Clinical trial and research by Novartis

This page covers research by Novartis including the phase I study of the ALK inhibitor called LDK378. It also covers research on the ALK inhibitor TAE684. At this time it is not clear how the two relate, but presumably Novartis had a reason for moving forward with Human testing on LDK378 instead of TAE684.

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11 Responses to Clinical trial and research by Novartis

  1. admin says:

    Here is a link to the first study results from a phase 1 trial of LDK378 on 56 patients (the majority of whom had previously taken Crizotinib).

    http://chicago2012.asco.org/ASCODailyNews/Abstract3007.aspx

  2. admin says:

    A group from Japan found that when TAE684 was combined with a MEK inhibitor they were more effective in some cases than TAE684 on it’s own.

    http://www.nature.com/bjc/journal/vaop/ncurrent/full/bjc2011586a.html

  3. admin says:

    Here is a link to a blog by one of the first patients to try LDK378 as part of a phase 1 study. she describes how her cancer has shrunk and her side effects.

    http://lifeandbreath.wordpress.com/2011/12/14/big-four-oh/

  4. admin says:

    Here is a link to a PowerPoint that on page 14 has some very preliminary results for LDK378. For the first three patients (all Crizotinib naive) 2 had partial responses (good given that the dosage is very low). Side effects are described as “no significant toxicity”

    http://www.gecp.org/congresos/co/noveno/viernes/9/Dra_Felip_SLCG-11.pdf

  5. admin says:

    Here is a Link to a Nov. 2011 abstract that discloses research on LDK378 in mice. It is the first one I have found. It indicates that LDK378 is able to effectively treat some tumors that have become resistant to Crizotinib. Some tumors that were treated for 14 days stayed in remission for an additional 4 months.

    http://mct.aacrjournals.org/cgi/content/meeting_abstract/10/11_MeetingAbstracts/B232?sid=3f506efe-d93a-4e54-b455-e00a21efa63a

  6. admin says:

    In an Aug. 2011 article by researchers in Taiwan the tested the effectiveness of TAE684. In it the drug was given to mice orally. The article covers 6 activating ALK point (not fusion) mutations. Only the 2 strongest were used to test the effectiveness of TAE684 and in both cases the tumors shrank and there were fewer metastasis.

    http://www.neoplasia.com/pdf/manuscript/v13i08/neo11222.pdf

  7. admin says:

    Research by Harvard Medical School indicates that 17-AAG (a HSP90 inhibitor), TAE684, and AP26113 can treat ALK positive lung cancer cells even if they have become resistant to Crizotinib as a result of the gatekeeper mutation L1196M. The L1196M mutation was the only mutation found as part of this research.

    See the following link for details: http://www.ncbi.nlm.nih.gov/pubmed/21502504

  8. admin says:

    As of January 2011, Novartis has posted a notice in ClinicalTrials.gov that they are going to run a phase I study of LDK378 for patients with ALK abnormalities Currently, worldwide there are 21 test sites, 7 of which are in the U.S.

    They list University of Colorado in Aurora, Massachusetts General Hospital and Dana Farber Cancer Institute in Boston, Memorial Sloan Kettering in NY, Fox Chase Cancer Center in Philadelphia, Huntsman Cancer Center, in Salt Lake City, and University of Washington in Seattle.

    The trial is open to people who have previously taken another ALK inhibitor. At this time there is no indication of how this relates to TAE684.

    See this link for details http://www.clinicaltrials.gov/ct2/show/NCT01283516?term=alk&rank=1

  9. admin says:

    Here is a study from January 2011 which includes a comparison of Crizotinib with TAE684. It finds that TAE684 is at least 10 times more potent than Crizotinib (i.e. patients would need to take smaller pills or take them less often). However, while the research suggests that TAE684 would also have a better therapeutic index it does not directly address this issue (i.e. that patients would be likely to experience fewer side effects or be able to tolerate a more effective dosage).

    Significantly, this study specifically tested the effectivness of TAE684 against the same ALK + cell line that TAE684 was NOT effective against in a previous study, and this time TAE684 was very effective at stopping growth in that cell line. The authors speculate that the two samples of the same cell line had for some unknown reason evolved into two distinct poplulations (i.e. the resistent population probably developed an unidentified secondary mutation).

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022423/

  10. admin says:

    As mentioned elsewhere Novartis has developed a drug called NVP-TAE684 which is an ALK inhibitor. There have been several research studies done using it as an effective ALK inhibitor but according to one review article from Sept 2010 it is no longer being developed by Novartis.

    Here are links to several studies that used NVP-TAE684
    http://www.ncbi.nlm.nih.gov/pubmed/20952506 (Oct. 2010) (see more detailed write up posted under “Other Drugs” on October 25, 2010 at 3:18 pm) (in short and with respect to TAE684 “all of the TAE684 treated mice achieved complete regression within 2 weeks.” Furthermore, “To date [~75 weeks], drug resistant tumors have not developed”).
    http://www.ncbi.nlm.nih.gov/pubmed/20207848 (Mar. 2010
    http://www.ncbi.nlm.nih.gov/pubmed/18923525 (Oct. 2008)
    http://www.ncbi.nlm.nih.gov/pubmed/18594010 from 2008 (this study may be why Novartis did not pursue this drug, because the drug only stopped growth in one of three cell lines on its own, it needed to be combined with a second drug (that worked against the EGFR mutation) in order to be effective against a second cell line, and it was not effective against a third cell line).
    http://www.ncbi.nlm.nih.gov/pubmed/17185414 (Feb. 2007)

  11. admin says:

    Here is a link to an article that was published in March 2008 about TAE684 (by Novartis). http://clincancerres.aacrjournals.org/content/14/13/4275.full

    The researchers screened 305 tumour samples and found that 8 of them (2.6%) had the ALK mutation. They also screened 83 lung cancer cell lines and found the ALK mutation in 3 of them ((3.6%). They also found that the ALK mutation was 6 times more common in non-smokers and that ALK patients were younger on average than other lung cancer patients. 100% of the ALK mutations were found in Adenocarcinoma cases.

    They then tested TAE-684 against the three cell lines that were ALK positive. They found that TAE-684 worked against one of the three cell lines on its own. They also found that one of the three cell lines also had a second mutation to the ERBB2 gene. TAE-684 worked against the second cell line when it was combined with an ERBB2 inhibitor.

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