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Thread: Cabozantinib ( XL184 ) for Solid Tumors (trial)

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    Cabozantinib ( XL184 ) for Solid Tumors (trial)

    Reuters
    Exelixis drug shown to control solid tumors
    Wed, May 18 2011
    * Tumor control high for liver, prostate, ovarian cancers
    * Effect on bone metastases called "unprecedented"

    By Deena Beasley

    LOS ANGELES, May 18 (Reuters) - Exelixis Inc's experimental cancer drug cabozantinib was shown in a mid-stage trial to help control advanced prostate, ovarian and liver cancers, according to research presented on Wednesday.

    The drug was also found to fully or partly eliminate cancer that had spread to the bone in patients with breast cancer, prostate cancer and melanoma, according to the American Society of Clinical Oncology, which featured the data ahead of its annual meeting in June.

    "We saw unprecedented bone scan improvement," said the study's lead author Dr. Michael Gordon, a medical oncologist at Pinnacle Oncology Hematology in Scottsdale, Arizona.

    Cabozantinib, also known as XL184, is the lead product for Exelixis.
    It is an oral drug designed to block the pathway that tumors need to form new blood vessels -- the same target as drugs like Roche's Avastin -- as well as MET, another driver of tumor formation.

    The Phase 2 study included 483 patients with advanced, progressive solid tumors.
    Patients received cabozantinib over 12 weeks. Those who responded stayed on the drug; patients with stable disease were randomized to cabozantinib or placebo; and patients whose cancer worsened were removed from the trial.

    Dr. Gordon said further trial results will be presented at the ASCO meeting in June.

    In the data released on Wednesday, for 398 evaluated patients with all types of cancer, 9 percent experienced partial tumor shrinkage.
    But the rates of cancer stabilization were much higher -- 76 percent of liver cancer patients, 71 percent of prostate cancer patients and 58 percent of ovarian cancer patients saw their tumors either shrink or remain unchanged.

    Also, 59 of 68 patients with cancer that had spread to the bone (mostly from prostate cancer, but also from breast cancer and melanoma) had either partial or complete disappearance of the cancer on bone scans.
    The effects were associated with improvement in pain, a reduction in narcotic requirements and improvement in anemia.

    The most common serious side effects seen in the trial were fatigue and hand/foot tenderness. Drug dosage was reduced in 41 percent of patients because of side effects and 12 percent of patients were removed from the trial for adverse events.

    (Reporting by Deena Beasley, editing by Matthew Lewis)
    DOB Sept. 1947. Prostate cancer Gleason 7 (3+4), PSA 5 in Oct 2010. Cryoablation Jan. 2011. Had some complications.
    Experienced nocturia, irritable bladder summer 2011. "Agent Orange"compensation from VA Oct 2011.
    PSA .05 01/26/2012, .06 6/26/2012, .04 12/24/2012, PSA .04 6/26/13, PSA .05 1/27/14
    I am eating vegan mostly plus a little fish. Take some supplements.
    (Any advice given is the personal opinion of a layman and is not intended to replace the advice of a health professional.)

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    Top User gdpawel's Avatar
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    Cabozantinib (XL184)

    They were looking for drugs to treat the inflammation seen in Crohn's disease and ulcerative colitis. They tested a compound called a PPAR-gamma modulator. It would never normally have been thought of as a cancer drug, or in fact a drug of any kind. They ran several tests and found the compound killed pretty much every epithelial tumor cell lines they have seen. Epithelial cells line organs such as the colon, and also make up skin.

    They reported in the journal International Cancer Research that it killed colon tumors in mice without making the mice sick. The compound worked in much the same way as the taxane drugs, including Taxol, which were originally derived from Pacific yew trees. It targets part of the cell cytoskeleton called tubulin. Tubulin is used to build microtubules, which in turn make up the cell's structure.

    Destroying it kills the cell, but cancer cells eventually evolve mechanisms to pump out the drugs that do this, a problem called resistance. Resistance to anti-tubulin therapies, like Taxol, is a huge problem in many cancers. They see this as another way to get to the tubulin. The PPAR-gamma compound does this in a different way from the taxanes, which might mean it could overcome the resistance that tumor cells often develop to chemotherapy.

    Most of the drugs like Taxol affect the ability of tubulin to form into microtubules. This doesn't do that -- it causes the tubulin itself to disappear. They do not know why. They planned to do more safety tests in mice. As the compound is already patented, the team will probably have to design something slightly different to be able to patent it as a new drug.

    How does Taxol work?

    Taxol-treated cells have defects in mitotic spindle assembly, chromosome segregation, and cell division. Unlike other tubulin targeted drugs such as colchicine that inhibit microtubule assembly, however, Taxol stabilizes the microtubule polymer and protects it from disassembly. The inability of the chromosomes to achieve a metaphase spindle configuration leads to a mitotic block in which there is prolonged activation of the mitotic checkpoint with the subsequent triggering of apoptosis or slippage back into the G1-phase of the cell cycle without cell division.

    The ability of Taxol to inhibit spindle function is generally attributed to its suppression of microtubule dynamics, but recent studies have demonstrated that suppression of dynamics occurs at concentrations lower than those needed to block mitosis. At the higher antimitotic concentrations, Taxol appears to act by suppressing microtubule detachment from centrosomes, a process normally activated during mitosis. The binding site for Taxol has been shown to reside on the beta-tubulin subunit.

    In other words, Taxol gumms up the innards (microtubules) of all rapidly dividing cells (good cells and bad cells). When microtubules get gummed up, the tumor cell commits suicide. A report in the journal International Cancer Research stated that taxane drugs, including Taxol, targets part of the cell cytoskeleton called the tubulin. Tubulin is used to build microtubules, which in turn make up the cell's structure. Destroying it kills the cell, but cancer cells eventually evolve mechanisms to pump out the drugs that do this (resistance). Resistance to anti-tubulin therapies, like Taxol, is a huge problem in many cancers.

    It's like a gasoline engine in an automobile. Say the motor is running and for some reason the key in the ignition is broken/jammed and you cannot shut the engine off, and you cannot open the bonnet to cut ignition wires to stop the engine. So the only other way is to pour sugar into the gasoline tank until the motor gummies up and stops running. Now, you shut off the engine the best way you possibly could because of the restrictions. However, while cutting ignition wires would save the engine for another day (replace just the wires), by placing sugar into the gas tank you virtually destroyed the engine, unless you can completely overhaul it.

    Sources:

    Bharadwaj R., Yu H. 2004. "The spindle checkpoint, aneuploidy, and cancer". Oncogene 23 (11): 2016–27. doi:10.1038/sj.onc.1207374. PMID 15021889.

    Brito D. A., Yang Z., Rieder C. L. 2008. "Microtubules do not promote mitotic slippage when the spindle assembly checkpoint cannot be satisfied". J. Cell Biol. 182 (4): 623–9. doi:10.1083/jcb.200805072. PMC 2518701. PMID 18710927.

    Jordan MA, Leslie W, Microtubules as a target for anticancer drugs Apr 4, 2004”, "[1]"

    Ganguly A, Yang H, Cabral F, Paclitaxel-dependent cell lines reveal a novel drug activity.Mol Cancer Ther. 2010 Nov;9(11):2914-23. Epub 2010 Oct 26.
    Gregory D. Pawelski

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    Top User gdpawel's Avatar
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    Cabozantinib Shows Promise against Bone Metastases

    The investigational drug cabozantinib is showing promise against several types of advanced cancer, and may also reduce or eliminate bone metastases (cancer that has spread to the bone) in some patients. These results will be presented at the 2011 annual meeting of the American Society of Clinical Oncology.

    Metastatic cancer refers to cancer that has spread to distant sites in the body. Several types of cancer—including cancers of the prostate, lung, and breast—have a tendency to spread to the bone. Bone metastases can lead to serious problems such as fracture and spinal cord compression, and may require treatment with surgery or radiation therapy.

    Cabozantinib is an investigational drug that targets two proteins—MET and VEGFR2—that play a role in the development and progression of many types of cancer.

    To evaluate cabozantinib in the treatment of advanced cancer, researchers conducted a Phase II clinical trial among 398 patients. The nine types of cancer included in the study were breast, stomach/gastroesophageal junction, non-small cell lung, ovarian, pancreatic, hormone-refractory prostate, small cell lung, liver, and melanoma. At the start of the study, 39% of the patients had bone metastases.

    Patients were initially treated with 12 weeks of cabozantinib. After 12 weeks, patients who had a partial response to treatment (a reduction in detectable cancer) remained on cabozantinib, patients with stable disease (no significant change in the cancer) were randomly assigned to either continue with cabozantinib or to take a placebo, and patients with progressive (worsening) cancer were withdrawn from the study.

    By week 12, 9% of patients responded to treatment.

    For some types of cancer, cabozantinib produced high disease control rates (defined as either a reduction in cancer or stable disease). The disease control rates were 76% for liver cancer, 71% for prostate cancer, and 58% for ovarian cancer.

    Among the 68 patients with bone metastases, 59 had partial or complete disappearance of the cancer on bone scans, often accompanied by significant pain relief. A majority of these patients had hormone-refractory prostate cancer, but patients with breast cancer and melanoma also experience a disappearance of bone metastases. The researchers had not expected this result.

    The most common side effects were fatigue and hand-foot syndrome (pain, swelling, numbness, tingling, or redness of the hands or feet).

    In a prepared statement, the lead author of the study noted “Cabozantinib appears to have significant effects on several treatment-resistant tumors, as well as impressive effects on bone metastases. In addition, these effects are associated with rapid improvement in pain, a reduction in opiate narcotic requirements and improvement in anemia. The implications of these results are very exciting—it is unusual to find a targeted therapy, absent of a molecular mutation in tumors, that works in bony disease and has this activity.”

    Reference: Gordon MS, Vogelzang NJ, Schoffski P et al. Cabozantinib (XL184) has activity in both soft tissue and bone: Results of a phase II randomized discontinuation trial (RDT) in patients (pts) w/ advanced solid tumors. Paper presented at: 2011 Annual Meeting of the American Society of Clinical Oncology; June 3-7, 2011; Chicago, IL. Abstract 3010.
    Gregory D. Pawelski

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    [Cabozantinib is being tested at lower doses due to embolisms and other side effects.]

    Thyroid cancer drug cabozantinib prolongs PFS
    OCTOBER 24, 2011
    (Reuters) - Exelixis Inc said preliminary results from a phase III trial show its experimental drug cabozantinib met the main primary goal of improving progression-free survival (PFS) in patients with medullary thyroid cancer.

    The median (PFS) was 11.2 months for patients taking cabozantinib versus 4 months for those on placebo (hazard ratio 0.28, p<0.0001).
    The ongoing trial, named EXAM, is being conducted under a special protocol assessment (SPA) agreement with the U.S. Food and Drug Administration.

    Exelixis said it was requesting permission to begin a rolling submission of the new drug application for cabozantinib in advanced medullary thyroid cancer and expects the filing will be completed in the first half of 2012.

    AstraZeneca Plc's vandetanib was approved in April by the U.S. health regulator for treatment of medullary thyroid cancer.
    Cabozantinib, which is also being tested for metastatic ovarian cancer and prostate cancer, is an oral drug designed to inhibit MET, RET and vascular endothelial growth factor 2.

    In June, the company reported data from a clinical trial showing the drug led to significant tumor shrinkage in several different types of solid tumors, including 24% of patients with metastatic ovarian cancer, but it caused the deaths of six patients.

 
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