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Purpose: MAVERICC compared the efficacy and safety of modified leucovorin/5-fluorouracil/oxaliplatin plus bevacizumab (mFOLFOX6-BV) with leucovorin/5-fluorouracil/irinotecan plus bevacizumab (FOLFIRI-BV) in patients with previously untreated metastatic colorectal cancer (mCRC). Patients and Methods: MAVERICC was a global, randomized, open-label, phase II study. Primary objectives were to assess associations between (i) excision repair cross-complementing 1 (ERCC1) expression with progression-free survival (PFS), and (ii) plasma VEGF A (VEGF-A) with PFS in patients with previously untreated mCRC receiving mFOLFOX6-BV or FOLFIRI-BV. Before randomization, patients were stratified by tumoral ERCC1/β-actin mRNA expression level and region. Results: Of 376 enrolled patients, 188 each received mFOLFOX6-BV and FOLFIRI-BV. PFS and overall survival (OS) were comparable between FOLFIRI-BV and mFOLFOX6-BV, with numerically higher PFS [HR = 0.79; 95% CI (confidence interval): 0.61–1.01; P = 0.06] and OS (HR = 0.76; 95% CI: 0.56–1.04; P = 0.09) observed for FOLFIRI-BV. In the high ERCC1 subgroup, PFS and OS were comparable between treatment groups (PFS, HR = 0.84; 95% CI: 0.56–1.26; P = 0.40; OS, HR = 0.80; 95% CI: 0.51–1.26; P = 0.33). Across treatment groups, high plasma VEGF-A levels (>5.1 pg/mL) were observed with shorter PFS (HR = 1.19; 95% CI: 0.93–1.53; P = 0.17) and significantly shorter OS (HR = 1.64; 95% CI: 1.20–2.24; P < 0.01) versus low levels (≤5.1 pg/mL). Safety findings for FOLFIRI-BV or mFOLFOX6-BV were comparable with those reported previously. Conclusions: First-line FOLFIRI-BV and mFOLFOX6-BV had comparable PFS and OS, similar to results in patients with high baseline tumor ERCC1 levels. There were no new safety signals with these bevacizumab-containing regimens.

Pulmonary sarcomatoid carcinoma (PSC) is a high-grade NSCLC characterized by poor prognosis and resistance to chemotherapy. Development of targeted therapeutic strategies for PSC has been hampered because of limited and inconsistent molecular characterization.Hybrid capture-based comprehensive genomic profiling was performed on DNA from formalin-fixed paraffin-embedded sections of 15,867 NSCLCs, including 125 PSCs (0.8%). Tumor mutational burden (TMB) was calculated from 1.11 megabases (Mb) of sequenced DNA.The median age of the patients with PSC was 67 years (range 32-87), 58% were male, and 78% had stage IV disease. Tumor protein p53 gene (TP53) genomic alterations (GAs) were identified in 74% of cases, which had genomics distinct from TP53 wild-type cases, and 62% featured a GA in KRAS (34%) or one of seven genes currently recommended for testing in the National Comprehensive Cancer Network NSCLC guidelines, including the following: hepatocyte growth factor receptor gene (MET) (13.6%), EGFR (8.8%), BRAF (7.2%), erb-b2 receptor tyrosine kinase 2 gene (HER2) (1.6%), and ret proto-oncogene (RET) (0.8%). MET exon 14 alterations were enriched in PSC (12%) compared with non-PSC NSCLCs (∼3%) (p0.0001) and were more prevalent in PSC cases with an adenocarcinoma component. The fraction of PSC with a high TMB (20 mutations per Mb) was notably higher than in non-PSC NSCLC (20% versus 14%, p = 0.056). Of nine patients with PSC treated with targeted or immunotherapies, three had partial responses and three had stable disease.Potentially targetable GAs in National Comprehensive Cancer Network NSCLC genes (30%) or intermediate or high TMB (43%,10 mutations per Mb) were identified in most of the PSC cases. Thus, the use of comprehensive genomic profiling in clinical care may provide important treatment options for a historically poorly characterized and difficult to treat disease.

Overexpression of insulin-like growth factor receptor type 1 (IGF-1R) may promote tumor development and progression in some cancer patients. Our objective was to assess tumor uptake of fluorodeoxyglucose by positron-emission tomography in patients with chemotherapy-refractory colorectal cancer treated with an anti-insulin-like growth factor receptor type 1 (anti-IGF-1R) monoclonal antibody, robatumumab. This was a randomized, open-label study with two periods (P1 and P2). Patients were randomized 3:1 into treatment arms R/R and C/R that received, respectively, one cycle of 0.3 mg/kg robatumumab or one or more cycles of second-line chemotherapy in P1, followed in either case by 10 mg/kg robatumumab biweekly in P2. The primary measure of fluorodeoxyglucose uptake was maximum standardized uptake value (SUV(max)). The primary endpoint was the proportion of patients in the R/R arm having a mean percent decrease from baseline in SUV(max) (DiSUV) greater than 20% 12-14 days postdose in P2. Secondary endpoints included Response Evaluation Criteria in Solid Tumors (RECIST)-defined tumor response and pharmacodynamic measures of target engagement. Among 41 patients who were evaluable for the primary endpoint, seven (17%, 95% CI 7%-32%) had DiSUV greater than 20%. Fifty robatumumab-treated patients were evaluable for RECIST-defined tumor response and six (12%) had stable disease lasting greater than or equal to 7 weeks in P2. Pharmacodynamic endpoints indicated target engagement after dosing with 10 mg/kg robatumumab, but not 0.3 mg/kg. The most frequently reported adverse events were fatigue/asthenia, nausea, anorexia, and gastrointestinal disturbances. In this study, few patients with chemotherapy-refractory colorectal cancer appeared to benefit from treatment with the IGF-1R antagonist robatumumab.

Background Salivary ductal carcinoma and carcinoma ex pleomorphic adenoma (CEPA) are aggressive salivary gland cancers with poor prognosis. The standard of care is resection with or without radiotherapy, and there are no established systemic therapy options. Methods We describe 1 patient with metastatic CEPA and 1 patient with metastatic recurrent salivary duct carcinoma whose tumors were evaluated by comprehensive genomic profiling. Testing identified human epidermal growth factor receptor 2 (HER2) amplification in both patients, and an additional activating HER2 mutation in the CEPA case. Results Both patients were treated with the HER2-targeting monoclonal antibody trastuzumab (herceptin) plus chemotherapy and experienced rapid responses. Subsequently, both patients were given single-agent maintenance trastuzumab and continue to experience durable disease control. Conclusion Given the poor prognosis for salivary gland cancers and the limited treatment options upon recurrence or metastasis, patients should be tested for all classes of HER2 alterations. In cases with HER2 overexpression or activation, targeted therapies, such as trastuzumab are promising. © 2016 Wiley Periodicals, Inc. Head Neck 39: E40–E44, 2017

Purpose Metastasis of solid tumors to regional lymph nodes is facilitated by tumor lymphangiogenesis, which is primarily mediated by the vascular endothelial growth factor receptor 3 (VEGFR-3). We conducted a phase 1 dose-escalation (part A) study of the VEGFR-3 human immunoglobulin G subclass 1 monoclonal antibody LY3022856 in advanced solid tumors, followed by a colorectal cancer (CRC) expansion (part B). Methods Part A evaluated the safety profile and maximum tolerated dose (MTD) of LY3022856 in patients treated intravenously at doses of 5-30 mg/kg weekly (qwk). Part B further evaluated tolerability in CRC patients treated with 30 mg/kg. Secondary objectives were pharmacokinetics, anti-tumor activity, and pharmacodynamics (exploratory). Results A total of 44 patients (23 in part A; 21 in part B) were treated; only one dose-limiting toxicity was observed at the lowest dose level. The MTD was not reached. Treatment-emergent adverse events (TEAEs) of any grade included in ≥15 % of all patients were: nausea (41 %), fatigue (32 %), vomiting (30 %), decreased appetite (27 %), pyrexia (25 %), peripheral edema (23 %), and urinary tract infection (UTI, 20 %). The most common grade 3/4 TEAEs included UTI and small intestinal obstruction (7 % each). No radiographic responses were noted. Median progression-free survival in part B was 6.3 weeks (95 % confidence interval: 5.1, 14.4), and a best overall response of stable disease was observed in 4 CRC patients (19.0 %). Conclusions LY3022856 was well tolerated up to a dose of 30 mg/kg qwk, but with minimal anti-tumor activity in CRC. CLINICALTRIALS. Gov identifier NCT01288989.

OBJECTIVE: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive tumor, with long term survival at ~30% in early stage disease. SCCOHT is caused by germline and somatic SMARCA4 mutations, but the effect of the mutation type on patients remains unknown. Furthermore, the rarity of SCCOHT has resulted in varied treatment, with no standardized protocols. We analyzed 293 cases to determine the effect of treatment modalities and SMARCA4 mutations on patient diagnosis and outcome. METHODS: In 293 SCCOHT patients we collected information on age and stage at diagnosis, treatment modality (surgery, chemotherapy, radiotherapy, and/or high-dose chemotherapy with autologous stem cell rescue (HDC-aSCR)), SMARCA4 mutation origin (germline/somatic), and overall survival. Cox analysis and log-rank tests were performed on 257 cases with available survival data. RESULTS: The strongest prognostic factors were stage at diagnosis (p = 2.72e-15) and treatment modality (p = 3.87e-13). For FIGO stages II-IV, 5-year survival was 71% for patients who received HDC-aSCR, compared to 25% in patients who received conventional chemotherapy alone following surgery (p = 0.002). Patients aged ≥40 had a worse outcome than younger patients (p = 0.04). Twenty-six of 60 tested patients carried a germline SMARCA4 mutation, including all patients diagnosed

Introduction Based on favorable preliminary clinical data and the need to identify effective, well-tolerated neoadjuvant regimens for patients with locally advanced esophageal cancer, this clinical trial was undertaken. Methods This phase II study tested 500 mg/m2 neoadjuvant pemetrexed intravenously and carboplatin with an area under the curve of 6 intravenously on days 1 and 22 in conjunction with concomitant radiation of 5040 centigray, which was given in 28 daily fractions of 180 centigray. The primary endpoint was the rate of pathologic complete response. Results This trial closed early because, during an interim analysis, the primary endpoint fell short. However, 26 eligible patients were accrued. Twenty (74%) were men. Performance scores of 0, 1, and 2 were seen in 16 (59%), 9 (33%), and 2 (7%), respectively. Among eligible patients, 6 of 26 (23%; 95% confidence interval 9-44%) demonstrated a pathologic complete response. Twenty-two underwent a complete cancer resection. The median survival was 17.8 months (95% confidence interval: 12.2-30.7 months). In the neoadjuvant setting, 22 patients had at least one grade 3 or worse adverse event, and 8 patients had at least one grade 4 event. Postoperatively (within 30 days of surgery), there were three deaths, one grade 4 event (thrombosis), and three grade 3 events. Conclusions The neoadjuvant regimen tested within this phase II trial demonstrated antineoplastic activity but fell short of yielding a complete pathologic response rate that merits further testing.

Objectives To determine the efficacy and safety of single agent sorafenib, an oral multi-targeted tyrosine kinase inhibitor, in patients with advanced uterine carcinoma and carcinosarcoma. Methods This multi-institutional non-randomized phase II trial enrolled two cohorts: patients with uterine carcinoma (cohort A) and uterine carcinosarcoma (cohort B). Eligibility criteria included measurable disease, 0–1 prior chemotherapy regimens, and ECOG performance status ≤2. Sorafenib at a dose of 400 mg was administered orally twice daily. A cycle was defined as 28 days. Objective tumor response was the primary endpoint and was assessed following every two cycles. Results Fifty-six patients (40 with carcinoma, 16 with carcinosarcoma) were enrolled between March 2005 and August 2007. Two (5%) patients with uterine carcinoma had a partial response (PR) and 17 (42.5%) achieved stable disease (SD). Five had SD lasting at least 4 months. The 6-month progression-free survival rate for patients with carcinoma was 29%, and the median overall survival was 11.4 months. No patients with carcinosarcoma had an objective response. Four (25%) had SD, and one had SD lasting 18 months. The 6-month progression-free survival rate was 13%, and the median overall survival was 5.0 months. Grade 3/4 drug related toxicities included: hypertension (13%), hand-foot syndrome (13%), hypophosphatemia (7%), anemia (5%), rash (5%), diarrhea (5%), thrombosis (5%), fatigue (5%) and bleeding (5%). Conclusion Sorafenib had minimal activity in patients with uterine carcinoma. Predictive factors for potential benefit are needed.

BACKGROUND Gemcitabine has broad activity in a variety of solid tumors including biliary tract carcinomas. The authors evaluated 6-month survival, response, and toxicity associated with a combination of gemcitabine, 5-fluorouracil (5-FU), and leucovorin (LV) in patients with unresectable or metastatic biliary tract or gallbladder adenocarcinoma (ACA). METHODS A 4-week course included 1000 mg/m2 gemcitabine by intravenous infusion over 30 minutes on Days 1, 8, and 15, 25 mg/m2 LV by intravenous push, and 600 mg/m2 5-FU by intravenous push after LV. RESULTS Forty-two patients were enrolled in 6 months, 35 of whom had metastatic disease. Patients with biliary tract ACA included 24 with hepatic disease (19 patients had intrahepatic disease and 5 patients had extrahepatic disease) and 4 with disease in the ampulla of Vater. All patients were evaluable and received a median of 4 courses of treatment (range, 1–21 courses). Commonly occurring severe toxicity (NCI CTC Grade 3 or worse) included: dyspnea (four patients), nausea (four patients), fatigue (seven patients), thrombocytopenia (six patients), emesis (four patients), and diarrhea (four patients). Five partial responses (9.5%) occurred, 3 of which were sustained for ≥ 8 weeks. No treatment-related deaths occurred. Thirty-two patients had disease progression and 38 died after a median follow-up of 20 months (range, 1.4–24 months). The median time to disease progression was 4.6 months (95% confidence interval [95% CI], 2.4–6.6%). The median survival period was 9.7 months (95% CI, 7–12%). CONCLUSIONS This combination regimen was manageable in patients with advanced biliary tract and gallbladder ACA. Of 42 patients, 24 (57%) survived ≥ 6 months, satisfying the primary end point of the trial. The length of survival suggested that gemcitabine, 5-FU, and LV had benefit equivalent to gemcitabine alone. Cancer 2005. © 2004 American Cancer Society.

The revised European-American classification of lymphoid neoplasms has been reported as reproducible among expert pathologists and feasible in a community setting. We evaluated the reproducibility of lymphoid neoplasm diagnoses between a community and an academic center. We subtyped 188 lymphoid neoplasms using revised European-American classification criteria. Clinical findings, histologic or cytologic preparations, paraffin-section immunostains, and flow cytometry data were reviewed as appropriate. Diagnoses were compared only after completion of the study. Lymphoma subtype was concordant for 167 (88.8%) of 188 cases. Discordant cases included 15 B-cell, 2 T-cell, and 4 Hodgkin lymphomas. For B-cell neoplasms, discordance was most often due to classifying diffuse large cell lymphoma as another aggressive subtype of lymphoma (n = 6), marginal zone lymphoma as another subtype (n = 4), or follicle center lymphoma grade II as grade III (n = 3). For Hodgkin disease, discordance was most often due to classifying nodular sclerosis as mixed cellularity type (n = 3). Comparison of community and academic center diagnoses demonstrated high concordance for most revised European-American classification subtypes. Some sources of discordance have been addressed in the new World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues.

BACKGROUND Topoisomerase I inhibitors have demonstrated clinical activity in patients with metastatic colorectal carcinoma. The authors performed a Phase II study to evaluate the objective tumor response rate of 2 different doses and schedules of 9-aminocamptothecin (9-AC) in previously untreated patients with measurable recurrent metastatic colorectal carcinoma. METHODS Fifty-one patients were registered. One schedule evaluated 9-AC given at 1100 μg/m2/24 hours by continuous infusion for 72 hours along with granulocyte-colony stimulating factor at 5 μg/kg/day on Days 5 through 12. Another schedule involved 9-AC at 480 μg/m2/24 hours by continuous infusion for 120 hours on Days 1, 8, and 15 given every 4 weeks. RESULTS Forty-eight of 51 patients (94%) were evaluable (28 patients who received 72-hour infusion and 20 patients who received 120-hour infusion) for response and toxicity. Significant hematologic toxicities were encountered, especially with the 72-hour infusion schedule, in which 43% (12 of 28) and 28% (8 of 28) experienced Grade 4 (National Cancer Institute Common Toxicity Criteria) leukopenia and thrombocytopenia, respectively. Grade 4 neutropenia was encountered in 61% (17 of 28) and 11% (2 of 19) of patients on the 72-hour and 120-hour infusion schedules, respectively. Diarrhea, nausea, vomiting, and hepatotoxicity were troublesome nonhematologic toxicities. Seventy-nine percent (11 of 14) and 57% (4 of 7) of the patients experiencing Grade 3 or 4 nonhematologic toxicity were on the 72-hour infusion schedule. Three patients died of chemotherapy-related toxicity. One response was observed in 48 evaluable patients (2%). CONCLUSIONS 9-AC did not demonstrate sufficient antitumor activity and had unacceptable toxicity in previously untreated patients with metastatic colorectal carcinoma. Cancer 2000;89:1699–705. © 2000 American Cancer Society.

PURPOSE To evaluate the objective tumor response rate and toxicities of patients with metastatic colorectal carcinoma treated with irinotecan hydrochloride (CPT-11). PATIENTS AND METHODS A total of 121 patients with advanced colorectal carcinoma--90 with prior fluorouracil (5-FU) exposure and 31 chemotherapeutically naive patients--were enrolled between May 1993 and June 1994. Patients were treated with CPT-11 at 125 mg/m2 intravenously weekly for 4 weeks followed by a 2-week rest. RESULTS Among 90 patients with prior 5-FU chemotherapy, 12 partial responses were observed (response rate, 13.3%; 95% confidence interval [CI], 7.1% to 22.1%). Among 31 chemotherapy-naive patients, eight had partial responses (response rate, 25.8%; 95% CI, 11.9% to 44.6%). The median response duration as measured from time of initial treatment for the two groups was 7.7 months and 7.6 months, respectively. The major adverse reactions were gastrointestinal and hematologic. The incidence of grade 3 or 4 diarrhea was 36.4%, while the overall incidence of grade 3 or 4 leukopenia was 21.5% of patients. Only four of 121 patients (3.3%) developed neutropenic fever (grade 4 neutropenia with > or = grade 2 fever). The incidence of grade 4 leukopenia was higher in patients with prior pelvic radiotherapy (chi2 test P = .04), while the incidence of grade 3 or 4 diarrhea demonstrated no association with previous pelvic irradiation. CONCLUSION According to the study design, CPT-11 showed promising activity in chemotherapy-naive patients with advanced colorectal carcinoma and modest activity in patients with prior 5-FU exposure. The toxicity with this schedule appears manageable with appropriate dose modification for individual patient tolerance and an intensive loperamide regimen for the management of diarrhea. Care should be taken when treating patients with prior pelvic radiotherapy because of the increased risk of neutropenia.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian tumor diagnosed in women below the age of 40. While it is uncommon, with only ∼500 cases reported, it is an extremely aggressive tumor, with long term survival rates of Citation Format: Leora Witkowski, Catherine Goudie, Pilar Ramos, Anthony N. Karnezis, Talia Boshari, Patricia Pautier, Michel Longy, James A. Knost, Emmanouil Saloustros, W Glenn McCluggage, Martin Hasselblatt, William P. Hendricks, David Huntsman, Douglas A. Levine, Jeffrey Trent, William D. Foulkes. The influence of genetic and clinical factors on the outcome following a diagnosis of small cell carcinoma of the ovary, hypercalcemic type. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3422.

TPS3630Background: Regorafenib is an oral multikinase inhibitor that blocks several protein kinases involved in angiogenesis and oncogenesis. It was recently shown to provide a survival benefit in ...

3515Background: Standard 1L mCRC treatment (tx) includes a CT backbone (e.g. modified leucovorin [LV]/5-fluorouracil [5-FU]/oxaliplatin [mFOLFOX6] or LV/ 5-FU/ irinotecan [FOLFIRI]) and a biologic ...

Background Treatment options for metastatic colorectal cancer (CRC) are limited after a fluoropyrimidine, oxaliplatin and irinotecan; novel agents need to be explored in this setting. Dasatinib, an oral inhibitor of Src family kinases, inhibits proliferation in CRC cell lines and has antitumor activity in CRC xenograft models. Patients and methods We conducted a multi-center phase II trial of dasatinib in unresectable, previously-treated metastatic CRC patients. No more than 2 prior chemotherapy regimens were permitted, which must have contained a fluoropyrimidine, oxaliplatin and irinotecan. The primary endpoint was progression-free survival (PFS) at 4 months. The Simon two-stage design required that at least 5 of the first 19 patients be progression-free at 4 months to expand to a second stage. Results Nineteen patients enrolled at 9 centers. The study was terminated after the first stage due to lack of efficacy. There were no objective responses; 1 patient (5%) had stable disease for 7.3 months. The PFS rate at 4 months was 5.3% (90% CI: 0.3, 22.6). Median PFS was 1.6 months (90% CI: 1.4, 1.8). Median overall survival was 5.1 months (90% CI: 2.4, 6.3). Grade 3/4 toxicities included fatigue in 16% of patients, and anemia, anorexia, nausea/vomiting and dyspnea in 11%. Conclusion Dasatinib is inactive as a single agent in previously treated metastatic CRC patients.

493 Background: Standard 1L mCRC treatment (tx) includes a CT backbone (e.g., modified leucovorin [LV]/5-fluorouracil [5-FU]/oxaliplatin [mFOLFOX6] or LV/ 5-FU/ irinotecan [FOLFIRI]) and biologic therapy (e.g., BV). The preferred CT backbone for anti VEGF tx is unknown. MAVERICC (NCT01374425), a global, randomized, open-label, phase 2 trial, assessed tx efficacy and safety of mFOLFOX6-BV vs FOLFIRI-BV in pts with mCRC. Intratumoral ERCC1 and plasma VEGF-A were studied as biomarkers for oxaliplatin- and BV-containing tx, respectively. Methods: Pts with mCRC (≥1 measurable metastatic lesion, ECOG performance status ≤1) were randomized 1:1 to receive BV (5 mg/kg) + mFOLFOX6 or FOLFIRI every 2 weeks, stratified by ERCC1 level (low [£1.7] vs high [>1.7]) and region. VEGF-A levels were measured at baseline. Primary objectives were to evaluate: ERCC1 as a biomarker of progression-free survival (PFS) in 1L mCRC tx (mFOLFOX-BV vs FOLFIRI); and VEGF-A as a biomarker for BV and as a biomarker in combination with ERCC1 for PFS following CT + BV. Secondary objectives were to evaluate: the effect of ERCC1 and VEGF-A on overall survival (OS), objective response rate, hepatic metastases resection, and safety. PFS and OS were estimated by Kaplan–Meier methods, hazard ratios (HR) were estimated by Cox regression, and p-values were based on stratified log-rank tests. ERCC1 biomarker analyses are presented here. Results: A total of 376 pts were randomized: median age, 61 yr; white race, 83%; US region, 85%. Baseline characteristics: ERCC1 high, 35%; KRAS mutant, 34%. Efficacy results are shown (see Table). Conclusion: Consistent with previous findings, PFS and OS were comparable in pts treated with either 1L mFOLFOX6-BV or FOLFIRI-BV. Exploratory analyses within pts with high ERCC1 levels suggest consistent results. VEGF-A analyses are ongoing. Clinical trial information: NCT01374425. [Table: see text] [Table: see text]

Introduction: The biology of DLBCL is complex, with a number of clinicopathologic and molecular features impacting outcome. MCT-1 is an oncogene that promotes lymphomagenesis via enhanced cell survival signaling, increased G1 cyclin/CDK activity and overriding cell cycle checkpoints; its expression is substantially elevated in DLBCL without a clear difference in germinal center versus non-germinal center subtypes. Our preliminary studies showed that 1) 85% of DLBCL samples have strong or increased expression of MCT-1via IHC, 2) MCT-1 knockdown induces apoptosis in cell lines, and 3) mutant MCT-1 protein expression attenuates the malignant phenotype via translational changes. (Dai Ca Res 2009 69(19): p. 7835-43) MCT-1 levels are directly regulated by MEK/ERK signaling, providing a rationale to test MEK pathway inhibition as a therapeutic target in DLBCL. AZD-6244 (ARRY-142886, selumetinib) is a novel second generation oral small molecule MEK inhibitor that induces dose dependent apoptosis in DLBCL cell lines and attenuates tumor growth in xenograft models. (Bhalla Blood 2011 118(4): p. 1052-61) In patients with solid tumors, AZD-6244 75mg twice daily has been established as the recommended phase II dose (RP2D). (Adjei JCO 2008 26(13): p. 2139-46) Methods: Eligible relapsed/refractory (R/R) DLBCL patients received AZD6244 hydrogen sulfate at a dose of 75 mg by mouth twice daily continuously for up to eight 28-day cycles or until disease progression or unacceptable toxicity. The primary objective of the study was overall response rate (ORR) with secondary objectives including safety, progression free survival (PFS), overall survival (OS) and pharmacodynamic (PD) analyses. The statistical design used a Simon two-stage design. Due to excessive early toxicity, the protocol was amended to reduce the dose to 50mg twice daily. Results : Sixteen R/R DLBCL pts (9 male, 7 female) with a median age of 70 years (range, 29-86 yrs), median 3 prior regimens (range, 0-6) were enrolled. Cell-of-origin was not prospectively determined, but only 3/10 pts were CD10 positive and 5/9 were MUM1 positive. The median Lactate Dehydrogenase (LDH) at study entry was 483 (range, 194-1128). Two patients withdrew consent prior to treatment exposure. Of 14 patients receiving at least one dose of selumetinib, two had stable disease and the remainder progressed. The median number of treatment cycles was one (range, 1-5). This was partly due to toxicity causing frequent dose interruptions of AZD-6244. Grade ³3 toxicities were observed in 37.5% (15.2 - 64.6%) and included anemia (44%), thrombocytopenia (25%), diarrhea (31%), transaminitis 44%), fatigue (44%); other infrequent toxicities included AV block, LV dysfunction, anorexia and rash. Median progression-free survival (PFS) in all patients was 34 days [95% CI 14-73 days]. Median overall survival (OS) was 129 days [CI 58-134 days]; all but 3 patients (including one patient lost to follow-up) have expired. Conclusion: Despite excellent preclinical rationale to test selective MEK antagonism as a means of modulating MCT-1 and MEK/ERK in DLBCL, AZD-6244 was not well tolerated and had limited clinical activity. Other MEK/ERK inhibitors with a more favorable toxicity profile and/or use of rational synergistic combination therapy should be considered to further evaluate the role of MEC inhibition in this heavily pretreated patient population. (Patel Cancer 2014 19(4): p. 799-805 (Supported by NCI contract N01-CM-2011-00071C) Disclosures Petrich: Seattle Genetics: Consultancy, Honoraria, Research Funding. Westin:Spectrum: Research Funding. Gordon:Northwestern University: Employment; Dr Leo I. Gordon: Patents & Royalties: Patent for gold nanoparticles pending.

In the Signature Program, patients with advanced solid and hematologic cancers without other standard treatment options are enrolled in 1 of 8 tissue-agnostic, mutation-specific protocols. With no predetermined study sites, the program is able to bring the protocol to the patient through local enrollment via physician-directed genomic profiling of tumors. The primary endpoint of each study is clinical benefit, including complete response, partial response, or stable disease [SD], at 16 weeks by investigator assessment using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 or appropriate hematologic criteria. This novel design allows rapid matching of patients to a relevant targeted therapy. Dovitinib, a tyrosine kinase inhibitor with activity against multiple receptor tyrosine kinases, is currently in clinical development. Eighty patients were accrued in the dovitinib (TKI258) protocol from May 2013 to January 2015. Here, we describe a head and neck cancer subset of this population, including adenoid cystic carcinoma (ADC; n = 6), head and neck squamous cell carcinoma (HNSCC; n = 5), and salivary gland cancer (n = 1). The median age was 62 years, and patients had a median of 2 prior lines of therapy; 69% of patients were male, 85% were Caucasian, and 31% and 69% had an Eastern Cooperative Oncology Group performance status of 0 and 1, respectively. Patients met mutational inclusion criteria, with mutations in PDGFRα/β, c-KIT, VEGFR2, FGFR1/2, and RET. There were no confirmed responses; however, 5 patients had SD on study. Of the 5 patients with SD, 4 had clinical benefit at 16 weeks (1 patient with SD at 8 weeks discontinued before 16 weeks). Consistent with other studies of dovitinib monotherapy, gastrointestinal adverse events (fatigue [69%], nausea [69%], diarrhea [54%], and vomiting [54%]) were the most common. In addition, pretreatment tissue biopsies from all patients were analyzed by a large multigene next-generation sequencing assay. Results to date indicate that the ADC cohort has a lower mutational load and fewer prior therapies than the HNSCC cohort. Further analysis of a correlation between clinical benefit and specific mutational profile is ongoing. Citation Format: Sarina A. Piha-Paul, James A. Knost, Luis E. Raez, Allen L. Cohn, Hussein A. Tawbi, Sudha Parasuraman, Barinder P. Kang, Renata M. Matys, Eric D. Slosberg. Outcomes and genomic mutational profiling results in patients with cancers of the head and neck treated with dovitinib in the Signature Program. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B22.

3530 Background: Many cancers metastasize to regional lymph nodes (LN). LN involvement by tumor is an adverse prognostic factor. 3C5 is a human IgG1 mab to VEGFR-3, which is a principal mediator of...

106 Background: Here we describe 8 ongoing single agent clinical protocols under Novartis’ “Signature” program involving buparlisib (BKM120, PI3Ki), dovitinib (TKI258, multikinase inhibitor), binim...

Purpose: Bryostatin-1 is a PKC modulator with direct anti-tumor activity and immunomodulatory properties. We combined different doses of Bryostatin-1 with IL-2 to determine effects on clinical response rate and T cell phenotype in patients with advanced kidney cancer. ExperimentalDesign: IL-2 naive patients were given 11×106 IU subcutaneously of IL-2 on days 1–4, 8–11, and 15–18 of every 28-day cycle. Twenty four patients were randomized to treatment cohorts of 5, 15 or 25 mcg/m2 of Bryostatin-1 on days 1, 8 and 15, starting in the second cycle. An additional nine, non-randomized patients were given 35 mcg/m2. Lymphocytes were analyzed for number, activation status, and production of IL-2, IL-4 and IFN-γ. Response evaluation was performed every 3 cycles. Results: Common grade 3 toxicities included fatigue (5), nausea/vomiting (5), myopathy (3), dyspnea (3), and syncope (3). Four patients, in the two highest dose cohorts, demonstrated evidence of tumor shrinkage, although there was only 1 objective PR. The median time to progression was 104 days (95% CI 88–120) and the median survival was 452 days (95% CI = 424–480). There was no significant boosting effect of Bryostatin-1 on lymphocytes. Conclusions: The addition of Bryostatin-1 to IL-2 was well tolerated, but the overall response rate was low (3.2%), indicating that further studies with this combination are not warranted.

Purpose: To determine whether (1) tailored nicotine patch therapy that is based on smoking rate can be carried out in a multisite oncology investigative group practice setting, (2) long-term use of bupropion reduces the rate of relapse to smoking in smokers who stop smoking with nicotine patch therapy, and (3) bupropion can initiate smoking abstinence among smokers who have failed to stop smoking after nicotine patch therapy. Participants and Methods: Fourteen North Central Cancer Treatment Group sites recruited generally healthy adult smokers from the general population for nicotine patch therapy and based the patch dosage on smoking rates. At completion of nicotine patch therapy, nonsmoking participants were eligible to be assigned to bupropion or placebo for 6 months (for relapse prevention). and smoking participants were eligible to be assigned to bupropion or placebo for 8 weeks of treatment. Results: Of 578 subjects, 31% were abstinent from smoking at the end of nicotine patch therapy. Of those subjects not smoking at the end of nicotine patch therapy who entered the relapse prevention phase, 28% and 25% were not smoking at 6 months (the end of the medication phase) for bupropion and placebo, respectively (P = .73). For those still smoking at the end of nicotine patch therapy, 3.1% and 0.0% stopped smoking with bupropion or placebo, respectively (P = .12). Conclusion: Tailored nicotine patch therapy for the general population of smokers can be provided in a multisite oncology investigative group setting. Bupropion did not reduce relapse to smoking in smokers who stopped smoking with nicotine patch therapy. Bupropion did not initiate abstinence among smokers who failed to stop smoking with nicotine patch therapy.

644 Background: This is a CRC cohort analysis from the novel Novartis “Signature” program of tissue-agnostic, genetic alteration specific signal-finding protocols. Potential patients are identified via standard-of-care profiling; we bring the ‘Protocol to the Patient’, with rapid start-up process. Buparlisib (BKM120) is an oral pan-PI3K inhibitor evaluated in this program. Methods: Patients had progressive/relapsed CRC harboring PI3K pathway activated tumors, measurable disease, ECOG PS ≤1, and adequate organ function. A local CLIA-certified test is sufficient for eligibility. Central post hoc broad tumor molecular profiling of genetic alteration is performed. BKM120 was given orally (100 mg) qd. The primary objective is to assess clinical benefit (SD or better at 16 weeks). Statistical design adaptively clusters patients into cohorts for independent analysis for early futility or efficacy. Results: 18 CRC patients were dosed: 10 females, 15 Caucasian, median age 58 years (40-80), all had ECOG PS ≤1. Median prior therapies: 4 (1-13). Actionable alterations present at baseline (local): 10 (55.6%) PIK3CA mutation, 4 (22.2%) PTEN loss (IHC), 3 (16.7%) each PTEN mutated and PIK3R1 mutated. Median time on study was 5.1 weeks (1-16). Frequently observed AEs: nausea (67%), fatigue (39%), vomiting (33%), diarrhea (33%), anxiety (28%) and decreased appetite (28%). Three patients discontinued due to AEs. At week 16: 13 patients did not meet clinical benefit criteria and 5 patients were non-evaluable. Two patients had SD at week 8. Central genomic profiling: DNA from 14 patients was assessed covering a panel of 288 cancer genes. All patients had a mutation in APC, 10 (71%) also had KRAS mutations and 11 (79%) had mutations in TP53. Three patients with the lowest PFS exhibited mutations in ERBB2 and ERBB4. Concordance between local and central lab results was 73%. Conclusions: This program facilitated the enrollment of molecularly profiled CRC patients with PI3K pathway alterations. In this cohort, BKM120 had a manageable safety profile with negligible activity as single agent. Further evaluation can determine the effect of BKM120 in combination with other agents. NCT01833169 Clinical trial information: NCT01833169.

A randomized phase III study was conducted to assess the addition of molgramostim (GM-CSF) to the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) in terms of response rate, progression-free survival, and survival in women with advanced, recurrent, or metastatic carcinoma of the cervix or vagina. Patients received four 4-week cycles of methotrexate 30 mg/m 2 IV days 1, 15, 22; vinblastine 3 mg/m 2 IV days 2, 15, 22; doxorubicin 30 mg/m 2 IV day 2; and cisplatin 70 mg/m 2 IV day 2 with or without GM-CSF 5 μg/kg every 12 hours subcutaneously days 3 to 12. They were then reevaluated for operability. Those who were not surgical candidates were offered additional chemotherapy until progression or toxicity. Those who were surgical candidates were offered surgical resection of remaining tumor followed by involved-field external beam irradiation to sites of no prior irradiation and intraoperative irradiation to sites of prior external beam irradiation. This trial closed after 36 eligible patients were entered because of poor accrual. Although more than 40% of patients on each arm received fewer than four cycles of MVAC, the clinical response rate was 78% (95% CI: 52-94%) and 50% (95% CI: 26-74%) for MVAC and MVAC + GM-CSF, respectively; the median time to progression was 10.2 and 11.8 months, respectively; and median survival was 13.8 and 16.0 months, respectively. Toxicity was substantial, with more than 40% experiencing grade III to IV leukopenia, and nearly 40% experiencing grade III to IV stomatitis. MVAC with or without GM-CSF support achieves high response rates in patients with advanced, recurrent, or metastatic cervical carcinoma despite dose reductions and deletions. Its progression-free survival and overall survival rates appear promising. These results need to be confirmed within a large randomized phase III clinical trial.

Introduction: Here we describe a novel signal-finding clinical trial protocol series, termed the Novartis “Signature” program. These are tissue-agnostic, genetic alteration (mutation, amplification, translocation, etc.) specific protocols that do not include pre-identified clinical trial sites. In part these are responsive to the increased frequency of molecular profiling in the oncology community, and the incidence of patients whose tumors are identified with actionable genetic alteration yet without automatic access to drugs targeting those alterations. As these patients are identified via standard of care physician-directed profiling, we bring the ‘Protocol to the Patient’, utilizing a rapid study start-up process, such that a de novo site can have one of these trials opened within weeks of the originating patient being identified. Currently the 8 open single agent protocols involve buparlisib (BKM120, PI3Ki), dovitinib (TKI258, multi-kinase inhibitor), binimetinib (MEK162, MEKi), encorafenib (LGX818, RAFi), LEE011 (CDK4/6i), BGJ398 (FGFRi), ceritinib (LDK378, ALKi) and sonidegib (LDE225; SMOi). Methods:Patients with advanced solid and hematologic cancers and no established standard therapy options are eligible. Patients are locally pre-identified with an actionable genetic alteration relevant to the particular compound being studied; a local test done in a CLIA laboratory is sufficient for eligibility. Central broad molecular profiling of patient’s tumors (including confirmatory analysis of inclusion genetic alteration) is performed post-hoc using a fresh or archived sample. The primary objective of these trials is to assess clinical benefit (SD or better for ≥ 16 weeks for solid tumors or appropriate hematologic criteria) associated with the study related compound. A novel statistical design is incorporated to adaptively cluster patients of like indications into cohorts for independent analysis for futility (minimum 10 patients) or efficacy (minimum 15 patients). Rare tumors of at least 4 patients can be clustered together into unique cohorts for determination of signals. To investigate mechanisms of resistance, an optional biopsy is taken upon progression for patients who have had a prior response to the study compound – these tissues are subjected to a broad molecular profiling analysis. Results: Between March 2013 - July 2014, 13 academic centers and another 74 unique community/network sites had screened 286 patients. On average the startup timelines were 5.2 weeks across the program. 147 patients with a genetic alteration received matched therapy and have been dosed: primarily colorectal (28; 19%), NSCLC (25; 17%), ovarian (13; 9%) and sarcoma (n=12; 8%). Rare tumors accrued include small intestine/duodenal (n=6), anal (n=3), thymus (n=2), cholangiocarcinoma (n=2) and appendix (n=2). The Signature program also accrued heme malignancies. Across the whole program, the identifying actionable alterations were mainly PIK3CA (35%), PTEN loss (23%), RAS (18%), NF1 (4.7%), and FGFR2 (3.5%), and also included BRAF, SMO, PTCH1, VEGFR2, RET, PDGFRa, PDGFRb, TRKa, FGFR3, MEK1 and FLT3. The median number of lines of prior treatment was 3 (mean = 3.4; range of 1 to 13), median patient age of 61 years (range of 22 to 82), 40.3 % male, ECOG PS of 0 in 38% of patients and ECOG PS of 1 in 61.5% of patients. Three patients with AML harboring RAS mutations and one patient with multiple myeloma with a BRAFV600E mutation were included in the binimetinib module. (3 female / 1 male; 1-6 prior lines of therapy; 31-80 years old. One AML patient received prior transplant). Additional data will be presented. Futility/Efficacy analyses for 5 cohorts (4 from buparlisib and 1 from binimetinib) are currently ongoing. Conclusions: This program effectively allows the enrollment of molecularly profiled patients with genetic alterations linked to cognate targeted agents. The cohort analysis will evaluate clinical activity in multiple tumor types in parallel. The Signature program could enable the identification of clinical signals using patient sparing designs, potentially leading to subsequent confirmatory trials. This trial model has successfully allowed enrollment of molecularly pre-selected rare tumors in a short timeline without pre-determined trial site selection. The next step of this model will include novel drug combination modules. Disclosures Giles: Novartis: Consultancy, Research Funding. Off Label Use: Ceritinib is approved for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), who have progressed on or who are intolerant to crizotinib. Here, ceritinib is being evaluated in other tumor types that express ALK mutations. All other agents are investigational.. Braiteh:Bayer: Consultancy, Speakers Bureau; Agendia: Consultancy; Incyte: Consultancy, Speakers Bureau; Genomic Health: Consultancy, Speakers Bureau; Foundation Medicine: Consultancy; Celgene: Consultancy, Speakers Bureau; Caris Life Sciences: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Amgen/Onyxx: Consultancy, Speakers Bureau; INSYS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Saladax: Consultancy; Sanofi: Consultancy, Speakers Bureau. Schwartzberg:Novartis: Honoraria, Speakers Bureau. Stein:Novartis: Employment, Equity Ownership. Salvado:Novartis: Employment. Lebedinsky:Novartis: Employment. Kang:Novartis: Employment. Slosberg:Novartis: Employment.

Context.—Flow cytometry immunophenotyping (FC) of needle aspiration/biopsy (NAB) samples has been reported to be useful for the diagnosis and classification of lymphoma in university and cancer center–based settings. Nevertheless, there is no agreement on the utility of these methods. Objective.—To further define the utility of adjunctive FC of clinical NAB for the diagnosis and classification of lymphoma, and to determine if this approach is practicable in a routine clinical practice setting. Setting.—A community-based hospital. Methods.—Clinical NABs were submitted for adjunctive FC between June 1996 and September 1999 if initial smears were suspicious for lymphoma. Smears and cell block or needle core tissues were routinely processed and paraffin-section immunostains were performed if indicated. The final diagnosis was determined by correlating clinical and pathologic data, and the revised European-American classification criteria were used to subtype lymphomas. Results.—Needle aspiration/biopsies from 60 different patients were submitted for FC. Final diagnoses were lymphoma (n = 38), other neoplasm (n = 15), benign (n = 6), or insufficient (n = 1). For 38 lymphomas (20 primary, 18 recurrent), patients ranged in age from 32 to 86 years (mean, 62 years); samples were obtained from the retroperitoneum (n = 11), lymph node (n = 9), abdomen (n = 8), mediastinum (n = 6), or other site (n = 4); and lymphoma subtypes were indolent B-cell (n = 20; 2 small lymphocytic, 14 follicle center, 4 not subtyped), aggressive B-cell (n = 14; 3 mantle cell, 10 large cell, 1 not subtyped), B-cell not further specified (n = 2), or Hodgkin disease (n = 2). For the diagnosis of these lymphomas, FC was necessary in 20 cases, useful in 14 cases, not useful in 2 cases, and misleading in 2 cases. Thirty-two of 36 lymphoma patients with follow-up data received antitumor therapy based on the results of NAB plus FC. Conclusions.—Adjunctive FC of NABs is potentially practicable in a community hospital, is necessary or useful for the diagnosis and subtyping of most B-cell lymphomas, and can help direct lymphoma therapy. Repeated NAB or surgical biopsy is necessary for diagnosis or treatment in some cases.

We conducted a randomized phase II trial of two different schedules of topotecan in patients with advanced-stage non small lung cancer (NSCLC) without prior cytotoxic chemotherapy. All patients had histologic or cytologic confirmation of stage IV (M1) or III-B NSCLC. Patients were stratified by performance status, stage and weight loss. Patients were randomized to receive topotecan at intravenous doses of 1.5 mg/m 2 /day over 30 min for 5 days every 3 weeks (Arm A) or 1.3 mg/m 2 /day by continuous infusion pump over 72 h every 4 weeks (Arm B). Thirty-eight patients in Arm A and 37 patients in Arm B were deemed evaluable for response and toxicity. Six tumor responses (16%, 4 PR, 2 REGR) were observed among 38 evaluable patients in Arm A and all responses occurred in patients with adenocarcinoma. In Arm B, 3 tumor responses (8%, 2 PR, 1 REGR) occurred among 37 evaluable patients and responses occurred in patients with squamous cell carcinoma (1) and adenocarcinoma (2). Toxicities >grade 3 in both arms included leukopenia, thrombocytopenia, malaise, constipation, diarrhea, lethargy, pulmonary, vomiting, infection and myalgia. Severe (≥ grade 3) thrombocytopenia occurred in 15.8% of Arm A patients and 37.8% of Arm B patients and this difference was statistically significant ( P =0.03). The median times to progression are 101 and 63 days ( P =0.75) and the median survival times are 257 and 179 days ( P =0.83) for Arms A and B, respectively. These differences in time to progression and overall survival are not statistically significant. Topotecan has limited, single agent activity in advanced NSCLC when given as 1.5 mg/m 2 /day over 30 min for 5 days every 3 weeks. We do not intend to pursue further investigations with topotecan in patients with NSCLC.

Metastatic colorectal cancer is very common in the Western hemisphere and current treatment modalities are not effective. In this study a prolonged (150-minute) infusion of gemcitabine at a constant dose rate of 10 mg/m2/min administered weekly for 3 consecutive weeks repeated every 4 weeks revealed a response rate of 4% (90% CI < 1%–18%). There were no complete responses. Treatment with gemcitabine produced moderate to severe toxicity as grade 3–4 neutropenia requiring dose modification was seen in 40% of patients treated. When used in this dose and schedule, gemcitabine does not appear to be effective for patients with metastatic colorectal cancer.

PURPOSE A three-arm randomized phase III trial in advanced colorectal cancer patients was designed to test whether substitution of an equivalent dose of (1) l-leucovorin or (2) oral leucovorin would more effectively potentiate fluorouracil (5-FU) than standard intravenous (I.V.) (d,l)-leucovorin. PATIENTS AND METHODS A total of 926 chemotherapy-naive patients participated. Patients received one of three treatments: (A) intensive-course 5-FU plus l-leucovorin with I.V. leucovorin (Immunex Corp, Seattle, WA) at 100 mg/m2 and I.V. 5-FU at 370 mg/m2; (B) intensive-course 5-FU plus oral (d,l)-leucovorin with oral leucovarin at 125 mg/m2 on hours 0, 1, 2, and 3 (total dose, 500 mg/m2) followed by 5-FU 370 mg/m2 on hour 4; or (C) intensive-course 5-FU plus I.V. (d,l)-leucovorin with I.V. leucovorin 200 mg/m2 and 5-FU 370 mg/m2. Drugs were administered daily for 5 consecutive days. Courses were repeated at 4 and 8 weeks, and every 5 weeks thereafter. Dosage was reduced for neutropenia, thrombocytopenia, diarrhea, stomatitis, and dermatitis. RESULTS Of 926 eligible patients, 756 have died. The overall response rate for patients with measurable disease was 32% (165 of 514). There were no differences between regimens in response rates (arm A, 28% [47 of 140]; arm B, 34% [60 of 174]; and arm C, 34% [58 of 170]) or in survival. There have been nine possible chemotherapy-related fatalities. Grade III to IV toxic effects did not differ appreciably by arm and included stomatitis (12% to 14%), diarrhea (15% to 19%), nausea (7% to 9%), and vomiting (6% to 8%). CONCLUSION There was no difference in response, survival, or toxicity between these three different leucovorin formulations combined with 5-FU.

3584 Background: This study was to evaluate the antitumor activity of SCH717454 (robatumumab) by positron emission tomography in patients with metastatic colorectal cancer. Methods: Eligible patien...

5585 Background: There is no effective treatment for UCA/CS pts who have progressed on platinum-taxane therapy. Increased levels of VEGF are frequently seen in UCA and CS, and antiangiogenic therapy has shown activity in a mouse model of UCA. Sorafenib is a multitargeted kinase inhibitor with antiangiogenic activity that is approved for use in renal and hepatocellular carcinoma. Methods: We initiated a multi-center phase II trial of SOR in pts with advanced/recurrent UCA (arm A) or CS (arm B) and 0–1 prior chemotherapy regimens. PS 0–2 and measurable disease were required. The starting SOR dose was 400 mg orally twice daily. The primary endpoint was objective response, which was evaluated every 8 weeks. The trial design required 1 response in the first 12 evaluable pts to proceed to second stage. Results: 55 pts (39 UCA, 16 CS) enrolled between 3/05 and 10/07. Pt characteristics arm A: median age 65 (range 44- 83); PS 0/1/2: 16/19/3. Pt characteristics arm B: median age 64 (range 40- 87); PS 0/1/2: 7/8/1....

PURPOSE: Hot flashes represent a significant clinical problem for some breast cancer survivors. Safe, effective treatment is needed for this prominent clinical problem. Although it has been shown that estrogen or progesterone replacement therapy can alleviate this problem, there are continued safety concerns regarding the use of hormonal therapies in these women. Based on anecdotal information, we hypothesized that soy-derived phytoestrogens, weak estrogen-like substances in the soybean that demonstrate estrogen agonist and/or antagonist effects when they bind to estrogen receptors, could alleviate hot flashes. This current trial was designed to investigate this hypothesis. PATIENTS AND METHODS: This double-blind clinical trial involved breast cancer survivors with substantial hot flashes. After randomization, patients underwent a 1-week baseline period with no therapy. This was followed by 4 weeks of either soy tablets or placebo. The patients then crossed over to the opposite arm in a double-blind manner for the last 4 weeks. Patients completed a daily questionnaire documenting hot flash frequency, intensity, and perceived side effects. RESULTS: Of the 177 women who were randomized and started the study substance, 155 (88%) provided useable data over the first 5 weeks; 149 provided usable data over the entire 9 weeks. There was no suggestion that the soy product was more effective in reducing hot flashes than the placebo. At study completion, patients preferred the soy product 33% of the time, the placebo 37% of the time, and neither substance 31% of the time. No toxicity was observed. CONCLUSION: The soy product did not alleviate hot flashes in breast cancer survivors.

Eighty-one patients with a variety of refractory disseminated malignant neoplasms have been treated in the first multiple fixed-dose phase I trial of recombinant leukocyte A interferon (IFL-rA). Each patient received IFL-rA by intramuscular injection, three times weekly for 28 days. Dosages were escalated in different patients from 1 to 136×106units per injection. The toxic reactions seen with IFL-rA resembled those of nonrecombinant leukocyte interferon and included fever, chills, fatigue, anorexia, myalgia, headache, occasional nausea and vomiting, and dose-dependent reversible leukopenia and hepatic transaminase elevations. The pharmacokinetics of IFL-rA were also comparable with nonrecombinant leukocyte interferon. Objective evidence of antitumor activity was seen in non-Hodgkin's lymphoma, chronic lymphocytic leukemia, Hodgkin's disease, breast cancer, and melanoma, indicating that IFL-rA, the first genetically engineered biological response modifier available for testing in cancer patients, is biologically active in vivo. (JAMA1982;248:2461-2466)

Nineteen patients with advanced refractory metastatic breast cancer no longer responsive to chemotherapy were treated in the first phase II efficacy trial of recombinant leukocyte A interferon (IFL-rA), a highly purified single molecular species of alpha interferon prepared by recombinant DNA methods. Patients received a previously determined maximum tolerated dose for this agent (50 X 10(6) U/m2 body surface area) by intramuscular injection three times weekly for up to 3 months. The symptoms of toxicity observed in this trial resemble those previously reported for alpha interferons and include fever, chills, fatigue, anorexia, and leukopenia. All patients required dose reductions, most often for reasons of severe fatigue. Of the 17 patients evaluable for tumor response, one patient had stable disease and 16 had evidence of tumor progression. We conclude that IFL-rA is not an active agent in the treatment of advanced, refractory breast cancer when used at a maximum tolerated dose on this treatment schedule.

Highly purified human lymphoblastoid interferon (HLBI) derived from virus-stimulated Namalwa cells was administered by 6-h IV infusion or IM injection to 40 patients with a variety of disseminated malignancies refractory to standard therapy. Each patient received doses escalating from 0.1 to 50 X 10(6) U for up to 5 weeks. Extensive monitoring for clinical effect, toxicity, and pharmacokinetics has revealed higher peak serum interferon levels and somewhat more pronounced systemic toxicity for the IV than for the IM route of administration. Objective evidence of tumor regression was observed in two patients receiving HLBI IV.