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Background BXCL701 is an oral competitive inhibitor of DPPs, primarily DPP8/9, that activates inflammasome mediated pyroptosis. BXCL701 therefore, can induce an innate immune reaction and tumor inflammation, bridging between innate and adaptive immunity, potentially leading to synergistic anticancer activity when combined with PD-1 antibody pembrolizumab. Methods This is a phase 2, open-label, single-center study (NCT04171219) of oral BXCL701 0.3 mg BID on days 1–14 and intravenous pembrolizumab 200 mg on day 1 of a 21-day cycle with a safety lead-in to evaluate RECIST/iRECIST response rate in patients with advanced solid cancers. After confirming safety and dose limiting toxicities (DLT) in the first 6 patients, additional patients are being enrolled to a PD-1/PD-L1 antibodies (ab) naive cohort and PD-1/PD-L1 ab pretreated cohort. Each cohort is planned to enroll 9 patients, and if a partial (PR) or complete response (CR) is observed the cohort is expanded to a total of 17 patients. The treatment is considered promising if at least 3 PRs or CRs are observed in a cohort of 17 patients. Results As of August 24, 2020, 14 patients were treated; 5 patients (prostate cancer, endometrial cancer, uveal melanoma, liposarcoma, basal cell carcinoma) were enrolled in the PD-1/PD-L1 ab naive cohort and 9 patients (leiomyosarcoma, squamous cell carcinoma of unknown primary, melanoma, myxoid sarcoma, pleomorphic sarcoma, colorectal cancer, anaplastic astrocytoma, prostate cancer) were enrolled to PD-1/PD-L1 ab pretreated cohort. Among all 14 patients, there was 1 episode of grade 4 hypotension (recovered) and 1 episode of grade 5 hypotension attributed to BXCL701. In the PD-1/PD-L1 ab naive cohort, of 3 patients with available imaging, 2 had a PR (uveal melanoma previously treated with PD-1/OX40 fusion protein [-31%] n=1; and microsatellite stable endometrial cancer [-62%], n=1). In the PD-1/PD-L1 ab pretreated cohort, there were no objective responses in 5 patients with available imaging; however, a patient with pleomorphic sarcoma refractory to PD-1 antibody monotherapy demonstrated a tumor shrinkage of -18% on the first restaging imaging. Conclusions BXCL701 in combination with pembrolizumab demonstrated encouraging signals of activity in selected difficult-to-treat cancers. Mitigation strategies to prevent events of high-grade hypotension are being implemented to allow the enrollment continuation. Trial Registration NCT04171219 Ethics Approval The study was approved by MD Anderson IRB

Background BXCL701 (talabostat) is an oral small molecule inhibitor of dipeptidyl peptidases (DPP) primarily DPP8 and DPP9, which triggers inflammasome mediated pyroptosis in macrophages leading to induction of IL-18 and IL-1beta, bridging between innate and adaptive immunity. PD-L1 expression correlates with amplification of DPP8 and DPP9. In syngeneic animal models, significant tumor growth inhibition was observed with BXCL701 plus checkpoint inhibition. In a prior clinical study, single-agent BXCL701 resulted in objective responses in patients (pts) with Stage IV melanoma (unpublished). Methods In Phase 1b portion of this multicenter study, eligible pts had progressing mCRPC (PCWG3), at least 1 prior systemic therapy, ≤ 2 lines of cytotoxicchemotherapy for mCRPC, no prior anti-PD-1/PD-L1 or other T-cell directed anticancertherapy. Using a 3+3 design, pts received fixed-dose pembro (200 mgIV q21-days) with escalating doses of BXCL701 on days 1–14. The primary endpoint was determination of the recommended Phase 2 dose (RP2D). Response (RECIST 1.1, PSA, CTC), plasma drug concentration and change in relevant immune effector cytokines were also evaluated. Results 13 pts were treated in 3 cohorts of BXCL701: 0.4 mg qd (n = 3); 0.6 mg qd (n = 3) and 0.6 mg split dose (n=7). 7 pts had adenocarcinoma, 6 had small cell/neuroendocrine prostate cancer features. Prior treatment included ADT (n = 10), 2nd-generation androgen signaling inhibitors (n = 9), chemotherapy (n = 11), RT (n = 11). On-target AEs consistent with cytokine activation were seen at the highest dose levels. In the 0.6 mg qd cohort, all pts had events consistent with cytokine release: 3/3 had hypotension (including 1 grade 3 syncope (DLT)) and 2pts each had dizziness and LE edema. Splitting the 0.6 mg dose improved the tolerability while maintaining the TDD previously associated with objective response; 3/7 pts had fatigue, and 1pt each had low grade hypotension, dyspnea, chills, myalgia. Preliminary anti-tumor activity was seen with 1 pt achieving a PSA response and 3 pts with RECIST1.1 stable disease. BXCL701 was quantifiable in plasma. Consistent dose and time dependent increases in serum IL-18 levels were observed with 0.6 mg split dose. Conclusions BXCL701 0.3 mg BID (0.6 mg TDD) administered on days 1–14 was identified as the RP2D when administered with pembro 200 mg every 21 days. Splitting the TDD was associated with improved tolerability as evidenced by no reported DLTs and lower rates of other adverse events of interest such as hypotension and peripheral edema. The Phase 2 portion of the study is enrolling. Acknowledgements All patients, their families, and caregivers who make this study possible; the participating investigators and their staff; Cedric Burg PhD and J. MacDougall PhD of BioXcel Therapeutics, Valery Chatikhine MD of Iqvia Biotech and the Iqvia Biotech team for assisting in the conduct of the study. Trial Registration NCT03910660EUDRACT 2018-003734-32 Ethics Approval This study was approved by Institution Review Boards or Ethics Committees affiliated with participating institutions.

Treatment with a frontline BCR-ABL1 tyrosine kinase inhibitor (TKI; e.g., imatinib, dasatinib, and nilotinib) allows patients with chronic myeloid leukemia (CML) in chronic phase (CP) to achieve a near normal life expectancy1, whereas treatment for CML in accelerated phase (AP) is more problematic. While reports describe outcomes for patients with CML-AP at initial diagnosis2,3, outcomes have been historically worse once CP disease has progressed to AP. Approximately 50% of patients with CML-AP who receive imatinib as initial treatment develop imatinib resistance4 and experience disease progression5. Second-generation TKIs are indicated for patients with CML-CP or advanced CML resistant to/intolerant of prior therapy (including imatinib)6. After initial approval of dasatinib twice a day (BID) for the treatment of patients with CML resistant to/intolerant of imatinib in all stages, this phase 3 CA180-035 study (NCT00123487) was developed to investigate once (QD) or twice (BID) a day dasatinib treatment in patients with CML-AP, CML in blast phase, or Ph+ acute lymphoblastic leukemia resistant to/intolerant of imatinib.

BACKGROUND: Nivolumab plus ipilimumab showed promising efficacy for the treatment of non-small-cell lung cancer (NSCLC) in a phase 1 trial, and tumor mutational burden has emerged as a potential biomarker of benefit. In this part of an open-label, multipart, phase 3 trial, we examined progression-free survival with nivolumab plus ipilimumab versus chemotherapy among patients with a high tumor mutational burden (≥10 mutations per megabase). METHODS: We enrolled patients with stage IV or recurrent NSCLC that was not previously treated with chemotherapy. Those with a level of tumor programmed death ligand 1 (PD-L1) expression of at least 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy; those with a tumor PD-L1 expression level of less than 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. Tumor mutational burden was determined by the FoundationOne CDx assay. RESULTS: Progression-free survival among patients with a high tumor mutational burden was significantly longer with nivolumab plus ipilimumab than with chemotherapy. The 1-year progression-free survival rate was 42.6% with nivolumab plus ipilimumab versus 13.2% with chemotherapy, and the median progression-free survival was 7.2 months (95% confidence interval [CI], 5.5 to 13.2) versus 5.5 months (95% CI, 4.4 to 5.8) (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41 to 0.81; P

Background Long-term data with immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) are limited. Two phase III trials demonstrated improved overall survival (OS) and a favorable safety profile with the anti-programmed death-1 antibody nivolumab versus docetaxel in patients with previously treated advanced squamous (CheckMate 017) and nonsquamous (CheckMate 057) NSCLC. We report results from ≥3 years’ follow-up, including subgroup analyses of patients with liver metastases, who historically have poorer prognosis among patients with NSCLC. Patients and methods Patients were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks) until progression or discontinuation. The primary end point of each study was OS. Patients with baseline liver metastases were pooled across studies by treatment for subgroup analyses. Results After 40.3 months’ minimum follow-up in CheckMate 017 and 057, nivolumab continued to show an OS benefit versus docetaxel: estimated 3-year OS rates were 17% [95% confidence interval (CI), 14% to 21%] versus 8% (95% CI, 6% to 11%) in the pooled population with squamous or nonsquamous NSCLC. Nivolumab was generally well tolerated, with no new safety concerns identified. Of 854 randomized patients across both studies, 193 had baseline liver metastases. Nivolumab resulted in improved OS compared with docetaxel in patients with liver metastases (hazard ratio, 0.68; 95% CI, 0.50–0.91), consistent with findings from the overall pooled study population (hazard ratio, 0.70; 95% CI, 0.61–0.81). Rates of treatment-related hepatic adverse events (primarily grade 1–2 liver enzyme elevations) were slightly higher in nivolumab-treated patients with liver metastases (10%) than in the overall pooled population (6%). Conclusions After 3 years’ minimum follow-up, nivolumab continued to demonstrate an OS benefit versus docetaxel in patients with advanced NSCLC. Similarly, nivolumab demonstrated an OS benefit versus docetaxel in patients with liver metastases, and remained well tolerated. Clinical trial registration CheckMate 017: NCT01642004; CheckMate 057: NCT01673867.

2558 Background: BXCL701 is an oral competitive inhibitor of dipeptidyl peptidases (DPPs), primarily DPP8/9, which triggers the inflammasome to alert and prime immune cells, leading to induction of IL-18 and IL-1ß. BXCL701 therefore, can induce an innate immune reaction and tumor inflammation, bridging between innate and adaptive immunity, potentially leading to synergistic anticancer activity when combined with PD-1 antibody pembrolizumab. Methods: This is a phase 2, open-label, single-center study (NCT04171219) of oral BXCL701 0.3 mg BID on days 1-14 and intravenous pembrolizumab 200 mg on day 1 of a 21-day cycle with a safety lead-in to evaluate RECIST/iRECIST response rate in patients with advanced solid cancers. After confirming safety and dose limiting toxicities (DLT) in the first 6 patients, additional patients are being enrolled to an immune checkpoint inhibitors (iCPI) naïve cohort and iCPI pretreated cohort. Each cohort is planned to enroll 9 patients in the first stage, and if a partial (PR) or complete response (CR) is observed the cohort is expanded to a total of 17 patients in the second stage. The treatment is considered promising if at least 3 PRs or CRs are observed in a cohort of 17 patients. Results: As of February 11, 2021, 16 patients were treated; 5 patients (prostate cancer, endometrial cancer, liposarcoma, basal cell carcinoma, squamous cell carcinoma of unknown primary) were enrolled in the iCPI naïve cohort and 11 patients (leiomyosarcoma [2], squamous cell carcinoma of unknown primary, triple negative breast cancer, uveal melanoma, melanoma, uterine myxoid sarcoma, pleomorphic sarcoma, colorectal cancer, anaplastic astrocytoma, prostate cancer) were enrolled to iCPI pretreated cohort. Among all 16 patients, there was 1 episode of grade 4 hypotension (recovered) and 1 episode of grade 5 hypotension attributed to BXCL701, which resulted in implementation of risk-mitigation strategies such as gradual dose escalation and blood pressure monitoring. In the CPI naïve cohort, of 4 patients with available imaging, 1 had a PR (microsatellite stable endometrial cancer [-62%]) and 1 durable stable disease (SD -10%, basal cell carcinoma on therapy for 6+ months). In the CPI pretreated cohort, of 9 patients with available imaging, 1 had a PR (-31%, uveal melanoma) and 3 durable SD (-22%, pleomorphic sarcoma on therapy for 8+ months; +4%, squamous cell carcinoma of unknown primary on therapy for 6 months; +5%, uterine myxoid sarcoma on therapy for 6 months). Conclusions: BXCL701 in combination with pembrolizumab demonstrated encouraging signals of activity in selected difficult-to-treat cancers. Prespecified efficacy endpoints were met in the first stage and both cohorts will proceed to second-stage of the study Clinical trial information: NCT04171219.

124 Background: BXCL701 (talabostat), oral small molecule inhibitor of dipeptidyl peptidases (DPP), primarily DPP8 and DPP9, triggers inflammasome mediated pyroptosis in macrophages, leading to induction of IL-18 and IL-1ß, bridging between innate and adaptive immunity. PD-L1 expression correlates with amplification of DPP8 and DPP9. In syngeneic animal models, significant tumor growth inhibition was observed with BXCL701 plus checkpoint inhibition. In a prior clinical study, single-agent BXCL701 resulted in objective responses in patients with Stage IV melanoma (unpublished). Methods: Eligible patients included in Phase 1b portion of this multicenter study, had progressing mCRPC (PCWG3), ≥1 prior systemic therapy, ≤2 lines of cytotoxic chemotherapy for mCRPC, no prior anti-PD-1/PD-L1 or other T-cell directed anticancer therapy. In Phase 2 portion, patients with adenocarcinoma must have received 1 or 2 2nd generation androgen signaling inhibitors; patients with SCNC/t-NEPC must have received ≥1 prior line of chemotherapy. Patients received fixed-dose pembrolizumab (200 mg IV q21-days) with BXCL701 on days 1-14 at recommended Phase 2 dose (RP2D)/schedule. Primary endpoint is Composite Response (RECIST 1.1, PSA, CTC). Change in relevant immune effector cells was also evaluated. Results: In Phase 1b portion 13 patients were treated with BXCL701 in 3 cohorts: 0.4 mg qd (n = 3); 0.6 mg qd (n = 3) and 0.6 mg split dose (n=7). 7 patients had adenocarcinoma, 6 had small cell/neuroendocrine prostate cancer phenotype. Prior treatment included androgen deprivation therapy (n = 10), 2nd-generation androgen signaling inhibitors (n = 9), chemotherapy (n = 11), radiation therapy (n = 11). On-target adverse events (AEs) consistent with cytokine activation were seen at highest dose levels. In 0.6 mg qd cohort, all patients had events consistent with cytokine release syndrome: 3/3 had hypotension, including 1 grade 3 syncope—dose-limiting toxicity (DLT)—and 2 patients each had dizziness and lower extremity edema. Splitting 0.6 mg dose improved tolerability while maintaining total daily dose (TDD) previously associated with objective response; 3/7 patients had fatigue, and 1 patient each had low grade hypotension, dyspnea, chills, myalgia. Preliminary anti-tumor activity was seen with 1 patient achieving a PSA response and 4 patients with RECIST1.1 stable disease. Consistent dose and time dependent increases in serum IL-18 levels were observed. Conclusions: BXCL701 0.3 mg BID (0.6mg TDD) administered on days 1-14 was identified as RP2D when administered with pembrolizumab 200 mg every 21 days. Splitting TDD was associated with improved tolerability as evidenced by no reported DLTs and lower rates of other AEs of interest e.g. hypotension and peripheral edema. Preliminary data from Phase 2 portion will be presented. Clinical trial information: NCT03910660.

Dasatinib was approved at 100 mg once daily for imatinib-resistant or -intolerant patients with chronic myeloid leukemia (CML) in chronic phase, based on results of the phase 3 CA180-034 (NCT00123474) study. Here we present the final 7-year analysis of this pivotal study, the longest follow-up to date of any second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI). Patients (n = 670) with imatinib-resistant or -intolerant CML in chronic phase received dasatinib. Nineteen percent of patients continued on study treatment, with a greater proportion in the 100 mg once daily arm remaining on therapy. Seven-year rates for major molecular response (MMR), progression-free survival (PFS), and overall survival (OS) were similar across doses; MMR, PFS, and OS results were 46, 42, and 65% at 100 mg once daily, respectively. Improved PFS and OS rates were reported in patients who achieved BCR-ABL1 ≤10% at 3 and 6 months. No new safety signals were identified. The incidence of drug-related pleural effusion was 28% at 100 mg once daily and 35% at the other three dose groups. Incidence of drug-related pulmonary hypertension and pulmonary arterial hypertension remained low (≤3% across all doses). Arterial ischemic events occurred in ≤4% of patients across all doses. These data support the long-term efficacy and well-established safety profile of dasatinib for patients with imatinib-resistant or -intolerant CML in chronic phase. Am. J. Hematol. 91:869-874, 2016. © 2016 Wiley Periodicals, Inc.

e17581 Background: BXCL701 (talabostat previously PT100) is an oral small molecule inhibitor of DPP4, DPP8 and DPP9, which trigger macrophage cell death via pyroptosis resulting in proinflammatory stimulation of the innate immunity pathway. Expression of PD-L1 correlates with amplification of DPP8 and DPP9. In syngeneic animal models, significant tumor responses were observed when BXCL701 was used with checkpoint inhibition. In a prior clinical study, BXCL701 at a total daily dose of 0.6mg (as 0.3mg BID) demonstrated single agent activity in 2 pts with Stage IV melanoma (unpublished). Methods: In this multi-center study, eligible patients (pts) had progressing mCRPC (PCWG3), at least 1 line of systemic therapy and ≤ 2 lines of cytotoxic chemotherapy for mCRPC, no prior anti-PD-1/PD-L1 or other T-cell directed anti-cancer therapy, and an ECOG PS of ≤ 2. Pts received fixed dose pembro (200mg IV q21 days) with escalating doses of BXCL701 (0.4mg and 0.6mg PO QD days 1-14 of 21-day cycles) using a 3X3 design. The key endpoints were safety and identification of the recommended phase 2 dose (RP2D) for the combination. Composite response (RECIST, PSA, CTC), plasma drug concentration and change in relevant immune effector cytokines were also evaluated. Results: Six pts were treated at 2 BXCL701 dose levels of 0.4mg qd (n = 3) and 0.6mg qd (n = 3), with 5 pts having adeno, 1 pt having mixed adeno and SC-NEPC. Prior tx included ADT (n = 6), 2nd generation androgen signaling inhibitors (n = 4), chemo (n = 4), RT (n = 5). Among 3 pts at the BXCL701 dose level of 0.6mg, 1 pt had a DLT of Grade 3 syncope (C1D6) and 1 pt had fatal acidosis (C3D8). A dose-dependent increase in pts with low-grade on-target clinical effects was observed. In the 0.4mg qd cohort 1 pt had lower extremity (LE) edema. Whereas in the 0.6mg qd cohort, all pts had events consistent with cytokine release: 3 had hypotension and 2 pts each had dizziness and LE edema. The 0.6mg/day dose level was expanded using a split dose strategy to improve tolerability while maintaining the daily dose previously associated with objective responses. BXCL701 was quantifiable in plasma. Conclusions: BXCL701 0.4 mg QD on days 1 to 14 of 21-day cycle plus pembrolizumab 200 mg IV on day 1 every 21 days was well tolerated in pts with mCRPC. A dose-dependent increase in on-target clinical effects expected with cytokine upregulation was seen. The final dose expansion using the split dose for the RP2D, plasma drug concentrations and relevant biomarkers will be presented. Clinical trial information: NCT03910660 .

140 Background: BXCL701 (talabostat previously PT100) is an oral small molecule inhibitor of dipeptidyl peptidases (DPP) specifically DPP4, DPP8 and DPP9, which trigger macrophage cell death via pyroptosis resulting in proinflammatory stimulation of the innate immunity pathway. BXCL701 also inhibits fibroblast activation protein (FAP) releasing the FAP-mediated block of T-cell migration into the tumor. Expression of PD-L1 correlates with amplification of DPP8 and DPP9. In syngeneic animal models, significant tumor responses were observed when BXCL701 was used with checkpoint inhibition. Methods: A phase 1b, multicenter study was undertaken. Eligible patients (pts) had progressing mCRPC (PCWG3), at least 1 line of systemic therapy and ≤ 2 lines of cytotoxic chemotherapy for mCRPC, no prior anti-PD-1/PD-L1 or other T-cell directed anti-cancer therapy, and an ECOG PS of ≤ 2. Pts received fixed dose pembro (200mg IV q21 days) with escalating doses of BXCL701 (0.4mg and 0.6mg PO QD days 1-14 of 21-day cycles) using a 3 X 3 design. The key endpoints were safety and identification of the recommended phase 2 dose (RP2D) for the combination. Composite response (RECIST, PSA, CTC) was also assessed. Results: 3 pts were treated at the initial dose level for at least 4 cycles. All pts remain on treatment. No DLT or SAEs were reported. Grade 3 treatment related adverse events (TRAE) were limited to thrombocytopenia with transfusion in 1 pt. The only TRAE reported in more than one pt was hypocalcemia (2 pts). Safety assessment of BXCL701+pembro is ongoing at the final dose escalation cohort. As DPP9 is amplified in approximately 17% of treatment associated small cell/neuroendocrine prostate cancer (tSCNC) compared to 5% or less in the broader prostate cancer population, the Phase 2 portion of this study will be limited to patients with evidence of t-SCNC or de novo SCNC, an aggressive phenotype with poor outcomes. Conclusions: BXCL701 0.4mg QD on days 1 to 14 of 21-day cycle plus pembrolizumab 200 mg IV on day 1 every 21 days is safe in pts with mCRPC. The final dose escalation supporting RP2D will be presented. Clinical trial information: NCT03910660.

Purpose Nivolumab, a programmed death-1 inhibitor, prolonged overall survival compared with docetaxel in two independent phase III studies in previously treated patients with advanced squamous (CheckMate 017; ClinicalTrials.gov identifier: NCT01642004) or nonsquamous (CheckMate 057; ClinicalTrials.gov identifier: NCT01673867) non–small-cell lung cancer (NSCLC). We report updated results, including a pooled analysis of the two studies. Methods Patients with stage IIIB/IV squamous (N = 272) or nonsquamous (N = 582) NSCLC and disease progression during or after prior platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks). Minimum follow-up for survival was 24.2 months. Results Two-year overall survival rates with nivolumab versus docetaxel were 23% (95% CI, 16% to 30%) versus 8% (95% CI, 4% to 13%) in squamous NSCLC and 29% (95% CI, 24% to 34%) versus 16% (95% CI, 12% to 20%) in nonsquamous NSCLC; relative reductions in the risk of death with nivolumab versus docetaxel remained similar to those reported in the primary analyses. Durable responses were observed with nivolumab; 10 (37%) of 27 confirmed responders with squamous NSCLC and 19 (34%) of 56 with nonsquamous NSCLC had ongoing responses after 2 years’ minimum follow-up. No patient in either docetaxel group had an ongoing response. In the pooled analysis, the relative reduction in the risk of death with nivolumab versus docetaxel was 28% (hazard ratio, 0.72; 95% CI, 0.62 to 0.84), and rates of treatment-related adverse events were lower with nivolumab than with docetaxel (any grade, 68% v 88%; grade 3 to 4, 10% v 55%). Conclusion Nivolumab provides long-term clinical benefit and a favorable tolerability profile compared with docetaxel in previously treated patients with advanced NSCLC.

BACKGROUND: On the basis of potential additive or synergistic immunostimulatory antitumor effects, in this phase 1 study, the authors evaluated the combination of sunitinib and tremelimumab (CP-675206; an antibody against cytotoxic T-lymphocyte–associated antigen 4 [CTLA4]) in patients with metastatic renal cell carcinoma (mRCC) was evaluated. METHODS: Adult patients with mRCC who had received ≤1 previous systemic treatment received tremelimumab (6 mg/kg, 10 mg/kg, or 15 mg/kg) intravenously once every 12 weeks and oral sunitinib (50 mg daily for 4 weeks then 2 weeks off or 37.5 mg daily as a continuous dose). The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives were to assess antitumor activity, safety, and pharmacokinetics. RESULTS: Twenty-eight patients were enrolled. Two of 5 patients who received 50 mg sunitinib plus tremelimumab 6 mg/kg experienced dose-limiting toxicities (DLTs), and no further enrollment to the combination with sunitinib 50 mg dosing was pursued. Among patients who received continuous sunitinib 37.5 mg daily, 1 of 7 patients who received tremelimumab 10 mg/kg plus sunitinib suffered a sudden death, and 3 of 6 patients who received tremelimumab 15 mg/kg plus sunitinib experienced DLTs. An expansion cohort (n = 7) was enrolled at tremelimumab 10 mg/kg plus sunitinib 37.5 mg daily; 3 of those patients experienced DLTs. Overall, rapid-onset renal failure was the most common DLT. Nine of 21 patients who were evaluable for response achieved partial responses (43%; 95% confidence interval, 22%-66%), and 4 of those responses were ongoing at the time of the current report. CONCLUSIONS: In this study of tremelimumab plus sunitinib, rapid-onset acute renal failure was observed unexpectedly, and further investigation of tremelimumab doses >6 mg/kg plus sunitinib 37.5 mg daily is not recommended. Preclinical investigation may be warranted to understand the mechanism of renal toxicity. Cancer 2011. © 2010 American Cancer Society.

Background: Nivo + ipi showed promising clinical activity and tolerability as 1L tx for advanced NSCLC in a phase 1 study. Tumor mutation burden (TMB) has emerged as an important biomarker for benefit of immune checkpoint blockade in lung cancer. CheckMate 227 (NCT02477826) is a large, open-label, phase 3 study of 1L nivo + ipi, nivo, or nivo + PT-DC vs PT-DC in advanced NSCLC. A preplanned co-primary endpoint was based on TMB to evaluate progression-free survival (PFS) of nivo + ipi vs PT-DC. This is the first phase 3 study to evaluate TMB as a predictive biomarker for immunotherapy as a co-primary endpoint. We report initial results from Part 1 of the study. Methods: Patients (pts; N=1739) with chemotherapy-naive, histologically confirmed stage IV or recurrent NSCLC, ECOG PS 0−1, and no known sensitizing EGFR/ALK mutations were enrolled in 2 groups: PD-L1 ≥1% or PD-L1 Results: Baseline characteristics were similar in pts with evaluable TMB and all randomized pts and were balanced between nivo + ipi and PT-DC arms. Minimum follow-up was 11.5 mo. PFS was significantly longer with nivo + ipi vs PT-DC in pts with TMB ≥10 mut/Mb (HR=0.58 [97.5% CI: 0.41, 0.81]; P=0.0002); results were broadly consistent across subgroups, including PD-L1 and histology. The HR for PFS was 1.07 (95% CI: 0.84, 1.35) in pts with TMB Conclusions: CheckMate 227 met its co-primary endpoint of significantly prolonged PFS with 1L nivo + ipi vs PT-DC in NSCLC with TMB ≥10 mut/Mb regardless of PD-L1 expression. Safety was consistent with previous reports of 1L nivo + ipi for this dose regimen. These results validate the benefit of dual immune checkpoint blockade and the role of TMB as a biomarker to select pts in 1L NSCLC. Citation Format: Matthew D. Hellmann, Tudor Eliade Ciuleanu, Adam Pluzanski, Jong Seok Lee, Gregory Otterson, Clarisse Audigier-Valette, Elisa Minenza, Helena Linardou, Sjaak Burgers, Pamela Salman, Hossein Borghaei, Suresh S. Ramalingam, Julie Brahmer, Martin Reck, Kenneth J. O'Byrne, William J. Geese, George Green, Han Chang, Joseph D. Szustakowski, Prabhu Bhagavatheeswaran, Diane Healey, Yali Fu, Faith Nathan, Luis Paz-Ares. Nivolumab (nivo) + ipilimumab (ipi) vs platinum-doublet chemotherapy (PT-DC) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): initial results from CheckMate 227 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT077.

Purpose Safety and efficacy of tremelimumab (CP-675,206), a fully human anti-cytotoxic T-lymphocyte–associated antigen 4 (CTLA4) monoclonal antibody, were assessed in patients with treatment-refractory colorectal cancer. Patients and Methods A single-arm, multicenter, phase II trial was conducted in patients with Eastern Cooperative Oncology Group performance status ≤ 1 and measurable colorectal carcinoma for whom standard treatments for metastatic disease had failed. Patients received 15 mg/kg tremelimumab intravenously every 90 days until progression. Primary end point was objective response status (per Response Evaluation Criteria in Solid Tumors). Secondary end points included safety, duration of response, progression-free survival, and overall survival. Results Forty-seven patients who had received extensive prior therapies (all had received fluoropyrimidines, oxaliplatin, and irinotecan; most [91%] had also received cetuximab) were treated. Grade 3/4 treatment-related adverse events (AEs) were diarrhea (n = 5; 11%), ulcerative colitis (n = 1; 2%), fatigue (n = 1; 2%), autoimmune thrombocytopenia (n = 1; 2%), and hypokalemia (n = 1; 2%), which resolved spontaneously or with interventions. Six patients discontinued because of an AE; two were considered treatment related. Of 45 response-evaluable patients, 44 did not reach second dose (43 progressive disease; one discontinuation). Twenty-one patients (45%) lived ≥ 180 days after enrollment. One patient (2%; 90% CI, < 1% to 10%) had a stable pelvic mass and substantial regression in an adrenal mass (partial response). This patient received five tremelimumab doses; response duration was 6 months (enrollment to disease progression, 15 months). Conclusion Tremelimumab did not demonstrate clinically meaningful single-agent activity in this patient population, although the number of survivors at 6 months and the one patient with confirmed partial response are potentially interesting. Further study of tremelimumab in combination with other agents may be warranted.

Introduction: Ph+ ALL comprises ~5% of childhood and adolescent ALL. Prior to development of tyrosine kinase inhibitor (TKI) therapy, survival rates were poor. Less than half of patients (pts) survived despite treatment with intensive chemotherapy and frequent use of allogeneic hematopoietic stem cell transplant (HSCT) in first remission (CR1). The Children's Oncology Group (COG) AALL0031 trial (Schultz, JCO 2009) and the EsPhALL trial (Biondi, Lancet Oncology 2012) showed adding imatinib to different intensive chemotherapy backbones improved event-free (EFS) and overall survival (OS) in pediatric Ph+ ALL. Dasatinib is attractive to study in Ph+ ALL because it is a dual ABL/SRC TKI that is 300 times more potent than imatinib in vitro, is active against most ABL1 TKI domain mutations that cause imatinib resistance, and accumulates in the central nervous system (CNS), a sanctuary site for ALL where imatinib penetration is poor. Methods: We conducted a phase 2 trial of dasatinib added to the EsPhALL chemotherapy backbone in pediatric (>1-17.99 years (yrs) of age) Ph+ ALL pts at COG sites in North America and Australia and EsPhALL sites in Italy and the United Kingdom. Protocol therapy added continuous daily dasatinib (60 mg/m2) at day 15 of induction chemotherapy. The study measured minimal residual disease (MRD) by Ig/TCR PCR, flow cytometry, and BCR - ABL1 RT-PCR, with clinical actions based upon a single method, in this hierarchical order. Pts with MRD ≥ 0.05% at the end of block Ib (day 78) and those with MRD 0.005-0.05% at end of Ib who remained MRD positive at any detectable level after three additional high-risk (HR) chemotherapy blocks underwent HSCT in CR1. Dasatinib treatment post HSCT was optional. The remaining pts received chemotherapy plus daily dasatinib for 2 yrs, with cranial irradiation limited to CNS3 pts. The primary study endpoint was 3-year EFS assessed when all patients completed 3 years of follow-up. Results: From April 2012 to May 2014, 109 pts enrolled; 3 did not meet inclusion criteria and received no trial therapy. The median age was 9.0 yrs (range 1-17), 54% were males, and 80% were Caucasian. 71% had CNS1 status at baseline, 24% CNS2, and 5% CNS3. Safety analysis included all treated pts (N=106) and efficacy analysis included all treated Ph+ ALL pts (N=104; 2 pts were retrospectively diagnosed with blast crisis CML). The database lock date was 8/17/16; at this time all pts had completed therapy and 75% had ≥3 yrs of follow-up. Two pts discontinued dasatinib for toxicity (1 allergy and 1 prolonged myelosuppression post HSCT). Nineteen pts met study criteria for HSCT, and 15 received HSCT in CR1 (14.2% of pts). The remaining 91 pts (85.8%) received EsPhALL chemotherapy plus dasatinib without HSCT. Patients tolerated dasatinib combined with chemotherapy well. The primary toxicity was febrile neutropenia and infection: Grade 3+ febrile neutropenia occurred in 75.5% of pts, Grade 3+ sepsis in 18.9%; and Grade 3+ bacteremia in 13.2%. Elevated ALT (21.7%) and AST (10.4%) were the only non-hematologic, non-infectious Grade 3+ adverse events attributed to dasatinib reported in >10% of pts. Relevant Grade 3+ non-hematologic, non-infectious toxicities attributed to dasatinib included pleural effusion (3.8%), edema (3.8%), hemorrhage (2.8%), and cardiac failure (0.8%). No cases of pulmonary hypertension or pulmonary arterial hypertension were reported. All 104 treated Ph+ ALL pts achieved CR. As of the database lock date, 33 events had occurred including 5 deaths (3 in HR3 and 2 in reinduction) due to proven or suspected infection in the 91 patients receiving chemotherapy plus dasatinib, 2 deaths from infection post-HSCT in the 15 HSCT pts, and 26 relapses (chemotherapy 22/86; HSCT 4/12). Sites of relapse included isolated bone marrow (BM; 14), CNS (4), BM+CNS (3), BM+other (2), and other (3). At the time of the interim analysis the 3-yr EFS is 66.0% (95% CI, 54.8-75.0) and the 3-yr OS is 92.3% (95% CI, 85.2-96.1); updated results with all patients having at least 3 years of follow-up will be presented. Conclusions: Addition of dasatinib to the EsPhALL chemotherapy regimen is safe and effective in pediatric Ph+ ALL pts. With only 14% of pts undergoing SCT in CR1, as compared to 80% in the EsPhALL imatinib trial, this trial demonstrates similar outcomes with 3-yr EFS/OS 66.0%/92.3% in this trial vs. published 4-yr EFS/OS 61.9%/72.1% in the EsPhALL imatinib trial. Disclosures Hunger: Novartis: Consultancy; Jazz Pharmaceuticals: Honoraria; Erytech Pharmaceuticals: Consultancy; Amgen: Consultancy, Equity Ownership. Saha: Shire: Research Funding. Gastier Foster: Bristol-Myers Squibb: Research Funding. Cazzaniga: Italian Association for Cancer Research: Research Funding; Fondazione Tettamanti onlus: Employment. Borowitz: Beckman Coulter: Honoraria; Becton-Dickinson Biosciences: Research Funding; HTG Molecular: Honoraria. Gramatges: Bristol Meyer Squibb: Research Funding. Sun: Baxalta: Consultancy. Swanink: Bristol-Myers Squibb: Employment. Schrappe: Baxalta: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; JAZZ Pharma: Consultancy, Research Funding; SigmaTau: Consultancy, Research Funding; Medac: Consultancy, Research Funding. Healey: Bristol-Myers Squibb: Employment, Equity Ownership; Pfizer: Equity Ownership.

To evaluate the toxicity profile and pharmacological properties of oral CP-547,632 alone and in combination with paclitaxel and carboplatin administered every 3 weeks, and to assess efficacy as measured by the objective response and progressive disease rates of oral CP-547,632 administered in combination with paclitaxel and carboplatin. Patients with stage IIIB/IV or recurrent non-small cell lung cancer receiving first-line chemotherapy were treated with oral daily CP-547,632 in combination with paclitaxel 225 mg/m2 and carboplatin AUC = 6 every 3 weeks. Pharmacokinetics parameters for CP-547,632 and paclitaxel were determined independently and during co-administration. Seventy patients were enrolled and 68 patients were treated, 37 in phase 1 and 31 in phase 2 (14 with the combination and 17 with chemotherapy alone). Dose-limiting toxicity of CP-547,632 250 mg by mouth daily in combination with paclitaxel and carboplatin was grade 3 rash and grade 3 diarrhea despite medical intervention. CP-547,632 did not significantly affect the pharmacologic profiles of paclitaxel and carboplatin. No subject had CR. In phase I, seven subjects (22.6%) had a confirmed partial response. In phase II, four subjects (28.6%) receiving CP-547,632 plus chemotherapy had a confirmed partial response. In the phase II chemotherapy alone group, four subjects (25%) had a confirmed partial response. The combination of CP-547,632 and paclitaxel and carboplatin was well-tolerated at doses up to 200 mg by mouth daily. Dose-limiting toxicity of CP-547,632 at 250 mg consisted of diarrhea and rash. CP-547,632 did not increase the objective response rate to chemotherapy alone in patients with advanced non-small cell lung cancer.

We present long-term follow-up of a dasatinib phase 3 study of patients with imatinib-resistant/-intolerant chronic myeloid leukemia (CML). In the CA180-034 study, 670 patients with imatinib-resistant/-intolerant CML in chronic phase (CML-CP) received dasatinib 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. At 6 years, 188 (28%) of 670 patients remained on study treatment. Estimated 6-year protocol-defined progression-free survival (PFS) rates were 49%, 51%, 40%, and 47%, respectively, and estimated 6-year overall survival (OS) rates were 71%, 74%, 77%, and 70%, respectively (intent-to-treat population, including protocol-defined progression or death after discontinuation). Estimated 6-year rates of survival without transformation on study treatment were 76%, 80%, 83%, and 74%, respectively. Major molecular response was achieved in 43% (100 mg once daily) and 40% (all other arms) of patients by 6 years. Molecular and cytogenetic responses at 3 and 6 months were highly predictive of PFS and OS. Notably, estimated 6-year PFS rates based on ≤1%, >1% to 10%, and >10% BCR-ABL transcripts at 3 months were 68%, 58%, and 26%, respectively. Most adverse events occurred by 2 years. Imatinib-resistant/-intolerant patients with CML-CP can experience long-term benefit with dasatinib therapy, particularly if achieving BCR-ABL ≤10% at 3 months. This study was registered at ClinicalTrials.gov: NCT00123474.

PURPOSE: We conducted a phase I clinical trial of BR96-Doxorubicin (BR96-Dox), a chimeric anti–Lewis Y (LeY) monoclonal antibody conjugated to doxorubicin, in patients whose tumors expressed the LeY antigen. The study aimed to determine the toxicity, maximum-tolerated dose, pharmacokinetics, and immunogenicity of BR96-Dox. PATIENTS AND METHODS: This was a phase I dose escalation study. BR96-Dox was initially administered alone as a 2-hour infusion every 3 weeks. The occurrence of gastrointestinal (GI) toxicity necessitated the administration of BR96-Dox as a continuous infusion over 24 hours and use of antiemetics and antigastritis premedication. Patients experiencing severe GI toxicity underwent GI endoscopy. All patients underwent restaging after two cycles. RESULTS: A total of 66 patients predominantly with metastatic colon and breast cancer were enrolled onto the study. The most common side effects were GI toxicity, fever, and elevation of pancreatic lipase. At higher doses, BR96-Dox was associated with nausea, vomiting, and endoscopically documented exudative gastritis of the upper GI tract, which was dose-limiting at a maximum dose of 875 mg/m2 (doxorubicin equivalent, 25 mg/m2) administered every 3 weeks. Toxicity was reversible and generally of short duration. Premedication with the antiemetic Kytril (granisetron hydrochloride; SmithKline Beecham, Philadelphia, PA), the antacid omeprazole, and dexamethasone was most effective in ameliorating GI toxicity. A dose of 700 mg/m2 BR96-Dox (doxorubicin equivalent, 19 mg/m2) every 3 weeks was determined to be the optimal phase II dose when administered with antiemetic and antigastritis prophylaxis. BR96-Dox deposition on tumor tissue was documented immunohistochemically and by confocal microscopy. At the 550-mg/m2 dose, the half-life (mean ± SD) of BR96 and doxorubicin was 300 ± 95 hours and 43 ± 4 hours, respectively. BR96-Dox elicited a weak immune response in 37% of patients. Objective clinical responses were seen in two patients. CONCLUSION: BR96-Dox provides a unique strategy to deliver doxorubicin to LeY-expressing tumor and was well tolerated at doses of 700 mg/m2 every 3 weeks. BR96-Dox was not associated with the typical side-effect profile of native doxorubicin and can potentially deliver high doses of doxorubicin to antigen-expressing tumors. A phase II study in doxorubicin-sensitive tumors is warranted.

9025Background: Nivo, afully human IgG4 programmed death-1 immune checkpoint inhibitor, is approved in the US for pts with previously treated metastatic NSCLC and in the EU for pretreated locally a...

9038Background: CNS mets occur in 20%–40% of pts with adv NSCLC and are associated with poor overall survival (OS; median ≈7 mo). We evaluated nivo in this subgroup by: 1) pooling nivo-treated pts ...

MRD assessment is used for risk stratification, prognosis, and treatment decisions (eg, hematopoietic stem cell transplant (HSCT) recommendation) in adult and childhood ALL. In Ph+ ALL, three distinct assay methods may be used to detect MRD: polymerase chain reaction (PCR) for clonal immunoglobulin (IG) and T-cell receptor (TR) gene rearrangements, quantitative RT-PCR (RQ-PCR) measurement of BCR-ABL1 transcripts, and flow cytometry (Flow). If results vary by assay method, different treatment decisions might be made. To assess this possibility, we examined the concordance of MRD levels and corresponding HSCT recommendations across the three methods for measuring MRD in patients (pts) enrolled to CA180372, a phase 2 study of dasatinib added to standard of care chemotherapy in pediatric pts with newly diagnosed Ph+ ALL. CA180372 (Children's Oncology Group (COG) AALL1122) was a collaboration between the COG, EsPhALL (European Intergroup Study on Post Induction Treatment of Ph+ ALL), and Bristol-Myers Squibb. Prior to study initiation, validation and proficiency testing were completed for standardization of methods used to detect MRD and for interpretation of IG/TR and BCR-ABL1 in accordance with guidelines developed by the EuroMRD consortium. All Flow analyses were performed at Johns Hopkins University. All pts received continuous treatment with dasatinib (60 mg/m2/d starting at day 15 of induction therapy) added to successive blocks of the EsPhALL multiagent chemotherapy regimen for a maximum of 2 y. MRD was analyzed 4 times during therapy (induction IA/baseline, end induction IA, start high risk block 1 (HR1), and end HR block 3 (HR3)). Pts were recommended for HSCT if: · Start of HR1 ≥0.05% by IG/TR PCR (or by Flow), less than 3-log reduction in MRD as measured by RQ-PCR for BCR-ABL1 OR · Start of HR1 0.005-0.05% by IG/TR PCR (or by Flow) or any positivity by BCR-ABL1 AND MRD remains positive at any detectable level (providing the assay limit is at least 0.1%) at the end of HR3 Clinical decisions were based on a single MRDmethodology, with the hierarchy of IG/TR > BCR-ABL1 > Flow. In this report we evaluated the concordance in HSCT recommendation among all three MRD methods. A total of 106 pts >1 y and These data were used to conduct inter-assay HSCT recommendation comparisons (Table). Rates of concordance in HSCT recommendations varied from 79.5-89.7% across methods. Among the discordant HSCT recommendations observed between each pair-wise comparison, 6/9 (IG/TR vs Flow), 2/4 (IG/TR vs BCR-ABL1), and 4/8 (BCR-ABL1 vs Flow) numerical MRD results were within 1-log, but fell on opposite sides of the assay cutoff point; assay-specific protocol criteria resulted in discordant HSCT recommendation in those cases. All pts enrolled to CA180372 were followed by at least one MRD method. HSCT recommendations could be made for most (98%) pts by Flow, while HSCT recommendation by IG/TR could be made for 84% of pts. Only 39% of pts could be recommended for HSCT based on BCR-ABL1 results. The main reason that BCR-ABL1 results were available for fewer pts was the requirement for at least 10,000 copies at baseline in order to assess if a 3-log reduction was achieved. Re-evaluation of assay-specific requirements is warranted. The overall concordance in HSCT recommendation was approx 80-90% across all three MRD methods. Overall, HSCT recommendation would have differed in 14 pts. Discordance between assays may be attributable (in part) to protocol-specific criteria, assay-specific threshold cut points, and/or differences in MRD results over different marrow pulls. Outcome data are not mature enough at this time to know whether pts recommended against HSCT by one method have increased risk for relapse when found to be eligible for HSCT by another method. Figure 1. HSCT Recommendation Concordance, by MRD Method Figure 1. HSCT Recommendation Concordance, by MRD Method Disclosures Borowitz: Becton Dickinson Biosciences, Medimmune: Research Funding. Geese:BMS: Employment. Healey:Bristol-Myers Squibb: Employment. Gastier-Foster:Bristol-Myers Squibb: Research Funding. Hunger:Bristol-Myers Squibb: Employment; Jazz Pharmaceuticals; Sigma Tau Pharmaceuticals; Erytech: Honoraria.

Background: Dasatinib is a potent BCR-ABL tyrosine kinase inhibitor (TKI) currently approved at 100 mg once daily (QD) as a first-line therapy in CML-CP pts and a second-line therapy in pts with CML resistant/intolerant to prior therapy. CA180-034 (NCT00123474), a prospective, randomized phase 3 study, was designed to compare the dose and schedule of dasatinib therapy for the optimal benefit/risk ratio among pts with imatinib-resistant or -intolerant CML-CP. Results from this study have previously demonstrated significant efficacy of dasatinib in this pt population. Here, we report the final 7-yr analysis of efficacy and safety outcomes of CA180-034, which represents the longest follow-up of any second-generation BCR-ABL TKI to date. Methods: The CA180-034 2 X 2 factorial study design has previously been described (Shah 2010, J Clin Oncol). Pts (n=670) were randomized to dasatinib: 100 mg QD (n=167), 50 mg twice daily (BID; n=168), 140 mg QD (n=167), or 70 mg BID (n=168). To manage inadequate response or adverse events (AEs), dose escalation (up to a total daily dose [TDD] of 180 mg) and dose interruption or reduction (down to a TDD of 20 mg) were allowed. After 2 yrs, the protocol was amended to allow switching to a QD regimen with the same TDD after at least one dose reduction for recurrent anemia, thrombocytopenia, neutropenia, pleural effusion, or any other fluid retention during study progress or at the investigator’s discretion (Shah 2014, Blood). Results: Approximately 55% (50 mg BID) and 51% (70 mg BID) of pts treated after the protocol amendment switched to QD dosing by the last recorded dose. The overall median duration of therapy was longer for the 100 mg QD group (37.4 months [mos]) compared with the 50 mg BID, 140 mg QD, and 70 mg BID groups (28.1 mos, 26.6 mos, and 28.9 mos, respectively).At 7 yrs of follow-up, progression-free survival (PFS) andoverall survival (OS) rates were similar for all doses, as were the proportions of pts with a best on-study molecular response of MMR (Table 1). In an exploratory landmark analysis, pts in the 100 mg QD arm with BCR-ABL ≤10% (on the International Scale) at 3 mos had improved PFS and OS rates at 7 yrs relative to pts with BCR-ABL>10% (Table 2). BCR-ABL mutations were assessed in pts prior to the start of dasatinib (baseline), at the time of disease progression, or at end of treatment. Three mutations persisted or developed in pts who discontinued dasatinib due to loss of response on 100 mg QD: V299L (n=3), T315I (n=6), and F317L (n=7). For 100 mg QD, most nonhematologic and hematologic AEs (all grades) typically first occurred within the first 24 mos of treatment. Rates of nonhematologic AEs (all grades) over 7 yrs for 100 mg QD compared with other treatment arms included fluid retention (51% vs 54%), diarrhea (42% vs 47%), nausea/vomiting (27% vs 43%), myalgias/arthralgias (38% vs 33%), fatigue (37% vs 34%), and rash (33% vs 36%). Within yr 7 of the study, new cases of pleural effusion occurred in 5% (2/42) of pts at risk treated with dasatinib 100 mg QD compared with 8% (7/88) in other treatment arms. Severe (grade 3–4) AEs (any relationship) occurred less frequently in the 100 mg QD group (98/165, 59%) relative to other treatment arms (341/497, 69%). Three pts died due to study drug toxicity (1 due to sepsis; 1 due to pulmonary edema, congestive heart failure, neck pain, and pleural effusion; 1 due to necrosis of the colon). Conclusions: Long-term follow-up of dasatinib continues to demonstrate durable efficacy and benefit for pts with CML-CP following imatinib therapy, particularly if achieving BCR-ABL ≤10% at 3 mos. Dasatinib is well-tolerated amongst pts, with most AEs occurring early on during the course of treatment; however, pleural effusion did occur through 7 yrs of treatment. No new safety signals were detected. Table 1 Efficacy results Patients 100 mg QD (n=167) 50 mg BID (n=168) 140 mg QD (n=167) 70 mg BID (n=168) MMR in assessed treated patients, n (%) 73 (46) 70 (44) 68 (44) 69 (46) PFS at 7 yrs, % (95% CI) 42 (33–51) 44 (35–53) 38 (30–47) 44 (35–52) OS at 7 yrs, % (95% CI) 65 (56–72) 70 (62–77) 73 (65–80) 68 (60–75) Table 2 Landmark analysis: Efficacy rates at 7 yrs Patients 100 mg QD (n=165) BCR-ABL ≤ 10% at 3 mos BCR-ABL > 10% at 3 mos PFS, % (95% CI) 56 (43–67) 21 (10–34) OS, % (95% CI) 72 (60–81) 56 (42–68) Transformation-free,a% (95% CI) 93 (84–97) 88 (67–96) a Limited to events during the study therapy as reason for progression not collected in follow-up. Disclosures Shah: ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding. Rousselot:Bristol-Myers Squibb: Consultancy, Research Funding. Schiffer:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees; Pfizer: DSMB Other. Rea:Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Ariad: Honoraria. Cortes:Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Milone:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mohamed:BMS: Employment. Healey:Bristol-Myers Squibb: Employment. Kantarjian:ARIAD: Research Funding; Pfizer: Research Funding; Amgen: Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Ariad: Research Funding; MSD: Research Funding. Saglio:BMS: Consultancy, Fees for occasional speeches Other; Novartis: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; Pfizer: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; ARIAD: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other.

PURPOSE To determine the maximum-tolerated dose of escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ) administered biweekly with a fixed dose of cisplatin, to assess the toxicity, and to evaluate the activity of this combination in a phase I/II trial in metastatic breast cancer. PATIENTS AND METHODS Twenty-nine women with metastatic breast cancer were enrolled; 27 were assessable for response and 29 for toxicity. All but two of the women had received prior adjuvant chemotherapy, with 23 receiving anthracyclines and six previous cisplatin. RESULTS The initial starting dose of paclitxel 90 mg/m2 and cisplatin 60 mg/m2 became the phase II dose due to dose-limiting neutropenia. Responses were seen in 85% of assessable patients, with three patients (11%) achieving a complete response (CR) and 20 patients (14%) a partial response (PR), for an overall response rate of 85% (95% confidence interval [CI], 66% to 96%). The time to disease progression for patients who achieved a CR was 110 to 200 days, and for those with a PR, it was 96 to 377+ days, with a median time to progression of 7.1 months and a median response duration of 7.9 months. Sites of CR were skin, soft tissue, and lung, and all occurred in women with previous exposure to anthracyclines. Septic events were rare, with two grade 3 infections (7%), only one of which required hospital admission. There were no grade 4 nonhematologic toxicity and minimal grade 3 toxicity. A total of 251 chemotherapy cycles were given -- 16 with paclitaxel alone in five patients. Forty-five percent of patients required dose reductions, while 52% had delays due to neutropenia. CONCLUSION Biweekly paclitaxel and cisplatin is an active combination in the treatment of metastatic breast cancer, including for patients with previous exposure to anthracyclines.

6506 Background: Dasatinib, a potent BCR-ABL inhibitor, is approved for use as 1st- and 2nd-line therapy for CML pts with newly diagnosed disease or resistance/intolerance to imatinib. This ongoing study in pts with imatinib-resistant/-intolerant CML provides the longest follow-up of a second-generation BCR-ABL inhibitor. Methods: Study design has been described (Shah, J Clin Oncol 2008). Pts with imatinib-resistant/-intolerant CML (N=670) were randomized to dasatinib 100 mg once daily (QD), 50 mg twice daily (BID), 140 mg QD, or 70 mg BID. Results: Five-yr data are reported here; 6-yr data will be presented. After a minimum of 5 yrs, 151 pts (74%) remain on QD dosing, 85 of whom (56%) are on ≥100 mg QD dosing. Overall, 205 pts (31%) remain on study therapy with 55 pts (53%) originally randomized to BID dosing having switched to QD dosing. For pts randomized to the 100 mg QD arm (n=167), progression-free survival (PFS) at 5 yrs is 57%, overall survival (OS) is 78% with an overall 5% rate of transformation to advanced disease. In exploratory analyses, 42% and 60% of pts had BCR-ABL levels ≤10% (International Scale) at 1 and 3 months (mos), respectively. In a landmark analysis, BCR-ABL ≤10% at 1 or 3 mos was associated with higher 5-yr PFS. For dasatinib 100 mg QD, nonhematologic adverse events (AEs; all grades) generally first occurred in

3040 Background: Tremelimumab is an investigational anti-CTLA4 monoclonal antibody that prolongs T-cell activation and expansion. It has been shown to induce durable tumor responses in patients with melanoma and is undergoing evaluation as a cancer therapy. Methods: An analysis of safety data across 6 single-agent clinical studies at the intended dose (15 mg/kg Q3mo) was performed. Adverse events (AEs) were graded according to NCI-CTC criteria. Results: As of November 2007, 786 pts (91% with melanoma) had received ≥1 cycles of tremelimumab constituting 1,249 doses (range 1–7 doses/pt). 60% of pts were male, 93% were white, and 29% were >65 years of age. Seventy-nine percent of pts reported one or more treatment-related AEs; 70% of which were mild to moderate (CTC grade 1 or 2). 15.4% of pts had grade 3 and 2.8% had grade 4 treatment-related events. Treatment discontinuation due to AEs was 6%. Event frequency and severity was lower in cycle ≥2. The most common and clinically significant AE was diarrhea (36...

3035 Background: The antitumor activity of antibodies to cytotoxic T lymphocyte-associated antigen 4 (CTLA4) has been demonstrated in a variety of murine tumor models, including rejection of established tumors and secondary exposure to tumor cells. This suggests that blockade of the inhibitory effects of CTLA4 can promote effective antitumor immune responses. CP-675,206 has also been shown to induce durable tumor responses in patients (pts) with metastatic melanoma in phase 1 and phase 2 clinical studies. The purpose of this study was to assess safety and efficacy of CTLA4 blockade with the fully human mAb CP-675,206 as single-agent therapy in pts with relapsed/ refractory colorectal cancer. Methods: A single-arm, multicenter, phase II trial of CP-675,206 was conducted in pts with measurable adenocarcinoma of the colon or rectum failing standard treatments and with an ECOG performance status of 0 or 1. Patients received 15 mg/kg Q90 days via IV infusion until disease progression. The primary objective was response rate by RECIST criteria. Secondary objectives included safety, duration of response, progression-free survival, and overall survival. Results: A total of 47 pts who received a median of 4 previous therapies (range, 1 to 9) were treated, and 46 experienced disease progression or death because of disease before reaching the planned second dose at 3 months. Grade 3 or 4 adverse events attributed to study drug were limited to diarrhea (n = 3, 6.4%) and idiopathic thrombocytopenia purpura (n = 1, 2.1%). Four pts (8.5%) had grade 2 diarrhea. Four pts received steroids and 2 received infliximab. One patient was removed for toxicity (diarrhea in the setting of what appeared to be treatment-related ulcerative colitis that was responsive to steroids). One patient (2%; 95% CI = 0%, 11%) had a stable ovarian mass and a substantial regression in an adrenal mass. This patient is continuing on study and has received a second dose. Conclusions: In heavily pretreated pts with colorectal cancer and good performance status, CP- 675,206 was tolerable. However, in this setting, CP-675,206 at 15 mg/kg did not demonstrate substantial single-agent activity. No significant financial relationships to disclose.

3014 Background: Overexpression of vascular endothelial growth factor (VEGF) portends a poor outcome in NSCLC. Tumor angiogenesis may be mediated by VEGF signaling through the VEGF receptor-2 (VEGFR-2). CP-547, 632 is a potent, selective inhibitor of VEGFR-2 tyrosine kinase activity. The addition of CP-547,632 to chemotherapy may enhance clinical benefit. Methods: This study examined the safety and PK of escalating oral QD doses of CP-547,632 given in combination with P(225mg/m2) and C( AUC = 6) administered in 21 day cycles to chemotherapy naive patients with PS 0–1 stage IIIb or IV NSCLC with or without stable brain mets and PS 0–1. Anti-tumor activity was also assessed. Results: 29 patients received a median of 2+ cycles (range 1–13) of study therapy. In this setting, the maximum tolerable dose for CP-547,632 was 200 mg/d. Preliminary safety data reveal the most common treatment emergent adverse events to be diarrhea, fatigue, nausea, neuropathy, emesis, alopecia, dyspnea and arthralgia/myalgia. CP-547...

PURPOSE: BMS-182248-1 (BR96-doxorubicin immunoconjugate) is a chimeric human/mouse monoclonal antibody linked to approximately eight doxorubicin molecules. The antibody is directed against the Lewis-Y antigen, which is expressed on 75% of all breast cancers but is limited in expression on normal tissues. Preclinical xenograft models demonstrated significant antitumor activity, including cures. A randomized phase II design was chosen to estimate the activity of the BR96-doxorubicin conjugate in metastatic breast cancer in a study population with confirmed sensitivity to single-agent doxorubicin. PATIENTS AND METHODS: Patients with measurable metastatic breast cancer and immunohistochemical evidence of Lewis-Y expression on their tumor received either BR96-doxorubicin conjugate 700 mg/m2 IV over 24 hours or doxorubicin 60 mg/m2 every 3 weeks. Patients were stratified on the basis of prior doxorubicin exposure, visceral disease, and institution. Cross-over to the opposite treatment arm was allowed with progressive or persistently stable disease. RESULTS: Twenty-three patients who had received a median of one prior chemotherapy regimen were assessable. There was one partial response (7%) in 14 patients receiving the BR96-doxorubicin conjugate and one complete response and three partial responses (44%) in nine assessable patients receiving doxorubicin. No patient experienced a clinically significant hypersensitivity reaction. The toxicities were significantly different between the two treatment groups, with the BR96-doxorubicin conjugate group having limited hematologic toxicity, whereas gastrointestinal toxicities, including marked serum amylase and lipase elevations, nausea, and vomiting with gastritis, were prominent. CONCLUSION: The BR96-doxorubicin immunoconjugate has limited clinical antitumor activity in metastatic breast cancer. The gastrointestinal toxicities likely represent binding of the agent to normal tissues expressing the target antigen and may have compromised the delivery of the immunoconjugate to the tumor sites.