Guest guest Posted May 24, 2008 Report Share Posted May 24, 2008 It sounds encouraging at this very early stage. I do note with some disappointment that the drug had a negative impact on platelet counts. I also note reading the clinical trial entry at clinicaltrials.gov, that the inclusion criteria for the trial is that one must be on Prozac??? I suspect that that is only in the case that one is already on a SSRI, one must be on a stable dose, but... oddly written. Here is the url for the clinical trial for CLL: http://www.clinicaltrials.gov/ct2/show/NCT00481091?term=ABT-263 & rank=4 --- KarlS@... wrote: > Very encouraging for a single agent in phase I ... > very : ) > > == > A phase 1 study evaluating the safety, > pharmacokinetics, and efficacy of > ABT-263 in subjects with refractory or relapsed > lymphoid malignancies. > > Sub-category:Lymphoma > Category:Lymphoma and Plasma Cell Disorders > Meeting:2008 ASCO Annual Meeting > > Abstract No:8511 > > Citation:J Clin Oncol 26: 2008 (May 20 suppl; abstr > 8511) > > Author(s):W. H. , M. S. Czuczman, A. S. > LaCasce, J. F. Gerecitano, J. > P. Leonard, K. Dunleavy, A. P. Krivoshik, H. Xiong, > Y. Chiu, O. A. O'Connor > > Abstract: > > Background: ABT-263 is a novel BH3 mimetic that > binds with high affinity (Ki > 1 nanoM) and inhibits multiple antiapoptotic Bcl-2 > family proteins. ABT-263 > displays potent mechanism-based cytotoxicity (EC50 1 > microM) against human > cell lines derived from lymphoid and small cell lung > cancers. > > The anticipated ABT-263 associated toxicities are > mechanism based, in > particular, Bcl- XL mediated decrease in circulating > platelet survival, > Bcl-w mediated testicular toxicity, and Bcl-2 > mediated effects on > lymphocytes. > > Methods: The safety and pharmacokinetic (PK) profile > of ABT-263 were studied > in patients with relapsed or refractory lymphoid > malignancies. For each > 21-day cycle, subjects received ABT-263 orally QD > for 14 consecutive days > followed by 7 days off drug. > > The drug dose was doubled in each cohort until a > grade 3 toxicity occurred, > after which escalations were in 40% increments. > > Results: Currently, 30 patients have been enrolled > in the lymphoma study > completing the 10, 20, 40, 80, 160, 225 and 315 mg > cohorts. > > One grade 3 dose limiting toxicity (DLT) occurred in > each of the 160 and 315 > mg cohorts (a URI and an ALT, respectively) > resulting in expansion of those > cohorts. > > Responses include: two patients with bulky CLL in > the 40 mg cohort had 99% > and 36% tumor reductions after cycles 8 and 7, > respectively, one patient > with bulky CLL/SLL in the 60 mg cohort had a 75% > reduction at cycle 4, one > patient with follicular lymphoma in the 80 mg cohort > had a 20% tumor > reduction after cycle 7 and one patient with NK/T > cell lymphoma at 315 mg > had a 75% reduction at cycle 2. > > These subjects remain on study with intrapatient > dose escalation of the 40 > mg patients. The PK profile of ABT-263 was linear > and the average terminal > half-life was 14 to 20 hours. > > ABT-263 reduced platelet levels in a dose-dependent > manner. Grade 3 > thrombocytopenia was observed in 5 patients without > any bleeding. > > Conclusions: ABT-263 is a novel, orally bioavailable > and active small > molecule Bcl-2 family protein inhibitor that shows > early evidence of > activity in lymphoid malignancies. > > Quote Link to comment Share on other sites More sharing options...
Guest guest Posted May 25, 2008 Report Share Posted May 25, 2008 Hi , I think it's a widely held expectation that what has a treatment effect will have a side effect ... identifying the maximum tolerated dose (MTD) is still the main way to identify the therapeutic dose with the exception of biologics (vaccines, growth factors) where even small doses can modulate and initiate other processes in the body. Targeted agents will likely bind to and adversely impact some other cells, so what will be important to look for I think is if the toxicities are reversible, not serious/mutagenic, etc. ~ Karl ... Subject: Re: ABT-263: It sounds encouraging at this very early stage. I do note with some disappointment that the drug had a negative impact on platelet counts. I also note reading the clinical trial entry at clinicaltrials.gov, that the inclusion criteria for the trial is that one must be on Prozac??? I suspect that that is only in the case that one is already on a SSRI, one must be on a stable dose, but... oddly written. Here is the url for the clinical trial for CLL: http://www.clinicaltrials.gov/ct2/show/NCT00481091?term=ABT-263 & rank=4 --- KarlS@... wrote: > Very encouraging for a single agent in phase I ... > very : ) > > == > A phase 1 study evaluating the safety, > pharmacokinetics, and efficacy of > ABT-263 in subjects with refractory or relapsed > lymphoid malignancies. > > Sub-category:Lymphoma > Category:Lymphoma and Plasma Cell Disorders > Meeting:2008 ASCO Annual Meeting > > Abstract No:8511 > > Citation:J Clin Oncol 26: 2008 (May 20 suppl; abstr > 8511) > > Author(s):W. H. , M. S. Czuczman, A. S. > LaCasce, J. F. Gerecitano, J. > P. Leonard, K. Dunleavy, A. P. Krivoshik, H. Xiong, > Y. Chiu, O. A. O'Connor > > Abstract: > > Background: ABT-263 is a novel BH3 mimetic that > binds with high affinity (Ki > 1 nanoM) and inhibits multiple antiapoptotic Bcl-2 > family proteins. ABT-263 > displays potent mechanism-based cytotoxicity (EC50 1 > microM) against human > cell lines derived from lymphoid and small cell lung > cancers. > > The anticipated ABT-263 associated toxicities are > mechanism based, in > particular, Bcl- XL mediated decrease in circulating > platelet survival, > Bcl-w mediated testicular toxicity, and Bcl-2 > mediated effects on > lymphocytes. > > Methods: The safety and pharmacokinetic (PK) profile > of ABT-263 were studied > in patients with relapsed or refractory lymphoid > malignancies. For each > 21-day cycle, subjects received ABT-263 orally QD > for 14 consecutive days > followed by 7 days off drug. > > The drug dose was doubled in each cohort until a > grade 3 toxicity occurred, > after which escalations were in 40% increments. > > Results: Currently, 30 patients have been enrolled > in the lymphoma study > completing the 10, 20, 40, 80, 160, 225 and 315 mg > cohorts. > > One grade 3 dose limiting toxicity (DLT) occurred in > each of the 160 and 315 > mg cohorts (a URI and an ALT, respectively) > resulting in expansion of those > cohorts. > > Responses include: two patients with bulky CLL in > the 40 mg cohort had 99% > and 36% tumor reductions after cycles 8 and 7, > respectively, one patient > with bulky CLL/SLL in the 60 mg cohort had a 75% > reduction at cycle 4, one > patient with follicular lymphoma in the 80 mg cohort > had a 20% tumor > reduction after cycle 7 and one patient with NK/T > cell lymphoma at 315 mg > had a 75% reduction at cycle 2. > > These subjects remain on study with intrapatient > dose escalation of the 40 > mg patients. The PK profile of ABT-263 was linear > and the average terminal > half-life was 14 to 20 hours. > > ABT-263 reduced platelet levels in a dose-dependent > manner. Grade 3 > thrombocytopenia was observed in 5 patients without > any bleeding. > > Conclusions: ABT-263 is a novel, orally bioavailable > and active small > molecule Bcl-2 family protein inhibitor that shows > early evidence of > activity in lymphoid malignancies. > > Quote Link to comment Share on other sites More sharing options...
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