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  • hbomb57108 hbomb57108 Feb 4, 2013 12:07 AM Flag

    Two Alliance Studies, One Drug: A Closer Look at Cabozantinib

    Renal study start date

    The study protocol for ALLIANCE A031203 is currently in development and it is projected to be activated in April 2013.

    ALLIANCE A031203 is a randomized phase II trial of cabozantinib versus sunitinib in patients with previously untreated metastatic renal cell cancer with intermediate/poor risk. These patients represent 80 percent of all patients and those who will likely need systemic therapy. The primary objective of this study is to compare PFS in patients treated with cabozantinib versus patients treated with sunitinib. At the time of progression, patients’ treatment will be unblinded and those who had been receiving sunitinib will be permitted to crossover to cabozantinib.

    Uveal melanoma start date

    The study protocol for ALLIANCE A091201 is currently in development and it is projected to be activated in April 2013.

    ALLIANCE A091201, a one-stage phase II trial, will #$%$ the anti-tumor efficacy of cabozantinib in uveal melanoma. Specifically, this study will #$%$ whether cabozantinib can improve the four-month progression-free survival (PFS) rate in patients with ocular melanoma from 15 percent, as reported with temozolomide and dacarbazine, to 40 percent with cabozantinib. The molecular impact of cabozantinib on metastatic uveal melanoma lesions in liver and bone will be evaluated usingFDG-PET/CT imaging. Secondary objectives
    of this study are to estimate the distribution of progression-free survival times and overall survival times using the method of Kaplan Meier, estimate the confirmed response rate as determined by RECIST criteria, #$%$ the toxicity profiles, and correlate the response with MET molecular status.

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    • "ALLIANCE A031203 is a randomized phase II trial of cabozantinib versus sunitinib in patients with previously untreated metastatic renal cell cancer..." This is a notable study for several reasons. It will be the first head to head comparison of Cabo vs another TKI. The study's primary endpoint is PFS with secondary of OS. At n=140 it will not be large enough to show statsig survival, especially because it has a crossover. A significant Cabo showing vs Sutent would be important proof of concept, would likely lead to a larger pivotal trial and could lead to listing in the NCCN in their Compendium. Since the control arm is getting the standard of care with a crossover opportunity, it should enroll quickly. Best guess is this trial will read out sometime in late 2014 or early 2015.

      • 1 Reply to erniewerner
      • $$$$

        Agreed...
        On the topic of speedy enrollment, bhukap posed some concerns last week wrt the recruiting status of Comet 1. Bhukap's an oncologist - he could not get one of his patients enlisted into the trial, and questioning the NY recruitment center led to commentary stating that w/o a planned trial crossover, patients were reluctant to commit to a Cabo vs predno trial for fear of getting the short stick w/ no provision for treatment other than prednisone - and I can certainly understand that reluctance. If Comet 1 cannot fully recruit soon, an acceptable OS signal in CRPC may not materialize in 2014. What happens if a trial cannot fully recruit? Ever seen this happen?
        Any thoughts?
        GL

    • Why Cabozantinib?
      Cabozantinib, also known as XL184, is a small molecule inhibitor of the tyrosine kinases, primarily c-Met (MET) and vascular endothelial growth factor receptor type 2 (VEGFR-2). These two key kinases are involved in the development and progression of many cancers. Other additional kinase targets include RET, AXL, KIT, and TIE-2. Pre-clinical studies demonstrated that XL-184 potently inhibited multiple receptor tyrosine kinases in various cancer cell lines and animal xenograft models and caused reductions in tumor growth, metastasis and angiogenesis.
      Recently, preclinical models have shown that treatment with selective inhibitors of VEGF signaling can result in tumors that are more invasive and aggressive compared to control treatment. In preclinical studies, upregulation of MET has been shown to occur in concert with development of tumor invasiveness after selective anti-VEGF therapy, and may constitute a mechanism of acquired or evasive resistance to agents that target VEGF signaling without inhibiting MET. Treatment with cabozantinib in similar preclinical studies resulted in tumors that were less invasive and aggressive compared to control or selective anti-VEGF treatment. As a result, cabozantinib has the potential for improving outcomes in a range of indications, including those where selective anti-VEGF therapy has shown minimal or no activity.
      Promising results have been reported from early phase clinical trials of castration-resistant prostate cancer, non-small cell lung cancer, hepatocellular cancer and other solid tumors. The safety profile reported is comparable to that of other VEGFR TKIs and includes diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal
      pain, and constipation.

      • 3 Replies to hbomb57108
      • $$$$

        Just a thought to share wrt the evolution of TKI cancer therapy, the BP dilemma of a pending patent cliff, and best use of existing pharmaceutical assets prior to patent expiration. Today's 2/5/12 OncLive published an interesting piece on Avastin: "Bevacizumab Results Offer Support for Upfront Therapy"...discussing the continued moving of bevacizumab into increasingly frontline therapeutic endeavors. Keep in mind, bevacizumab is but one successful VEGF inhibitor. There are many others that could easily be included in this hypothesis.

        The above "read" induced me to revisit the following commentary wrt selective VEGF inhibition and the ensuing MET upregulation, resulting in tumors that are "more invasive and aggressive"...

        "Recently, preclinical models have shown that treatment with selective inhibitors of VEGF signaling can result in tumors that are more invasive and aggressive compared to control treatment. In preclinical studies, upregulation of MET has been shown to occur in concert with development of tumor invasiveness after selective anti-VEGF therapy, and may constitute a mechanism of acquired or evasive resistance to agents that target VEGF signaling without inhibiting MET. Treatment with cabozantinib in similar preclinical studies resulted in tumors that were less invasive and aggressive compared to control or selective anti-VEGF treatment. As a result, cabozantinib has the potential for improving outcomes in a range of indications, including those where selective anti-VEGF therapy has shown minimal or no activity."

        Here's the scam: "Hook" as many cancer patients on bevacizumab (or the VEGF inhibitor of your choice) as possible, prior to patent expiration. In the short term, patients are looking better, feeling better, and showing signs of clinical improvement - hands down. Yet the cancers are being deleteriously modified by VEGF inhibition, and the patient groups are progressing slowly & steadily toward advanced MET upregulation.

        Enter Roche - who owns Genetech - and thus, Avastin. Roche buys EXEL for a non-inflated price that has been negotiated far in advance, including a sweetheart deal for the management team and the BOD, because...far in advance, the Roche BOD had hired Hedgepappy, Nomad, and the Devil's minions to "sit on" the EXEL PPS till the scam reached maturity.

        "Treatment with cabozantinib in similar preclinical studies resulted in tumors that were less invasive and aggressive compared to control or selective anti-VEGF treatment. As a result, cabozantinib has the potential for improving outcomes in a range of indications, including those where selective anti-VEGF therapy has shown minimal or no activity."

        Not a conspiracy theory, simply the politics of revenue - and best use of existing assets.
        Is Cabo to become the MET inhibitor of choice when the Avastin patent expires?
        Is wide-spread selective VEGF inhibition "setting up" the Cabo success story?
        GLTA

      • Thanks for a detailed explanation of Cabo's inhibition capacity. A good refresher.

      • good stuff hbomb, "where there is smoke there must be fire".

        Sentiment: Strong Buy

 
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