Renal Cell Carcinoma

October 5, 2015

Exelixis has issued results of a phase III trial comparing cabozantinib to everolimus in 658 patients with renal cell carcinoma who have experienced disease progression following treatment with a VEGF receptor tyrosine kinase inhibitor. The median PFS was 7.4 months for the cabozantinib arm v. 3.8 months for the everolimus arm, corresponding to a 42% reduction in the rate of disease progression or death for cabozantinib as compared to the everolimus arm (hazard ratio [HR]=0.58, 95% confidence interval [CI] 0.45-0.75, p<0.001). The company is on track to complete an NDA filing with the FDA by the end of 2015. Cabozantinib has received Breakthrough Therapy designation in the U.S. and Exelixis expects a European filing to follow in early 2016.

August 4, 2014

Lpath issued results of a phase IIa trial of ASONEP as a treatment for metastatic renal cell carcinoma (RCC) in patients who have failed at least one therapy involving a VEGF inhibitor and no more than one mTOR inhibitor, with a maximum of three failed treatments. Lpath enrolled 26 patients in the single-arm, openlabel trial. The first 17 patients were initiated at a dose of 15mg/kg. Seven had progressive disease at or before the end of four months; eight were progression-free at the four-month mark (with one of these patients deemed a partial responder per Response Evaluation Criteria in Solid Tumors (RECIST) criteria and with three of these patients experiencing reduced tumor volume, but not enough to be categorized as a RECIST-based partial responder); and two exited the study due to SAEs unrelated to the drug prior to the four-month mark. The next nine patients were initiated at a dose of 24mg/ kg. Of these higher-dose patients, four had progressive disease at or before the end of four months; two were progression-free at the fourmonth mark (with one of these two deemed a partial responder per RECIST criteria); and the remaining three have not yet reached their four-month mark.

February 25, 2013

Argos Therapeutics reported results from a phase II trial of AGS-003 for metastatic renal cell carcinoma (mRCC). This open-label study enrolled 21 patients with unfavorable risk mRCC and with an expected survival of approximately 15 months. Subjects received standard six-week cycles of sunitinib plus AGS-003, administered every three weeks for five doses, and then every 12 weeks until progression. Results showed median overall survival was 30.2 months. When analyzed by baseline Heng risk status, the median overall survival for intermediate risk patients (n=11) has not been reached, but is estimated to be longer than 39.5 months with continued follow-up. Median overall survival for poor risk patients (n=10) was 9.1 months. Of the 21 patients who participated in the study, seven (33%) patients are still alive after nearly four years or longer following study registration. Argos Therapeutics is currently enrolling patients in a global phase III study of AGS-003.

February 18, 2013

AVEO Oncology and Astellas Pharma reported results from a phase III trial of tivozanib compared to sorafenib for the treatment of advanced renal cell carcinoma (RCC). This global, randomized study, TIVO-1, enrolled 517 patients with RCC. Subjects received either tivozanib or sorafenib. The final overall survival (OS) analysis showed a median OS of 28.8 months (95% confidence interval [CI]: 22.5–NA) for tivozanib versus a median OS of 29.3 months (95% CI: 29.3–NA) for the comparator arm, sorafenib. No statistical difference between the two arms (HR=1.245, p=0.105) was observed. Patients randomized to the sorafenib arm were eligible to cross over to tivozanib therapy under a separate protocol after radiographic confirmation of disease progression. No crossover protocol was available for patients randomized to the tivozanib arm. Tivozanib was well tolerated. Based on these data, AVEO and Astellas have filed a New Drug Application (NDA) for tivozanib for the treatment of RCC.

May 28, 2012

Astellas Pharma Europe and AVEO Oncology released results from a phase III trial of tivozanib compared to sorafenib for the treatment of advanced renal cell carcinoma (RCC). This randomized, superiority trial enrolled 517 patients who had clear cell RCC, had undergone a prior nephrectomy and had not previously been treated with a targeted therapy. Subjects received daily doses of tivozanib or sorafenib. Tivozanib demonstrated a statistically significant improvement in progression-free survival (PFS) with 11.9 months compared to a median PFS of 9.1 months for sorafenib in the overall population (HR≡0.797, 95% CI 0.6390.993; p=0.042). Tivozanib was generally well-tolerated. The most common adverse events were hypertension, diarrhea, fatigue and neutropaenia. Astellas and AVEO will present the data at the annual ASCO meeting in June.

January 9, 2012

AVEO and Astellas reported results from a phase III trial of tivozanib for the treatment of renal cell carcinoma. This open-label, randomized, controlled, multi-national, multi-center, parallel-arm trial, TIVO-1, enrolled 517 subjects with advanced renal cell carcinoma. The subjects received tivozanib 1.5 mg orally once daily or sorafenib 400 mg orally twice daily. In the overall study population tivozanib demonstrated a statistically significant improvement in progression free survival (PFS), with a median PFS of 11.9 months compared to a median PFS of 9.1 months for sorafenib. In a pre-specified subpopulation of treatment nave subjects, approximately 70% of the population, tivozanib also demonstrated a statistically significant improvement in PFS with a median PFS of 12.7 months compared to a median PFS of 9.1 months for sorafenib. Tivozanib was well-tolerated and the most common adverse event was hypertension.

March 15, 2010

Argos released positive results from a phase I/II trial of AGS-003, a personalized, RNA-loaded, dendritic cell-based immunotherapy for metastatic renal cell carcinoma (mRCC). This open label study enrolled 20 newly diagnosed post-nephrectomy patients with clear cell mRCC. The subjects received intradermal injections of AGS-003 in the following sequence: five biweekly doses, four monthly doses, and one dose every three months until disease progression. Primary endpoints of the study included clinical and immune response. At baseline, the majority of evaluable subjects suffered impaired cellular immunity to RCC tumor antigens. Following AGS-003 treatment, the majority of evaluable patients experienced detectable cellular immunity to these same antigens, demonstrating that AGS-003 induced a tumor-specific immune response. In addition, 50% of subjects had restored T cell-mediated interleukin-2 and interferon-3 responses, indicating general immune reconstitution. Secondary endpoints included progression free survival (PFS). The median length of PFS was 5.6 months, in contrast to the historical median PFS for interferon of 5.1 and 2.5 months for intermediate and poor-risk subjects, respectively. Clinical benefit, defined as either a partial response or stable disease, was reached by 41% of the subjects. AGS-003 was well tolerated, with no drug-related serious adverse events.

March 2, 2009

AVEO issued positive interim results from a phase II trial of AV-951 for the treatment of advanced renal cell carcinoma (RCC). This placebo-controlled, randomized discontinuation trial enrolled 272 subjects with with locally advanced or metastatic RCC who had no prior VEGF-targeted therapy, in Europe and India. The subjects received 1.5 mg/d of AV-951 (three weeks on, one week off) for the first 16 weeks, after which time they were evaluated for response. Those subjects who achieved >25% tumor regression remained on therapy, while those who experienced <25% change from baseline were randomized to receive AV-951 or placebo in a double-blind fashion. The primary endpoints are objective response rate at 16 weeks, progression free disease at 12 weeks and safety. Objective response rate at 16 weeks was 26.4% by investigator assessment and 20.1% by independent radiology assessment using standard RECIST criteria. Disease control rate at 16 weeks was 88.8% by investigator assessment and 91.7% by independent radiology assessment. Among patients with ≥25% tumor regression who continued uninterrupted treatment on AV-951, the median progression free survival has not been reached during a follow-up duration of 12.6 months.

October 27, 2008

ZymoGenetics reported positive interim results from a phase I/II trial of IL-21 in combination with Nexavar for the second or third line treatment of renal cell carcinoma. This open-label, dose-escalation trial enrolled 48 subjects in the US. In the phase I portion, the subjects received IL-21 in two five-day cycles, in combination with the standard dose of Nexavar, for six weeks. The primary endpoint was to establish the optimal tolerated dose of IL-21, which was determined to be 30 mcg/kg. The phase II portion was designed to determine the safety and preliminary anti-tumor activity of the combination treatment over six weeks. Of the 18 subjects treated, three had a confirmed partial response, for an overall response rate of 17%. Stable disease or partial or complete response at any time on study was observed in 16 of 18 (89%) of the evaluated subjects. Seven (54%) of 13 subjects who completed three treatment courses had stable disease or better. Treatment was generally well tolerated. Full results are expected the first half of 2009

October 6, 2008

Idera reported negative results from a phase II trial of IMO-2055 for the treatment of renal cell carcinoma. This study enrolled 92 treatment-naive and second-line subjects with metastatic or recurrent clear cell renal carcinoma, in the U.S. The subjects were randomized to receive IMO-2055 subcutaneously at either 0.16 mg/kg/week or 0.64 mg/kg/week until disease progression or toxicity. The primary endpoint was tumor response according to RECIST (Response Evaluation Criteria In Solid Tumors) criteria and progression free survival. The primary endpoints were not reached. Median progression-free survival for each of the four arms was 2 months, 3 months, 4 months, and 4 months. Treatment was generally well tolerated. IMO-2055 is currently undergoing trials for a variety of other cancers.

July 28, 2008

Agennix released positive results from a phase II trial of talactoferrin alfa for the treatment of renal cell carcinoma (RCC). This open label, single arm trial enrolled 44 subjects with advanced or metastatic RCC who had failed prior treatment. Talactoferrin was administered at a dose of 1.5 grams twice a day in 14-week cycles (12 weeks on, two weeks off) for up to four cycles or until disease progression. The study's co-primary endpoints were to detect an increase in the 14-week progression-free survival (PFS) rate from 20% to 40% or a 12.5% response rate; results from a previous phase II trial were used as the historical reference for comparison. The primary endpoints were reached, with a 14-week PFS rate of 59% (p<0.0001 for comparison to 20%). The response rate was 4.5%, with 70.5% of subjects demonstrating stable disease for at least eight weeks. The disease control (complete or partial response + stable disease) rate was 75%. The median PFS was 6.4 months. The median overall survival was 21.1 months, and the one year survival rate was 77%. Talactoferrin was well tolerated with no significant hematological, renal or hepatic toxicities reported. Based on the results, Agennix plans to move the development into phase IIb trials.

The GI Company released positive results from a phase II trial of Intestinal Trefoil Factor (rhITF) Oral Spray for the treatment of oral mucositis. This study enrolled 99 subjects with colorectal cancer at high risk for developing chemotherapy-induced oral mucositis. The subjects received 10 or 80 mg/mL of rhITF via oral spray for 14 days in their second chemotherapy cycle. The primary endpoint was reached, with a statistically significant reduction in the proportion of subjects developing World Health Organization (WHO) Scale grade 2 oral mucositis compared to placebo (low dose rhITF arm 81% decrease; high dose rhITF arm 75% decrease; p=<0.001). The secondary endpoint, reduction on the Oral Mucositis Assessment Scale (OMAS) score, was also reached. Mean OMAS scores were consistently and significantly lower in the low and high dose rhITF treatment arms compared to placebo over days 7 to 14, post-chemotherapy (p<0.001 to 0.013) and showed significant reduction in the frequency of grade 2 oral mucositis. Treatment was safe and well tolerated. Based on the results, The GI Company plans to move forward with the development of rhITF.

May 26, 2008

Novartis reported positive results from a phase III trial of everolimus for the treatment of renal cell carcinoma (RCC). This randomized, double-blind placebo-controlled multicenter trial, dubbed RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily), enrolled 400 subjects with RCC whose cancer worsened despite prior treatment. The subjects received everolimus or placebo in combination with best supportive care (BSC). The primary endpoint was progression-free survival. This was reached with statistical significance over placebo, with a median progression free survival of four months versus 1.9 months, respectively (p< 0.0001); the risk of cancer progression was reduced by 70% (p< 0.0001). There was no significant difference between everolimus and placebo in the main secondary endpoints of overall survival (p= 0.23) and objective response rate (1% versus 0% of responders). However, in a group of subjects evaluable for best percentage change in target lesions, tumor shrinkage was observed in 50% of subjects receiving everolimus during the double- blind portion of the study versus 8% of subjects receiving placebo. Based on the results, Novartis plans to file an NDA with the FDA in the second half of 2008.

April 15, 2002

Positive results were reported from a phase II trial of Wilex AG's naked chimeric antibody, WX-G250, in subjects with metastatic renal cell carcinoma (RCC). Results demonstrated that weekly intravenous treatment with WX-G250 over 12 weeks produced an overall clinical benefit rate of 25% and a median survival of 15 months. The 32-subject, open-label, multicenter trial, which was conducted at five European centers, evaluated repeated doses of the drug. Nineteen of the subjects were pre-treated, while 13 were treatment naïve. Two of the subjects experienced sustained tumor remission, and six experienced disease stabilization for over six months.

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