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Brian I Rini

Publications and source records attributed to Brian I Rini.

At least 37 records · Page 2Linked to original sources
PubMed2006

Clinical activity of sorafenib and sunitinib in renal cell carcinoma refractory to previous vascular endothelial growth factor-targeted therapy: two case reports.

Sunitinib and sorafenib are multitargeted receptor tyrosine kinase inhibitors of the vascular endothelial growth factor and platelet-derived growth factor receptor families with antiangiogenic and antitumor activity in metastatic renal cell carcinoma. The utility of these agents in patients refractory to previous treatment with the other agent is unknown. We report 2 cases highlighting that efficacy of these agents is possible after failure of the other agent. Further prospective study is needed.

Antineoplastic Agents↗
PubMed2006

Current data with mammalian target of rapamycin inhibitors in advanced-stage renal cell carcinoma.

Mammalian target of rapamycin (mTOR) is the key regulator of cell growth and proliferation. Alterations in the mTOR signaling pathway can lead to neoplastic transformation and progression. The inhibition of mTOR blocks the progression of the cell cycle from G1 to S phase, leading to cell growth arrest and apoptosis. Thus, mTOR is a promising target for the treatment of human malignancies. Rapamycin and its analogues, including temsirolimus, everolimus, and AP23573, block the mTOR signaling pathway and induce a cellular state akin to starvation, with significant antitumor activity in a variety of malignancies, including renal cell carcinoma (RCC). Current data from ongoing clinical trials suggest that mTOR-targeted therapy with rapamycin derivatives is well tolerated with significant clinical activity in patients with advanced-stage RCC. Specifically, temsirolimus as monotherapy has demonstrated improved progression-free and overall survival in patients with poor-risk advanced-stage RCC. Everolimus has also demonstrated promising antitumor activity in patients with metastatic RCC. However, optimal dose, treatment schedule, selection of patients, and appropriate combination strategies with other novel agents need to be defined for mTOR-targeted therapies in the treatment of advanced-stage RCC.

Antineoplastic Agents↗
PubMed2005

Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma.

PURPOSE: Renal cell carcinoma (RCC) is characterized by loss of von Hippel Lindau tumor suppressor gene activity, resulting in high expression of pro-angiogenic growth factors: vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). SU11248 (sunitinib malate), a small molecule inhibitor with high binding affinity for VEGF and PDGF receptors, was tested for clinical activity in patients with metastatic RCC. PATIENTS AND METHODS: Patients with metastatic RCC and progression on first-line cytokine therapy were enrolled onto a multicenter phase II trial. SU11248 monotherapy was administered in repeated 6-week cycles of daily oral therapy for 4 weeks, followed by 2 weeks off. Overall response rate was the primary end point, and time to progression and safety were secondary end points. Results Twenty-five (40%) of 63 patients treated with SU11248 achieved partial responses; 17 additional patients (27%) demonstrated stable disease lasting > or = 3 months. Median time to progression in the 63 patients was 8.7 months. Dosing was generally tolerated with manageable toxicities. CONCLUSION: SU11248, a multitargeted receptor tyrosine kinase inhibitor of VEGF and PDGF receptors, demonstrates antitumor activity in metastatic RCC as second-line therapy, a setting where no effective systemic therapy is presently recognized. The genetics of RCC and these promising clinical results support the hypothesis that VEGF and PDGF receptor-mediated signaling is an effective therapeutic target in RCC.

Adult↗
PubMed2005

Prostate cancer immunology: biology, therapeutics, and challenges.

A number of recently developed and promising approaches to antitumoral immunotherapy are being investigated as potential treatments for advanced prostate cancer. These approaches largely revolve around strategies to increase antigen-specific T-cell activation against prostate tumors as well as precise manipulations of critical co-regulatory receptors that help to maintain and prolong the activity of antigen-presenting cells and T cells that are capable of mediating tumor regression. Herein, we describe the experience with the most recent and promising approaches pertaining to prostate cancer immunotherapy. Additionally, we discuss the mechanistic basis for these approaches as well as current limitations that must still be addressed in order to propel immunotherapy into the forefront of prostate cancer treatment.

Humans↗
PubMed2005

A phase I trial of fixed dose rate gemcitabine and capecitabine in metastatic renal cell carcinoma.

BACKGROUND: Metastatic renal cell carcinoma (RCC) has modest response rates to chemotherapy with gemcitabine and 5-fluorouracil (5-FU). Fixed dose rate gemcitabine infusion leads to enhanced intracellular accumulation of drug and possible augmented clinical effect. To determine the toxicity of this combination therapy in metastatic RCC, a Phase I trial was conducted. METHODS: Patients with metastatic RCC were enrolled in a Phase I dose escalation trial. Patients received fixed dose rate gemcitabine on Days 1, 8, and 15 in combination with capecitabine, an oral 5-FU analog, given on Days 1-21 of a 28-day cycle. RESULTS: Nine patients were enrolled at one of two dose levels. The initial dose level produced dose-limiting toxicity (DLT), including prominent palmar-plantar erythrodysesthesia (hand-foot syndrome). A modified second dose level also resulted in DLT, precluding further study. No central nervous system (CNS) toxicity was observed in three patients with CNS metastases. Two patients demonstrated an objective partial response. CONCLUSIONS: Fixed dose rate gemcitabine in combination with capecitabine produced unacceptable toxicity in patients with advanced RCC. Further development of this schedule in RCC cannot be recommended.

Adult↗
PubMed2005

Renal cell carcinoma.

PURPOSE OF REVIEW: This review focuses on recent developments in the biology and clinical therapeutics of renal cell carcinoma. Given historically limited advances in this disease, a more thorough understanding and testing of rationally targeted agents is needed. RECENT FINDINGS: Von Hippel-Lindau gene inactivation is observed in most clear cell renal carcinoma, driving the malignant phenotype. The resulting vascular endothelial growth factor overexpression has been targeted though various approaches, with a clear signal of anti-tumor activity. In addition, immunotherapy remains a therapeutic standard in renal cell carcinoma and an area of ongoing investigation. Observation of small renal masses may represent a viable clinical option. SUMMARY: Renal cell carcinoma has become a model disease for rationally targeted therapeutics based on significant understanding of the underlying biology. Recent advances have increased the potential for meaningful improvements in clinical outcomes for renal cell carcinoma patients.

Angiogenesis Inhibitors↗
PubMed2005

Molecularly targeted therapy in renal cell carcinoma.

Recent developments in the molecular biology of renal cell carcinoma have identified multiple pathways associated with the development of this cancer. Multiple strategies have been investigated targeting these pathways, with significant clinical benefits shown in early studies. This review aims to overview the findings of recent clinical trials and clarify the development of these compounds for use in renal cell carcinoma. The authors also aim to clarify the molecular pathways implicated in renal cell carcinoma and the clinical results in metastatic renal cell carcinoma with agents targeting these pathways. The relevant literature was reviewed concerning pathways implicated in the pathophysiology of renal cell carcinoma including pathways activated secondary to von Hippel-Lindau gene inactivation and PI-3 kinase/Akt/mammalian target of rapamycin pathway activation. Therapeutic targeting based upon underlying molecular biology in renal cell carcinoma has strong rationale. Substantial clinical activity has been reported with various agents targeting these pathways, most notably with vascular endothelial growth factor-targeted therapy. However, investigation is needed to optimally utilize these agents at the appropriate stage of disease and in the best combinations for maximal clinical benefit.

Animals↗
PubMed2005

VEGF-targeted therapy in metastatic renal cell carcinoma.

PURPOSE: To review the biology of renal cell carcinoma (RCC) and the clinical results of vascular endothelial growth factor (VEGF) blockade in metastatic RCC. METHODS: A review of relevant published literature regarding VEGF, von Hippel-Lindau (VHL) gene inactivation, and VEGF overexpression in RCC was performed. Further, a review of the mechanism, toxicity, and clinical development of VEGF-targeted therapy in metastatic RCC was undertaken. RESULTS: VHL tumor suppressor gene inactivation is observed in the majority of clear cell RCC cases, leading to VEGF overexpression. Therapy with agents directed against the VEGF protein or the VEGF receptor have demonstrated initial clinical activity in metastatic RCC. CONCLUSIONS: Therapeutic targeting of VEGF in RCC has strong biologic rationale. Substantial clinical activity has been reported in initial clinical trials with VEGF-targeting agents. Further investigation is needed to optimally use these agents for maximal clinical benefit.

Carcinoma, Renal Cell↗
PubMed2005

Antigen-presenting cells 8015 (Provenge) in patients with androgen-dependent, biochemically relapsed prostate cancer.

BACKGROUND: Antigen-presenting cells 8015 (APC8015; Provenge) is an immunotherapeutic product designed to initiate a T-cell-mediated immune response against prostatic acid phosphatase, an antigen overexpressed in 95% of prostate cancer cells. In phase I/II trials, APC8015 has shown immunologic and clinical responses in patients with androgen-independent prostate cancer. This phase II trial was conducted to assess the prostate-specific antigen (PSA)-modulating effects of APC8015 in patients with androgen-dependent prostate cancer (ADPC) with biochemical progression. PATIENTS AND METHODS: Patients with nonmetastatic recurrent disease as manifested by increasing PSA levels (0.4-6.0 ng/mL) and who had undergone previous definitive surgical or radiation therapy were enrolled. Therapy consisted of APC8015 infusion on weeks 0, 2, and 4 (ie, 3 infusions). Prostate-specific antigen was measured at baseline and monthly until disease progression, defined as a doubling of the baseline or nadir PSA value (whichever was lower) to > or = 4 ng/mL or development of distant metastases. RESULTS: Thirteen of 18 patients demonstrated an increase in PSA doubling time (PSADT), with a median increase of 62% (4.9 months before treatment vs. 7.9 months after treatment; P = 0.09; signed-rank test). CONCLUSION: Therapy was well tolerated. APC8015 as single-agent immunotherapy for patients with ADPC and biochemical progression did not result in > or = 50% decrease in PSA from baseline levels but did appear to modulate PSADT in some patients. Further manipulations of host immunity may be required to achieve a significant antitumor effect.

Adenocarcinoma↗
PubMed2005

SU11248 and AG013736: current data and future trials in renal cell carcinoma.

Several molecular pathways are implicated in renal cell carcinoma (RCC) pathogenesis, including the von Hippel-Lindau gene inactivation leading to vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) expression. SU11248 and AG013736 are small-molecule inhibitors of the tyrosine kinase portion of the VEGF and PDGF receptors. Substantial clinical activity has been reported for these agents in metastatic RCC trials, leading to additional investigations in a variety of settings.

Antineoplastic Agents↗
PubMed2004

Biology and clinical development of vascular endothelial growth factor-targeted therapy in renal cell carcinoma.

PURPOSE: To review the biology of renal cell carcinoma (RCC) leading to vascular endothelial growth factor (VEGF) overexpression and the clinical results of VEGF blockade in metastatic RCC. METHODS: A review of relevant published literature regarding VEGF, von Hippel-Lindau (VHL) gene inactivation and VEGF overexpression in RCC was performed. Further, a review of the mechanism, toxicity, and clinical development of VEGF-targeted therapy in metastatic RCC was undertaken. RESULTS: VEGF is the major proangiogenic protein that exerts a biologic effect through interaction with cellular receptors. The majority of sporadic clear-cell RCC tumors are characterized by VHL tumor suppressor gene inactivation. The resulting VHL gene silencing leads to VEGF overexpression. An antibody to VEGF (bevacizumab) has demonstrated a significant prolongation of time to disease progression compared with placebo in patients with metastatic RCC. Small molecules with inhibitory effects against the VEGF receptor have undergone initial clinical testing in metastatic RCC with substantial objective response rates. CONCLUSION: Therapeutic targeting of VEGF in RCC has strong biologic rationale and preliminary clinical efficacy. Further investigation will determine the optimal timing, sequence, and utility of these agents in RCC.

Adenocarcinoma, Clear Cell↗
PubMed2004

Prospective, multicenter, randomized phase II trial of the herbal supplement, PC-SPES, and diethylstilbestrol in patients with androgen-independent prostate cancer.

PURPOSE: To evaluate the herbal combination, PC-SPES, and diethylstilbestrol (DES) in patients with androgen independent prostate cancer (AIPC). PATIENTS AND METHODS: A randomized phase II study was conducted with cross-over design. Patients were randomly assigned to receive either three PC-SPES capsules orally three times a day or DES 3 mg orally once a day. Prophylactic warfarin was administered. At clinical or prostate-specific antigen progression, patients received the other therapy. The study closed prematurely after PC-SPES was withdrawn from the market. Chemical analyses were performed on multiple lots of PC-SPES. RESULTS: Ninety patients were enrolled, of whom 85 were assessable for response. Prostate-specific antigen declines > or = 50% were noted in 40% (95% CI, 25% to 56%) with PC-SPES, and 24% (95% CI, 12% to 39%) with DES. Median response duration was not reached with PC-SPES, and was 3.8 months with DES. Median time to progression for randomly assigned patients was 5.5 months for PC-SPES and 2.9 months for DES. Common toxicities included mild fatigue, gynecomastia, and mastodynia. Five thromboembolic events occurred (one PC-SPES, four DES). Responses in the cross-over phase were inconclusive. Four lots of PC-SPES had measurable quantities of DES, ranging from 0.01% to 3.1% of the dose used in the DES arm. Ethinyl estradiol was also detected in PC-SPES lots. CONCLUSION: PC-SPES and DES demonstrate activity in AIPC and are well tolerated. However, the synthetic estrogens, DES and ethinyl estradiol, were detected in various lots of PC-SPES, including those used in this trial. Clinical trials that utilize herbal therapies must account for issues of purity and consistency.

Administration, Oral↗
PubMed2004

Time to disease progression to evaluate a novel protein kinase C inhibitor, UCN-01, in renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) is characterized by von Hippel-Lindau gene inactivation and vascular endothelial growth factor (VEGF) overproduction. The mechanism of VEGF overproduction may involve protein kinase C (PKC) delta and zeta isoforms. UCN-01 (7-hydroxystaurosporine) is a selective inhibitor of PKC. Given the historically low objective response rate in RCC, time to disease progression (TTP) as an alternative endpoint was employed to evaluate the antitumor activity of UCN-01 in RCC. METHODS: Patients with progressive, metastatic RCC received UCN-01 intravenously on Day 1 of each 21-day cycle. The initial dose was 90 mg/m(2) and all subsequent doses were 45 mg/m(2) unless modified for toxicity. TTP was the primary endpoint, defined as the period from the first day of treatment until disease progression. Detection of circulating EpCAM-positive renal carcinoma cells was undertaken for predictive or prognostic potential. RESULTS: Twenty-one patients were enrolled in this Phase II study. Accrual was halted after failure to reach a predetermined efficacy requirement with 7 patients remaining disease progression free after 4 months (6 cycles). The median TTP for all patients was 2.67 months (range, 0.4-7.6 months). There were no objective responses. Therapy was generally well tolerated. Thirteen patients had < 0.6 EpCAM-positive cells/mL (considered negative) at all time points measured. Two patients had detectable EpCAM-positive cells at a single time point with other measurements being negative. CONCLUSIONS: TTP is a novel endpoint for the evaluation of agents in RCC. UCN-01 did not demonstrate significant antitumor activity. No evidence for significant circulating EpCAM-positive cells was found in this study cohort.

Adult↗
PubMed2004

Cancer and Leukemia Group B 90206: A randomized phase III trial of interferon-alpha or interferon-alpha plus anti-vascular endothelial growth factor antibody (bevacizumab) in metastatic renal cell carcinoma.

The majority of sporadic clear cell renal cell carcinoma (RCC) is characterized by loss of heterozygosity of the von Hippel-Lindau (VHL) tumor suppressor gene and somatic inactivation of the remaining VHL allele. The resulting VHL gene silencing leads to induction of hypoxia-regulated genes including vascular endothelial growth factor (VEGF). Thus, therapeutic inhibition of VEGF holds promise for treatment of this historically refractory malignancy. An antibody to VEGF (bevacizumab, Avastin) has demonstrated a significant prolongation of time to disease progression compared with placebo in patients with metastatic RCC. Interferon-alpha (IFN-alpha) is a standard initial cytokine therapy in RCC with a modest response rate and a survival advantage demonstrated in randomized trials. We hypothesized that the addition of anti-VEGF therapy to IFN-alpha would prolong survival in untreated metastatic RCC patients. A Phase III trial is now being conducted randomizing untreated, metastatic clear cell RCC patients to IFN-alpha alone or IFN-alpha plus Avastin.

Alleles↗
PubMed2004

Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583).

PURPOSE: Antiandrogen withdrawal (AAWD) results in a prostate-specific antigen (PSA) response (decline in PSA level of > or =50%) in 15% to 30% of androgen-independent prostate cancer (AiPCa) patients. Thereafter, adrenal androgen ablation with agents such as ketoconazole (K) is commonly utilized. The therapeutic effect of AAWD alone was compared with simultaneous AAWD and K therapy. PATIENTS AND METHODS: AiPCa patients were randomized to undergo AAWD alone (n=132), or together with K (400 mg orally [p.o.] tid) and hydrocortisone (30 mg p.o. each morning, 10 mg p.o. each evening; n=128). Patients who developed progressive disease after AAWD alone were eligible for deferred treatment with K. RESULTS: Eleven percent of patients undergoing AAWD alone had a PSA response, compared to 27% of patients who underwent AAWD and simultaneous K (P=.0002). Objective responses were observed in 2% of patients treated with AAWD alone compared to 20% in patients treated with AAWD/K (P=.02). There was no difference in survival. PSA and objective responses were observed in 32% and 7%, respectively, of patients receiving deferred K, and were more common in patients with prior AAWD response. Treatment with K was well tolerated, and resulted in a decline in adrenal androgen levels, which rose at the time of disease progression. CONCLUSION: K has modest activity in AiPCa patients, while AAWD alone has minimal activity. Adrenal androgen levels fall with treatment with K and then climb at the time of progression, suggesting that progressive disease while on K may be due to tachyphylaxis to the adrenolytic properties of K.

Adenocarcinoma↗
PubMed2004

Practice and progress in kidney cancer: methodology for novel drug development.

PURPOSE: The minimal efficacy of standard therapy for metastatic renal cell carcinoma (RCC) has resulted in the evaluation of numerous novel agents. Some agents have shown promise in phase II trials and yet none have improved survival over standard therapy in phase III trials. We examined existing data relevant to standard therapy and clinical trial methodology in RCC to understand patient, disease and trial design factors that have impacted clinical trial outcome and drug evaluation. Furthermore, we describe new paradigms for the evaluation of novel agents to optimize the yield of clinical research in RCC. MATERIALS AND METHODS: A comprehensive review of published retrospective analyses and phase II/phase III trials in patients with metastatic RCC was undertaken. Publications with patient selection and/or therapeutic implications in our judgment are presented and evaluated. RESULTS: Patients with good performance status and access to centers with experienced staff may appropriately receive high dose interleukin-2 after consideration of the relative risks and benefits. Alternatively low dose, single agent cytokine regimens are acceptable. Novel agents may be tested in untreated and refractory RCC. Consideration of the prognostic factors of a given phase II cohort is essential when interpreting single arm clinical trial results. RCC histological subtypes continue to be distinguished biologically and treatment relevant to the vascular endothelial growth factor pathway is most appropriately targeted to clear cell RCC. Nephrectomy in metastatic RCC may impact evaluation of the tumor response and survival in metastatic RCC. Thus, consideration of nephrectomy status in phase II trials and stratification in phase III trials is warranted. Clinical trials that include patients with central nervous system metastases should have standardized treatment of these metastases prior to systemic therapy. Objective response rate as an end point should be used with caution, given its unreliable history in metastatic RCC. Novel trial designs using time to disease progression may allow for interpretation of the antitumor effect in the absence of tumor shrinkage. CONCLUSIONS: Metastatic renal carcinoma is a model disease for the design of clinical trials and testing of novel agents. Novel trial designs and end points should be considered to evaluate new agents in RCC. Phase III trials must be carefully performed with the most promising agents to impact survival in this disease.

Antineoplastic Agents↗