Kooperativer Bibliotheksverbund

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 21, No. 4 ( 2003-02-15), p. 679-689

Abstract: Purpose: To evaluate the efficacy and safety of atrasentan (ABT-627), an endothelin-A receptor antagonist, in the treatment of asymptomatic, hormone-refractory prostatic adenocarcinoma. Patients and Methods: A double-blind, randomized, placebo-controlled clinical trial of hormone-refractory prostate cancer (HRPCa) patients was conducted in the United States and Europe. Two hundred eighty-eight asymptomatic patients with HRPCa and evidence of metastatic disease were randomly assigned to one of three study groups receiving a once-daily oral dose of placebo, 2.5 mg atrasentan, or 10 mg atrasentan, respectively. Primary end point was time to progression; secondary end points included time to prostate-specific antigen (PSA) progression, bone scan changes, and changes in bone and tumor markers. Results: The three treatment groups were similar in all baseline characteristics. Median time to progression in intent-to-treat (ITT) patients (n = 288) was longer in the 10-mg atrasentan group compared with the placebo group: 183 v 137 days, respectively; (P = .13). Median time to progression in evaluable patients (n = 244) was significantly prolonged, from 129 days (placebo group) to 196 days (10-mg atrasentan group; P = .021). For both ITT and evaluable populations in the 10-mg atrasentan group, median time to PSA progression was twice that of the placebo group (155 v 71 days; P = .002). Patients who received placebo continued to have significant increases from baseline in serum (lactate dehydrogenase [LDH]), a marker of disease burden; elevations in LDH were uniformly attenuated by atrasentan in the ITT population. Headache, peripheral edema, and rhinitis were primary side effects, typically of mild to moderate severity. Quality of life was not adversely affected by atrasentan. Conclusion: Atrasentan is an oral, targeted therapy with favorable tolerability and the potential to delay progression of HRPCa.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2003.04.176

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2003

detail.hit.zdb_id: 2005181-5

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 23, No. 22 ( 2005-08-01), p. 5188-5197

Abstract: ABT-510 is an angiogenesis inhibitor derived from thrombospondin-1, a naturally occurring inhibitor of angiogenesis. We investigated ABT-510, which was administered subcutaneously in patients with advanced solid malignancies, to assess safety, pharmacokinetics, and serum markers of angiogenesis. Patients and Methods ABT-510 was administered subcutaneously as a continuous infusion (100 mg/24 h) and bolus injections (100, 200, and 260 mg once daily; 50 and 100 mg twice daily) in 28-day cycles. Results Thirty-nine patients received a total of 144 treatment cycles. Administration by continuous infusion was hampered by the onset of painful skin infiltrates at the injection site. In the bolus injection regimens, the most common toxicities observed were mild injection-site reactions and fatigue. Maximum-tolerated dose was not defined, but 260 mg was defined as the maximum clinically practical dose. ABT-510 pharmacokinetics were linear across the dosage ranges tested, and the potential therapeutic threshold (plasma concentrations 〉 100 ng/mL 〉 3 h/d) was achieved with all dose regimens. Median serum basic fibroblast growth factor (bFGF) levels decreased from 14.1 pg/mL (range, 0.5 to 77.7 pg/mL) at baseline to 3.2 pg/mL (range, 0.2 to 29.4 pg/mL) after 56 days of treatment (P = .003). No correlations with time on study or ABT-510 dose or exposure were observed for individual changes in bFGF. Stable disease lasting for six cycles or more was seen in six patients. Conclusion ABT-510 demonstrated a favorable toxicity profile and linear and time-independent pharmacokinetics with biologically relevant plasma concentrations. The significant number of patients with prolonged stable disease and the convenient method of dosing merit further studies with this angiogenesis inhibitor.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2005.05.013

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2005

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 304-304

Abstract: Abstract 304 Background: BCL-2 is highly expressed in indolent non-Hodgkin lymphomas (NHL), mantle cell lymphoma (MCL) and other selected aggressive lymphomas, and is a promising target for therapeutic intervention. The first-generation BCL-2 inhibitor navitoclax showed some activity in indolent lymphoma, but its co-inhibition of BCL-xL resulted in dose-limiting thrombocytopenia, precluding the full exploration of the potential of BCL-2 inhibition with this drug in NHL. ABT-199 is an orally bioavailable, second-generation BH3-mimetic that inhibits BCL-2 (Ki 〈 0.10 nM), but has 500-fold less activity for BCL-xL (Ki=48 nM). ABT-199 demonstrated antitumor activity against a variety of human cell lines and xenograft models that include B cell NHL, follicular lymphomas (FL), diffuse large B-cell Lymphoma (DLBCL) and MCL. Methods: This is a phase-I dose-escalation trial using a modified Fibonacci design in patients with relapsed/refractory NHL. The primary objectives of this study are to determine the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of ABT-199; to recommend a phase-2 dose; and to assess efficacy and biomarkers in patients with relapsed/refractory NHL. Adult patients requiring therapy, with ECOG performance status £1, and adequate marrow function received ABT-199 on Week 1 Day −7 (W1D-7), followed by continuous once-daily dosing from W1D1, until progressive disease (PD) or unacceptable toxicity. Due to concerns of potential tumor lysis, a strategy of commencing with a 2 to 3 week lead-in period with step-wise increases to the target cohort dose is being evaluated. In the first four cohorts, the starting dose increased from 50 to 200 mg (50, 100, 200, and 200 mg, respectively), with target cohort doses of 200 mg [n=3], 300 mg [n=3] , 400 mg [n=4], and 600 mg [n=7] . Evaluations include: adverse events (AE; NCI-CTCAE-V4) and tumor response (IWG 2007 criteria). Results: To date, 17 patients (median age, 71 [35–85]) have been treated with ABT-199. Median prior therapies were 3 (range, 1–7) and 6 patients had bulky adenopathy ( 〉 5cm). Most common AEs (experienced by 〉 2 patients) were nausea (41%), diarrhea (24%), dyspepsia (24%), fatigue (24%), extremity pain (24%); and anemia, constipation, upper respiratory tract infection and cough (18% each). Grade 3 or 4 AEs occurring in 〉 1 patient were anemia (18%) and neutropenia (12%). Treatment-related thrombocytopenia has not been reported and no dose-limiting toxicities (DLTs) have been identified to date. After a single dose administration with a high-fat meal, ABT-199 reached Cmax at approximately 7 hrs with a terminal half-life of about 15 hrs. Food increased ABT-199 exposure by approximately 3-fold. With a median follow-up of 2.8 months (range, 1.2 to 10.8), 14 patients remain on study and 3 have discontinued due to PD. In patients who have completed at least a W6 assessment, reductions of 〉 50% in target lesions have been observed in 8/15 patients (53%); 6/6 patients with MCL, 1/2 patients with WM and 1/2 patients with DLBCL. Additionally, 5 FL patients have been evaluated (3 with rituxan-refractory disease) with a median time on study of 6.4 months (range, 3.5 to 10.8). 4/5 FL patients had nodal disease reductions ranging from 18% to 40%. Conclusions: ABT-199 shows single agent anti-tumor activity in patients with NHL; particularly in MCL. Activity is also observed in DLBCL and WM. To date, no DLTs have been identified and tumor lysis syndrome related to ABT-199 has not been reported. Dose escalation is continuing to identify the optimal dosing regimen and MTD of ABT-199 in NHL. Updated results will be presented. Disclosures: Roberts: Abbott: Research Funding; Genentech: Research Funding. Anderson:Genentech: Research Funding; Abbott: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment, receives commercial income related to ABT-199, receives commercial income related to ABT-199 Other. Kahl:Genentech: Consultancy, Research Funding; Abbott: Research Funding. Darden:Abbott: Employment, owner of Abbott stock Other. Nolan:Abbott: Employment, own Abbott stock Other. Gressick:Abbott: Employment, stock owner Other. Yang:Abbott: Employment, own Abbott stock Other. Chyla:Abbott: Employment, Stock owner Other. Busman:Abbott: Employment, Stock owner Other. Graham:Abbott: Employment, Stock owner Other. Cerri:Abbott: Employment, Stock owner Other. Enschede:Abbott: Employment, own Abbott stocks Other. Humerickhouse:Abbott: Employment, own Abbott stocks Other. Seymour:Roche: Advisory board member, Advisory board member Other, Consultancy; Genentech: Advisory board member, Advisory board member Other, Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.304.304

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 26, No. 34 ( 2008-12-01), p. 5583-5588

Abstract: Sarcomas are among the most proangiogenic malignancies in preclinical models. Phase I study results for ABT-510, which inhibits angiogenesis via a novel thrombospondin-mimetic mechanism, suggested activity in soft tissue sarcoma (STS) patients. This phase II study further evaluated the safety and efficacy of ABT-510 in advanced STS patients. Patients and Methods Patients with metastatic or unresectable STS were randomly assigned to treatment with one of two ABT-510 dose schedules (20 mg once a day [20 mg], n = 42; or 100 mg twice a day [200 mg] , n = 46), which were self-administered subcutaneously in 28-day treatment periods. End points included progression-free survival (PFS), objective response rate (ORR), overall survival (OS), and safety. Results Median PFS for the 20-mg arm was 94 days, with 4- and 6-month PFS rate estimates of 42% and 24%, respectively. Median PFS for the 200-mg arm was 64 days, with 4- and 6-month PFS rate estimates of 41% and 32%, respectively. Although only one objective response was noted, stable disease was observed in 52% (20 mg) and 48% (200 mg) of patients. Median OS was 431 days (20 mg) and 295 days (200 mg). ABT-510 was well tolerated. Rare treatment-related grade 3 or 4 adverse events were one event each of hypotension, deep vein thrombosis, and hypophosphatemia. ABT-510 pharmacokinetics were dose proportional, time independent, and consistent with those in previous studies. Conclusion ABT-510 had a favorable safety profile, and the rate of disease control and OS times were encouraging. However, with low ORR and lack of dose response, the study failed to yield compelling evidence of strong single-agent activity in STS.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2008.17.4706

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2008

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3923-3923

Abstract: Abstract 3923 Background: BCL-2 is highly expressed in indolent non-Hodgkin lymphomas (NHL), mantle cell lymphoma (MCL) and other selected aggressive lymphomas, and is a promising target for therapeutic intervention. The first-generation BCL-2 inhibitor navitoclax showed some activity in indolent lymphoma, but its co-inhibition of BCL-xL resulted in dose-limiting thrombocytopenia, precluding the full exploration of the potential of BCL-2 inhibition with this drug in NHL. ABT-199 is an orally bioavailable, second-generation BH3-mimetic that inhibits BCL-2 (Ki 〈 0.10 nM), but has 500-fold less activity for BCL-xL (Ki=48 nM). ABT-199 demonstrated antitumor activity against a variety of human cell lines and xenograft models that include B cell NHL, follicular lymphomas (FL), diffuse large B-cell Lymphoma (DLBCL) and MCL. Methods: This is a phase-I dose-escalation trial using a modified Fibonacci design in patients with relapsed/refractory NHL. The primary objectives of this study are to determine the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of ABT-199; to recommend a phase-2 dose; and to assess efficacy and biomarkers in patients with relapsed/refractory NHL. Adult patients requiring therapy, with ECOG performance status £1, and adequate marrow function received ABT-199 on Week 1 Day −7 (W1D-7), followed by continuous once-daily dosing from W1D1, until progressive disease (PD) or unacceptable toxicity. Due to concerns of potential tumor lysis, a strategy of commencing with a 2 to 3 week lead-in period with step-wise increases to the target cohort dose is being evaluated. In the first four cohorts, the starting dose increased from 50 to 200 mg (50, 100, 200, and 200 mg, respectively), with target cohort doses of 200 mg [n=3], 300 mg [n=3] , 400 mg [n=4], and 600 mg [n=7] . Evaluations include: adverse events (AE; NCI-CTCAE-V4) and tumor response (IWG 2007 criteria). Results: To date, 17 patients (median age, 71 [35–85]) have been treated with ABT-199. Median prior therapies were 3 (range, 1–7) and 6 patients had bulky adenopathy ( 〉 5cm). Most common AEs (experienced by 〉 2 patients) were nausea (41%), diarrhea (24%), dyspepsia (24%), fatigue (24%), extremity pain (24%); and anemia, constipation, upper respiratory tract infection and cough (18% each). Grade 3 or 4 AEs occurring in 〉 1 patient were anemia (18%) and neutropenia (12%). Treatment-related thrombocytopenia has not been reported and no dose-limiting toxicities (DLTs) have been identified to date. After a single dose administration with a high-fat meal, ABT-199 reached Cmax at approximately 7 hrs with a terminal half-life of about 15 hrs. Food increased ABT-199 exposure by approximately 3-fold. With a median follow-up of 2.8 months (range, 1.2 to 10.8), 14 patients remain on study and 3 have discontinued due to PD. In patients who have completed at least a W6 assessment, reductions of 〉 50% in target lesions have been observed in 8/15 patients (53%); 6/6 patients with MCL, 1/2 patients with WM and 1/2 patients with DLBCL. Additionally, 5 FL patients have been evaluated (3 with rituxan-refractory disease) with a median time on study of 6.4 months (range, 3.5 to 10.8). 4/5 FL patients had nodal disease reductions ranging from 18% to 40%. Conclusions: ABT-199 shows single agent anti-tumor activity in patients with NHL; particularly in MCL. Activity is also observed in DLBCL and WM. To date, no DLTs have been identified and tumor lysis syndrome related to ABT-199 has not been reported. Dose escalation is continuing to identify the optimal dosing regimen and MTD of ABT-199 in NHL. Updated results will be presented. Disclosures: Seymour: Roche: Advisory Board member Other, Consultancy; Genentech: Advisory Board member, Advisory Board member Other, Consultancy. Anderson:Abbott: Research Funding; Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment, receives commercial income related to ABT-199, receives commercial income related to ABT-199 Other. Kipps:Abbott: Consultancy, Research Funding. Wierda:Abbott: Research Funding; Genentech: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; AmGen: Research Funding; Merck: Consultancy; Celgene: Consultancy; Pharmacyclics: Consultancy; Genzyme: Consultancy. Kahl:Abbott: Research Funding; Genentech: Consultancy, Research Funding. Miller:Abbott: Research Funding; Genentech: Research Funding. Darden:Abbott: Employment, owner of Abbott stock Other. Nolan:Abbott: Employment, own Abbott stock Other. Gressick:Abbott: Employment, stock owner Other. Xiong:Abbott: Employment, own Abbott stock Other. Huang:Genentech: Research Funding; Abbott: Research Funding; Walter and Eliza Hall Institiute of Medical Research: Employment, receives commercial income related to ABT-199, receives commercial income related to ABT-199 Other. Chyla:Abbott: Employment, Stock owner Other. Busman:Abbott: Employment, Stock owner Other. Graham:Abbott: Employment, Stock owner Other. Cerri:Abbott: Employment, Stock owner Other. Enschede:Abbott: Employment, own Abbott stocks Other. Humerickhouse:Abbott: Employment, own Abbott stocks Other. Roberts:Abbott: Research Funding; Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment, Receives commercial income related to ABT-199, Receives commercial income related to ABT-199 Other.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.3923.3923

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 8520-8520

Abstract: 8520 Background: BCL-2 is highly expressed in NHL, including mantle cell lymphoma (MCL), and is a promising therapeutic target as it is involved in NHL pathogenesis and mediates resistance to many cytotoxics. ABT-199 is a second generation inhibitor with 500-fold higher affinity for BCL-2 (K i 〈 0.10 nM) than BCL-X L (K i =48 nM). Methods: Objectives of this Ph 1 dose-escalation study include evaluations of safety, pharmacokinetics and preliminary efficacy in patients (pts) with relapsed or refractory (R/R) NHL. A single oral dose (50-400 mg) was administered followed by 6 days off drug prior to the initiation of continuous once daily dosing. Due to concerns of potential tumor lysis syndrome (TLS), a 2 to 3 wk lead-in period with step-wise escalation to the target cohort dose was implemented. Dose cohorts up to 900 mg have been evaluated to date. Results: As of January 2013, 31 pts have been enrolled (median age 68 y (range 35-85); 20 males; median prior therapies 3 (range 1-7). 13 (42%) and 4 (13%) had bulky adenopathy ( 〉 5 and 〉 10 cm, respectively). The most common AEs (≥15% of patients) were nausea (36%), diarrhea (26%), dyspepsia, vomiting, fatigue, pyrexia and cough (16% each). Gr 3/4 AEs occurring in 〉 1 patient were anemia, neutropenia (4 pts each), and febrile neutropenia (2 pts). Two of 14 pts in cohort 5 experienced DLTs at the target dose of 600 mg: Gr 3 febrile neutropenia and Gr 4 neutropenia. Although Gr 3/4 thrombocytopenia was observed in 3 pts, it was not dose dependent. Gr 3 TLS was seen after the initial dose in 1 pt with very bulky MCL ( 〉 10 cm). With a median follow-up of 5 months (range 0.5-15), 17 have discontinued: 13 due to PD, 2 due to AEs and 2 who received a BMT. Of the 29 pts evaluable for efficacy, the overall best response rate was 55% with 1 DLBCL pt achieving a CR and 15 (52%) a PR (8/8 MCL, 3/3 Waldenstrom macroglobulinemia, 2/7 follicular lymphoma and 2/7 DLBCL pts). Conclusions: ABT-199 is highly active in R/R NHL, particularly in MCL. Additional dosing and scheduling modifications are currently being explored to optimize the efficacy/safety profile of this active new agent. ABT-199 warrants further single-agent and combination trials in NHL. Clinical trial information: NCT01328626.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/jco.2013.31.15_suppl.8520

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2013

detail.hit.zdb_id: 2005181-5

In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 11_Supplement ( 2011-11-12), p. A92-A92

Abstract: Background: Navitoclax (N; ABT-263) is a first-in-class orally available Bcl-2 protein inhibitor that in vitro and in vivo potentiates docetaxel (D) activity across a variety of solid tumor types. This ongoing phase I study evaluates the maximum tolerated dose (MTD) and safety and pharmacokinetic (PK) profile of N plus D. Methods: Patients (pts) with advanced solid tumors, adequate organ function and ECOG PS ≤1 were eligible. Pts were treated with (a) N 150 mg or 200 mg PO, QD on days (d) 1–3 or d1–5 q21 plus D 75 mg/m2 IV on d1 q21; or (b) N 150 mg PO, QD on d1–3, d8–10, and d15–17 q28 plus D 30 mg/m2 IV given on d1, 8, and 15 q28. To compare the PK of either agent alone, N was given on d3–5 or d3–7 only in cycle 2 of q21. PK samples were collected for N and D in cycles 1 and 2. Treatment-emergent adverse events (TAEs) were graded by NCI CTCAE V3.0. Results: Of 37 pts (M/F, 24/13) enrolled, data on 31 pts are available for safety, 33 pts for tumor response, and 13 pts for PK analysis. Pts (median age, 59 y; range, 30–83 y) were treated at 3 dose levels of N: 150 mg and 200 mg on d1–5 q21; 200 mg on d1–3 q21; and 150 mg on d1–3, d8–10, and d15–17 q28. Dose-limiting toxicities (DLTs) were grade (gr) 3 febrile neutropenia, and gr 4 thrombocytopenia (TCP) at N 200 mg d1–5 plus D 75 mg/m2 q21; gr 3/4 febrile neutropenia, gr 4 neutropenia, and gr 3 fatigue at N 200 mg d1–3 plus D 75 mg/m2 q21; gr 3 febrile neutropenia, gr 4 TCP, and death at N 150 mg d1–5 plus D 75 mg/m2 q21. The MTD of N with D at 75 mg/m2 q21 was 150 mg on d1–5. Other gr 3/4 TAEs (≥20%) were neutropenia (55%), leukopenia (32%), febrile neutropenia (29%), TCP (29%), and fatigue (13%); frequently occurring TAEs (≥20%) were fatigue (55%), TCP (45%), alopecia (42%), nausea (42%), anemia (36%), constipation (32%), decreased appetite (32%), diarrhea (32%), vomiting (32%), and dyspnoea (26%). Best tumor responses were 3 confirmed partial responses (PR), 2 currently unconfirmed PR, 8 stable disease (SD), 13 progressive disease, and 7 pts had incomplete data. Based on limited data, there was no significant PK interaction between N and D (Table). Conclusions: Navitoclax may be administered safely with D in 2 schedules; 150 mg with D 75 mg/m2 q21 and with D 30 mg/m2 q28. Both combinations were tolerable with no significant PK interactions in the D 75 mg/m2 q21 schedule. Antitumor activity was observed. Exploration of N 200 mg with weekly D is ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A92.

Type of Medium: Online Resource

ISSN: 1535-7163 , 1538-8514

URL: Article

DOI: 10.1158/1535-7163.TARG-11-A92

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2011

detail.hit.zdb_id: 2062135-8

SSG: 12

In: Cancer, Wiley, Vol. 113, No. 12 ( 2008-12-15), p. 3420-3429

Type of Medium: Online Resource

ISSN: 0008-543X , 1097-0142

URL: Issue

URL: Article

DOI: 10.1002/cncr.v113:12

DOI: 10.1002/cncr.23953

Language: English

Publisher: Wiley

Publication Date: 2008

detail.hit.zdb_id: 1479932-7

detail.hit.zdb_id: 2599218-1

detail.hit.zdb_id: 2594979-2

detail.hit.zdb_id: 1429-1

In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 8, No. 12_Supplement ( 2009-12-10), p. C126-C126

Abstract: Background: Thrombocytopenia is the most prominent dose-limiting toxicity in animals and humans following ABT-263 administration. ABT-263 induces apoptosis, rather than lysis, of circulating platelets resulting in premature platelet senescence. This differs from typical chemotherapy induced thrombocytopenia, which is related to myelosuppression. Bcl-XL is believed to play a key role in the thrombocytopenia induced by ABT-263. Platelet transfusion has been widely adopted in clinical practice when platelet count drops below 10,000/ L. The effect of platelet transfusions on circulating platelet levels have been examined in four studies in dogs. Methods: Pharmacokinetic (PK) and pharmacodynamic (PD) data from a total of 76 dogs from the four studies were analyzed sequentially. First, ABT-263 plasma concentration data in dogs were described using a two-compartment model with first-order absorption (for oral dosing only) and elimination. Then, the time courses of circulating platelet levels were described using a semi-physiological model. The model includes a progenitor compartment for proliferating blood cells linked to a series of three compartments representing the maturation chain in the bone marrow and the central circulation compartment. A feedback system is included in the model to allow the system to respond to disturbances in the platelet concentrations. It is assumed that ABT-263 increases the degradation rate of circulating platelets in a concentration-dependent manner. Results: The medians of the E-R model parameters were comparable among the studies, indicating that the E-R relationships between ABT-263 concentrations and platelet response are consistent across all four studies in dogs. Simulations using the model further supported that platelet transfusion is an effective rescue method for low platelet counts caused by ABT-263 treatment both at clinically-relevant ABT-263 concentrations (∼4 g/mL) and at the higher ABT-263 concentrations (7 g/mL) in dogs. The effects of platelet transfusion were smaller and more transient when the transfusion was administered at higher ABT-263 concentrations (7 g/mL) compared to those administered at lower ABT-263 concentrations (∼4 g/mL). Multiple transfusions are expected to produce larger and more prolonged effects on circulating platelet levels than a single transfusion. Conclusion: Thrombocytopenia induced by ABT-263 in dogs is dependent on ABT-263 concentrations and could be well described by a semi-physiological E-R model. Platelet transfusion should be started after ABT-263 concentration has dropped and multiple transfusions are needed to produce larger and more prolonged effects on circulating platelet levels. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C126.

Type of Medium: Online Resource

ISSN: 1535-7163 , 1538-8514

URL: Article

DOI: 10.1158/1535-7163.TARG-09-C126

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2009

detail.hit.zdb_id: 2062135-8

SSG: 12

In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 18, No. 11 ( 2012-06-01), p. 3163-3169

Abstract: Purpose: Bcl-2 is a critical regulator of apoptosis that is overexpressed in the majority of small cell lung cancers (SCLC). Nativoclax (ABT-263) is a potent and selective inhibitor of Bcl-2 and Bcl-xL. The primary objectives of this phase IIa study included safety at the recommended phase II dose and preliminary, exploratory efficacy assessment in patients with recurrent and progressive SCLC after at least one prior therapy. Experimental Design: Thirty-nine patients received navitoclax 325 mg daily, following an initial lead-in of 150 mg daily for 7 days. Study endpoints included safety and toxicity assessment, response rate, progression-free and overall survival (PFS and OS), as well as exploratory pharmacodynamic correlates. Results: The most common toxicity associated with navitoclax was thrombocytopenia, which reached grade III–IV in 41% of patients. Partial response was observed in one (2.6%) patient and stable disease in 9 (23%) patients. Median PFS was 1.5 months and median OS was 3.2 months. A strong association between plasma pro–gastrin-releasing peptide (pro-GRP) level and tumor Bcl-2 copy number (R = 0.93) was confirmed. Exploratory analyses revealed baseline levels of cytokeratin 19 fragment antigen 21-1, neuron-specific enolase, pro-GRP, and circulating tumor cell number as correlates of clinical benefit. Conclusion: Bcl-2 targeting by navitoclax shows limited single-agent activity against advanced and recurrent SCLC. Correlative analyses suggest several putative biomarkers of clinical benefit. Preclinical models support that navitoclax may enhance sensitivity of SCLC and other solid tumors to standard cytotoxics. Future studies will focus on combination therapies. Clin Cancer Res; 18(11); 3163–9. ©2012 AACR.

Type of Medium: Online Resource

ISSN: 1078-0432 , 1557-3265

URL: Article

DOI: 10.1158/1078-0432.CCR-11-3090

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2012

detail.hit.zdb_id: 1225457-5

detail.hit.zdb_id: 2036787-9