Aim: This Phase I study investigated safety of navitoclax and docetaxel in patients (n = 41) with advanced solid tumors. Patients & methods: Two navitoclax plus docetaxel dosing schedules (21 and 28 days) were evaluated. Maximum tolerated dose, dose-limiting toxicities and preliminary antitumor activity were assessed. Results: Ten (24%) patients experienced dose-limiting toxicities; dose-escalation cohorts: n = 7 (21-day schedule: n = 5; 28-day schedule: n = 2) and 21-day expanded safety cohort: n = 3. Navitoclax 150-mg days 1-5 every 21 days with docetaxel 75 mg/m2 day 1 was the maximum tolerated dose and optimal schedule. Adverse events included thrombocytopenia (63%), fatigue (61%), nausea (59%) and neutropenia (51%). Four confirmed partial responses occurred. Conclusion: Navitoclax 150-mg orally once/day was safely administered with docetaxel. Myelosuppression limited dose escalation; antitumor activity was observed. Clinical trial registration: NCT00888108 (ClinicalTrials.gov).

The oral BCL2 inhibitor navitoclax has moderate single‐agent efficacy in chronic lymphocytic leukaemia (CLL) and minor activity in lymphoma in Phase 1 trials. Navitoclax synergizes with rituximab in preclinical models of B‐cell lymphoid cancers. We report the safety, pharmacokinetics and clinical activity of this combination. Patients received navitoclax (200–325 mg) daily and four standard weekly doses of rituximab. Twenty‐nine patients were enrolled across three dose‐escalation cohorts and a safety expansion cohort (250 mg/d navitoclax). The combination was well tolerated. Common toxicities were mild diarrhoea (79%) and nausea (72%). Grade 4 thrombocytopenia occurred in 17% of patients (dose limiting at 325 mg/d). CD19+ counts were severely reduced, while CD3+ cells (~ 20%) and serum immunoglobulin M levels (~ 33%) were also reduced during the first year. The maximum tolerated dose for navitoclax in combination was 250 mg/d. Pharmacokinetic analyses revealed no apparent interactions between the drugs. The response rate in patients with follicular lymphoma was 9/12, including five complete responses. All five patients with CLL/small lymphocytic leukaemia achieved partial responses. One of nine patients with aggressive lymphoma responded. The addition of rituximab to navitoclax 250 mg/d is safe; the combination demonstrates higher response rates for low‐grade lymphoid cancers than observed for either agent alone in previous Phase 1 trials.

PURPOSE:The oral Bcl-2 inhibitor navitoclax demonstrated activity in solid and hematologic malignancies as monotherapy and in combination with other cytotoxic agents in preclinical and early clinical studies. We evaluated the safety, pharmacokinetics (PK), and antitumor activity of navitoclax plus irinotecan.METHODS:In this multicenter, open-label, phase 1 dose escalation study, adults with advanced solid tumors received navitoclax (starting dose 150 mg/day) in combination with 1 of 2 irinotecan schedules during a 21-day cycle: a once-every-3-week regimen (Q3W 180, 250, or 350 mg/m(2)) or a once-weekly regimen (QW 75 or 100 mg/m(2)). Enrollment occurred until a maximum tolerated dose (MTD) and/or recommended phase 2 dose (RPTD) was reached.RESULTS:All patients (Q3W, n = 14; QW, n = 17) were evaluable for safety, PK, and efficacy. The most common adverse event in both groups was diarrhea (Q3W 92.9 %; QW 76.5 %), which was the most frequent grade 3/grade 4 adverse event (Q3W 42.9 %; QW 29.4 %). The study was amended to exclude 4 UGT1A1*28 7/7 homozygous patients due to frequent irinotecan-related grade 3/grade 4 diarrhea and/or febrile neutropenia. No apparent PK interactions between navitoclax and irinotecan were observed. The MTD of the combination was exceeded in the Q3W group at the lowest dose administered. In the QW group, the MTD and RPTD for navitoclax were 150 mg when combined with irinotecan 75 mg/m(2). One patient in each group achieved a partial response.CONCLUSION:The RPTD of navitoclax in combination with irinotecan 75 mg/m(2) QW during a 21-day cycle was 150 mg in these heavily pretreated patients.

7015 Background: Overexpression of Bcl-2 in relapsed CLL/SLL is associated with dysregulated apoptosis and chemoresistance. ABT-199 is an orally bioavailable, selective Bcl-2 inhibitor that triggers apoptosis of CLL cells in vitro and in vivo, making it a promising agent for the treatment of patients (pts) with CLL/SLL. Methods: The primary objectives of this phase I study were to evaluate the safety and pharmacokinetics (PK) and to determine the maximum tolerated dose and a recommended phase 2 dose (RPTD) of ABT-199. A secondary objective was to assess preliminary efficacy. Following early events of tumor lysis syndrome (TLS), a weekly ramp-up period to the final cohort dose (150 – 1200 mg) was implemented. Pts are now being enrolled in the safety expansion (SE) cohort. A ramp-up period with weekly dose increases occurred from 20, 50, 100, 200 mg to the final RPTD of 400 mg. Results: As of 12/04/2013, 84 pts (11 in SE) were enrolled with a median time on study of 14.7 (range, 0.5-29.3) months. 23 (27%) pts had del(17p) and 48 (57%) had fludarabine (F)-refractory CLL. Most common AEs were diarrhea (37%), nausea (36%), neutropenia (35%), upper respiratory tract infection (29%), and fatigue (27%). Grade 3/4 AEs (≥3 pts) were neutropenia (32%), anemia (8%), TLS (8% including 1 G5), and febrile neutropenia, thrombocytopenia, hyperglycemia, and hypokalemia (6% each). 28 have discontinued: 18 for progressive disease, 8 for AEs, and 2 for other reasons. The objective response rate (ORR) was 79% (CR/CRi 22%) with a median duration of response (DOR) of 20.5 months [95% CI; 13.8, 20.5] for the 63 pts evaluable for efficacy. At 12 months, 91% of CR and 65% of PR pts remain progression free. The ORR was 78% for del(17p) and 79% for F-refractory CLL. Of the 14 CR/CRi pts, 9 were evaluated in local labs for minimal residual disease (MRD); 5 were negative and 4 of these were F-refractory. Conclusions: ABT-199 induces a high rate of response in pts with R/R CLL, including those with del(17p) and F-refractory disease. Responses are durable, especially in the 22% achieving CR/CRi, with several of these high risk pts achieving MRD negativity. Enrollment in the SE cohort is continuing. Clinical trial information: NCT01328626.

Bcl-2 family proteins are the key regulators of the intrinsic apoptotic pathway, controlling the point-of no-return and setting the threshold to engage the death machinery in response to chemical damage. Bcl-2 proteins have emerged as attractive targets for anti-cancer drug development. Navitoclax is a selective, potent, orally bioavailable, small molecule Bcl-2 inhibitor. Primary endpoints assessed the safety and pharmacokinetic (PK) interactions between navitoclax in combination with carboplatin/paclitaxel or paclitaxel alone in patients with solid tumors The study comprised two arms, one a combination of navitoclax with paclitaxel and carboplatin, the second with navitoclax and paclitaxel alone. Nineteen patients were enrolled in this study. The most frequently reported treatment-emergent AEs were alopecia (57.9 %), anemia (52.6 %), nausea (52.6 %), constipation (42.1 %), diarrhea (42.1 %), fatigue (42.1 %), neutropenia (36.8 %), thrombocytopenia (36.8 %), vomiting (31.6 %), decreased appetite (31.6 %), dehydration (26.3 %), and hypomagnesaemia (26.3 %). In the light of significant hematological and non-hematological toxicity the study was ended before de-escalation of navitoclax. Only one partial response was obtained at any dose tested, thus lowering doses could not have increased efficacy. It is the combination of toxicity with modest efficacy that led to discontinuation. No apparent PK interaction was observed between navitoclax and carboplatin or paclitaxel and the combination of navitoclax and paclitaxel had modest anti-tumor activity.

BACKGROUND AND AIM:Navitoclax is a targeted B-cell lymphoma-2 (Bcl-2) family protein inhibitor. The present study evaluated the effect of ketoconazole, a strong cytochrome P450 (CYP) 3A4 inhibitor, on the pharmacokinetics of navitoclax in patients with cancer. PATIENTS AND METHODS:Eleven patients with cancer were enrolled in this Phase I study. Single doses of navitoclax at 60 mg were administered orally on days 1 and 8. Ketoconazole at 400 mg was given once daily from days 7 through 10. Blood samples were collected pre-dose through 72 h after each navitoclax dose. RESULTS:Ten patients had evaluable pharmacokinetic data and were, therefore, included in pharmacokinetic statistical analyses. The maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) from time 0 to infinite time (AUC∞) of navitoclax in the presence of ketoconazole was 94% (90% confidence interval (CI)=53165%) and 155% (90% CI=91264%), respectively of those observed with navitoclax when administered alone. The increase in navitoclax AUC∞ was primarily driven by two patients, who had 5-fold and 11-fold increases, respectively, in navitoclax AUC∞ in the presence of ketoconazole. These two participants had unusually low plasma drug exposure when navitoclax was administered alone, and their navitoclax exposure in the presence of ketoconazole increased to be within the range of the other 8 patients. There were no adverse events related to navitoclax exposure reported in these 2 patients. CONCLUSION:Co-administration of navitoclax with ketoconazole did not increase navitoclax exposure above that observed with navitoclax monotherapy and did not appear to affect its safety profile. Results suggest CYP3A does not play a major role in elimination of navitoclax.

8522 Background: The anti-apoptotic protein Bcl-2 is a highly expressed in NHL and contributes to chemotherapy resistance. ABT-199 is a selective, orally bioavailable, small molecule Bcl-2 inhibitor that is a promising agent for the treatment of patients (pts) with NHL. Methods: Objectives of this Phase I, dose-escalation study include evaluations of safety, pharmacokinetics (PK), and preliminary efficacy in pts with R/R NHL. ABT-199 was given on Week 1 Day -7 (W1D-7), followed by continuous, once-daily dosing from W1D1 until progressive disease or unacceptable toxicity. A 2 to 3 week lead-in period with stepwise dose titration was implemented. Final cohort doses of 200 - 900 mg have been evaluated. Results: As of December 4, 2013, 44 pts have been enrolled, 15 (35%) with mantle cell lymphoma (MCL), 11 (26%) with FL, 10 (23%) with DLBCL, 4 (9%) with Waldenström macroglobulinemia (WM), 2 (5%) with marginal zone (MZL), 1 (2%) with primary mediastinal B-cell lymphoma (PMBCL), and 1 (2%) with multiple myeloma (MM). The most common AEs (≥20% of pts) were nausea (34%), upper respiratory tract infection (27%), diarrhea (25%), and fatigue (21%). Grade (G) 3/4 AEs occurring in >3 pts were anemia (14%), neutropenia (11%), and thrombocytopenia (9%). G 3/4 thrombocytopenia was not dose-dependent or dose-limiting. Two of 10 pts in cohort 5 experienced a DLT (G3 febrile neutropenia and G4 neutropenia) at the target dose of 600 mg. G3 laboratory tumor lysis syndrome was seen after the initial dose in 1 pt with bulky MCL (elevations in phosphate and potassium only) and 1 pt with DLBCL (elevations in phosphate and uric acid only). For the 40 pts evaluable for efficacy, the overall response rate was 48%, 9/12 MCL (1 CR); 3/11 FL; 3/9 DLBCL (1 CR); 3/4 WM (1 CR); 1/2 MZL; 0/1 PMBCL; 0/1 MM. All responses in DLBCL and FL pts were observed at doses ≥600 mg; 3/8 DLBCL (38%) and 3/6 FL (50%). Conclusions: ABT-199 monotherapy showed anti-tumor activity across the range of ABT-199 cohort doses for several NHL subtypes, most notably in MCL and WM. In DLBCL and FL, responses were observed at higher doses. Dose escalation is continuing to determine the MTD and RP2D. Clinical trial information: NCT01328626.

Purpose: To investigate the safety, optimal dosing, pharmacokinetics and clinical activity of a regimen of navitoclax (ABT-263) combined with gemcitabine in patients with solid tumors. Experimental Design: Patients with solid tumors for which gemcitabine was deemed an appropriate therapy were enrolled into one of two different dosing schedules (21-day dosing schedule: navitoclax administered orally on days 1–3 and 8–10,; and gemcitabine 1,000 mg/m2 on days 1 and 8; 28-day dosing schedule: navitoclax administrated orally on days 1–3, 8–10, and 15–17; and gemcitabine 1,000 mg/m2 on days 1, 8 and 15). Navitoclax doses were escalated from 150 to 425 mg. An expanded safety cohort was conducted for the 21-day dosing schedule at the maximum tolerated dose (MTD) of navitoclax. Results: Forty-six patients were enrolled at three U.S. centers. The most common adverse events included: hematologic abnormalities (thrombocytopenia, neutropenia, and anemia), liver enzyme elevations (ALT and AST), and gastrointestinal disturbances (diarrhea, nausea, and vomiting). Dose-limiting toxicities (DLTs) observed in cycle 1 were grade 4 thrombocytopenia (2 patients), grade 4 neutropenia (1 patient), and grade 3 AST elevation (2 patients). The MTD of navitoclax was 325 mg co-administered with gemcitabine 1,000 mg/m2 for the 21-day schedule. No clinically significant pharmacokinetic drug–drug interactions were observed. There were no objective responses. Stable disease, reported at the end of cycle 2, was the best response in 54 % of evaluable patients (n = 39). Conclusions: The combination of navitoclax 325 mg with gemcitabine 1,000 mg/m2 was generally well tolerated and exhibited a favorable safety profile in patients with advanced solid tumors.

Introduction: ABT-199 is a selective, orally bioavailable BCL-2 inhibitor that rapidly induces responses in ~80% of patients (pts) with relapsed/refractory (R/R) CLL or small lymphocytic lymphoma (SLL) as a single agent (Seymour, EHA 2014). Rituximab (R) has only modest and short-lived activity as a single-agent in CLL; it can enhance the activity of other agents with minimal additional toxicity. ABT-199 and R demonstrate synergy in preclinical models of CD20-positive lymphoid malignancies, and the combination has the potential to improve efficacy. Methods: Primary objectives of this phase 1b, open-label, dose-escalation, multicenter study were to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RPTD) of ABT-199 + R in pts with R/R CLL/SLL and evaluate the safety profile; secondary objectives examine the pharmacokinetics (PK) and efficacy of the combination. Eligible pts began treatment with 20 or 50 mg ABT-199 (modified to 20 mg during the study) daily, with weekly increases in a ramp-up phase to a final cohort dose of 200 - 600 mg. After completion of the ramp-up phase, R was added starting at 375 mg/m2 and then 500 mg/m2 monthly for a total of 6 doses. ABT-199 was continued daily until progressive disease (PD) or unacceptable toxicity. Adverse events (AEs) were graded according to NCI-CTCAE v4.0. The MTD was determined using the Continual Reassessment Method. Responses were assessed using established criteria for CLL/SLL, including CT scan at month 3 and CT scan and bone marrow (BM) biopsy at the end of combination therapy. MRD was assessed using four color flow cytometry in peripheral blood (PB) and/or BM aspirate ≥2 months after response criteria were first met, and in PB every 12 weeks until MRD negativity was achieved. Results: As of July 6, 2014, 49 pts enrolled in 5 dose escalation cohorts (n = 41) and a safety expansion cohort (n = 8), with a median time on study of 201 days (1 – 624). Median age was 68 years (range 50–88) and 30 (61%) were male. The median number of prior therapies was 3 (1–10). Thirteen (27%) had fludarabine-refractory disease and 9 (18%) R-refractory. Nine (18%) had del (17p) and 19/27 (70%) with available data had unmutated IGVH. Thirteen pts have discontinued therapy: 6 due to PD; 3 after attaining complete remission; 2 due to AEs and 2 withdrew consent. Preliminary PK data suggest a negligible effect of R on ABT-199 exposure. The most common overall treatment-emergent AEs (>25% pts) were neutropenia (47%), nausea (41%), diarrhea (37%), pyrexia (31%), headache (31%), fatigue, upper respiratory tract infection, and cough (each 29%). The most common overall grade 3/4 AEs were neutropenia (47%), thrombocytopenia (16%), and anemia (14%). Treatment-emergent SAEs occurred in 20 (41%) pts; the most common were pyrexia (6%), and febrile neutropenia, infusion-related reaction, TLS, and Richter's Transformation (each 4%). Six pts experienced a DLT: 1 febrile neutropenia (200mg), 1 each thrombocytopenia, hematophagocytic syndrome, neutropenia (300mg), 1 neutropenia (600mg), and 1 pt experienced a fatal event of hyperkalemia in the setting of TLS after the first dose (50mg). That event led to a modified dosing scheme; no TLS was observed in the 32 subsequent pts using the revised ramp up dosing scheme. No MTD was identified. Of 34 pts who were evaluable for response in dose escalation cohorts, the overall response rate (ORR) was 88%, with 11 (32%) achieving a CR/CRi and 20 (56%) achieving a partial response (PR). MRD was quantified by local laboratory in 19 pts. Thirteen pts (7 in CR (6 at 10-4 and 1 at 10-3 sensitivity) and 6 in PR (10-4 sensitivity)) were MRD negative in bone marrow while one was MRD negative in peripheral blood (10-4 sensitivity). The RPTD of ABT-199 is 400 mg daily based on safety data; key safety and efficacy data for the dose selection are summarized in the table. Conclusions: The combination of ABT-199 and R is well-tolerated and achieves an overall response rate of 86% with 31% CRs in pts with CLL/SLL. Efficacy was observed across all dose cohorts. The RPTD of ABT-199 is 400mg daily, supported by a trend of lower rates of neutropenia and GI toxicity events in the absence of a clear difference in efficacy, compared to the higher doses. A phase 3 trial comparing ABT-199 and R versus bendamustine and R in pts with previously treated CLL is underway. Figure 1 Figure 1. Disclosures Roberts: Walter and Eliza Hall Institute of Medical Research : Employment, Research Funding; AbbVie: Research Funding; Genentech: Research Funding. Ma:Genentech: Consultancy; AbbVie: Research Funding. Kipps:AbbVie: Consultancy, Research Funding. Barrientos:Gilead: institutional funding Other; Pharmacyclics: Consultancy, institutional funding, institutional funding Other; AbbVie: institutional funding, institutional funding Other; Celgene: Consultancy. Davids:Genentech: Consultancy; Infinity Pharmaceuticals: Consultancy. Anderson:Walter and Eliza Hall Institute of Medical Research: Employment, milestone payments related to ABT-199 Other; AbbVie: Research Funding; Genentech: Research Funding. Tam:Roche: Honoraria. Mason-Bright:AbbVie : Employment. Rudersdorf:AbbVie: Employment. Gressick:AbbVie: Employment. Yang:AbbVie, Inc: Employment. Munasinghe:AbbVie: Employment. Zhu:AbbVie, Inc: Employment. Cerri:AbbVie: Employment. Enschede:AbbVie, Inc: Employment. Humerickhouse:AbbVie, Inc: Employment. Seymour:AbbVie: Research Funding; Genentech: Consultancy, Research Funding; Roche: Consultancy.

Abstract Introduction: BCL-2 is an anti-apoptotic protein that is commonly overexpressed in hematologic malignancies, including Non-Hodgkin Lymphoma (NHL). ABT-199 is a selective, potent, orally bioavailable BCL-2 inhibitor. It has demonstrated antitumor activity as monotherapy in patients with NHL in a Phase Ib single agent study. Patients with indolent NHL typically recur after standard treatments (R-CHOP, R-CVP). Bendamustine (B) and rituximab (R) combination therapy has demonstrated clinical activity in relapsed or refractory (R/R) patients. Preclinical evidence suggests that ABT-199 enhances the efficacy of BR. Here we report findings from a Phase I, open-label, multicenter study of ABT-199 in combination with BR in patients with R/R NHL. Methods: The primary objectives were evaluation of the safety, pharmacokinetics (PK), preliminary efficacy, and maximum tolerated dose (MTD) as well as recommended Phase 2 dose (RPTD) of ABT-199 in combination with BR in patients with R/R NHL. In the dose-escalation portion of the study, patients were treated on a 28 day cycle with ABT-199 with doses from 50 to 400 mg and following 3 dosing schedules: 3 days/cycle (d/cycle), 7 d/cycle, 28 d/cycle. The BR regimen was 6 cycles of treatment: B (2 d/cycle, 90mg/m2) and R (1 d/cycle, 375mg/m2). The dosing schedule of ABT-199 and BR was staggered during Cycles 1–3 for PK analyses; ABT-199 followed by BR was administered on Day 1 of Cycles 4-6. Patients could continue ABT-199 monotherapy following completion of BR. Dose limiting toxicities (DLTs), adverse events (AEs), PK parameters, and disease responses by IWG criteria were evaluated. Response assessments occurred on day 1 of cycle 3, 5 and 7. Results: As of July 3, 2014, 26 patients have been treated with ABT-199 in combination with BR. The median age was 61.5 (range 29-80) years and 17 (65%) patients were male. Fifteen (57.7%) patients had follicular lymphoma (FL), 8 (30.8%) had diffuse large B-cell lymphoma (DLBCL), and 3 (11.5%) had marginal zone lymphoma (MZL). All were previously treated with R or R-based combination therapy. Thirteen (50%) have discontinued due to progressive disease (PD); there were no discontinuations due to AEs. Eleven (42%) had completed 6 cycles of BR treatment. The most common treatment-emergent AEs (in >25% patients) in a pooled dataset were nausea (65.4%), anemia and neutropenia (each in 42.3%), diarrhea (38.5%), thrombocytopenia (34.6%), hyperglycemia (30.8%), vomiting and hypokalemia (each in 26.9%). Grade 3/4 AEs (in >10% patients) were neutropenia (26.9%), anemia and thrombocytopenia (each in 19.2%), leukopenia (15.4%), febrile neutropenia and decreased lymphocyte count (each in 11.5%). Febrile neutropenia (11.5%) was the SAE occurring in more than 10% of patients. There were no AEs leading to death. One patient in cohort 3 (100 mg x 7d/cycle) experienced a DLT of neutropenia and 2 patients in cohort 5 (200 mg x 28 d/cycle) experienced a DLT (n=1 febrile neutropenia; n=1 thrombocytopenia). Dose frequency was decreased to 7 d/cycle for patients in cohort 6. No DLTs were observed in subsequent cohorts following an amendment to G-CSF prophylaxis and DLT criteria. Preliminary PK data suggest there is no apparent interaction between ABT-199 and B. Of 26 evaluable patients, 5 (19.2%) had a complete response (CR) and 11 (42.3%) had a partial response (PR). To date, the overall response rate (CR+PR) for ABT-199+BR is 61.5% (16/26) for all patients, 73.3% (11/15) for patients with FL, and 37.5% (3/8) for patients with DLBCL. Conclusions: Preliminary data demonstrated a tolerable safety profile of ABT-199 in combination with BR across all dosing cohorts. There was no apparent PK interaction between ABT-199 and B; analysis for R is ongoing. Enrollment is ongoing at 400 mg ABT-199 with re-examination of a 28-day cycle schedule with G-CSF prophylaxis in heavily pre-treated patients. Early responses (CR and PR) are seen across all dose cohorts in patients with FL, many of whom have been heavily pretreated. A phase 2 study (NCT02187861; BO29337) of ABT-199 in combination with BR in R/R FL is planned. Figure 1 Figure 1. Disclosures Flowers: Genentech: LymphoCare Scientific Advisory Board Other; Celgene: Other; AbbVie, Inc: Research Funding; Acerta: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Gilead Sciences: Research Funding; Infinity Pharmaceuticals: Research Funding; Janssen: Research Funding; Millennium/Takeda: Research Funding; Onyx Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Spectrum: Research Funding; OptumRx: Consultancy; Seattle Genetics: Consultancy. Fowler:Roche: Membership on an entity's Board of Directors or advisory committees. Gifford:AbbVie, Inc: Employment. D'Amico:AbbVie, Inc: Employment. Dunbar:AbbVie, Inc: Employment. Zhu:AbbVie, Inc: Employment. Yang:AbbVie, Inc: Employment. Enschede:AbbVie, Inc: Employment. Ricker:AbbVie, Inc: Employment. Chien:AbbVie, Inc: Employment. Humerickhouse:AbbVie, Inc: Employment. Kozloff:Genentech: Consultancy; Roche: Consultancy.

7013 Background: ABT-199 is a selective, orally bioavailable Bcl-2 antagonist that induces rapid apoptosis of CLL cells and > 80% response rate as monotherapy in pts with R/R CLL. R synergizes with ABT-199 in preclinical models of CD20+ve lymphoid cancers. Methods: Objectives were to assess safety, pharmacokinetics (PK) and preliminary efficacy of ABT-199 + R and to determine a recommended phase 2 dose. Daily ABT-199 began at 50mg (modified to 20mg), with weekly increases to a final cohort dose (200-600mg). R was then initially dosed at 375 mg/m2 then 500mg/m2 monthly for 6 months (cohort 1-2 had 8 doses) with daily ABT-199 until progressive disease (PD). Results: As of Jan 17, 2014, 37 pts were enrolled in 5 cohorts (median age 68, 14/23 F/M) with a median time on study: 4.8 (range 0 - 15.2) months, median number of prior therapies: 2 (range 1 - 5); 9 pts were fludarabine-refractory, 9 R-refractory, and 9 had del(17p). Six pts discontinued: 4 due to PD (3 Richter’s transformation, 1 CLL), 1 withdrew consent (WC), 1 due to fatal hyperkalemia in the setting of tumor lysis syndrome (TLS) at 1st dose (50mg). The most common treatment-emergent adverse events (AEs, >25% pts) were neutropenia (43%), nausea (38%), diarrhea (30%). The most common grade 3/4 AEs were neutropenia (43%), thrombocytopenia (16%), and anemia (11%). Two dose limiting toxicities occurred with ABT-199 + R: thrombocytopenia (300mg/375mg/m2) and hemophagocytic syndrome (300mg/500mg/m2). Preliminary PK data suggest a negligible effect of R on ABT-199 exposure. Of 18 pts who have completed combination therapy or discontinued prior to completion, 7 (39%) achieved CR/CRi and 7 (39%) PR, 2PD, 1WC, 1 fatal event. Minimal Residual Disease (MRD) was quantified locally in 6/7 CR pts: 5 pts were MRD negative. Of the 19 yet to complete combination therapy, 4 have confirmed PR, 9 have unconfirmed PR, and 6 are not yet evaluable. Conclusions: To date, the addition of R to ABT-199 has identified no new toxicities. The combination is active in R/R CLL with a substantial CR rate. A fatal episode of TLS occurred during the ABT-199 lead-in period; with dosing modifications and increased monitoring no further TLS events occurred. Clinical trial information: NCT01682616.

Navitoclax is a first-in-class, orally bioavailable, targeted Bcl-2 family protein inhibitor and promotes apoptosis. Thrombocytopenia is a primary dose-limiting toxicity of navitoclax which exhibited a distinct time profile in circulating platelets from that caused by traditional chemotherapies. A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the pharmacokinetic of navitoclax as well as the time course of the platelet counts in cancer patients receiving navitoclax.

Abstract Introduction New treatment options are needed for patients (pts) with R/R NHL, particularly in MCL where there are no curative options. Dysregulation of the anti-apoptotic protein Bcl-2 is a hallmark of NHL pathogenesis and contributes to chemotherapy resistance. ABT-199 is a selective, potent, orally bioavailable small molecule Bcl-2 inhibitor that is a promising agent for the treatment of pts with NHL. Methods The primary objectives of this phase I, dose-escalation study were to evaluate the safety and pharmacokinetics (PK), and to determine a maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ABT-199. Secondary objectives were to assess the efficacy of ABT-199 and to explore biomarkers for response. Adult pts requiring therapy, with ECOG performance status ≤1 and adequate marrow function (ANC ≥1.0 x 109/L, Plt ≥50 x 109/L) received ABT-199 on Week 1 Day -7 (W1D-7), followed by continuous, once-daily dosing from W1D1 until progressive disease or unacceptable toxicity. A 2 to 3 week lead-in period with stepwise escalation starting with lower doses to final cohort doses of 200, 300, 400, 600, and 900 mg was implemented. Evaluations include adverse events (AE; NCI-CTCAE-V4), PK parameters and disease responses (IWG 2007 criteria). Results As of July 4, 2013, 32 pts were enrolled, 11 (34%) with follicular (FL), 8 (25%) with MCL, 8 (25%) with diffuse large B-cell (DLBCL), 1 (3%) with marginal zone (MZL), 3 (9%) with Waldenström macroglobulinemia (WM), and 1 (3%) multiple myeloma (MM). The median age was 68 (range 35-85), 63% were male with a median of 3.5 prior therapies (range 1-7), and the median time on study was 6.0 months (range 0.5-15.0). 44% of the pts had bulky disease ≥5 cm, including ≥10 cm in 16%. 22 pts have discontinued (D/C) drug: 18 due to progressive disease, 2 due to AEs, and 2 who proceeded to stem cell transplant in ongoing response. The most common AEs of any grade (G) occurring in ≥20% of pts were nausea (41%), diarrhea (31%), vomiting (22%), fatigue (22%), and upper respiratory tract infection (22%). G 3/4 AEs occurring in >3 pts were anemia (15%), neutropenia (13%), and thrombocytopenia (13%). G 3/4 thrombocytopenia was not dose-dependent or dose-limiting. Two of 10 pts in cohort 5 experienced a DLT (G3 febrile neutropenia and G4 neutropenia) at the target dose of 600 mg. G3 laboratory tumor lysis syndrome was seen after the initial dose in 1 pt with bulky MCL (elevations in phosphate and potassium only) and 1 pt with DLBCL (elevations in phosphate and uric acid only). After a single dose with food, ABT-199 had Tmax and T1/2 of approximately 8 and 15 hours, respectively. Food increased ABT-199 bioavailability by 3-4 fold. Preliminary efficacy data are summarized in the table. Conclusions ABT-199 showed anti-tumor activity as monotherapy for several NHL subtypes, with an overall response rate of 53% in this R/R population. Anti-tumor activity was seen in all MCL and WM pts treated across the range of ABT-199 cohort doses, and responses in DLBCL and FL pts were observed at doses ≥600 mg. Dose escalation is continuing to determine the MTD and RP2D. Biomarker studies are also underway in various NHL subtypes to explore a potential correlation with response. Disclosures: Seymour: Genentech: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Gerecitano:AbbVie: Research Funding; Genentech: Research Funding. Kahl:AbbVie, Inc.: Research Funding; Genentech: Consultancy, Research Funding. Wierda:AbbVie, Inc.: Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau. Anderson:Genentech: Research Funding; AbbVie, Inc.: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employee, which recieves commercial income related to ABT-199, Employee, which recieves commercial income related to ABT-199 Other. Rudersdorf:AbbVie, Inc.: Employment, Stock Other. Gressick:AbbVie, Inc: Employment, Stock Other. Montalvo:AbbVie, Inc.: Employment, Stock Other. Yang:AbbVie, Inc.: Employment, Stock Other. Busman:AbbVie, Inc.: Employment, Stock Other. Dunbar:AbbVie, Inc.: Employment, Stock Other. Cerri:AbbVie, Inc.: Employment, Stock Other. Enschede:AbbVie, Inc.: Employment, Stock Other. Humerickhouse:AbbVie, Inc.: Employment, Stock Other. Roberts:AbbVie, Inc.: Research Funding; Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employee, recieves commercial income related to ABT-199, Employee, recieves commercial income related to ABT-199 Other, Employment.

7018 Background: Targeting BCL-2 is a promising strategy for treating CLL, including disease refractory to fludarabine (F), or with (del(17p). ABT-199 is a selective BCL-2 inhibitor with >500-fold higher affinity for BCL-2 (Ki<0.10 nM) than for BCL-XL (Ki=48 nM). Methods: Objectives of this Ph I dose-escalation study include evaluations of safety, pharmacokinetics and preliminary efficacy of ABT-199 in patients (pts) with R/R CLL. A single oral dose was given followed by 6 days off drug, before continuous once daily dosing. After cohort 1, the initial dose was reduced and daily dosing modified to include a 2 or 3 step dose-escalation to the target dose for each cohort. Results: As of January 11, 2013, 56 pts have been enrolled; median age 67 y (range 36-86); 41 males; median 3.5 prior therapies (range 1-10). 16 (29%) had del(17p) and 18 (32%) F-refractory CLL. Median follow up is 6.3 months (range 0.03-16.5); 7 pts have been on study for more than 1 yr. 13 pts discontinued; 7 due to PD, 6 for other reasons: tumor lysis syndrome (TLS; 2), other illness (2), thromboembolic event (1), consent withdrawal (1). The most common non-hematological AEs (>15% pts) were nausea (36%), diarrhea (30%), fatigue (25%), upper respiratory tract infection (23%), and cough (16%). Grade 3/4 AEs occurring in > 5 pts were neutropenia 21(38%), thrombocytopenia 6 (11%) and TLS 5 (9%). TLS occurred in 3/3 pts in cohort 1 and 2/53 pts with the modified stepped dosing schedule (DLTs). Additionally, 1 fatal AE occurred within 48 hrs of dose-escalation to 1200 mg in a pt with laboratory evidence of TLS (DLT). 46 of 54 pts (85%) evaluable for efficacy achieved a response to ABT-199; 7 (13%) a CR or CR with incomplete count recovery and 39 (72%) a PR (30 confirmed by consecutive scans). 14/16 (88%) and 12/16 (75%) of pts with del(17p) and F-refractory CLL, respectively, achieved at least a PR. Conclusions: ABT-199 is highly active achieving a 85% overall response rate in R/R CLL, independent of high risk markers such as del(17p) and F-refractory disease. Additional dosing and scheduling modifications are currently being explored to minimize the risk of TLS. Clinical trial information: NCT01328626.

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 (Ki<0.10 nM) than BCL-XL (Ki=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.

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.

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/m 2 IV on d1 q21; or (b) N 150 mg PO, QD on d1–3, d8–10, and d15–17 q28 plus D 30 mg/m 2 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/m 2 q21; gr 3/4 febrile neutropenia, gr 4 neutropenia, and gr 3 fatigue at N 200 mg d1–3 plus D 75 mg/m 2 q21; gr 3 febrile neutropenia, gr 4 TCP, and death at N 150 mg d1–5 plus D 75 mg/m 2 q21. The MTD of N with D at 75 mg/m 2 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/m 2 q21 and with D 30 mg/m 2 q28. Both combinations were tolerable with no significant PK interactions in the D 75 mg/m 2 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.

Abstract Introduction: Navitoclax (Nav), a novel BH3 mimetic that binds with high affinity and inhibits antiapoptotic Bcl-2 family proteins, enhances chemotherapy activity by lowering the apoptotic threshold. Preclinically, navitoclax enhanced irinotecan (Ir) efficacy in colon, gastric, pancreatic, and small cell lung cancer tumor models. Methods: This phase 1 study in cancer patients (pts), assessed safety, pharmacokinetics (PK), and tumor activity of Nav in combination with Ir on 2 different schedules. Eligible pts had an ECOG performance score of ≤2 and a malignancy refractory to standard therapy. Pts were assigned to 1 of 2 dosing schedules. A continual reassessment method for dose escalation was used. Pts were assigned to 21-day (D)-cycle dosing schedules, either 3-week (Q3W) (Nav D1–3 [18 off]; Ir D1) or weekly (W) (Nav D1–3 and D8–10 [11 days off]; Ir D1 and D8). Oral Nav was dosed once daily starting at 150 mg in both schedules; Ir was dosed intravenously over 90 min at 180, 250 or 350 mg/m2 (Q3W), and over 45 min at 75 or 100 mg/m2 (W). PK was assessed for Nav and Ir; safety was assessed per NCI-CTCAE v3.0; disease response/progression was assessed per standard of care for each tumor type (RECIST, PSA, CEA, CA-125, etc). Results: 31 pts (15 women, 16 men) were enrolled; median age (range) 58 years (31–73); median (range) prior therapies was 4 (1–17). The most common adverse events (Q3W and W) that were Nav-related, irrespective of relationship to Ir, were diarrhea 77% (86% and 71%), nausea 45% (50% and 41%), vomiting 39% (29% and 47%), fatigue 32% (21% and 41%), and febrile neutropenia 26% (36% and 18%). Dose-limiting toxicities (DLT) (Q3W and W) were reported by 11 pts (6 and 5), and included febrile neutropenia 7 pts (5 and 2), diarrhea 7 pts (4 and 3), fatigue 2 pts (0 and 2), and colitis 1 pt (1 and 0). The recommended phase 2 dose (RPTD) in the W schedule was Nav 150 mg and Ir 75 mg/m2. The lowest level explored on the Q3W schedule (Nav 150 mg and IR 180 mg/m2) was determined to be not tolerable and therefore the highest administrated dose exceeded a maximum tolerated dose (MTD). Tumor response is available for 17 pts (Q3W and W); 2 had a partial response (1 Merkel cell carcinoma and 1 colon cancer; neither pt had received prior Ir), 6 had stable disease (2 and 4), 9 had progressive disease (PD) (5 and 4). Objective response rate was 6.5% [95% CI: 0.8, 21.4]. 19 pts discontinued treatment due to PD, 7 due to AEs, 3 withdrew consent, and 1 due to DLT (1 pt is still on study). Median [95% CI] time on study (Q3W and W) was 25 days [10, 32] (25 days [3, 32], 26 days [3, 53]). Preliminary results indicate no apparent PK interaction between Nav and Ir. The average SN-38 exposure appeared to be higher in pts with DLTs. After febrile neutropenia was observed in the first dose level explored, the study was amended to include only those pts with functional UGT1A1 enzyme activity. The frequency of UGT1A1 genotypes (%) was *1/*1 (32); *1/*28 (52); *28/*28 (13); *28/*37 (3). Conclusions: The RPTD in the W schedule was Nav 150 mg and Ir 75 mg/m2. The Q3W schedule had a high rate of toxicities and an MTD was not identified. Despite limiting enrollment to those with functional UGT1A1 enzyme activity, the SN-38 exposures remained highly variable and may have contributed to the high rate of toxicities observed. The 2 tumor responses were notable in this highly chemotherapy-refractory pt population. 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 A93.

Abstract INTRODUCTION: Navitoclax (ABT-263) is a novel, orally bioavailable small molecule that inhibits Bcl-2 family proteins and promotes apoptosis. The current Phase 1 formulation is a lipid solution, which has a short shelf-life. A new lipid solution with improved shelf-life was developed to support Phase 2/3 clinical development. Relative bioavailability studies in patients were expected to have large variability, which would make the interpretation challenging. Meanwhile, the toxicity profile of navitoclax limited an evaluation at the recommended phase II dose in healthy volunteers. Therefore, relative bioavailability studies for the new formulation were conducted in both healthy volunteers (at doses with minimal safety risk) and cancer patients (at therapeutic doses). METHODS: Two randomized, crossover studies were conducted to evaluate the bioavailability of the new formulation relative to that of the Phase 1 formulation. Study I was conducted in 12 healthy female subjects with non-childbearing potential at a single dose of 25 mg navitoclax. Study II was conducted in 12 cancer patients at a single dose of 250 mg navitoclax. Both studies were conducted under low-fat conditions. RESULTS: The new lipid solution was bioequivalent to the Phase 1 formulation in healthy subjects. In patients, the point estimates of the bioavailability of the new lipid solution were 30% higher than the Phase 1 formulation; nevertheless, the point estimates were associated with wide 90% confidence intervals indicating high uncertainty in the point estimate. The percent coefficient of variation for navitoclax exposure in patients (49%) was markedly higher than that in healthy subjects (25%). CONCLUSION: Relative bioavailability assessment in healthy volunteers had substantially lower variability compared to that in cancer patients, therefore served as the primary basis for decision making. However, results from patients provided supportive information at the therapeutic dose levels. Overall results from both studies in healthy subjects and patients provided strong evidence that the new lipid solution has comparable bioavailability as the Phase 1 formulation under low-fat conditions at therapeutic doses, and enabled a decision to select the new lipid formulation without dose modification for Phase 2/3 studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1300. doi:10.1158/1538-7445.AM2011-1300