A multicenter, open-label, randomized, phase II study of cediranib with or without lenalidomide in iodine 131-refractory differentiated thyroid cancer.

BACKGROUND: Multitargeted tyrosine kinase inhibitors (TKIs) of the vascular endothelial growth factor receptor (VEGFR) pathway have activity in differentiated thyroid cancer (DTC). Lenalidomide demonstrated preliminary efficacy in DTC, but its safety and efficacy in combination with VEGFR-targeted TKIs is unknown. We sought to determine the safety and efficacy of cediranib, a VEGFR-targeted TKI, with or without lenalidomide, in the treatment of iodine 131-refractory DTC. PATIENTS AND METHODS: In this multicenter, open-label, randomized, phase II clinical trial, 110 patients were enrolled and randomized to cediranib alone or cediranib with lenalidomide. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate, duration of response, toxicity, and overall survival (OS). Patients (≥18 years of age) with DTC who were refractory to further surgical or radioactive iodine (RAI) therapy as reviewed at a multispecialty tumor board conference, and evidence of disease progression within the previous 12 months and no more than one prior line of systemic therapy were eligible. RESULTS: Of the 110 patients, 108 started therapy and were assessable for efficacy. The median PFS was 14.8 months [95% confidence interval (CI) 8.5-23.8 months] in the cediranib arm and 11.3 months (95% CI 8.7-18.9 months) in the cediranib with lenalidomide arm (P = 0.36). The 2-year OS was 64.8% (95% CI 43.3% to 86.4%) and 75.3% (95% CI 59.4% to 91.0%), respectively (P = 0.80). The serious adverse event rate was 41% in the cediranib arm and 46% in the cediranib with lenalidomide arm. CONCLUSIONS: Single-agent therapy with cediranib showed promising efficacy in RAI-refractory DTC similar to other VEGFR-targeted TKIs, while the addition of lenalidomide did not result in clinically meaningful improvements in outcomes.

Pharmacogenomics-Based Point-of-Care Clinical Decision Support Significantly Alters Drug Prescribing.

Changes in behavior are necessary to apply genomic discoveries to practice. We prospectively studied medication changes made by providers representing eight different medicine specialty clinics whose patients had submitted to preemptive pharmacogenomic genotyping. An institutional clinical decision support (CDS) system provided pharmacogenomic results using traffic light alerts: green = genomically favorable, yellow = genomic caution, red = high risk. The influence of pharmacogenomic alerts on prescribing behaviors was the primary endpoint. In all, 2,279 outpatient encounters were analyzed. Independent of other potential prescribing mediators, medications with high pharmacogenomic risk were changed significantly more often than prescription drugs lacking pharmacogenomic information (odds ratio (OR) = 26.2 (9.0-75.3), P < 0.0001). Medications with cautionary pharmacogenomic information were also changed more frequently (OR = 2.4 (1.7-3.5), P < 0.0001). No pharmacogenomically high-risk medications were prescribed during the entire study when physicians consulted the CDS tool. Pharmacogenomic information improved prescribing in patterns aimed at reducing patient risk, demonstrating that enhanced prescription decision-making is achievable through clinical integration of genomic medicine.

Patient Perceptions of Care as Influenced by a Large Institutional Pharmacogenomic Implementation Program.

Despite growing clinical use of genomic information, patient perceptions of genomic-based care are poorly understood. We prospectively studied patient-physician pairs who participated in an institutional pharmacogenomic implementation program. Trust/privacy/empathy/medical decision-making (MDM)/personalized care dimensions were assessed through patient surveys after clinic visits at which physicians had access to preemptive pharmacogenomic results (Likert scale, 1 = minimum/5 = maximum; mean [SD]). From 2012-2015, 1,261 surveys were issued to 507 patients, with 792 (62.8%) returned. Privacy, empathy, MDM, and personalized care scores were significantly higher after visits when physicians considered pharmacogenomic results. Importantly, personalized care scores were significantly higher after physicians used pharmacogenomic information to guide medication changes (4.0 [1.4] vs. 3.0 [1.6]; P < 0.001) compared with prescribing visits without genomic guidance. Multivariable modeling controlling for clinical factors confirmed personalized care scores were more favorable after visits with genomic-influenced prescribing (odds ratio [OR] = 3.26; 95% confidence interval [CI] = (1.31-8.14); P < 0.05). Physicians seem to individualize care when utilizing pharmacogenomic results and this decision-making augmentation is perceived positively by patients.

Doxorubicin plus the IGF-1R antibody cixutumumab in soft tissue sarcoma: a phase I study using the TITE-CRM model.

BACKGROUND: Insulin-like growth factor receptor (IGF-1R) has been studied as an oncologic target in soft tissue sarcoma (STS), but its role in sarcoma biology is unclear. Anti-IGF-1R antibody cixutumumab demonstrated acceptable toxicity but limited activity as a single agent in STS. We carried out a dose-escalation study of cixutumumab with doxorubicin to evaluate safety and dosing of the combination. PATIENTS AND METHODS: Eligible patients with advanced STS were treated with cixutumumab intravenously on days 1/8/15 at one of three dose levels (A: 1 mg/kg, B: 3 mg/kg, C: 6 mg/kg) with doxorubicin at 75 mg/m(2) as a 48 h infusion on day 1 of a 21 day cycle. After six cycles of the combination, patients could receive cixutumumab alone. The Time-to-Event Continual Reassessment Method was used to estimate the probability of dose-limiting toxicity (DLT) and to assign patients to the dose with an estimated probability of DLT≤20%. RESULTS: Between September 2008 and January 2012, 30 patients with advanced STS received a median of six cycles of therapy (range <1-22). Two DLTs were observed, grade 3 mucositis (dose level B) and grade 4 hyperglycemia (dose level C). Grade 2 and 3 reduced left ventricular ejection fraction was seen in three and two patients, respectively. Five partial responses were observed, and estimated progression-free survival was 5.3 months (95% confidence interval 3.0-6.3) in 26 response-assessable patients. Immunohistochemical staining of 11 available tumor samples for IGF-1R and phospho-IGF-1R was not significantly different among responders and non-responders, and serum analysis of select single-nucleotide polymorphisms did not predict for cardiotoxicity. CONCLUSION: The maximum tolerated dose was doxorubicin 75 mg/m(2) on day 1 and cixitumumab 6 mg/kg on days 1/8/15 of a 21 day cycle. Cardiac toxicity was observed and should be monitored in subsequent studies, which should be considered in STS only if a predictive biomarker of benefit to anti-IGF-1R therapy is identified. TRIAL REGISTRATION: ClinicalTrials.gov:NCT00720174.

Long-term survival and biomarker correlates of tasquinimod efficacy in a multicenter randomized study of men with minimally symptomatic metastatic castration-resistant prostate cancer.

PURPOSE: Tasquinimod (Active Biotech) is an oral immunomodulatory, anti-angiogenic, and anti-metastatic agent that delayed metastatic disease progression in a randomized placebo-controlled phase II trial in men with metastatic castration-resistant prostate cancer (mCRPC). Here, we report long-term survival with biomarker correlates from this trial. EXPERIMENTAL DESIGN: Two hundred and one (134 tasquinimod and 67 placebo) men with mCRPC were evaluated. Forty-one men randomized to placebo crossed over to tasquinimod. Survival data were collected with a median follow-up time of 37 months. Exploratory biomarker studies at baseline and over time were collected to evaluate potential mechanism-based correlates with tasquinimod efficacy including progression-free survival (PFS) and overall survival (OS). RESULTS: With 111 mortality events, median OS was 33.4 months for tasquinimod versus 30.4 months for placebo overall, and 34.2 versus 27.1 months in men with bone metastases (n = 136), respectively. Multivariable analysis demonstrated an adjusted HR of 0.52 [95% confidence interval (CI), 0.35-0.78; P = 0.001] for PFS and 0.64 (95% CI, 0.42-0.97; P = 0.034) for OS, favoring tasquinimod. Time-to-symptomatic progression was improved with tasquinimod (P = 0.039, HR = 0.42). Toxicities tended to be mild in nature and improved over time. Biomarker analyses suggested a favorable impact on bone alkaline phosphatase and lactate dehydrogenase (LDH) over time and a transient induction of inflammatory biomarkers, VEGF-A, and thrombospondin-1 levels with tasquinimod. Baseline levels of thrombospondin-1 less than the median were predictive of treatment benefit. CONCLUSIONS: The survival observed in this trial of men with minimally symptomatic mCRPC suggests that the prolongation in PFS with tasquinimod may lead to a survival advantage in this setting, particularly among men with skeletal metastases, and has a favorable risk:benefit ratio.

Estimation of renal cell carcinoma treatment effects from disease progression modeling.

To improve future drug development efficiency in renal cell carcinoma (RCC), a disease-progression model was developed with longitudinal tumor size data from a phase III trial of sorafenib in RCC. The best-fit model was externally evaluated on 145 placebo-treated patients in a phase III trial of pazopanib; the model incorporated baseline tumor size, a linear disease-progression component, and an exponential drug effect (DE) parameter. With the model-estimated effect of sorafenib on RCC growth, we calculated the power of randomized phase II trials between sorafenib and hypothetical comparators over a range of effects. A hypothetical comparator with 80% greater DE than sorafenib would have 82% power (one-sided α = 0.1) with 50 patients per arm. Model-based quantitation of treatment effect with computed tomography (CT) imaging offers a scaffold on which to develop new, more efficient, phase II trial end points and analytic strategies for RCC.

Monitoring anti-angiogenic therapy in colorectal cancer murine model using dynamic contrast-enhanced MRI: comparing pixel-by-pixel with region of interest analysis.

Sorafenib is a multi-kinase inhibitor that blocks cell proliferation and angiogenesis. It is currently approved for advanced hepatocellular and renal cell carcinomas in humans, where its major mechanism of action is thought to be through inhibition of vascular endothelial growth factor and platelet-derived growth factor receptors. The purpose of this study was to determine whether pixel-by-pixel analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is better able to capture the heterogeneous response of Sorafenib in a murine model of colorectal tumor xenografts (as compared with region of interest analysis). MRI was performed on a 9.4 T pre-clinical scanner on the initial treatment day. Then either vehicle or drug were gavaged daily (3 days) up to the final image. Four days later, the mice were again imaged. The two-compartment model and reference tissue method of DCE-MRI were used to analyze the data. The results demonstrated that the contrast agent distribution rate constant (K(trans)) were significantly reduced (p < 0.005) at day-4 of Sorafenib treatment. In addition, the K(trans) of nearby muscle was also reduced after Sorafenib treatment. The pixel-by-pixel analysis (compared to region of interest analysis) was better able to capture the heterogeneity of the tumor and the decrease in K(trans) four days after treatment. For both methods, the volume of the extravascular extracellular space did not change significantly after treatment. These results confirm that parameters such as K(trans), could provide a non-invasive biomarker to assess the response to anti-angiogenic therapies such as Sorafenib, but that the heterogeneity of response across a tumor requires a more detailed analysis than has typically been undertaken.

A randomized, phase II study of pazopanib in castrate-sensitive prostate cancer: a University of Chicago Phase II Consortium/Department of Defense Prostate Cancer Clinical Trials Consortium study.

BACKGROUND: Intermittent androgen suppression (IAS) is an increasingly popular treatment option for castrate-sensitive prostate cancer. On the basis of previous data with anti-angiogenic strategies, we hypothesized that pan-inhibition of the vascular endothelial growth factor receptor using pazopanib during the IAS off period would result in prolonged time to PSA failure. METHODS: Men with biochemically recurrent prostate cancer, whose PSA was <0.5 ng ml(-1) after 6 months of androgen deprivation therapy were randomized to pazopanib 800 mg daily or observation. The planned primary outcome was time to PSA progression >4.0 ng ml(-1). RESULTS: Thirty-seven patients were randomized. Of 18 patients randomized to pazopanib, at the time of study closure, 4 had progressive disease, 1 remained on treatment and 13 (72%) electively disenrolled, the most common reason being patient request due to grade 1/2 toxicity (8 patients). Two additional patients were removed from treatment due to adverse events. Of 19 patients randomized to observation, at the time of study closure, 4 had progressive disease, 7 remained under protocol-defined observation and 8 (42%) had disenrolled, most commonly due to non-compliance with protocol visits (3 patients). Because of high dropout rates in both arms, the study was halted. CONCLUSIONS: IAS is a treatment approach that may facilitate investigation of novel agents in the hormone-sensitive state. This trial attempted to investigate the role of antiangiogenic therapy in this setting, but encountered several barriers, including toxicities and patient non-compliance, which can make implementation of such a study difficult. Future investigative efforts in this arena should carefully consider drug toxicity and employ a design that maximizes patient convenience to reduce the dropout rate.

A phase I study of sirolimus and bevacizumab in patients with advanced malignancies.

BACKGROUND: We performed a single institution, phase I study of sirolimus and bevacizumab, in order to determine the dose limiting toxicity (DLT) and recommended phase II doses. PATIENTS AND METHODS: Eligible patients had previously treated advanced malignancies and were enrolled in three cohorts. Sirolimus 90 mg PO weekly (45 mg on days 1 and 2) was combined with bevacizumab 7.5mg/kg (cohort #1) or bevacizumab 15 mg/kg (cohort #2) IV q3weeks. Sirolimus 4 mg PO daily was combined with bevacizumab 15 mg/kg IV q3weeks (cohort #3). RESULTS: Twenty-eight patients enrolled. The most common tumour types were colorectal (21%), head/neck (14%), and renal cell (11%). No DLTs were observed in cohorts #1 (4 patients) and #2 (12 patients), while two DLTs (grade 3 confusion and grade 3 fatigue) were observed in the first six patients in cohort #3 (12 patients). The most common grade 3 toxicities were fatigue (18%), hypertension (14%) and anorexia (11%). There were no responses, but one patient has had stable disease for 78 weeks. CONCLUSIONS: The combination of sirolimus and bevacizumab at full doses is tolerable in the majority of patients. The availability and cost of sirolimus compared with other mTOR inhibitors make this an attractive agent to combine with bevacizumab.

Novel approaches and future directions in castration-resistant prostate cancer.

Recent advances in the treatment of castration-resistant prostate cancer (CRPC) have started to change the therapeutic landscape allowing clinicians to choose from a broad range of treatment options. Understanding the mechanisms that transform prostate cancer (PCA) into a castration-resistant state has enabled investigators to explore critical pathways involved in such process allowing for rational therapeutic design. These novel therapies complement the modest success that chemotherapy has demonstrated in recent years. In this review, we discuss the different mechanisms that render PCA castration resistant and elaborate on the nonchemotherapy approaches evolving in CRPC. These include agents targeting the epidermal growth factor receptor, endothelin receptor antagonists, angiogenesis inhibitors, immunomodulatory agents, immunotherapy, novel antiandrogens, and delivery of cytotoxic agents via therapeutic antibodies. This timely review coincides with the identification of newer therapies in this setting affirming our steady movement towards better disease control.

Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor (HDACi) romidepsin in metastatic castration-resistant prostate cancer (CRPC).

BACKGROUND: Histone deacetylase blockade can promote heat shock protein 90 (HSP90) acetylation, abrogating androgen receptor signaling. A phase II trial of the histone deacetylase inhibitor (HDACi) romidepsin was conducted in patients with progressing, metastatic, castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: A dose of 13 mg/m(2) was administered i.v. over 4 h on days 1, 8 and 15 every 28 days. The primary end point was rate of disease control defined as no evidence of radiological progression at 6 months. A sample size of 16 assessable patients in stage 1 and nine assessable patients in stage 2 was selected; progression to stage 2 required one or more patients with disease control in stage 1 (H(o) = 0.10, H(a) = 0.30; alpha and beta = 0.10). RESULTS: Thirty-five patients were enrolled. Two patients achieved a confirmed radiological partial response (RECIST) lasting > or = 6 months, along with a confirmed prostate-specific antigen decline of > or = 50%. Eleven patients experienced toxicity necessitating early discontinuation. The commonest adverse events were nausea (30 patients; 85.7%), fatigue (28 patients; 80.0%), vomiting (23 patients; 65.7%) and anorexia (20 patients; 57.1%). There was no significant cardiac toxicity. CONCLUSIONS: At the dose and schedule selected, romidepsin demonstrated minimal antitumor activity in chemonaive patients with CRPC. Further studies of improved HDACi, alone and in combination with other therapies, should nevertheless be investigated.

MVA-MUC1-IL2 vaccine immunotherapy (TG4010) improves PSA doubling time in patients with prostate cancer with biochemical failure.

PURPOSE: TG4010 is a recombinant MVA vector expressing the tumor-associated antigen MUC1 and IL2. We explored the effect two schedules of TG4010 on PSA in men with PSA progression. PATIENTS AND METHODS: A randomized phase II trial was conducted in 40 patients with PSA progression. Patients had PSA doubling times less than 10 months, with no overt evidence of disease. Patients received either weekly subcutaneous injection (sc) of TG4010 10(8) pfu for 6 weeks, then one injection every 3 weeks or sc injection of TG4010 10(8) pfu every 3 weeks. RESULTS: The primary endpoint of a 50% decrease in PSA values from baseline was not observed. Nevertheless, 13 of 40 patients had a more than two fold improvement in PSA doubling time. Ten patients had their PSA stabilized for over 8 months. Therapy was well tolerated. CONCLUSIONS: Although the primary endpoint was not achieved, there is evidence of biologic activity of TG4010 in patients with PSA progression, further investigation in prostate cancer is warranted.

Inflammation of actinic keratoses subsequent to therapy with sorafenib, a multitargeted tyrosine-kinase inhibitor.

The Ras-Raf-MEK-ERK signalling pathway is frequently dysregulated in human malignancies, as is angiogenesis and the vascular endothelial growth factor receptor (VEGF/VEGFR) pathway. These kinases are therefore important anticancer targets. The novel, oral treatment sorafenib (BAY 43-9006), has been shown to be an inhibitor of VEGFR, Raf and platelet-derived growth factor in clinical trials against a variety of cancers, with the greatest activity to date observed in metastatic renal cancer. Although side-effects with this targeted therapy are usually not dose-limiting, they frequently involve the skin, and consist of a maculopapular rash, palmar-plantar dysaesthesia, alopecia and xerosis. In this report, we present two patients in whom treatment with sorafenib resulted in inflammation of actinic keratosis, which in some cases progressed to invasive squamous cell carcinoma. This side-effect is of clinical importance, as early recognition is critical for early treatment and may represent a source of additional morbidity to these patients.

A phase I study of antisense oligonucleotide GTI-2040 given by continuous intravenous infusion in patients with advanced solid tumors.

BACKGROUND: This study of GTI-2040, a 20-mer phosphorothioate oligonucleotide complementary to the messenger ribonucleic acid (mRNA) of the R2 subunit of ribonucleotide reductase (RNR), was conducted to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of the agent in patients with advanced solid tumors or lymphoma. Plasma pharmacokinetics of GTI-2040 and suppression of RNR expression in peripheral blood mononuclear cells were also studied. PATIENTS AND METHODS: GTI-2040 was administered as a continuous intravenous infusion for 21 days every 4 weeks. Dose escalation was performed using an accelerated, dose-doubling schedule until any drug related toxicity > or = grade 2 was observed; subsequent dose escalation followed a more conservative dose escalation scheme with three patients/cohort. RESULTS: A total of 49 cycles of therapy were administered to 36 patients at GTI-2040 doses ranging from 18.5 mg/m(2)/day to 222 mg/m(2)/day. GTI-2040 was generally well tolerated. At the highest dose level examined, two patients experienced dose limiting reversible hepatic toxicity. Constitutional toxicities consisting of fatigue and anorexia were the most common toxicities. CONCLUSIONS: The recommended dose of GTI-2040 given on this infusion schedule is 185 mg/m(2)/day. GTI-2040 appears to have a manageable toxicity profile and is generally well tolerated as a single agent.

Long-term follow-up of nonmyeloablative allogeneic stem cell transplantation for renal cell carcinoma: The University of Chicago Experience.

Nonmyeloablative allogeneic stem cell transplantation (NST) has considerable activity in patients with metastatic renal cell carcinoma (RCC), although there are limited long-term follow-up data. Between February 1999 and May 2003, 18 patients with metastatic RCC underwent 19 matched-sibling NSTs after conditioning with fludarabine and cyclophosphamide with tacrolimus and mycophenolate mofetil as post-transplant immunosuppression. Among the four objective responses, all were partial and have relapsed with a median response duration of 609 days (range, 107-926). All responders are alive at a median of 41 months. Median overall survival for the entire cohort was 14 months. There were four early treatment-related deaths and one late treatment-related death. Eight patients died from progressive disease and five (28%) from treatment-related mortality. Stratifying transplant outcome as early death, intermediate (no response, no early death), or response, the combination of pre-treatment anemia and decreased performance status, was associated with adverse outcome (P = 0.015) and reduced survival (HR 5.4, 95% confidence interval of 1.4 to 21, P = 0.007). Responders demonstrated prolonged survival compared to nonresponders (P = 0.002). NST leads to durable responses in a minority of metastatic RCC patients. Appropriate patient selection is paramount. Anemia and decreased performance status may enable risk stratification.

Depletion of normal B cells with rituximab as an adjunct to IL-2 therapy for renal cell carcinoma and melanoma.

BACKGROUND: We postulated that in patients with metastatic renal cell carcinoma (RCC) or melanoma, depletion of normal B cells using the anti-CD20 mAb rituximab before treatment with low-dose interleukin (IL)-2 would improve clinical outcome. PATIENTS AND METHODS: Rituximab (375 mg/m(2)) weekly for 4 weeks. IL-2 [11 (million units) daily] s.c., 4 days a week for weeks 5-8, followed by a 2-week rest (weeks 9 and 10). Patients without disease progression continued on IL-2. Disease re-evaluation was performed after rituximab and after every course of IL-2. RESULTS: Fifteen patients with RCC and six with melanoma were enrolled. One patient had a partial response and seven patients had stable disease. Toxicities were similar to those expected with IL-2 alone, and there were no grade 4 events. Circulating B cells were depleted in all patients. The subsequent low-dose IL-2 increased absolute numbers of natural killer cells, activated CD4(+) and activated CD8(+) T cells. Expanded T cells produced interferon-gamma, but not IL-4. Proliferation of peripheral blood lymphocytes to phytohemagglutinin was diminished following rituximab treatment, suggesting that B cells participate in this response in vitro. CONCLUSIONS: Our results suggest that depletion of circulating B cells with rituximab does not increase the response rate, alter the toxicity profile or change the biological activity in response to low-dose IL-2 in patients with RCC or melanoma.

A phase II trial of oral temozolomide in patients with metastatic renal cell cancer.

PURPOSE: To determine the activity of temozolomide, an oral imidazotetrazine alkylating agent that has exhibited broad antitumor activity in preclinical studies, in renal cell cancer (RCC) patients. METHODS. Metastatic RCC patients were treated with temozolomide, 200 mg/m(2) per day orally, and traditional radiologic response endpoints were assessed. O(6)-Alkylguanine-DNA alkyltransferase (AGT) activity was measured in four pretreatment biopsies. RESULTS: Among 12 patients, there were no responses. High AGT activity was observed in all four biopsies analyzed. CONCLUSIONS: Temozolomide is not active against RCC and this clinical observation may be due to high levels of AGT in this tumor.

A phase II trial of weekly intravenous gemcitabine and cisplatin with continuous infusion fluorouracil in patients with metastatic renal cell carcinoma.

BACKGROUND: We reported previously that the combination of gemcitabine and continuous infusion fluorouracil (5-FU) has activity in renal cell carcinoma. Based upon in vitro synergy of gemcitabine/cisplatin and 5-FU/cisplatin, we hypothesized that the addition of cisplatin could improve the objective response rate of gemcitabine and 5-FU with manageable toxicity. PATIENTS AND METHODS: Twenty-one patients with metastatic renal cell carcinoma (RCC) and a Cancer and Leukemia Group B performance status of 0 to 2 were enrolled. Ten had received prior systemic therapy. Treatment consisted of gemcitabine 600 mg/m2 and cisplatin 20 mg/m2 on days 1, 8 and 15 of each 28-day cycle. Continuous infusion 5-FU was given from day 1 to day 21. RESULTS: No complete responses and one partial response were observed for an objective response rate of 5% (95% confidence interval 0% to 24%). Two minor responses (25% to 50% regression) were also observed. The median overall survival was 10 months with 35% of patients surviving at 1 year. Grade 3-4 myelosuppression (mostly thrombocytopenia) occurred in nine (43%) patients. Nausea/vomiting and neuropathy were dose-limiting in an additional five patients. Only 51% of treatment cycles were delivered on time and without dose reduction. CONCLUSIONS: The addition of cisplatin to gemcitabine and 5-FU did not improve the objective response rate of gemcitabine and 5-FU alone and added to the toxicity. Due to the cumulative toxicity, further trials with this cisplatin-containing regimen in RCC are not indicated.

Phase I study to evaluate multiple regimens of intravenous 5-fluorouracil administered in combination with weekly gemcitabine in patients with advanced solid tumors: a potential broadly active regimen for advanced solid tumor malignancies.

BACKGROUND: The purpose of this study was to determine the maximum tolerated dose and toxicity profile of gemcitabine given on a weekly schedule with continuous infusion 5-fluorouracil. PATIENTS AND METHODS: Eligible patients with advanced solid tumors received escalating doses of gemcitabine 200 and 300 mg/m(2) weekly as a 30-minute infusion on Days 1, 8, and 15 every 4 weeks (schedule 1) or 450, 600, 800, 1000, 1250, 1500, 1800, and 2200 mg/m(2) on Days 1 and 8 (schedule 2) every 3 weeks, respectively. At the completion of gemcitabine infusion (Day 1), patients received fixed dose continuous infusion of 5-fluorouracil at either 300 mg/m(2) (Days 1-21) or 200 mg/m(2) (Days 1-21; schedule 1) every 4 weeks or 200 mg/m(2) (Days 1-14; schedule 2] every 3 weeks, respectively. Toxicity assessments were performed weekly on study, and efficacy measurements were performed every 6-8 weeks. RESULTS: Seventy patients with advanced solid malignancies received a total of 220 cycles of combination chemotherapy. Eleven (14.3%) patients received no more than 1 treatment cycle of combination therapy. Schedule 1 maximum tolerated dose of gemcitabine was 600 mg/m(2)/week when combined with 5-fluorouracil (5-FU) at 200 mg/m(2)/day (Days 1-21) repeated every 4 weeks. The schedule 2 maximum tolerated dose of gemcitabine was 2200 mg/m(2)/week when combined with 5-FU dosed at 200 mg/m(2)/day (Days 1-14) repeated every 3 weeks. In schedule 1, the limiting factor for gemcitabine delivery was the Day 15 dose that often was omitted because of myelosuppression and/or mucositis. In schedule 1 cycle 1, nonhematologic toxicity was common and included Grade 3-4 toxicities: mucositis (8 patients), fatigue (2 patients), and anorexia (1 patient). One patient had Grade 3-4 neutropenia at dose level 5 (maximum tolerated dose). In schedule 2 cycle 1, hematologic toxicities were more common than nonhematologic toxicity and included Grade 3 anemia (3 patients), Grade 3 neutropenia (4 patients), and Grade 3 thrombocytopenia (2 patients). The nonhematologic toxicities included Grade 3 mucositis (3 patients), Grade 3 fatigue (2 patients), and Grade 3 dehydration (1 patient). Overall, antitumor activity was observed in seven patients. Three of 30 patients with cytokine refractory renal cell carcinoma (RCC; relative risk [RR] 10 %; 95% confidence interval [CI], 0.82-22%) had a partial response. Of the remaining 27 patients with RCC, 4 patients had a minor response, and 10 patients had stable disease lasting a median of 6.4 (range, 4-12) months. The remaining 5 responses occurred in 40 patients (RR, 12.5%; 95% CI, 4.2-26.8%): 2 patients with 5-FU refractory colon carcinoma, 1 patient with hepatoma, 1 patient with paclitaxel-cisplatin-resistant ovarian carcinoma, and 1 patient with cisplatin-resistant head and neck squamous cell carcinoma had a partial response. CONCLUSIONS: For Phase II development, gemcitabine 450-600 mg/m(2) on Days 1, 8, and 15 can be safely combined with 5-FU 200 mg/m(2) given as a continuous infusion (Days 1-21) of a 28-day cycle or gemcitabine 1800 mg/m(2) Days 1 and 8 given with 5-FU 200 mg/m(2) as a continuous infusion (Days 1-14) of a 21-day cycle. The observed antitumor activity in several solid tumors, especially in renal cell carcinoma, warrants broad Phase II evaluation.