Phase 1b Trial of Ficlatuzumab, a Humanized Hepatocyte Growth Factor Inhibitory Monoclonal Antibody, in Combination With Gefitinib in Asian Patients With NSCLC.

Hepatocyte growth factor (HGF)/c-Met pathway dysregulation is a mechanism for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Ficlatuzumab (AV-299; SCH 900105), a humanized IgG1 κ HGF inhibitory monoclonal antibody, prevents HGF/c-Met pathway ligand-mediated activation. This phase 1b study assessed the safety/tolerability, pharmacokinetics/pharmacodynamics, and antitumor activity of ficlatuzumab plus gefitinib in Asian patients with previously treated advanced non-small cell lung cancer (NSCLC). Patients received intravenous ficlatuzumab either 10 mg/kg (cohort 1; n = 3) or 20 mg/kg (cohort 2; n = 12) every 2 weeks plus oral gefitinib 250 mg daily. Patients tolerated the drug combination well. Four treatment-related grade 3/4 adverse events were reported in 3 patients (cohort 2). Pharmacokinetic profiles for ficlatuzumab and gefitinib were consistent with prior single-agent trials. Partial responses were achieved in 5 patients (4 confirmed), all in cohort 2; objective response rate (ORR) was 33% (duration, 1.9-6.4 months). Responding patients had no prior EGFR TKI treatment, 2 without an EGFR mutation. Four additional patients had disease stabilization (cohort 2; duration, 2.7-9.1 months; 42% ORR). The recommended phase 2 dose for ficlatuzumab plus gefitinib 250 mg/day was 20 mg/kg every 2 weeks. This drug combination has shown preliminary dose-related antitumor activity in advanced NSCLC.

Vaccination of renal cell cancer patients with modified vaccinia Ankara delivering the tumor antigen 5T4 (TroVax) alone or administered in combination with interferon-alpha (IFN-alpha): a phase 2 trial.

Attenuated vaccinia virus, modified vaccinia Ankara (MVA) has been engineered to deliver the tumor antigen 5T4 (TroVax). MVA-5T4 has been evaluated in an open-label phase 2 trial in metastatic renal cell cancer patients in which the vaccine was administered alone or in combination with interferon-alpha-2b (IFN-alpha). The safety, immunologic, and clinical efficacy of MVA-5T4 with or without IFN-alpha was determined. Twenty-eight patients with metastatic renal cell cancer were treated with MVA-5T4 alone (13) or plus IFN-alpha (15). The 5T4-specific cellular and humoral responses were monitored throughout the study. Clinical responses were assessed by measuring changes in tumor burden by computed tomography or magnetic resonance imaging scan. MVA-5T4 was well tolerated with no serious adverse event attributed to vaccination. Of 23 intent-to-treat patients tested for immune responses postvaccination, 22 (96%) mounted 5T4-specific antibody and/or cellular responses. One patient treated with MVA-5T4 plus IFN-alpha showed a partial response for >7 months, whereas an additional 14 patients (7 receiving MVA-5T4 plus IFN and 7 receiving MVA-5T4 alone) showed periods of disease stabilization ranging from 1.73 to 9.60 months. Median progression free survival and overall survival for all intent-to-treat patients was 3.8 months (range: 1 to 11.47 mo) and 12.1 months (range: 1 to 27 mo), respectively. MVA-5T4 administered alone or in combination with IFN-alpha was well tolerated in all patients. Despite the high frequency of 5T4-specific immune responses, it is not possible to conclude that patients are receiving clinical benefit. The results are encouraging and warrant further investigation.

A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer.

BACKGROUND: Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, affects tumor growth by blocking growth factor stimulation, arresting cell cycle progression, and inhibiting angiogenesis. mTOR inhibitors and agents with primarily antiangiogenic activity have been shown to have efficacy in renal cell cancer (RCC). This phase 2 study assessed the efficacy of daily oral dosing with everolimus in patients with RCC. METHODS: Patients had confirmed predominantly clear cell RCC; had received or=3 months was reported in 27 (73%) patients, and stable disease lasting >or=6 months was reported in 21 (57%) patients. Nausea (38% of patients), anorexia (38% of patients), diarrhea (31% of patients), stomatitis (31% of patients), pneumonitis (31% of patients), and rash (26% of patients) were common. Grade 3 of 4 adverse events included pneumonitis (18% of patients); transaminase elevations (10% of patients); thrombocytopenia, hyperglycemia, and alkaline phosphatase elevations (8% each of patients); and hyperlipidemia (5% of patients). CONCLUSIONS: In the current study, everolimus demonstrated encouraging antitumor activity against metastatic RCC as indicated by a PFS >or= 6 months for approximately 70% of patients.

Vaccination of renal cell cancer patients with modified vaccinia ankara delivering tumor antigen 5T4 (TroVax) administered with interleukin 2: a phase II trial.

PURPOSE: The attenuated vaccinia virus modified vaccinia ankara (MVA) has been engineered to deliver the tumor antigen 5T4 (TroVax). TroVax has been evaluated in an open-label phase II trial in metastatic renal cell cancer patients in which the vaccine was administered in combination with interleukin-2 (IL-2). The safety, immunologic, and clinical efficacy of TroVax in combination with IL-2 was determined. EXPERIMENTAL DESIGN: Twenty-five patients with metastatic renal cell cancer were treated with TroVax plus IL-2. 5T4-specific cellular and humoral responses were monitored throughout the study. Clinical responses were assessed by measuring changes in tumor burden by computed tomography or magnetic resonance imaging scan. RESULTS: TroVax was well tolerated with no serious adverse event attributed to vaccination. Of 25 intention-to-treat patients, 21 mounted 5T4-specific antibody responses. Two patients showed a complete response for > 24 months and one a partial response for > 12 months. Six patients had disease stabilization from 6 to > 21 months. Median progression-free survival (PFS) and overall survival (OS) were > 3.37 months (range, 1.50- > 24.76) and > 12.87 months (range, 1.90- > 24.76), respectively. A statistically significant relationship was detected between the magnitude of 5T4-specific antibody responses and PFS and OS. CONCLUSION: TroVax in combination with IL-2 was safe and well tolerated in all patients. The high frequency of 5T4-specific immune responses and good clinical response rate are encouraging and warrant further investigation.

Motexafin gadolinium for the treatment of metastatic renal cell carcinoma: phase II study results.

BACKGROUND: Thioredoxin reductase (Trx) has been implicated in activation of hypoxia-inducible factor-1alpha, which is overexpressed in > 85% of renal cell carcinomas (RCCs). We evaluated the safety and efficacy of motexafin gadolinium (MGd), a Trx inhibitor, as a single-agent therapy for metastatic RCC. PATIENTS AND METHODS: Patients with metastatic RCC were infused daily with MGd 5 mg/kg on days 1-5 and days 15-19 of each 28-day cycle. Patients were evaluated for response on days 21-28 of every third cycle. Those with tumor response or stable disease (SD) continued treatment for < or = 12 cycles. Twenty-five patients with confirmed metastatic RCC were enrolled. All were evaluable for toxicity, and 20 were evaluable for response. RESULTS: While no clinical responses were observed, 8 patients had SD after 3 treatment cycles, as did 4 after 6 cycles. Median overall survival was 10.1 months, and median progression- free survival was 2.7 months. The most common treatment-related toxicities were grade 1/2 pain, nausea, skin discoloration, fatigue, blisters, and headache. The most common grade 3 toxicity was hypophosphatemia, observed in 5 patients. MGd was reasonably tolerated, and disease stabilization was observed in several patients with metastatic RCC. CONCLUSION: These results show promise for the use of MGd in combination with other molecularly targeted therapies in previously treated patients with metastatic RCC. However, further investigation of MGd alone for metastatic RCC is not recommended.

Pilot study of rapamycin in patients with hormone-refractory prostate cancer.

BACKGROUND: Currently, no second-line treatment exists for hormonerefractory prostate cancer (HRPC) cases that fail docetaxel regimens. Rapamycin, an immunosuppressive macrolide, inhibits metastatic prostate tumor growth and angiogenesis in in vivo mouse models. This pilot study assessed the antitumor activity, safety, and toxicity of rapamycin in patients with HRPC. PATIENTS AND METHODS: Eligible patients had HRPC and disease progression. The initial dose of rapamycin was 0.15 mg/kg followed by 0.04 mg/kg daily without interruption. Rapamycin levels were measured every 28 days with dose adjustments of 0.04-0.06 mg/kg as necessary to maintain levels between 6-10 ng/mL. Patients were evaluated every 4 weeks for prostate-specific antigen (PSA) and safety and every 8 weeks for radiographic response. RESULTS: Thirteen patients were enrolled from January 2005 to February 2006. One was not evaluable for response. Responses were seen in 2 of 12 evaluable patients (17%). One patient experienced a 50% decrease in absolute PSA and partial radiographic response; another experienced a PSA response only. Four patients had stable disease (33%). The median progression-free survival was 4.2 months (range, 1.9-23.3 months), and overall survival was 23.3+ months (range, 1.9-34.3+ months). Diarrhea (69%), fatigue (46%), and nausea (46%) were the most common adverse events. Rapamycin was well tolerated and showed signs of antitumor activity. CONCLUSION: Rapamycin and other inhibitors of mammalian targets of rapamycin warrant further study in developing combination therapies with chemotherapy or radiation.

Vaccination of prostate cancer patients with modified vaccinia ankara delivering the tumor antigen 5T4 (TroVax): a phase 2 trial.

The attenuated vaccinia virus, modified vaccinia Ankara, has been engineered to deliver the tumor antigen 5T4 (TroVax). TroVax has been evaluated in an open-label phase 2 trial in hormone refractory prostate cancer patients in which the vaccine was administered either alone or in combination with granulocyte macrophage-colony stimulating factor (GM-CSF). The comparative safety and immunologic and clinical efficacy of TroVax alone or in combination with GM-CSF was determined. Twenty-seven patients with metastatic hormone refractory prostate cancer were treated with TroVax alone (n=14) or TroVax+GM-CSF (n=13). 5T4-specific cellular and humoral responses were monitored throughout the study. Clinical responses were assessed by quantifying prostate-specific antigen concentrations and measuring changes in tumor burden by computer-assisted tomography scan. TroVax was well tolerated in all patients with no serious adverse events attributed to vaccination. Of 24 immunologically evaluable patients, all mounted 5T4-specific antibody responses. Periods of disease stabilization from 2 to >10 months were observed. Time to progression was significantly greater in patients who mounted 5T4-specific cellular responses compared with those who did not (5.6 vs. 2.3 mo, respectively). There were no objective clinical responses seen in this study. In this study, the combination of GM-CSF with TroVax showed similar clinical and immunologic responses to TroVax alone. The high frequency of 5T4-specific immune responses and relationship with enhanced time to progression is encouraging and warrants further investigation.

Interferon-alpha in combination with either imatinib (Gleevec) or gefitinib (Iressa) in metastatic renal cell carcinoma: a phase II trial.

Treatments for metastatic renal cell carcinoma (MRCC) are limited. RCCs frequently overexpress epithelial growth factor receptor and express c-Kit and platelet-derived growth factor receptor-beta. Combination of interferon with tyrosine kinase inhibitors of epithelial growth factor receptor [gefitinib (Iressa)] or c-Kit and platelet-derived growth factor receptor-beta [imatinib (Gleevec)] was evaluated for efficacy and safety. Patients with MRCC received 12-week cycles of interferon [3 million units (MU) subcutaneously thrice in week 1 and 6 MU thrice weekly thereafter] and either gefitinib (500 mg daily) or imatinib (600 mg daily). The gefitinib/imatinib dose was reduced as needed owing to toxicity. The primary endpoint was objective tumor response. Secondary endpoints were time to tumor progression, overall survival, and safety. Seventeen patients were enrolled. Most had clear cell [36% (6/17)] or papillary [36% (6/17)] tumors. Most (n=14) were treated on the gefitinib arm, including two patients who crossed over from the imatinib arm after experiencing disease progression. Objective tumor responses were evaluable in 14 patients (82%). Of these 14, partial responses occurred in three (21%), stable disease in seven (50%), and progressive disease in four (29%). The most frequent treatment-related adverse events were skin rash, flu-like symptoms, and fatigue (both treatment arms); diarrhea (gefitinib arm only); and thrombocytopenia and leukopenia (imatinib arm only). Median time to tumor progression (range) for patients on the gefitinib arm only was 4.27 (1.13-15.97) months and median overall survival (range) was 11.42+ (1.13-29.07+) months. Combination of gefitinib with interferon safely delays progression of refractory MRCC. Further studies in this setting are warranted.

Targeted anti-cancer therapies for renal cancer.

In the past several years, significant advances in the underlying biological mechanisms of renal cell cancer, particularly the role of tumour angiogenesis, have permitted the design of molecularly targeted therapeutics. For this review, single-agent therapies inhibiting the following different targets were identified in the published literature: epithelial growth factor receptor, vascular endothelial growth factor receptor, basic fibroblast growth factor receptor, platelet-derived growth factor, nuclear factor-kappabeta, the mammalian target of rapamycin (mTOR) pathway, raf kinase pathway and tyrosine kinase pathway. Distinct fields of clinical research have emerged--monoclonal antibodies, small molecules, nanopeptides and immunomodulators. All therapies demonstrated acceptable toxicity profiles. Clinical benefit was assessed on the basis of the reported criteria for each study, and antitumour response (regression or delay in progression-free survival) ranged from 5% to 71%. On the basis of the limited studies to date, targeted therapies offer the greatest clinical benefit in the management of this malignancy, although additional basic research is still warranted to further improve clinical outcome.