INNO-206 protocol:
clinicaltrials.gov
Started in May. I can find no PR, but they seem to have started on time. Recommended dose from the P1 program was 200mg/m^2 to 260mg/m^2.
We should be getting data on INNO-305 P1 by early '08. It's a one year study at MSKCC, and it started last October:
clinicaltrials.gov
Innovive never mentioned the use of adjuvants, but it probably goes without saying for an immunotherapeutic approach. Fixed dose, but I can't find what that dose may be.
This year, we are still waiting for start of STAR-1 (pivotal Tamibarotene study) & start of INNO-406 P2 in 3rd line CML.
Regarding mutations that INNO-406 hits . . . while it apparently doesn't hit the T315I mutation, it does hit several p-loop mutations that are known to give Gleevec and nilotonib* trouble. The following are among the ones that it hits: p-loop mutations clinically observed in imatinib-resistant patients (ranked by order of occurrence, highest to lowest): E255K, Q252H, M244V, G250E.
Conspicuously absent is the ability to hit the Y253H mutation, a relatively common one. L248V & Q252R are also not on the list, but are not very common, so less of a concern. Note that G250E has the highest occurrence in in vitro screens of imatinib resistance, followed by Q252H. See
bloodjournal.hematologylibrary.org
particularly figure 2, for the low down on this. PD166326, the focus of that article, would belong to Pfizer. Don't know where it is in development.
In general, the above mutations confer resistance by interfering with drug binding in the kinase domain of BCR-ABL.
* Source for this is here:
>> Blood. 2006 Aug 15;108(4):1328-33. Epub 2006 Apr 13.
Bcr-Abl resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107).
von Bubnoff N, Manley PW, Mestan J, Sanger J, Peschel C, Duyster J.
Department of Internal Medicine III, Technical University of Munich, D-81675 Munich, Germany. n.bubnoff@lrz.tum.de
In advanced-phase chronic myeloid leukemia (CML), resistance to imatinib mesylate is associated with point mutations in the BCR-ABL kinase domain. A new generation of potent ABL kinase inhibitors is undergoing clinical evaluation. It is important to generate specific resistance profiles for each of these compounds, which could translate into combinatorial and sequential treatment strategies. Having characterized nilotinib (AMN107) against a large panel of imatinib mesylate-resistant Bcr-Abl mutants, we investigated which mutants might arise under nilotinib therapy using a cell-based resistance screen. In contrast to imatinib mesylate, resistance to nilotinib was associated with a limited spectrum of Bcr-Abl kinase mutations. Among these were mutations affecting the P-loop and T315I. Rarely emerging resistant colonies at a concentration of 400 nM nilotinib exclusively expressed the T315I mutation. With the exception of T315I, all of the mutations that were identified were effectively suppressed when the nilotinib concentration was increased to 2000 nM, which falls within the peak-trough range in plasma levels (3.6-1.7 microM) measured in patients treated with 400 mg twice daily. Our findings suggest that nilotinib might be superior to imatinib mesylate in terms of the development of resistance. However, our study indicates that clinical resistance to nilotinib may be associated with the predominant emergence of T315I.<<
This is also a full text freebie:
bloodjournal.hematologylibrary.org
A newer article on this theme is here ( but is not free till next year):
>>Blood. 2007 Jun 1;109(11):5011-5. Epub 2007 Feb 15.
Identification of BCR-ABL point mutations conferring resistance to the Abl kinase inhibitor AMN107 (nilotinib) by a random mutagenesis study.
Ray A, Cowan-Jacob SW, Manley PW, Mestan J, Griffin JD.
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Patients with advanced stages of chronic myeloid leukemia (CML) often manifest imatinib mesylate resistance associated with point mutations in BCR-ABL. AMN107 is a new higher-potency inhibitor of BCR-ABL. To identify mutations in BCR-ABL that could result in resistance to AMN107, a cDNA library of BCR-ABL mutants was introduced into Ba/F3 cells followed by selection in AMN107 (0.125-0.5 microM). A total of 86 individual, drug-resistant colonies were recovered, and the SH3, SH2, and kinase domains of BCR-ABL were sequenced. A total of 46 colonies had single point mutations in BCR-ABL, with a total of 17 different mutations, all within the kinase domain. The other 40 colonies had multiple point mutations and were not analyzed further. Each of the 17 single point mutants were reconstructed by site-directed mutagenesis of native BCR-ABL and found to be approximately 2.5- to 800-fold more resistant to AMN107 than native BCR-ABL. The mutations included 6 known imatinib mesylate-resistant mutations, including T315I, which showed complete resistance to AMN107. Interestingly, most AMN107-resistant mutants were also resistant to imatinib mesylate. These results may predict some of the resistance mutations that will be detected in clinical trials with this kinase inhibitor.<<
Cheers, Tuck |
