Action to Cure Kidney Cancer

A poster presentation on the results of a Phase II trial of the investigational tyrosine kinase inhibitor (TKI), AV-951, aka tivozanib, was made by Pankaj Bhargava, the VP for Clinical Research at AVEO, the developer of the drug. Tivozanib is a very potent TKI (others are Sutent, Nexavar, etc) as measured by its IC₅₀ value (see the end of this report for the meaning IC₅₀). The potency of the drug allows the dosage to be set at 1.5 mg/day, which Dr. Bhargava, in our conversation with him, attributes as the reason for its reasonably low side effects, with manageable hypertension being the most prevalent one (hypertension was reported in over 50% of patients but grade 3/4 hypertension was found in fewer than 10% of patients). Brian Rini, of the Cleveland Clinic, who discussed the poster in the ASCO Poster Discussion Session, also remarked on the low side effects of tivozanib.

Following are details of the study.

Cora Sternberg, from the San Camillo and Fortanini Hospitals, Rome, Italy, made an oral presentation of the results of a randomized, double-blind, Phase III study of pazopanib in treatment-naïve and cytokine (either Interferon-alpha or Interleukin-2) refractory (pre-treated) patients with advanced renal cell carcinoma. The trial was conducted from April 2006 to April 2007 at 80 sites in 22 countries outside of North America. Pazopanib is an oral angiogenic inhibitor that especially targets VEGEFR-1, VEGFR-2, and VEGFR-3.

The trial was restricted to patients with clear cell histology. Of the 435 patients, 233 were treatment-naïve and 202 experienced one prior cytokine treatment. Patients were then randomized 2:1 to either pazopanib 800 mg/day (290 patients) or to a placebo (145 patients), with the option of receiving pazopanib upon progression.

This year's ASCO Conference was held in sunny Orlando. Although well attended, it held no surprises or blockbuster announcements for kidney cancer drugs. Avastin was approved by the FDA for metastatic kidney cancer on August 3^rd, but that was based on data that was presented at ASCO 2007. Of the 100 abstracts presented on kidney cancer, 40% of concerned studies for three drugs: Sutent (sunitinib), Nexavar (sorafenib), and Avastin (bevacizumab). The abstracts can be viewed at the ASCO website http://tinyurl.com/n7lzsq. 19 of the reports were presented on investigational therapies, that is, they are not approved by the FDA for kidney cancer treatment. Three of these, GlaxoSmithKline's pazopanib, Aveo's tivozanib (AV-951), and Pfizer's axitinib, are likely to be approved within the next year or two.

Daniel Heng, from the Tom Baker Cancer Center in Calgary, Alberta, presented a multi-center, retrospective study in a poster session, delineating the prognostic factors for overall survival in patients with metastatic renal cell carcinoma who are treated with VEGF-targeted agents, i.e. Sutent, Nexavar, or Avastin. 645 patients at seven sites were included in the study, which has now (August 2009) been expanded to 11 international sites. This study was undertaken to update the widely used risk factors that are currently used by kidney cancer oncologists, the MSKCC risk factors, which were developed by Dr. Robert Motzer at Memorial Sloan-Kettering, and the CCF model developed at the Cleveland Clinic. Both of these models were developed in the era of immunotherapies (these two models are summarized at the end of this article). Dr. Heng wanted to update these factors in a large study where targeted agents were used.

In a pre-surgical study, Eric Jonasch from MD Anderson in Houston, in an oral session, presented data on a Phase II presurgical study of the use of Avastin (bevacizumab) in untreated kidney cancer patients. Unlike the Cleveland Clinic study, the investigators' hypotheses in this trial were that Avastin therapy was safe and also prolonged time to progression. He also wanted to develop biomarkers from the treated tissue samples.

Shailender Bhatia from the University of Washington presented the results, in a poster session, of a Phase II trial of the combination of Interleukin-21 (IL-21) and sorafenib (Nexavar) as a second-line therapy in kidney cancer. IL-21, like IL-2, is an immunotherapy that activates the body's T-cells and natural killer cells to attack and destroy foreign substances like tumors. Unlike IL-2, IL-21 does not activate T-reg cells, which have an inhibiting effect on the immune system. The object of this study is to combine low dosage IL-21 with the normal dosage, 400 mg twice a day, of Nexavar, to gauge the effect of combining an immunotherapy and a targeted therapy (in this case, a tyrosine kinase inhibitor) in the fight against kidney cancer. This being a second-line trial, 79% of patients had one prior therapy while 21% had two priors. The most prevalent prior therapies were Sutent (58%) and IL-2 (33%).

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