Stella, Philip J.

2014 Background: PFS6 is low (2.3%) and med OS brief (4 mos) for recurrent GBM pts who progress after prior RT/TMZ and bevacizumab (Bev), and then receive non-Bev containing regimens (Reardon et al, Br J Canc 2012). Following VEGFi exposure, tumor cell resistance potentially may result from activation of Ras/Raf/MEK/ERK (MAPK) and PI3K/Akt/mTOR signaling pathways. Temsirolimus (mTOR inhibitor) and sorafenib (Raf, PDGFR, VEGFR inhibitor) have previously shown limited single agent activity in GBM. Methods: Recurrent GBM pts who showed radiographic progression despite prior surgery, RT + temozolomide, and VEGFi (initially or at recurrence) received sorafenib 200 mg PO bid and temsirolimus 20 mg IV weekly (the NCCTG N0572 phase I MTD) until progression. All pts had received < 2 prior chemo regimens. A two-stage design was used, with 90% power to detect an increase in PFS6 from 8% to 23%, requiring 41 evaluable pts. The primary endpoint was PFS6; secondary endpoints included OS, TTP, and ORR. Toxicity (TOX) was assessed using CTC ver 3.0. Results: 44 evaluable pts were accrued. Four of the first 40 (10%) reached PFS6, but this did not meet the pre-study threshold for success. Median TTP was 1.8 mos. (40 events, 95% CI: 1.5 – 2.3); median OS was 5 mos. (36 events, 95% CI: 6.6 – 3.1), and no objective responses were reported. Eight pts are alive; 4 have not progressed (median F/U 3.1 mos.; max, 12.2 mos.). Grade 3+ non-heme AE were observed in 51% (23/45; fatigue-5, hypophosphatemia-7, hypercholesterolemia-5, hypertriglyceridemia-5). One grade 4 hematologic AE (thrombocytopenia) occurred. 13.3% (6/45 pts) went off due to TOX, and 71.1% (32/45) due to disease progression. Conclusions: Sorafenib plus temsirolimus was tolerable, but the primary endpoint threshold for success (PFS6) was not met in post-VEGFi recurrent GBM patients. Nevertheless, PFS6 (10%) and OS (5 mos.) compared favorably to contemporary series of Bev-refractory, recurrent GBM pts who are subsequently treated with a non-Bev containing regimen. Supported by NCI CA-25224. Clinical trial information: NCT00329719.

1059 Background: Relapsed TNBC is characterized by its poor prognosis. B is a synthetic DNA minor groove binding non-cross resistant agent that is fully active against DNA-mismatch repair deficient tumor cells. C increases GSH/GST in which enhances the efficacy of B. Methods: Phase II study in pts with mTNBC. C Day 1 followed by B Day 2, repeated every 21 days. Aim: Efficacy of C + B in mTNBC. Primary endpoint: PFS at 3 mo. Secondary endpoints include ORR, duration of response (DOR), 6-mo PFS, OS and AE profile. Tertiary endpoints include assessment of baseline GSH levels, prevalence of BCRA1 mutation and pERK, and correlations with outcome. Results: Closed 3/2012. 48 pts accrued (1 ineligible pt). Median f/u 11.4 mo (6.6-14.8); 2 pts still on treatment. 47 pts evaluable for the PFS endpoint and AEs. 49% received therapy as 3rd-5th line. Median number of cycles = 4 (range 1-15). There are currently 9 confirmed responses (8 PR and 1 CR); DOR = 2.6-14.5 mo. The 3-mo PFS = 51%; 6-mo PFS = 28%; the median TTP is 3.2 mo. AE data: 75% G3/4 hematologic AE: febrile neutropenia 19%. Non-hematologic AEs included G3 (47%) and G4 (15%): G3 fatigue 17%; and no G5 non-heme AE. No correlation of GSH/GST levels with outcome was found. Among 35 pts with evaluable data, no association between BRCA1 expression and outcomes was found. pERK expression was negatively associated with 3-mo PFS, but not 6-mo PFS. Cytoplasmic pERK expression was negatively associated with tumor response (p=0.03). No significant effect of BRCA-1 or pERK expression was found on OS. Conclusions: This trial showed B + C is an active regimen, especially in heavily pretreated mTNBC pts. Correlative data demonstrated a negative association between pERK expression and outcomes. A randomized phase II trial is in development. Clinical trial information: NCT01091454.

19503 Background: This study was performed to assess the value of combined modality therapy in elderly patients by comparing the differences in outcome of those who received radiotherapy (RT) alone or RT plus chemotherapy for stage III NSCLC. Methods: North Central Cancer Treatment Group (NCCTG) performed 2 recent phase III trials for stage III NSCLC. The first trial, 90–24–51, included 3 arms: once-daily radiotherapy (QDRT) alone, twice daily RT (BIDRT) alone, and concurrent chemotherapy plus BIDRT. The second trial, 94–24- 52 included 2 arms and compared concurrent chemotherapy with either QDRT or BIDRT. The chemotherapy arms of both trials included etoposide and cisplatin administered concurrently with RT. Only the patients ≥65 years of age (elderly) who participated in these trials were included in this analysis. Results: Of the 166 elderly patients included in this analysis, 37 received RT alone and 129 received concurrent chemotherapy plus RT. The median and 5-year survival rates were 10.5 months and 5.4% for the RT alone group compared to 13.7 months and 14.7% for the RT plus chemotherapy group (log-rank p=0.05). Patients who received RT plus chemotherapy experienced significantly greater severe (grade ≥3) toxicity than those who received RT alone (89.9% versus 32.4%, p < 0.01). Conclusions: Elderly patients who participated in these trials appear to gain a survival advantage from RT and chemotherapy compared to RT alone. As is the case with younger patients, this benefit comes at the cost of additional toxicity. No significant financial relationships to disclose.

Background: Bevacizumab (BEV), a monoclonal antibody against vascular endothelial growth factor-A (VEGF-A), is a standard component of medical therapy of metastatic colorectal cancer (mCRC). Activation of alternative angiogenesis pathways has been implicated in resistance to BEV. This phase II study examines the activity of combined vertical blockade of VEGF signaling with sorafenib and BEV as salvage therapy in patients with progressive disease (PD) on all standard therapy in mCRC. Methods: mCRC patients with documented PD on standard therapy, received sorafenib (200 mg orally twice daily, days 1–5 and 8–12) and BEV (5 mg/kg intravenously, day 1) every 2 weeks. Primary endpoint was 3-month progression-free survival (PFS) rate and secondary endpoints were overall survival (OS), response rate (RR), safety, and feasibility. Results: Of the 83 patients enrolled, 79 were evaluable. Of these, 42 (53%) were progression-free at 3 months. Median PFS was 3.5 months and median OS was 8.3 months. One patient had a partial response and 50 patients (63.3%) had at least one stable tumor assessment. Of 79 evaluable patients, 54 (68%) experienced grade 3/4 adverse events (AEs) at least possibly related to treatment. Most frequent grade 3/4 AEs were: fatigue (24.1%), hypertension (16.5%), elevated lipase (8.9%), hand-foot skin reaction (8.9%), diarrhea (7.6%), and proteinuria (7.6%). Reasons for treatment discontinuation were PD (72%), AEs (18%), patient refusal (8%), physician decision (1%), and death (1%). Conclusions: The combination of BEV and sorafenib as salvage therapy in heavily pretreated mCRC patients is tolerable and manageable, with evidence of promising activity. ClinicalTrials.gov identifier: NCT00826540, URL: http://clinicaltrials.gov/ct2/show/NCT00826540

102 Background: Combination irinotecan and cetuximab is approved for irinotecan-refractory mCRC; it is unknown if the addition of bevacizumab would improve outcomes. We studied the efficacy and safety of CBI compared with CI in patients (pts) with RAS wildtype, irinotecan-refractory mCRC. Methods: In this multicenter, randomized, double-blind, placebo-controlled phase II trial, pts with RAS wildtype mCRC and no prior anti-epidermal growth factor receptor therapy who failed at least 1 irinotecan-based chemotherapy regimen and received bevacizumab in at least 1 prior line of therapy were randomized 1:1 to irinotecan 180 mg/m2 (or previously tolerated dose), cetuximab 500 mg/m2, and bevacizumab 5 mg/kg vs CI every 2 wks until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was progression free survival (PFS). Multivariable Cox proportional hazard models stratified by number of prior lines of therapy and bevacizumab receipt in immediate prior line were performed. Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). The study was closed early in January 2018 for reasons related to accrual and funding after enrollment of 36 out of a planned 60 pts. Results: Between July 2015 and December 2017, 36 pts were randomized (19 to CBI, 17 to CI). 34 pts (94%) were treated with 2 or more prior chemotherapy regimens. Baseline characteristics were similar between arms. Median PFS was 9.7 vs 5.5 mo for CBI and CI arms, respectively (log-rank P =0.76; multivariable HR = 0.64; 95% CI, 0.25-1.66). Median OS was 19.7 vs 10.2 mo for CBI and CI (log-rank P= 0.04; multivariable HR = 0.41; 95% CI, 0.15-1.09). ORR was 37% for CBI vs 12% for CI ( P =0.13). Grade 3 or higher AEs occurred in 47% of pts receiving CBI vs 35% for CI ( P =0.46). Conclusions: In this prematurely discontinued trial, there were non-significant increases in PFS and ORR and a statistically significant 9.5 mo increase in median OS in favor of CBI compared to CI. Further investigation of CBI for treatment of irinotecan-refractory mCRC is warranted. Clinical trial information: NCT02292758.

Abstract Abstract 630 Introduction: Erythropoiesis stimulating agents (ESAs) improve hemoglobin (Hb) levels and reduce red blood cell (RBC) transfusion requirements in patients (pts) with chemotherapy-associated anemia (CAA), but many pts with CAA do not respond to ESAs. Functional iron deficiency due to inflammation-related hepcidin production and pathological sequestration of bioavailable iron may be an important reason for lack of ESA response in iron-replete pts. The common clinical practice of co-administering oral iron with ESAs does not appear to alter the disordered iron processing in CAA. We conducted a prospective trial to evaluate whether parenteral iron might overcome functional iron deficiency and benefit iron-replete pts with CAA undergoing ESA treatment. Patients and Methods: Eligible pts were receiving chemotherapy for a non-myeloid neoplasm and had Hb level <11.0 g/dL, ferritin >20 ng/mL, transferrin saturation <60%, and ECOG performance score ≤2. All pts received darbepoetin alfa (DA) 500 mcg subcutaneously q3wks until Hb reached >11 g/dL, and thereafter DA 300 mcg q3wks; DA was held for Hb >13 g/dL until Hb fell to <12 g/dL, then restarted with 25% dose reduction. Pts were randomized 1:1:1 to receive either sodium ferric gluconate complex in sucrose (Ferrlecit) 187.5 mg intravenously q3wks (total dose 1,125 mg), oral ferrous sulfate 325 mg once daily, or oral placebo. Quality of life (QOL) was measured using the Symptom Distress Scale, Brief Fatigue Inventory, FACT-An, and LASA instruments. The primary endpoint was the proportion of patients achieving Hb ≥12.0 g/dL or ≥2.0 g/dL Hb increment from baseline by the end of the 16-week study. Secondary endpoints included transfusion requirements. changes in QOL, changes in iron parameters, and adverse events (AEs). Results: Planned enrollment was 582 pts, but the study met an early stopping rule due to an excess of serious AEs in the IV iron arm; 502 pts enrolled at 14 MCCRC sites between February 2006 and December 2008. The median age of the 490 evaluable pts was 64 years; 65% were female and 94% white; 6% had hematological neoplasms (lymphoma or multiple myeloma), 25% had severe anemia (Hb <9.5 g/dL), 48% received platinum-containing therapy, and 66% completed all 16 weeks of the study. Baseline characteristics were comparable between groups. With respect to the primary endpoint, 69.5% of IV iron-treated pts achieved a Hb response (median Hb increase from baseline to end of study, 2.7 g/dl), compared to 66.9% with oral iron (median increase, 2.4 g/dL) and 65.0% with placebo (median increase 2.3 g/dl) (p=0.73). There were no significant differences in the proportion of patients requiring RBC transfusion (12.8% for IV iron, 12.9% for oral iron, 13.5% for placebo; p=0.87) or QOL changes. A total of 17 pts (3%) died on study–8 in the IV iron arm, 6 oral iron, 3 placebo (p=0.22). Grade 3 or higher AEs occurred in 54% of IV iron pts compared to 43% for oral iron and 45% placebo (p=0.03). The end-of-study ferritin level was higher in the IV iron arm (median 501 ng/mL) compared to the oral iron (229 ng/mL) and placebo (193 ng/mL) arms (p=0.0022). The median total DA dose administered was similar between arms (p=0.71). Conclusions: Co-administration of DA with intravenous ferrous gluconate q3wks did not result in improvement in Hb levels, reduce transfusions, improve QOL endpoints, or allow lower doses of DA, compared with DA + oral iron or DA + placebo. IV iron increased AEs. The reason for discordant results with 5 previous smaller studies is unclear. Disclosure: The study was supported by a grant from Amgen (Thousand Oaks, CA) to the MCCRC. Disclosures: Off Label Use: Ferrlecit, chemotherapy-associated anemia.