Action to Cure Kidney Cancer

Dr. SrikalaSridhar , from the Princess Margaret Hospital in Toronto, presented the results of a multi-center, open-label phase II trial of the drug cediranib. Cediranib is a VEGFR tyrosine kinase inhibitor, like sunitinib (Sutent) and sorafenib (Nexavar), and works by preventing tumors from growing blood vessels, specifically inhibiting VEGFR1, VEGFR2, and VEGFR3.

This Phase II trial, which enrolled patients who had no prior systemic therapy, achieved a disease control rate, by RECIST-defined response standards, of 86% (the total of partial responses and stable disease).

Methods

Forty-three patients were enrolled in the cediranib trial, with a median age of 62. They were each administered 45 mg of the drug daily until disease progression. Dose reductions were required in 34 patients.

Adverse Events

ACKC attended the AACR Conference, which took place April 12-16 in San Diego. 29,000 researchers, advocates, and other interested members of the public attended. The following are summaries of some of the presentations.

  

AV-951 in Phase 1 Trial in the Netherlands

At the American Association for Cancer Research in April 2008, Ferry Eskens of the Erasmus Medical Center in Rotterdam presented in, an oral session, the results of a Phase 1, single-center trial of the anti-angiogenic drug AV-951 in 41 solid tumor cancer patients, 9 of whom were RCC patients (others included colon, lung, pancreas, and other tumor sites). AV-951 is a highly potent drug that has inhibitory activity against VEGF Receptors 1, 2, and 3. The objectives of the trial were to determine the maximum tolerated dose and dose limiting toxicities. Dosage levels were given of 1 mg, 1.5 mg, and 2 mg per day.

Response

Since 2003, the direction of kidney cancer clinical research has shifted from almost total reliance on immunotherapies (Interleukin-2 and Interferon), to an emphasis on investigational drugs that target various cellular mechanisms that regulate cancer cell growth and proliferation. Specifically, the new therapies are targeted to work by at least three and perhaps more mechanisms of action:

1. by inhibiting the growth of new blood vessels which in turn nourish the growth of new tumor cells (angiogenesis)
2. by inhibiting cells (pericytes) which stabilize new blood vessels
3. by correcting the normal body mechanism that allow living cells, including cancer cells, to naturally die. The latter is known as apoptosis. Most body cells divide about seven times before they undergo genetically programmed cell death, but cancer cells continue dividing as infinitum

Robert Motzer made an oral presentation of the updated results of a multi-institutional, Phase 3 trial of Sutent versus Interferon in a first-line setting. The original Phase 3 trial, presented at ASCO in 2006, showed superiority of Sutent over Interferon. This was a 750-patient trial, with all patients having clear cell pathology. 375 patients (pts) were randomized to each arm of the trial.

Sutent versus Interferon Results

	Sutent	Interferon
	Patients (%)	Patients (%)
Objective Response	142 (39%) Kidney Cancer Info Read more Sutent and Avastin In a poster session, Darren Feldman reported on a current Phase 1 trial of the combined therapies, Avastin and Sutent, at a single institution, Memorial Sloan-Kettering (MSKCC). The theory behind combining these two therapies is that while Sutent is an inhibitor of the vascular endothelial growth factor receptor (VEGFR), a promoter of angiogenesis, it also increases VEGF itself. Avastin blocks VEGF so the combination would theoretically have a longer lasting effect. This trial is similar to the one presented at last year's ASCO conference by Jeffrey Sosman of Vanbderbilt University in which the combination of Nexavar and Avastin was used. In that trial, dose limiting toxicities prevented investigators from reaching the standard dosage for Nexavar of 800 mg per day, which impacted the response rate. Kidney Cancer Info Read more Sequential Use of Sutent and Nexavar A poster was presented by Anu Dahm of the University of Minnesota of a study to evaluate the response of sequential use of Sutent and Nexavar. Patients whose disease had progressed or who had suffered unacceptable toxicities with the first line drug were then given the second drug. 37 patients entered the study and were divided into two groups. Group A had 23 patients receiving Nexavar then Sutent, while Group B had 14 receiving Sutent then Nexavar. Three people in Group A and two in Group B switched therapies due to toxicities. The others switched due to disease progression. The risk factors of both groups were similar. Sequential Use Results Group A Group B Nexavar --> Sutent Kidney Cancer Info Read more RAD001 In a poster presentation, Jaroslaw Jac reported on a Phase 2 study of RAD001 (everlolimus) at a single institution, the Methodist Hospital in Houston, TX (this is a Robert Amato study). RAD001 is an mTOR inhibitor, where mTOR is a protein that can promote tumor cell growth and proliferation and angiogenesis. 41 patients were enrolled in the trial with 37 evaluable. The treatment plan was 10 mg daily reduced to 5 mg for grade 3/4 toxicities. Over 80% of the patients had failed prior systemic therapy. Only two patients were non-clear cell. There were 12 dose reductions, 7 due to pneumonitis (inflammation of the lungs). There were no other single significant grade 3/4 toxicities. For the 37 evaluable patients the response was. RAD001 Response Patients (%) Kidney Cancer Info Read more Pazopanib Thomas Hutson from the Baylor Sammons Cancer Center presented a poster on the interim results of a randomized discontinuation trial of Pazopanib in metastatic kidney cancer patients. Pazopanib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), and c-kit. In other words, it blocks tumor growth and has anti-angiogenic activity. The dosage was 800 mg of pazopanib taken orally once daily for 12 weeks. At the end of this cycle, the complete and partial responders were to be continued on treatment, but the patients with stable disease were to be randomized to either continue on pazopanib or be given a placebo. However, based on the positive activity of the drug, the randomization was discontinued, the patients on the placebo arm were crossed over to pazopanib, and the trial continued as a single-arm study. Kidney Cancer Info Read more Nexavar versus Interferon Cezary Szczylik from the Military Medical Institute, Warsaw, Poland, made an oral presentation of a randomized, multi-institutional, Phase 2 trial of first-line treatment with Nexavar versus Interferon. All patients had clear cell pathology. This was a dose escalated trial separated into two phases, the first before tumor progression, and the second after tumor progression. This was a two-arm trial, which, for Period 1, 97 patients received the standard Nexavar dose of 400 mg twice a day on the first arm, and 92 patients received Interferon on the second arm. After progression, for Period 2, the Nexavar arm was upped to 600 mg twice a day, and the Interferon arm was crossed over to Nexavar at 400 mg twice a day. The primary endpoints were progression free survival (PFS) and quality of life. Period 1 Results Nexavar Kidney Cancer Info Read more Nexavar versus a Placebo, Final Results Ronald Bukowski of the Cleveland Clinic made an oral presentation, describing the final results of the randomized Phase 3 trial of 451 patients taking Nexavar versus 452 patients taking a placebo. All patients had clear cell pathology and were rated as having low or intermediate prognostic risk. The dosage was 400 mg of Nexavar twice a day with endpoints of progression free survival and overall survival. The patients must have failed one prior systemic therapy no more than eight months prior to their participation in the trial. This is the trial that led to FDA approval for Nexavar in December 2005. Kidney Cancer Info Read more 12next ›last »