A Randomized, Open-Label, Safety and Exploratory Efficacy Study of Kanglaite Injection (KLTi) plus Gemcitabine versus Gemcitabine in Patients with Advanced Pancreatic Cancer.

Background: This study was designed to assess the safety and preliminary efficacy of KLTi plus gemcitabine in patients with locally advanced or metastatic pancreatic cancer. Methods: In a randomized, open-label study, patients with locally advanced or metastatic pancreatic cancer were randomized 2:1 to receive KLTi plus gemcitabine or gemcitabine monotherapy. Three sequential cohorts were tested at 30 g/day, 50 g/day, and 30 g/day. Gemcitabine was administered at 1000 mg/m2 on days 1, 8 and 15 of each 28 day cycle. KLTi was administered on days 1-5, 8-12, and 15-19 of each 28 day cycle. Patients received study treatment until disease progression. The primary endpoint was progression-free survival in the ITT population. Safety evaluation was based on patients who received any study treatment. ClinicalTrials.gov identifier NCT00733850. Results: Eighty-five patients were randomized including 41 (28:13) in Cohort 1, 18 (12:6) in Cohort 2, and 26 (17:9) in Cohort 3. Due to a different dose and/or shift in patient populations in Cohort 2 and 3, efficacy data for the 30 gm dose are presented in this manuscript for Cohort 1 alone, and for the combination of Cohort 1+3. The 30 gm KLTi + gemcitabine group had a statistically significant improvement in progression-free survival (PFS) as assessed by blinded independent radiology review in the ITT population, with a median of 112 days, versus 58 days in the gemcitabine group (HR 0.50; 95% CI: 0.27, 0.92), p = 0.0240. The incidence rates of TEAEs, CTCAE Grade 3 or higher TEAEs, and SAEs were similar between the two arms. There were no deaths related to KLTi + gemcitabine treatment. Conclusion: Kanglaite Injection (30 g/day) plus a standard regimen of gemcitabine demonstrated encouraging clinical evidence of anti-neoplastic activity and a well-tolerated safety profile.

Phase 1 Study of Monotherapy with KHK2866, an Anti-Heparin-Binding Epidermal Growth Factor-Like Growth Factor Monoclonal Antibody, in Patients with Advanced Cancer.

BACKGROUND: KHK2866 is a recombinant, humanized, non-fucosylated, monoclonal antibody directed at heparin-binding epidermal growth factor-like growth factor (HB-EGF). OBJECTIVE: To determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, potential immunogenicity, and preliminary clinical efficacy of KHK2866 monotherapy in patients with advanced and refractory cancer in a first-in-human, phase 1 study. MATERIALS AND METHODS: Using a standard 3 + 3 dose-escalation design, 20 patients received KHK2866 (0.3, 1, and 3 mg/kg) intravenously once weekly. Two additional patients received 0.1 mg/kg in a cohort which was subsequently added following protocol amendment. RESULTS: The first three patients enrolled experienced grade 2 hypersensitivity (acute infusion reactions) after the first dose of KHK2866. After prophylactic treatment with an H1-blocker and corticosteroids in subsequently recruited patients, two grade 2 hypersensitivity reactions were observed in the remaining 19 patients. Grade 2/3 neurotoxicity appeared to be dose-limiting at 3 mg/kg in the original dose-escalation cohorts (n = 2), at 1 mg/kg in the MTD dose expansion cohort (n = 1), and at 0.1 mg/kg (n = 1). Neurotoxicity was manifested as complex partial seizure activity, aphasia, and confusion after first-dose administration. Pharmacokinetic exposure to KHK2866 increased proportionally to dose. Mean elimination half-life was 71.9-118 h over the dose range from 0.3 to 3 mg/kg. All KHK2866 doses decreased serum free HB-EGF levels, generally below the lower limit of quantification. CONCLUSIONS: The study was terminated because of neuropsychiatric toxicity. The only predictive factor for neuropsychiatric toxicity was administration of KHK2866. These effects were reversible, but were not predictable. Their etiology is not presently understood. [Study registered at ClinicalTrials.gov #NCT0179291].

Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial.

BACKGROUND: Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. METHODS: We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759. FINDINGS: Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7-22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2-4·8), and median duration of response was not reached (95% CI 8·31-not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7-10·9). 20 (17%) of 117 patients reported grade 3-4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. INTERPRETATION: Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. FUNDING: Bristol-Myers Squibb.

Randomized placebo-controlled phase II trial of perifosine plus capecitabine as second- or third-line therapy in patients with metastatic colorectal cancer.

PURPOSE: In a multicenter, double-blind phase II trial, we compared the efficacy and safety of perifosine plus capecitabine (P-CAP) with placebo plus capecitabine (CAP) in patients with metastatic colorectal cancer (mCRC) who had progressed after as many as two prior therapies. PATIENTS AND METHODS: Patients (n = 38) not previously treated with capecitabine received P-CAP (perifosine 50 mg orally once daily, days 1 to 21 and CAP 825 mg/m(2) orally twice daily, days 1 to 14) or CAP (825 mg/m(2) orally twice daily, days 1 to 14) in 21-day cycles until disease progression. The primary end point was time to progression (TTP). Secondary end points included overall survival (OS), overall response rate (ORR), safety, and tolerability. RESULTS: Twenty patients were randomly assigned to P-CAP and 18 to CAP. Median TTP (27.5 v 10.1 weeks; P < .001) and median OS (17.7 v 7.6 months; P = .0052) were improved in patients receiving P-CAP versus CAP. ORR was 20% v 7% in the P-CAP and CAP groups, respectively, and one patient in the P-CAP group had a complete response. A subset analysis of fluorouracil-refractory patients showed a median TTP of 17.6 v 9.0 weeks (P < .001) and median OS of 15.1 v 6.5 months (P = .0061). Toxicities, including diarrhea, nausea, fatigue, and hand-foot syndrome, were manageable. CONCLUSION: P-CAP showed promising clinical activity compared with CAP in previously treated patients with mCRC. A phase III trial is underway comparing P-CAP with CAP in patients with refractory mCRC.

Chemokine expression in tumor-to-tumor metastasis.

Chemokines play an important role in cancer metastasis by modulating the directional cell movement and migration of tumor cells. The most commonly overexpressed chemokine receptor in human cancer is CXCR4. Once activated by its ligand CXCL12 (stromal cell-derived factor-1 ligand/SDF1), CXCR4 stimulates several key migratory, proliferative and survival signaling cellular pathways. CXCR4 is expressed in small-cell lung carcinoma (SCLC) cells and other tumors. To further characterize the role of chemokines in tumor-to-tumor metastasis, we analyzed the tissue expression of CXCR4 and CXCL12 in the surgical specimen of a patient with this phenomenon. We performed immunohistochemical analysis for the expression of CXCR4 and CXCL12 in metastatic tumor tissue of a 69-year-old Caucasian male with extensive SCLC metastatic to a renal oncocytoma. The oncocytoma tissue harboring SCLC showed CXCL12 expression, but not CXCR4. A high expression of the two molecules was found in a normal renal parenchymal control. Our results suggest that CXCR4 and CXCL12 plays a role in this condition, but their expression may be affected by the microenvironment of the harboring malignancy. Further characterization of these phenomena is needed to shed light on the biological mechanisms of tumor metastasis.

Observational study of the prevalence of febrile neutropenia in patients who received filgrastim or pegfilgrastim associated with 3-4 week chemotherapy regimens in community oncology practices.

BACKGROUND: Colony-stimulating factors (CSFs) significantly decrease the risk of febrile neutropenia (FN), a common complication of myelosuppressive chemotherapy. Pegfilgrastim (6 mg), introduced in 2002, has a sustained duration of action, with a single dose comparable in efficacy to daily injections of filgrastim (5 g per kg per day) for 10 to 11 days; both agents should be initiated 24 hours after completing chemotherapy. OBJECTIVES: To (1) describe the use of pegfilgrastim and filgrastim in oncology practices throughout the United States and (2) compare their effectiveness in actual practice as measured by the outcome of febrile neutropenia in patients who received chemotherapy regimens administered every 3 to 4 weeks for breast, lung, ovarian, colon cancer, or lymphoma and who received a CSF prior to developing FN. METHODS: Data were retrospectively obtained from the medical records of a cohort of adult patients aged 18 years or older treated in 99 community oncology practices in the United States in 2001 and 2003. Eligible patients were treated with chemotherapy every 3 to 4 weeks for breast, lung, ovarian, colon cancer, or lymphoma and were users of filgrastim in 2001 (prior to the U.S. Food and Drug Administration approval of pegfilgrastim in January 2002) or users of either filgrastim or pegfilgrastim or both CSF agents in 2003. RESULTS: Pegfilgrastim was initiated, on average, 2.4 days (SD +/-3.2) after chemotherapy in the first cycle of use and 1.9 (+/-3.0) days in subsequent cycles of use. In contrast, filgrastim was started on average 7.7 (+/-6.5) days and 4.9 (4.6) days after chemotherapy in the first and subsequent cycles of use in 2001, increasing to 9.6 (+/-6.2) and 6.4 (+/-6.4) days in 2003. In the first cycle of CSF use, filgrastim was administered for an average of 5.2 (+/-3.5) days to 583 patients in 2001 and 3.7 (+/-2.8) days to 868 patients in 2003 (P <0.001). Among patients who received more than 1 cycle of filgrastim (n = 457 in 2001 and n = 489 in 2003; 78.4% and 56.3% of filgrastim users, respectively), the mean days of filgrastim administered in subsequent cycles was 6.0 (+/-3.5) in 2001 and 4.6 (+/-3.2) in 2003. Pegfilgrastim was administered as a single dose per chemotherapy course to 1,412 patients in 2003. Patients who received pegfilgrastim were more likely to have at least 1 myelosuppressive drug (74.8%) in the regimen compared with patients who received filgrastim in 2003 (70.0%, P = 0.013), but a greater proportion of filgrastim patients in 2003 (19.4%) had advanced-stage disease compared with pegfilgrastim patients (14.8%, P = 0.005). More patients who received filgrastim in 2003 (36.2%) had a cancer other than breast cancer or non-Hodgkin's lymphoma compared with those who received pegfilgrastim (29.5%, P = 0.001). A total of 94 of 1,451 patients (6.5%) who received filgrastim experienced FN compared with 67 of 1,412 patients (4.7%) for pegfilgrastim. The odds ratio of developing FN among patients who received filgrastim versus pegfilgrastim was 1.41 (95% confidence interval, 1.02-1.96; P = 0.040) after adjusting for patient and chemotherapy regimen characteristics. CONCLUSION: In this retrospective study of patients treated in 99 community oncology practices, patients who received filgrastim often initiated treatment later than recommended and received fewer days per cycle than demonstrated to be effective in randomized controlled trials. Pegfilgrastim was generally initiated earlier within the course of chemotherapy compared with filgrastim, and because of its sustained duration of action, only a single injection was required. In these patients treated with a heterogeneous group of chemotherapy regimens with a broad range of risk of FN, overall, an absolute 1.8% increase in the incidence of developing FN was observed in patients who received filgrastim compared with patients who received pegfilgrastim, (absolute rates of 6.5% and 4.7%, respectively).