Mar 14, 2013 - 11:10 am
There are many new treatments for RCC currently in Clinical Trials around the world. Below is my compilation of what I believe are the most promising treatments that are on the horizon for RCC. Hopefully, these new drugs/treatments will receive FDA approval within the next 1-3 years. Each drug I mention contains snippets of information that I have copied from the Internet. - BDS
Tivozanib (Aveo Pharmaceuticals) is a potent pan-VEGF receptor tyrosine kinase inhibitor. The biological activity of tivozanib seems to outstand that of other VEGF tyrosine kinase inhibitors. In Phase I studies, observed side effects are generally mild, with hypertension being the most common adverse event. In single-agent Phase II and III studies in patients with advanced or metastatic renal cell carcinoma, tivozanib has demonstrated convincing clinical activity.
In a statement, Aveo said that the FDA has accepted the company’s NDA, submitted in September, for tivozanib as a treatment for advanced renal cell carcinoma (RCC), or kidney cancer. The FDA’s review of the candidate is expected to be completed by July 28, 2013, the company said. The NDA includes results of the global Phase 3 trial, TIVO-1, of 517 patients with advanced RCC. The study showed that tivozanib was the first product to demonstrate more than one year of progression-free survival for patients who had never taken medication for the disease before. In a head-to-head comparison, AVEO’s drug candidate bested Nexavar, the current standard of care, made by Onyx Pharmaceuticals.
AVEO Oncology Astellas Pharma Inc. today announced that new clinical data on tivozanib, an investigational agent for the treatment of metastatic renal cell carcinoma (mRCC), will be presented at the 2013 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), taking place February 14-16 2013 in Orlando, Florida Presenter: Robert Motzer, M.D. Date & Time: Saturday, February 16, 2013; 6:45-7:55am
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BMS-936558/Nivolumab (Bristol-Myers Squibb): It is proposed that the anti-PD-1 treatments currently being investigated work against the cancer cells by blocking them from binding to and activating PD-1. This helps the body reactivate the immune response and fight back against the cancer.
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BNC-105P: There is an Australian company called Bionomics that is conducting clinical trials of a new promising drug called BNC105 or BNC105P. BNC105 is a vascular disrupting agent that shuts down the blood supply to solid tumors.
Web Link: http://www.bionomics.com.au/index.php )
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IMA901 vaccine: Completed a European multi-centerphase 2 clinical trial in renal cell carcinoma in Q4 2009. 68 patients with advanced renal cell carcinoma were treated and highly encouraging overall survival rates were observed in the treated patients, significantly improving on the data seen from market-leading drugs in previous studies. Furthermore, IMA901 showed an excellent safety profile. Based on these very encouraging results and on discussions with regulatory bodies in the US (FDA) and Europe (EMA), immatics initiated a pivotal, randomized, controlled phase 3 study that, presenting positive outcomes could soon lead to the market approval of IMA901.
Web Links: http://www.immatics.com/index.php
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TVAX Biomedical is a clinical stage drug development company advancing its novel targeted cell-based immunotherapy for the treatment of cancer.
TVI-Kidney-1 is being evaluated for the treatment of kidney cancer and targets stage IV renal cell carcinoma.As with TVI-Brain-1, this drug candidate is supported by positive Phase 2 clinical data, as well as extensive preclinical and Phase 1 safety studies. Based on these supportive data, TVAX has been authorized by the United States Food and Drug Administration (FDA) to conduct pivotal Phase 3 trials for TVI-Kidney-1 to support the therapy’s potential FDA approval. The company has prioritized the TVI-Brain-1 program at this time, but intends to initiate the TVI-Kidney-1 pivotal Phase 3 trial in the near future.
Web Links: http://www.tvaxbiomedical.com/index.shtml
AGS-003 is an investigational, fully personalized, cancer immunotherapy being evaluated in a phase 3 clinical study in combination with targeted drug therapy for the treatment of metastatic renal cell carcinoma (mRCC).
To make AGS-003, a small tumor sample is obtained during the initial, standard surgery (nephrectomy). Following recovery from surgery, a blood donation procedure (leukapheresis) is performed to collect a certain type of blood cell which is required to make powerful dendritic cells. Once these elements are combined, up to 5 years of treatment is made for each patient.
Where AGS-003 Fits:
Adding AGS-003 to targeted drug therapy may represent an important advancement in the treatment of advanced kidney cancer. In a previous clinical trial, AGS-003 was safely added to a commonly used targeted therapy and appeared to trigger an immune response which helped patients fight their cancer.
Web Link: http://adaptkidneycancer.com/
Not Sure Who Makes this Drug: AGS-16C3F is an antibody-drug conjugate. It is composed of an antibody which binds to a specific receptor on cancer cells. Once there, a chemotherapy drug that is bound to the antibody can kill the cancer cell. AGS-16C3F is given intravenously (by vein).
Cabozantinib (Exelixis Inc.) is an inhibitor of both VEGFR2 and c-Met, both of which promote angiogenesis. 25 patients were evaluated, all of whom had prior therapies for kidney cancer, mostly VEGF or mTOR inhibitors. This was an experienced group as close to half of the patients had three or more prior therapies. For example, 14 of the 25 had previously taken sunitnib (Sutent). The dosage was 140 mg/daily, which was previously determined to be the maximum tolerated dose (MTD). Other studies have used 40 mg to 140 mg, with the lower dose showing efficacy in prostate cancer. Exelixis, the biotech company that developed the drug, will consider dose reduction in the future for RCC.
Based on prostate trial data, cabozantinib has demonstrated significant efficacy in reducing or eliminating bone lesions. There were four rcc patients with bone lesions at baseline, two with pain. The pain resolved for both and one has continued to be pain-free for 73 weeks. One patient did develop new bone lesions. According to Exelixis, in addition to cabozantinib’s effect on osteoblasts and osteoclasts, an anti-tumor effect was also noticed in the bone lesions. It will be interesting to see further elucidation of this since, as compared with Zometa, which is an agent that has been used successfully to treat bone metastases, it is still unclear if there is an anti-tumor effect.
What stands out in this trial is the response rate, specifically the pfs of 14.7 months and some tumor shrinkage in 19 of the 21 evaluated patients for a patient mix that was heavily pre-treated. For example, of the 7 patients who showed partial tumor response (> 30% shrinkage), 4 of them had four or more prior treatments. The best pfs in current therapies is about a year, and this is mostly for treatment-naïve patients. The axitinib-sorafenib second-line trial (with one prior therapy) yielded a pfs of 6.7 months and 4.7 months for axitinib and sorafenib, respectively. Additionally, the patients on this trial were all in the intermediate and poor risk categories. Most trials have patients who have good and intermediate risk for recurrence. Cabozantinib also demonstrated efficacy against bone lesions, following its similar history with prostate cancer. The drug also seems to be well-tolerated without the significant hypertension and possibly concomitant heart issues found in other tyrosine kinase inhibitors.
Although the numbers are small, there doesn’t seem to be a relationship between number of prior therapies and response to cabozantinib. In other words, it doesn’t matter how many priors you’ve had, you still have a possibility of tumor response to cabozantinib.
Note – (I could be wrong on this But…) Only a Phase 1 trial has been completed with Cabozantinib for RCC. From what I can currently determine the company (Exelixis) is not vigorously pursuing a Phase 2 clinical trial. I cannot find any mention of it on ClinicalTrials.gov only on Exelixis website where it is in a status of “Not Yet Recruiting”. - BDS
Dalantercept: February 5, 2013 – Acceleron Pharma, Inc., a biopharmaceutical company developing protein therapeutics for cancer and orphan diseases, announced the initiation of a phase 2 study of dalantercept, a novel angiogenesis inhibitor that targets the activin receptor-like kinase 1 (ALK1) pathway. The phase 2 study is a two-part, randomized study of dalantercept in combination with axitinib (Inlyta®, Pfizer), a vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, to treat patients with metastatic renal cell carcinoma (RCC). Acceleron, its partners, and collaborators have now initiated seven phase 2 studies across three of Acceleron’s programs – dalantercept (ACE-041), sotatercept (ACE-011), and ACE-536 – since November of 2012.
“Many patients with renal cell carcinoma respond to treatment with a VEGF inhibitor yet their disease subsequently progresses,” said Michael B. Atkins, M.D., Deputy Director, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center. “We are optimistic that combining two therapies with distinct anti-angiogenesis mechanisms, a VEGF inhibitor and dalantercept, an ALK1 signaling inhibitor, can provide a more effective and durable antitumor response in these patients.”
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