Days Of Last Dose Research Articles

1459PD - Efficacy of durvalumab in patients with stage III NSCLC who experience pneumonitis (PACIFIC)

1459PD - Efficacy of durvalumab in patients with stage III NSCLC who experience pneumonitis (PACIFIC)

Safety and efficacy of nivolumab plus ipilimumab (NIVO+IPI) in patients with advanced renal cell carcinoma (aRCC) with brain metastases: Interim analysis of CheckMate 920.

4517 Background: Previous clinical trials of patients (pts) with aRCC, including CheckMate 214, have mostly excluded pts with brain metastases. However, antitumor activity in pts with brain metastases has been observed in pts with melanoma treated with NIVO 1 mg/kg + IPI 3mg/kg and pts with non-small cell lung cancer treated with NIVO 240 mg + IPI 1mg/kg. CheckMate 920 is an ongoing, phase 3b/4 clinical trial of NIVO + IPI treatment in pts with aRCC with a high unmet medical need. Here, we present the safety and efficacy interim results for the cohort of pts with brain metastases. Methods: Pts with previously untreated aRCC of any histology, with asymptomatic brain metastases (not on corticosteroids or receiving radiation), and Karnofsky performance status ≥70% were assigned to treatment with NIVO 3 mg/kg + IPI 1 mg/kg every 3 weeks for 4 doses, followed by NIVO 480 mg every 4 weeks. Pts were treated until disease progression, unacceptable toxicity, or for a maximum of 2 years. The primary endpoint was the incidence of high-grade immune-mediated adverse events (IMAEs). Key secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by RECIST v1.1 per investigator. Exploratory endpoints included additional safety analyses and overall survival (OS). Results: Overall, 28 patients were enrolled in the brain metastases cohort. With a minimum follow-up of 6.47 months, grade 3-4 IMAEs within 100 days of last dose were reported in 6 cases. The grade 3-4 IMAEs observed in ≥ 1 patient were diarrhea, colitis, diabetic ketoacidosis, immune-mediated hepatitis, hypophysitis, and rash of any type (n = 1 each). No treatment-related grade 5 IMAEs were reported. ORR by RECIST v1.1 per investigator in all treated subjects was 28.6% (95% CI 13.2–48.7). Median PFS in all treated subjects was 9.0 months (95% CI 2.9–not estimable [NE]). Median OS has not been reached (95% CI 13.1–NE). Conclusions: In pts with aRCC and brain metastases who are often excluded from clinical trials, NIVO + IPI treatment showed a safety profile consistent with previous reports of this dosing regimen, with encouraging antitumor activity. Clinical trial information: NCT02982954.

End-of-life care and immune checkpoint inhibitors.

11531 Background: In the era of cytotoxic chemotherapy, aggressive cancer treatment and hospitalization at the end of life (EOL) has been associated with a worse quality of death. Meanwhile, in the era of immunotherapy (IO), little is known of the impact of these novel agents on EOL care. The aim of this study was to evaluate the EOL care of metastatic cancer patients treated with immune checkpoint inhibitors. Methods: We conducted a retrospective analysis of patients prescribedPD1/L1 or CTLA-4 antibodies in Cork University Hospital (CUH) and Mercy University Hospital (MUH) between January 2013 to December 2018. Patients treated on a clinical trial were excluded. Results: We identified 224 patients treated with immune checkpoint inhibitors (outside of a clinical trial) in CUH and MUH over the described 6 year period. 108 of these patients were deceased, 102 electronic files were available for analysis. Of the 102 patients, 57 had metastatic melanoma, 33 non small cell lung cancer, 8 renal cell carcinoma, 4 had other advanced malignancies. 43% were female and 57% were male. 6% of patients had an ECOG performance status (PS) of 0 at diagnosis, 80% PS of 1 and 10% PS of 2. Median age at death was 62 years. 47 patients were treated with pembrolizumab, 26 nivolumab, 25 ipilimumab, 2 nivolumab/ipilimumab and 2 received atezolizumab. 29 patients received IO as first line treatment, 50 as second line, 17 as third line and 6 as fourth line. Median number of IO cycles received was 4 (range 1 - 41). Progression of disease (62%) and declining performance status (14%) were the most common reasons for discontinuation of IO treatment. 16 of the 102 patients received a further line of systemic therapy. Median time from last dose of IO to death was 57 days. 20 patients (20%) died within 30 days of last dose of IO. Of these 20 patients, the median number of cycles of IO received was 2 (range 1-7), 8 of these 20 patients received one cycle of IO only. 39 patients (38%) attended the ED in the last month of life. 47 (46%) patients had at least one hospital admission in the last month of life, the median hospital length of stay was 6 days (range 1-30) and 22 patients died in hospital. 94% of patients were referred to palliative care, the median time from palliative care referral to death was 64 days (range 1- 1010), 62% of patients died in hospice. Conclusions: Patients with advanced cancer treated with immunotherapy have high rates of hospital admissions and ED attendances despite early palliative care involvement. 20% of patients died within 30 days of IO. More research is needed to help physicians identify patients who are least likely to benefit from IO so as not to treat futile cases.

Biochemical Studies of (5-P-chlorophenyl -2-benzo 5, 6-coumarin-3-yelthylidene aminothiazole) as Antitumor Agent

Heterocyclic compounds have a large spectrum of biological activities including antitumor activity. The present study describes the cytotoxic effect of newly synthesized thiazole derivative (TD2) that can prove effective antitumor activity on both in vivo and in vitro studies.
 Objective: the essential objective of this research is to prove the cytotoxic effect of newly synthesized thiazole derivative (TD2) up on EAC bearing mice and many kinds of human cell lines.
 Materials and Methods: Antitumor activity of TD2 was examined on EAC in Swiss albino Mice at dose of 2.5 mg/kg. TD2 was injected for 10 following days after transplantation of tumor. After one day of last dose and 18 hours of fasting, 7 Mice were sacrificed and the remaining was kept to evaluate ILS %.
 Antitumor activity of TD2 was assessed by inspecting tumor volume, tumor weight, viable cell count and nonviable cell count, hematological, biochemical and antioxidant parameters of mice.
 Results: TD2 demonstrated an inhibitory effect on both cancer cell lines in vitro and Ehrlich ascites cells in vivo.TD2 increased in life span of Ehrlich–bearing mice compared to control. Cell cycle and flow cytometric analysis revealed that TD2 directed Ehrlich cells toward apoptosis by increasing of P53 expression.
 Conclusion: It was concluded that TD2 have a potent antitumor activity against Ehrlich ascites carcinoma in mice beside a cytotoxic effect on MCF-7, PC3, HepG2 and HCT-116.

Natural History of Patients with Multiple Myeloma Refractory to Elotuzumab and Outcomes of Subsequent Therapy with Anti-CD38 Monoclonal Antibodies

Introduction: Monoclonal antibodies (MoAbs) have shown activity in relapsed and refractory multiple myeloma (MM). Elotuzumab is an anti-SLAMF7 MoAb that synergizes with immunomodulatory agents (IMiDs) and is approved for treatment of relapsed and refractory MM. Anti-CD38 MoAbs (daratumumab, FDA approved and isatuximab, in clinical trials) have also entered the therapeutic MM landscape but little is known about how to best sequence MoAbs and the existence of cross resistance between different classes of MoAbs. We analyzed outcomes of patients who become refractory to elotuzumab with emphasis on the activity of anti-CD38 MoAbs in the post-elotuzumab setting. Methods: We identified patients from 14 academic institutions within the US who were refractory to elotuzumab administered alone or in combination with other agents. Patients were considered refractory to elotuzumab if treated with at least 4 weeks of therapy and had evidence of progressive disease (PD) within 60 days of last dose. Time zero (T0) was defined as point when myeloma became refractory to elotuzumab-containing regimen. Data were collected with an electronic platform and submitted to peer-based quality check for completeness and internal consistency. We analyzed demographics, characteristics of their myeloma and prior therapy including number and type of therapy prior to elotuzumab, duration of elotuzumab therapy, and outcome after becoming refractory to elotuzumab. We performed a multi-variable analysis of these factors to determine significant factors associated with survival post T0. We subsequently identified a subset of patients who received an anti-CD38 MoAb alone or in combination as next or subsequent line of therapy after T0 and report their outcomes. Results: Eighty-nine patients were evaluated. Eighty-six (96.6%) had progression on elotuzumab in combination with IMiD (N=82) or another agent (N=4). Median age at T0 was 65 years (range 28-90), 51% of patients were males, 65% were White, 54% had IgG subtype, 27% had ISS stage III at diagnosis, and 27% had high-risk cytogenetics. Patients received a median of 4 prior lines of treatment (range 1-11) prior to elotuzumab-containing regimen, including 66% who underwent autologous transplant. Sixty-one patients (69%) were refractory to at least one IMiD and one proteasome inhibitor (PI) at T0, classified as double-refractory. Twenty-one (23.6%) were quad-refractory, i.e. refractory to 2 IMiDs and 2 PIs. Twenty-eight patients (31.5%) were refractory to prior anti-CD38 MoAb. The median time from diagnosis to T0 was 59.5 months and duration of elotuzumab therapy was 3 months (range 0.4 - 59.5). Median OS from T0 for the entire cohort was 15.1 months (95% C.I. 9.3-20.9). In multivariate analysis, the only factors affecting OS after T0 were high-risk cytogenetics (HR 3.31, 95% C.I. 1.74-6.27, P Conclusion: Patient who become refractory to elotuzumab have guarded prognosis, particularly dismal among patients also refractory to anti-CD38 MoAb, defining a population with great need for novel therapies. Failure of elotuzumab-based therapy does not preclude disease control with anti-CD38 MoAb, particularly in combination. Disclosures Paul:Bristol Myer Squibb: Other: Stock and pension plan (past employee). Amarendra:Amgen: Consultancy; Celgene: Consultancy. Liedtke:Caelum: Membership on an entity9s Board of Directors or advisory committees; celgene: Research Funding; Takeda: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; BlueBirdBio: Research Funding; Prothena: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Gilead: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Hari:Kite Pharma: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Janssen: Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Amgen Inc.: Research Funding; Spectrum: Consultancy, Research Funding. Vij:Karyopharm: Honoraria; Jazz Pharmaceuticals: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria, Research Funding; Bristol Myer Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Kumar:Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity9s Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Costa:Karyopharm: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Research Funding; Sanofi: Honoraria; Janssen: Research Funding.

Second-Line Bosutinib in Patients with Chronic Phase Chronic Myeloid Leukemia (CP CML) Resistant or Intolerant to Prior Imatinib: An 8-Year Update

Bosutinib is an orally active, dual SRC/ABL tyrosine kinase inhibitor (TKI) approved for treating adult patients with chronic phase, accelerated phase (AP), or blast phase (BP) Philadelphia chromosome-positive (Ph+) CML with resistance or intolerance to prior therapy. In an open-label, phase 1/2 study (NCT00261846), second-line bosutinib demonstrated durable hematologic and cytogenetic responses and good tolerability in patients with Ph+ CP CML who were imatinib resistant (IM-R) or imatinib intolerant (IM-I) (Cortes, Am J Hematol, 2016). Here we report a 96-month update of this study and its ongoing extension study (NCT01903733).Adult patients with Ph+ CP CML who were resistant or intolerant to first-line imatinib were included in this analysis. 195 IM-R and 89 IM-I patients received bosutinib starting at 500 mg/d. Median age (range) was 53 yr (18-91 yr), time from CML diagnosis was 3.7 yr (0.1-15.1 yr), treatment duration was 25.6 mo (0.2-133 mo), and follow-up duration was 53.7 mo (0.5-133 mo). Bosutinib dose was increased to 600 mg/d in 13% of patients. For the last enrolled IM-R and IM-I patients, time from first dose of bosutinib to data cutoff was 96.5 mo and 94.2 mo, respectively. At 8 yr, 26% of patients were still receiving bosutinib.Major cytogenetic response (MCyR) was achieved by 60% of patients in both groups (Table). Median duration of MCyR was not reached as of the minimum follow-up, and the Kaplan-Meier probability of maintaining MCyR at 8 yr was 60% (IM-R) and 75% (IM-I). Complete cytogenetic response (CCyR) was achieved by 49% (IM-R) and 51% (IM-I) of patients. Median duration CCyR was not reached as of the minimum follow-up, and the Kaplan-Meier probability of maintaining CCyR at 8 yr was 57% (IM-R) and 69% (IM-I) of patients. On-treatment transformation to accelerated phase or blast phase occurred in 7% (IM-R) and 2% (IM-I) of patients with no new events since the 5-yr follow-up. The cumulative incidence of on-treatment progression or death at 8 yr was 28% (IM-R) and 11% (IM-I), respectively (Table). Overall survival at 8 yr on study was 75% for the IM-R group and 87% for the IM-I group.Dose delays due to adverse events (AEs) occurred in 133 (68%) and 76 (85%) of IM-R and IM-I patients, resulting in median cumulative treatment delays of 25 d and 27 d, respectively. Dose reductions due to AEs occurred in 93 (48%) and 54 (61%) of IM-R and IM-I patients, respectively. Median cumulative duration of dose reduction was 357 d and 267 d, and median time to dose reduction was 49 d and 54 d in the IM-R and IM-I cohorts, respectively. By 8 yr, treatment was discontinued in 141 (72%) and 69 (78%) of IM-R and IM-I patients, respectively. The most common reasons for discontinuation were disease progression (23%) and AEs (16%) in the IM-R cohort, and AEs (42%) and patient request (13%) in the IM-I cohort. In the IM-R cohort, the most frequent AEs leading to permanent treatment discontinuation were thrombocytopenia (4%), increased ALT (2%), and diarrhea (2%). In the IM-I cohort the most frequent AEs leading to permanent treatment discontinuation were thrombocytopenia (11%), neutropenia (5%), increased ALT (3%), and rash (3%). Among the 40 patients (21%) in the IM-R cohort who died on study, the most frequent reasons for death were disease progression (12%) and AEs unrelated to study drug (7%). For the 11 patients (12%) in the IM-I cohort who died on study, the most frequent reasons were disease progression (7%) and unknown (3%). No patients died due to an AE related to study drug and 13 patients (5%) died within 30 days of last dose. Five subjects died since the 5-yr follow-up; 3 within 30 days of last dose.These long-term (8-yr) data are consistent with previous findings associating second-line bosutinib therapy with similar rates of durable major cytogenetic responses in the majority of patients with imatinib-resistant and imatinib-intolerant CP CML. Most AEs could be managed through temporary treatment interruptions and dose reductions. [Display omitted] DisclosuresBrümmendorf:Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Gambacorti-Passerini:BMS: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Pagnano:Roche: Speakers Bureau; Amgen: Consultancy; Bristol-Meirs Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy. Aguiar:Pfizer: Employment, Equity Ownership. Leip:Pfizer: Employment, Equity Ownership. Cortes:Teva: Research Funding; Pfizer: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Sun Pharma: Research Funding; ARIAD: Consultancy, Research Funding.

Bosutinib Vs Imatinib for Newly Diagnosed Chronic Myeloid Leukemia (CML) in the BFORE Trial: 18 Month Follow-up

Bosutinib Vs Imatinib for Newly Diagnosed Chronic Myeloid Leukemia (CML) in the BFORE Trial: 18 Month Follow-up

Real-world Evaluation of Ceftolozane/Tazobactam (C/T) Use and Clinical Outcomes at an Academic Medical Center in Las Vegas

BackgroundThere is a global increase in Gram-negative (GN) pathogens, with Enterobacteriaceae and Pseudomonas aeruginosa(PSA) being the major threats in clinical practice. C/T is a novel antipseudomonal cephalosporin combined with an established β-lactamase inhibitor, approved for the treatment of complicated intra-abdominal and urinary tract infections. The objective was to describe the real-world clinical use and outcomes associated with C/T.MethodsThis retrospective descriptive study included adult patients treated with C/T > 48 hours from July 1, 2015–February 28, 2017 at University Medical Center of Southern Nevada. Treatment was considered empiric when antibiotic was given prior to culture results. Escalation was the additional of an aminoglycoside or colistin after the start of C/T.ResultsThere were 30 patients in the study. Average age was 57 (SD = 16) and most 19 (63%) were male, Caucasian 22 (73%) and were admitted from the community or home 18 (60%). The most frequent comorbidities were diabetes 13 (43%), heart disease 12 (40%) and chronic pulmonary disease 10 (33%). Previous medical history within 90 days included 15 (50%) hospitalizations, 13 (43%) infections, 6 (20%) Intensive Care Unit stays and 7 (23%) surgeries. All patients received a GN antimicrobial within 30 days prior to C/T. Ninety-three percent of infections were due to PSA and 17 (57%) were polymicrobial. All but 4 patients had multidrug-resistant PSA. The most frequent source of infection (some multiple sources) was respiratory 20 (67%), cUTI 8(27%) and sepsis 5 (17%). Empiric C/T therapy was given to 7 (23%) patients. One patient required escalation of therapy after C/T. Average duration of C/T was 10 (SD = 5.4) days. 23 (77%) patients were discharged within 30 days of last dose of therapy. Microbiological eradication was documented for 12 patients. There were 5 (17%) readmissions, but none associated with a GN infection. Six patients died (1 bilateral stroke, 1 cancer, 2 septic shock, 1 pneumonia and 1 complications of burn).ConclusionIn this study, C/T was used in patients with serious infections primarily due to PSA, with most patients discharged within 30 days and no patients readmitted due to GN infection. This study provides important insights on how C/T is used in clinical practice.Disclosures R. Kullar, Merck & Co., Inc.: Employee, Salary. B. Jayakumar, Merck: Grant Investigator, Research grant. L. Puzniak, Merck: Employee, Salary.

Abstract CT158: Unmutated IGHV is not an adverse predictor of outcome to therapy with ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)

Abstract Background: Patients (pts) with CLL/SLL who use unmutated IGHV (u-CLL) have a less favorable outcome with standard chemotherapy than pts who use mutated IGHV (m-CLL). Ibrutinib (ibr) inhibits B-cell receptor signaling through Bruton’s tyrosine kinase and has robust clinical activity against CLL. This integrated analysis of 3 phase 3 studies examined the impact of IGHV status on ibr- and comparator (comp)-treated pts. Methods: Pooled data from 3 studies of ibr (420 mg/d) in CLL/SLL pts (RESONATE: relapsed/refractory [R/R] pts, ibr vs ≤ 24 weeks ofatumumab; RESONATE-2: treatment-naïve [TN] pts ≥ 65 yrs of age [no del17p], ibr vs ≤ 12 cycles chlorambucil; HELIOS: R/R pts [no del17p], ≤ 6 cycles bendamustine-rituximab with ibr vs placebo) were analyzed by IGHV status. Analyses included Kaplan-Meier method (overall survival [OS]; progression-free survival [PFS]); log-rank test (group comparisons); and Cox multivariate analysis (prognostic factors; Table). Results: For 491 ibr- (366 u-CLL, 125 m-CLL) and 494 comp-treated (351 u-CLL, 143 m-CLL) pts with IGHV data, baseline characteristics were similar for u-CLL vs m-CLL, except for the proportions of pts who were TN (17 vs 31%), had bulky disease (60 vs 37%), or had CLL cells with del11q (32 vs 16%). Median follow up was 21.4 mos for ibr and 20.6 mos for comp. PFS and OS were similar for u-CLL and m-CLL ibr-treated pts; u-CLL had poorer outcomes than m-CLL in comp-treated pts, which remained after adjustment for prognostic factors (Table). Ibr treatment was more effective than comp regardless of IGHV status. Incidence of adverse events (AEs) was similar between groups. For ibr vs comp pts (u-CLL/m-CLL): serious AEs: 49% (50%/47%) vs 36.5% (37%/35%); AEs that led to discontinuation: 12% (11%/15%) vs 13% (13%/14%); death within 30 days of last dose: 5% (6%/3%) vs 5% (6%/2%). Conclusions: U-CLL was an adverse predictor of outcome for comp-treated, but not for ibr-treated pts. Table.Efficacy Outcomes in Ibr- and Comparator-Treated Patients by IGHV Mutation StatusIbrutinib (N=491)Comparator (N =494)u-CLL (n=717)m-CLL (n=268)u-CLL(n=366): m-CLL(n=125)u-CLL(n=351): m-CLL(n=143)Ibr(n=366): Comp(n=351)Ibr (n=125): Comp (n=143)PFS24-month rate HR78%:81%10%:32%78%:10%81%:32%0.93a1.99a0.12b0.21bp = 0.78p < 0.0001p < 0.0001p <0.0001Adjusted HRc1.02a1.94a0.11b0.17bp = 0.93p < 0.0001p < 0.0001p < 0.0001OS24-month rate HR88%:89%78%:87%88%:78%89%:87%0.95a1.96a0.49b0.85b,ep = 0.86p = 0.02p < 0.01p = 0.66Adjusted HRc1.21a2.10a0.49bNAp =0.57p = 0.01p < 0.001Response ratesu-CLLm-CLLu-CLLm-CLLIbrCompIbrCompORR, %d8990475189479051p = 0.96p = 0.36p < 0.0001p < 0.0001CR, %d221546224156p = 0.10p = 0.44p < 0.0001p = 0.01CI, confidence interval; CR, complete response; HR, hazard ratio; ORR, overall response rate; NA, not applicable. aHR < 1 favors unmutated. bHR < 1 favors ibrutinib. cMultivariate Cox model adjusted for age, sex, current Rai stage, baseline ECOG performance status score, del11q, del17p, number of prior therapies, and cytopenias. dp value is from a Cochran-Mantel-Haenszel chi-square test. eInsufficient number of events prevents meaningful analysis, only 13 and 16 events observed in ibr and comp groups, respectively, and 46 (32%) pts in comp arm crossed over to ibr arm; interpret results with caution. Citation Format: Thomas J. Kipps, Graeme Fraser, Steven Coutre, Jennifer R. Brown, Jacqueline C. Barrientos, Paul M. Barr, John C. Byrd, Susan M. O'Brien, Marie-Sarah Dilhuydy, Stephen Devereux, Ulrich Jaeger, Carol Moreno, Paula Cramer, Stephan Stilgenbauer, Asher A. Chanan-Khan, Michelle Mahler, Mariya Salman, Mei Cheng, Anil Londhe, Joi Ninomoto, Angela Howes, Danelle James, Michael Hallek. Unmutated IGHV is not an adverse predictor of outcome to therapy with ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT158. doi:10.1158/1538-7445.AM2017-CT158

Second-line tivantinib (ARQ 197) vs placebo in patients (Pts) with MET-high hepatocellular carcinoma (HCC): Results of the METIV-HCC phase III trial.

4000 Background: Tivantinib (T), a selective, oral MET inhibitor, improved overall survival (OS) and progression-free survival (PFS) versus placebo (P) in a phase II study in MET-High HCC pts. Methods: This randomized, placebo-controlled phase III trial (NCT01755767) enrolled pts with: advanced HCC; Child Pugh A; ECOG PS ≤1; adequate bone marrow, liver, kidney functions; no liver transplant; radiographic disease progression (PD) after or intolerance to sorafenib; tumor MET-High (MET ≥2+ in ≥50% of tumor cells) by centralized immunohistochemistry. Pts were randomly assigned 2:1 to oral T or P, stratified by vascular invasion (VI), extrahepatic spread (ES), AFP ( < / > 200ng/mL), treated until PD or unacceptable toxicity. Response (RECIST 1.1) was evaluated by CT / MRI every 8 weeks. Primary endpoint of OS and secondary endpoints including PFS and safety were assessed in the intent-to-treat (ITT) population. Results: From Dec 2012 to Dec 2015, 1209 pts were consented in Australia, the Americas, Europe, New Zealand: 589 MET-High, 43 initially randomized at the dose of 240mg BID, then reduced due to high neutropenia rate, 340 randomized at 120mg BID: 226 to T, 114 to P (ITT population). Characteristics of pts were balanced between arms: 306 (90%) male; median age: 67; PS 0: 207 (61%); VI: 117 (34%); ES: 197 (58%); AFP ≤200: 195 (57%); radiographic PD on sorafenib: 275 (81%). Median OS (95% CI) was 8.4 months (m) (6.8-10.0) in T, 9.1 m (7.3-10.4) in P, HR = 0.97 (0.75-1.25), P = 0.81. Median PFS (95% CI) was 2.1 m (1.9-3.0) in T, 2.0 m (1.9-3.6) in P, HR = 0.96 (0.75-1.22), P = 0.72. No OS difference was seen in pts with VI (HR 1.19, 0.79-1.79), ES (HR 1.09, 0.78-1.52), AFP > 200ng/mL (HR 1.00, 0.71-1.41). Grade (G) > 3 AEs were 55.6% in T, 55.3% in P. In T, most common G > 3 AEs were ascites (7.1%), general deterioration (5.8%), anemia (4.9%); most common serious AE was general deterioration (4.9%). Deaths within 30 days of last dose were 22.1% on T vs 15.8% on P (most common causes: general deterioration 3.5%, hepatic failure 2.6%). Conclusion: Tivantinib at the 120mg BID dose did not improve OS or PFS over placebo in patients with advanced MET-High HCC who failed previous treatment with sorafenib. Clinical trial information: NCT01755767.

11q Deletion (del11q) Is Not a Prognostic Factor for Adverse Outcomes for Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Treated with Ibrutinib: Pooled Data from 3 Randomized Phase 3 Studies

11q Deletion (del11q) Is Not a Prognostic Factor for Adverse Outcomes for Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Treated with Ibrutinib: Pooled Data from 3 Randomized Phase 3 Studies

The effects of a CXCR1/CXCR2 antagonist on neutrophil migration in mild atopic asthmatic subjects

BackgroundNeutrophils are effector cells recruited to airways in patients with asthma. Migration of neutrophils occurs predominantly through activation of the CXCR1 and CXCR2 receptors by CXC chemokines, including IL-8 and Gro-α. The dual CXCR1/CXCR2 antagonist SCH 527123 has been developed to target neutrophil migration to alleviate airway neutrophilia. This study investigated the effects of SCH 527123 on neutrophil levels within the bone marrow, peripheral blood and airways, and on isolated bone marrow and peripheral blood neutrophil migration from mild allergic asthmatics. MethodsThirteen subjects with mild allergic asthma completed a double blind, placebo-controlled, multi-center crossover study and were randomized to daily dosing of 30 mg SCH 527123 and placebo for 8 days. Subjects provided bone marrow, peripheral blood and sputum samples pre-dosing and on the last day of dosing. Neutrophil numbers were quantified in all samples and chemotaxis assays were performed on neutrophils purified from bone marrow and peripheral blood. ResultsNeutrophil numbers fell significantly in the peripheral blood and sputum following treatment with SCH 527123 compared to placebo treatment. No change in neutrophil numbers was observed in bone marrow. SCH 527123 reduced IL-8-induced migration of purified peripheral blood neutrophils (p < 0.05), but had limited effects on migration of neutrophils purified from bone marrow. ConclusionsThe results from this study demonstrate that oral administration of the dual CXCR1/CXCR2 antagonist SCH 527123 reduces neutrophil levels in the circulation and airways through inhibition of migration. There were no toxic effects of SCH 527123 on granulocytic progenitor cells in the bone marrow.

A Dose Finding Phase II Trial of Isatuximab (SAR650984, Anti-CD38 mAb) As a Single Agent in Relapsed/Refractory Multiple Myeloma

A Dose Finding Phase II Trial of Isatuximab (SAR650984, Anti-CD38 mAb) As a Single Agent in Relapsed/Refractory Multiple Myeloma

A Model for Predicting Effect of Treatment on Progression-Free Survival Using Minimal Residual Disease As a Surrogate Endpoint in Chronic Lymphocytic Leukemia

A Model for Predicting Effect of Treatment on Progression-Free Survival Using Minimal Residual Disease As a Surrogate Endpoint in Chronic Lymphocytic Leukemia

Second Myeloid and Lymphoid Malignancies in patients with Chronic Lymphocytic Leukemia

in relapsed/refractory (R/R) CLL. Ofatumumab, an anti-CD20 antibody, has activity in combination with chemotherapy in CLL. Objective: Evaluate safety and activity of ibrutinib combined with ofatumumab (phase Ib/II) in 3 different sequences. Patients: Patients with R/R CLL/SLL, PLL, or Richter’s transformation (RT) after 2 prior therapies, including a purine analogue. Intervention: 420 mg oral ibrutinib daily and IV ofatumumab 300/2000 mg (12 doses). Group (G) 1: 1 cycle of ibrutinib, then ofatumumab added; G2: ofatumumab on day (D) 1/cycle (C) 1 and ibrutinib on D2/C1; G3: 2 cycles of ofatumumab, then ibrutinib added on D1/ C3. Results: 71 patients (27, 20, 24 in G1, G2, G3) enrolled; median age 64 years; Rai stage III/IV 61%; 65 had CLL, 1 SLL, 2 PLL, and 3 RT; bulky disease ( 5 cm) in 75%; del(17p) in 44%; del(11q) in 31%. Most frequent AEs included diarrhea (68%), infusion-related reaction (IRR, 45%), peripheral sensory neuropathy (42%), and stomatitis (37%). AEs grade 3 occurred in 61%; most common grade 3-4 AE was neutropenia (17%). Serious AEs occurred in 39%, including grade 3 IRR in 1 patient (G2). AEs led to ibrutinib discontinuation in 6 patients. Nine patients died within 30 days of last dose and 2 within follow-up. ORR in CLL/SLL was 100% in G1, 79% in G2, and 71% in G3. One patient had complete response; 2 additional patients achieved partial response with lymphocytosis. Four patients in G3 progressed before starting ibrutinib. At study end, 52/58 responders (90%) remained progression-free with follow-up of 16, 12, and 11 months for G1, G2, and G3, respectively. The three RT patients had disease control followed by progression on days 471, 168, and 137. At 12 months, PFS was 89%, 85%, and 75% in G1, G2, and G3, respectively; 76% continued ibrutinib in long-term extension study; 2 patients underwent transplant. Conclusions: Ibrutinib combined with ofatumumab is well tolerated and highly active in R/R CLL/SLL with all 3 dosing sequences. Based on these compelling results, randomized trials evaluating anti-CD20 antibody in combination with ibrutinib are ongoing. 310 Second Myeloid and Lymphoid Malignancies in patients with Chronic Lymphocytic Leukemia Jose Sandoval, Gabriela Corrales, Jennifer Rock-Klotz, Javier Pinilla-Ibarz, Julio Chavez Malignant Hematology, H. Lee Moffitt Cancer Center, University of South Florida; Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute Introduction: Chronic lymphocytic Leukemia (CLL) as the most common chronic leukemia is associated with increased second malignancies. We describe the characteristics of CLL patients who develop second myeloid (SMD) or lymphoid disorders (SLD). Methods: This is a retrospective review of CLL patients with of SLD and SMD from 01/2000 to 12/2012 using the Moffitt Cancer Canter and Total Cancer Care databases. The primary objective was to identify risk factors for SLD and SMD development. CLL patients with no malignancies were the control. Overall survival (OS) was estimated and compared by the Kaplan-Meier method and the long-rank test. Results: We identified 211 CLL patients with second malignancies in a cohort of 844. Sixty-nine patients had SLD (47) and SMD (22). SLD diagnosis included: DLBCL1⁄4 40, MM1⁄44, PLL1⁄4 1, HCL1⁄41, CTCL1⁄41. SMD diagnosis included MDS1⁄4 15, AML/MDS1⁄47. The OS for patients with SLD, SMD and control were 11.4, 8.1 (p1⁄4 0.063) and 10.7 years (p1⁄4 0.261), respectively. The median OS from SLD and SMD diagnosis were 1.2 and 1.3 years, respectively. Table 1 shows Chi-square analysis. Conclusions: Advanced Rai stage and unmutated IgVH status were associated with increased risk of SLD while no factors were found for SMD. Secondary hematological malignancies in CLL patients show a short median OS. Clinical Lymphoma, Myeloma & Leukemia June 2015 S207 Table 1 Chi-Square Analysis No second malignancies SLD p-Value SMD p-Value Gender M 400 (63%) 33 (70%) 0.43 15 (68%) 0.82 F 233 (37%) 14 (30%) 7 (32%) Age >60 304 (48%) 24 (51%) 0.76 13 (59%) 0.66 <60 329 (52%) 23 (49%) 9 (41%) Clinical and laboratory

Updated Results from a Phase 2 Extension Study of Patients with Multiple Myeloma or Solid Tumors Previously Enrolled in Carfilzomib Company-Sponsored Phase 1 and 2 Clinical Trials (PX-171-010)

Introduction: PX-171-010 (010; NCT00884312) is an extension study of patients who completed a phase 1 or 2 carfilzomib study that aims to provide insights into the long-term tolerability, safety, and clinical benefit of carfilzomib.Methods: Patients who completed a carfilzomib study were eligible to enroll and continue receiving carfilzomib at the same dosing level, with dose adjustments permitted per protocol. Addition of other approved anticancer agents at the time of progression was allowed. The primary end point was safety; efficacy was also evaluated.Results: Between 2009 and 2012, patients with multiple myeloma (MM; n=91) or solid tumors (ST; n=9) were enrolled in this extension study. Patients were enrolled from the PX-171-002, PX-171-003-A0, PX-171-003-A1, PX-171-004, PX-171-005, PX-171-006, PX-171-007, and PX-171-008 studies (Table 1). Among patients with MM, 57.1% had prior bortezomib exposure and 95.6% had prior immunomodulatory agent (IMiD) exposure; 37.4% were refractory to bortezomib, 61.5% were refractory to an IMiD, and 31.9% were refractory to both bortezomib and an IMiD. In the initial studies, patients received 15–70 mg/m2 carfilzomib. In 010, patients received a median dose of 27 mg/m2 carfilzomib (range, 13–52 mg/m2). Median duration of carfilzomib treatment (initial study+010) was 88.9 weeks (range, 4.4–273.4 weeks). Median number of carfilzomib treatment cycles was 22.5 (range, 2–67); 60.0% of patients received carfilzomib for ≥19 cycles and 27.0% for ≥37 cycles. Treatment-emergent grade ≥3 adverse events (AEs) and serious AEs are presented in Table 2. Twenty-three patients (23.0%) had treatment-emergent AEs that led to discontinuation of study treatment, including 18 patients with MM (19.8%). Eight patients (8.0%) died on the 010 study or within 30 days of last dose of study drug, including 7 patients with MM (4 deaths due to AEs, 3 due to disease progression). One patient with ST died due to disease progression. The 4 AE deaths were due to myocardial infarction (MI; n=2), pneumonia (n=1), and pneumonia with MI (n=1). The 3 patients with MI had pre-existing cardiac disease and died after 9–47 cycles on study. None of the 8 deaths were assessed as carfilzomib-related. Overall, 74 patients (74.0%) had ≥1 regimen change. Among patients with MM, 72 patients (79.1%) had ≥1 regimen change; 22 (30.6%) of these patients continued receiving single-agent carfilzomib at a different dose/schedule, and 50 (69.4%) received additional combination therapy, including 48 patients (66.7%) who received dexamethasone, 26 (36.1%) who received lenalidomide, and 25 (34.7%) who received cyclophosphamide. Notably, responses were observed among patients with MM after regimen change due to disease progression: the overall response rate was 20.0% after first progression, 35.0% after second progression, and 30.8% after third progression.Conclusion: The types and rates of AEs in 010 were similar to those previously reported with single-agent carfilzomib. Patients were able to receive carfilzomib for an average of 89 weeks (up to 273 weeks; median of 22.5 treatment cycles) and continued receiving clinical benefit, with no new significant safety signals noted from additional cumulative exposure. [Display omitted] [Display omitted] DisclosuresOff Label Use: Carfilzomib as treatment in multiple myeloma and solid tumors. Kaufman:Millennium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Spectrum: Consultancy, Honoraria; Merck: Research Funding. Wang:Onyx: Honoraria, Research Funding. Martin:Sanofi: Research Funding; Novartis: Speakers Bureau. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding, Speakers Bureau. Reu:Onyx: Consultancy, Speakers Bureau. Jagannath:Millennium: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Merck: Honoraria; Ortho Biotech: Membership on an entity’s Board of Directors or advisory committees; Imedex: Membership on an entity’s Board of Directors or advisory committees; Medicom Worldwide: Membership on an entity’s Board of Directors or advisory committees; Optum Health Worldwide: Membership on an entity’s Board of Directors or advisory committees; PER group: Membership on an entity’s Board of Directors or advisory committees. Rajangam:Onyx Pharmaceuticals, an Amgen subsidiary: Employment, Equity Ownership. Huang:Onyx Pharmaceuticals: Employment. Vij:Celgene: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Sanofi: Honoraria; Jannsen: Honoraria; Novartis: Honoraria; Millennium: Honoraria; Array: Honoraria.

Brentuximab Vedotin Monotherapy in DLBCL Patients with Undetectable CD30: Preliminary Results from a Phase 2 Study

Background Patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) have a poor outcome. In pts who progress A phase 2, open-label study was initiated to assess antitumor activity of brentuximab vedotin (ADCETRIS®), an anti-CD30 antibody-drug conjugate, in relapsed/refractory CD30+ non-Hodgkin lymphoma, including DLBCL. Significant antitumor activity was observed in DLBCL over a wide range of CD30 expression, including very low levels ( Methods Eligible pts must have DLBCL with undetectable CD30 expression on tumor cells by visual assessment using routine IHC (anti-CD30 BerH2 antibody) per local lab. Pts must also have had 1–3 prior therapies and an ECOG performance status ≤2. Brentuximab vedotin 1.8 mg/kg is administered every 3 weeks until disease progression or unacceptable toxicity for pts who achieve stable disease or better. The primary endpoint is objective response rate per Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Key secondary endpoints include safety and duration of response. Results Thus far, 27 DLBCL pts with undetectable CD30 expression per local lab have been enrolled and treated. All patients had elevated soluble CD30 at baseline with a median of 166 ng/mL and range of 55–1,696 ng/mL (normal, ≤29 ng/mL). Most pts had advanced stage disease at baseline (78%); median age was 65 years (range, 42–91); and 81% had an ECOG performance status of 1–2. The median number of prior therapies was 2, and 8 pts had 3 prior therapies. Six (22%) pts had received prior autologous SCT. Of 14 pts (52%) with refractory disease at study entry, 11 were also refractory to their frontline treatment. To date, pts have received a median of 2 cycles of brentuximab vedotin (range, 1–10), and 12 (44%) pts remain on treatment. Thirteen pts discontinued treatment due to progressive disease, 1 withdrew consent, and 1 pt died due to an unrelated serious adverse event (SAE) of cardiac arrest. At the time of this analysis, 6 (27%) of 22 pts who have had restaging assessments achieved an objective response, including 1 CR and 5 PRs. The CR began at Cycle 6 and is ongoing after 9 weeks. It is too early to assess median response duration. For the 6 pts who achieved an objective response, undetectable CD30 was confirmed by central review. Peripheral sensory neuropathy and nausea were the most frequently occurring adverse events (AEs; 22% each). AEs ≥ Grade 3 occurring in more than 1 pt included hypokalemia, neutropenia (11% each), dehydration, diarrhea, nausea, and vomiting (7% each). All were Grade 3 in severity with the exception of 1 Grade 4 neutropenia. Four deaths occurred within 30 days of last dose; all were disease related except one due to cardiac arrest unrelated to study drug in a pt with prior cardiovascular disease and co-existing risk factors. Conclusions In this interim analysis of DLBCL pts with undetectable CD30, objective responses have been observed in 6 of 22 pts (27%) who have undergone restaging assessments. Safety data are consistent with historic results and pts continue to enroll on study. Activity of brentuximab vedotin in pts with undetectable CD30 by IHC may be explained wholly or in part by one of several factors, including tumor heterogeneity, levels of CD30 on tumor below the level of IHC sensitivity, uptake by cells in the tumor microenvironment that can release the cytotoxic payload, or deletion of repressive cells within the tumor microenvironment. Correlative work to better understand this activity is ongoing. Disclosures Bartlett: ImaginAb: Research Funding; Celgene: Research Funding; MedImmune: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Pfizer: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics, Inc.: Research Funding, Travel expenses Other; Janssen: Research Funding; Genentech: Research Funding; AstraZeneca: Research Funding. Off Label Use: Brentuximab vedotin is indicated in the US for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. Smith: Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Advani: Janssen Pharmaceuticals: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Takeda International Pharmaceuticals Co.: Research Funding; Seattle Genetics, Inc.: Research Funding, Travel expenses Other. Feldman: Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Savage: Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Palanca-Wessels: Seattle Genetics, Inc.: Employment, Equity Ownership. Siddiqi: Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau.

Abstract 4029: BL-011256 is a novel VEGFR3 selective inhibitor, which suppresses tumor lymphatics and lymph node metastasis in an animal model of melanoma

Abstract The role of VEGFR3 in lymphangiogenesis has been well established. Targeting VEGFR3 has been shown to curtail tumor progression mediated via lymphatic dissemination. More recently VEGFR3 was shown to play an important role in the mediation of tumor-induced immune cell tolerance. We have identified BL-011256, a novel inhibitor of VEGFR3 that exhibits 17-fold selectivity over VEGFR2 and a narrow tyrosine kinase inhibition spectrum. A 7-day b.i.d repeat oral dose study showed that BL-011256 is well tolerated in mice. Mouse plasma exposure experiments demonstrated that BL-011256 attains free drug plasma concentration levels that exceed the concentration required for IC50 activity on VEGFR3 in vitro but are considerably lower than the in vitro IC50 required for activity on VEGFR2. In the B16F10 mouse melanoma model, animals bearing melanoma tumors displayed considerably attenuated signs of tumor progression when treated with BL-011256. BL-011256 caused a 70% reduction in primary lesion growth and a 50% reduction in metastasis to the draining lymph node. Furthermore, BL-011256 was active in reducing the number of satellite in-transit metastases. Immunohistochemical whole mount analyses on ears with primary tumor lesions derived from BL-011256 treated and vehicle-treated mice using Lyve-1 for the identification of lymphatic vessels and CD31 for the identification of blood vessels was conducted. Tumors in vehicle-treated mice displayed a peri-tumoral area densely populated by lymphatic vessels. In contrast, tumors derived from BL-011256 treated mice were devoid of peri-tumoral lymphatic vessels. Notably, both vehicle-treated and BL-011256-treated animals displayed similar staining for peritumoral blood vessels, suggesting no effect on blood vessels (this is consistent with no activity on VEGFR2). Furthermore, PK sampling during the last day of dosing in a 14-day dosing schedule demonstrated that there is no compound accumulation during the repeat dosing schedule utilised in the B16F10 tumour efficacy experiment. In conclusion BL-011256 has been identified as a selective inhibitor of VEGFR3 that supresses both primary tumor growth and lymph node metastasis. Citation Format: Annabell Leske, Richard Foitzik, Donna Beaumont, John Bentley, Ylva Bergman, Chloe Brown, Michelle Camerino, Susan Charman, Neil Choi, Melanie De Silva, Matthew Chung, Hendrik Falk, Danny Ganame, Alison Gregg, Julian Grusovin, Andrew Harvey, Catherine Hemley, Ian Holmes, Belinda Huff, Daniel Inglis, Wilhelmus Kersten, Tina Lavranos, Romina Lessene, Gillian Lunniss, Brendon Monahan, Benjamin Morrow, Marica Nikac, George Nikolakopoulos, Dharam Paul, Tom Peat, Justin Ripper, Michaela Scherer, Paul Stupple, Karen White, Ian Street, Gabriel Kremmidiotis. BL-011256 is a novel VEGFR3 selective inhibitor, which suppresses tumor lymphatics and lymph node metastasis in an animal model of melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4029. doi:10.1158/1538-7445.AM2014-4029

OP0154 Integrated Safety Analysis of Tofacitinib in RA Clinical Trials with A Cumulative Exposure of 12,664 Patient-Years

BackgroundTofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). Phase (P) 2, P3, and open-label long-term extension (LTE) studies described the safety profile of...

Characterization of immune-related adverse events (irAEs) in a phase 3 trial of ipilimumab (Ipi) versus placebo (Pbo) in post-docetaxel mCRPC.

52 Background: Ipi enhances antitumor immunity by blocking cytotoxic T-lymphocyte antigen-4. We recently reported the results of CA184-043, a phase 3 study of post-docetaxel mCRPC with Ipi vs Pbo, following single-dose radiotherapy (RT). While the study did not meet the primary endpoint of improving overall survival (HR=0.85, p=0.053), Ipi demonstrated antitumor activity in other efficacy endpoints, including progression-free survival. The present analyses further characterize the safety profile of Ipi in this study. Methods: Safety was evaluated for all treated patients (pts; N=393 for Ipi 10 mg/kg, N=396 for Pbo) starting from first study dose and ending 70 days after the last study dose, including maintenance dosing. Results: Any grade (Gr) irAEs occurred in 63.4% and 21.7% of pts in the Ipi and Pbo arms, respectively. Most common Gr 3/4 irAEs were gastrointestinal (GI) (18.1%; mostly diarrhea and colitis). Gr 3/4 liver irAEs (4.6%) were mostly elevations in AST or ALT. Other Gr 3/4 irAEs were uncommon: endocrine (2.0%), skin (1.0%), and neurological (0.3%). Among Ipi-treated pts, there were no meaningful differences in the frequency or severity of GI AEs between those who received baseline pelvic RT and those who did not (n=141 vs 252; any Gr 77.3% vs 69.8%; Gr 3/4 25.5% vs 21.8%, respectively). There were 5 GI perforations in the Ipi arm (3 within 70 days of last dose [2 related, 1 unrelated], 2 after 70 days of last dose, both related), and none in the Pbo arm. Deaths due to study drug toxicity, as per the investigators, occurred in 4 pts (4, Ipi and 0, Pbo). Conclusions: In this study of Ipi in mCRPC, the most frequent severe irAEs were diarrhea and colitis. Most irAEs were manageable using established treatment algorithms. Clinical trial information: NCT00861614. [Table: see text]