation as a 30-minute intravenous infusion on Days 1, 8, and 15 of each 28-day cycle. In general, treatment was continued until disease progression.. Two patients had significant objective responses, although methodologic problems made interpretation difficult. The median time to progression for all patients was 2.1 months; the median overall survival was 13.1 months. The treatment was generally well tolerated. Myalgia was the most common adverse event. One patient died while on study. This was a sudden death for a patient receiving a 15th cycle of therapy. Aside from this patient (for whom the correlation of study drug to death was not clear), no Grade 4 nonhematologic toxicity was encountered in more than 150 treatment courses delivered.. There is minimal, if any, clinically relevant single-agent activity of bryostatin-1 at this dose and schedule for patients with metastatic renal cell carcinoma.

Topics: Adult; Aged; Antineoplastic Agents; Bryostatins; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Lactones; Macrolides; Male; Middle Aged; Survival Analysis