Sylvie Assadourian

Randomised, placebo-controlled, double-blind, parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer

BACKGROUND This phase III study investigated the addition of aflibercept to gemcitabine, in patients with advanced pancreatic cancer. PATIENTS AND METHODS Patients with metastatic pancreatic cancer were randomly assigned to receive either intravenous (i.v.) aflibercept, 4 mg/kg every 2 weeks, or matching placebo combined with gemcitabine, 1000 mg/m(2) i.v. weekly for 7 weeks out of 8, then weekly for 3 weeks out of 4 until progressive disease, unacceptable toxicity or withdrawal of consent. The primary objective was to demonstrate an improvement in overall survival (OS) between the treatment arms. RESULTS The study was stopped for futility following a planned interim analysis of OS in 427 randomised patients. With a median follow-up of 7.9 months, based on the 546 patients at study termination, median OS was 7.8 months in the gemcitabine plus placebo arm (n=275) versus 6.5 months in the gemcitabine plus aflibercept arm (n=271), which was not significant (hazard ratio 1.165, 95% confidence interval (CI) 0.921-1.473, p=0.2034). Median progression-free survival was 3.7 months in both arms. Treatment discontinuations due to adverse events were more frequent in the aflibercept than in the placebo-containing arm (23% versus 12%). CONCLUSION Adding aflibercept to gemcitabine did not improve OS in patients with metastatic pancreatic cancer.

Phase I pharmacokinetic, food effect, and pharmacogenetic study of oral irinotecan given as semisolid matrix capsules in patients with solid tumors.

Purpose: To characterize the maximum-tolerated dose, recommended dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and food effect of orally administered irinotecan formulated as new semisolid matrix capsules. Experimental Design: Irinotecan was given orally in fasted patients once daily for 5 consecutive days and repeated every 3 weeks. Patients were randomly assigned to take the drug along with a high-fat, high-calorie breakfast for the administration at day 1 of the first or second cycle. Dosages tested were 70 and 80 mg/m2/day. Results: Twenty-five patients received 101 cycles of therapy (median two cycles, range 1-15). During the first cycle, grade 3 delayed diarrhea and grade 3 fever were the DLTs at the dosage of 80 mg/m2/day in three out of five patients. Hematologic and nonhematologic toxicities were mild to moderate. Exposure to the active metabolite SN-38 was relatively high compared with i.v. infusion, but no relevant accumulation was observed. Food had no significant effect on irinotecan pharmacokinetics. One confirmed partial remission and 10 disease stabilizations were observed in previously treated patients. No association was found between the UGT1A1*28 genotype and the risk of severe irinotecan-induced toxicity. Conclusions: For oral irinotecan, a dose of 70 mg/m2/day for 5 consecutive days every 3 weeks is recommended for further studies. Delayed diarrhea was the main DLT, similar to that observed with intravenously administered irinotecan. This study confirms that oral administration of irinotecan is feasible and may have favorable pharmacokinetic characteristics.

Phase II Trial of Irinotecan in Children With Relapsed or Refractory Rhabdomyosarcoma: A Joint Study of the French Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group

PURPOSE This phase II study was designed to evaluate the efficacy of irinotecan administered intravenously once every 3 weeks in pediatric patients with recurrent or refractory rhabdomyosarcoma. PATIENTS AND METHODS A total of 35 patients younger than age 20 years, with refractory or relapsed rhabdomyosarcoma for which standard treatments have failed, received irinotecan at 600 mg/m2 administered as a 60-minute infusion every 3 weeks. Concomitant treatments included atropine for cholinergic symptoms, loperamide for diarrhea at the first liquid stool, and preventive antiemetic treatment. Tumor response was assessed every two cycles until progression according to WHO criteria. RESULTS The best overall response rate to irinotecan was 11.4% (95% CI, 3.2 to 26.7%; 2.9% complete responses, 8.5% partial responses) from all patients recruited. The median times to progression and survival were 1.4 and 5.8 months, respectively. A total of 112 cycles were administered, with a median number of two cycles per patient (range, 1 to 16). The most common grade 3/4 toxicities were neutropenia (46%), abdominal pain or cramping (17%), cholinergic syndrome (14%), nausea/vomiting (11%), anemia (11%), thrombocytopenia (9%), and diarrhea (6%). CONCLUSION In heavily pretreated children with a high tumor burden who have been treated with multiagent chemotherapy, irinotecan administered intravenously as a single agent, at 600 mg/m2 every 3 weeks, showed an interesting objective response rate and a good tolerance profile in rhabdomyosarcoma.

Phase I Dose-Escalation Study of Intravenous Aflibercept in Combination With Docetaxel in Patients With Advanced Solid Tumors

Purpose: This phase I study cohort investigated aflibercept in combination with docetaxel in patients with advanced solid tumors. Materials and Methods: Eligible patients had metastatic or nonresectable cancer for which docetaxel was considered appropriate. Patients received intravenous aflibercept (either 2, 4, 5, 6, 7, or 9 mg/kg) with docetaxel (75 mg/m2) on day 1 every 3 weeks until disease progression or unacceptable toxicity. Primary objectives were to evaluate dose-limiting toxicities (DLT) during cycle 1 and to determine the aflibercept recommended phase II trial dose (RP2D) for combination with docetaxel. Pharmacokinetics, tolerability, and antitumor activity were also investigated. Results: Fifty-four patients (mean age, 56 y) were enrolled. Most had prior chemotherapy (96%) and most (24.1%) had breast cancer. In the dose-escalation phase (n = 34), there were three DLTs: grade 4 neutropenic infection (2 mg/kg), grade 3 dysphonia (7 mg/kg), and grade 2 hypertension (9 mg/kg). An excess of free-over-bound aflibercept was observed at doses of 5 mg/kg or more. The pharmacokinetics of aflibercept and docetaxel were not modified by coadministration. Aflibercept (6 mg/kg) was defined as the RP2D based on DLT and pharmacokinetic data. Overall, the most frequent grade 3/4 adverse events (AE) were neutropenia (85.2%), leukopenia (74.1%), hypertension (18.5%), and stomatitis (16.7%). AEs associated with vascular endothelial growth factor blockade included epistaxis (all grades, 83.3%), proteinuria (68.5%), dysphonia (68.5%), and hypertension (53.7%). Seven patients had partial responses, and 32 patients had stable disease (>3 months in 18 patients). Conclusion: On the basis of findings from this study, aflibercept (6 mg/kg) was the dose recommended for further clinical development. Clin Cancer Res; 18(6); 1743–50. ©2012 AACR.

A phase II study of irinotecan in children with relapsed or refractory neuroblastoma : A European cooperation of the Société Francaise d'Oncologie Pediatrique (SFOP) and the United Kingdom Children Cancer Study Group (UKCCSG)

PURPOSE To evaluate the efficacy and safety of irinotecan in paediatric recurrent or refractory neuroblastoma. PATIENTS AND METHODS Thirty seven patients aged between 6 months and < or = 20 years, with relapsed or refractory neuroblastoma, received irinotecan at 600 mg/m(2) administered as a 60-min infusion, every 3 weeks. Tumour response was evaluated by conventional radiological and mIBG scans every two cycles. RESULTS No objective response was observed during the study. Stable disease was observed in 13% of evaluable patients. Median times to progression and survival were 1.4 months (range, 1.2-1.5 months) and 8.8 months (range, 6.7-11.3 months), respectively. One forty two cycles were administered, with a median of two cycles per patient (range, 1-17 cycles). The most common grade 3-4 toxicities were neutropenia (65% of patients), anaemia (43%), thrombocytopenia (38%), vomiting (14%), abdominal pain or cramping (8%), and nausea (5%). CONCLUSION Irinotecan administered intravenously as a single agent every 3 weeks induced no objective response in relapsed or refractory neuroblastoma.

Phase I dose-escalation study of intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours

BACKGROUND To determine dose-limiting toxicities (DLTs), recommended phase II trial dose (RPTD), safety, preliminary antitumour activity and pharmacokinetics of intravenous aflibercept with irinotecan, 5-fluorouracil and leucovorin (LV5FU2). PATIENTS AND METHODS In this open-label study, 38 patients with advanced solid tumours received aflibercept 2, 4, 5, or 6 mg/kg on day 1, then irinotecan and LV5FU2 on days 1 and 2 every 2 weeks. RESULTS Two grade 3/4 aflibercept-associated DLTs occurred with 4 mg/kg: proteinuria lasting >2 weeks and acute nephrotic syndrome with thrombotic microangiopathy. Two DLTs with 5mg/kg (grade 3 stomatitis and grade 3 oesophagitis reflux) and three with 6 mg/kg (febrile neutropenia, grade 3 stomatitis and grade 3 abdominal pain) were considered related to concurrent chemotherapy and underlying disease. The most common grade 3/4 adverse events were neutropenia, hypertension and diarrhoea. Nine patients had partial responses, five with 4 mg/kg. Twenty-two patients had stable disease (five with 4 mg/kg), lasting >3 months in 17 patients. No anti-aflibercept antibodies were detected. Free aflibercept was in excess of bound in most patients on 4 mg/kg. CONCLUSION Based on pharmacokinetics, acceptable safety and encouraging antitumour activity, aflibercept 4 mg/kg was selected as the RPTD with irinotecan and LV5FU2 every 2 weeks.

Phase I and Pharmacokinetic Study of Oral Irinotecan Given Once Daily for 5 Days Every 3 Weeks in Combination With Capecitabine in Patients With Solid Tumors

PURPOSE To assess the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary antitumor activity of oral irinotecan given in combination with capecitabine to patients with advanced, refractory solid tumors. PATIENTS AND METHODS Patients were treated from day 1 with irinotecan capsules given once daily for 5 consecutive days (50 to 60 mg/m2/d) concomitantly with capecitabine given twice daily for 14 consecutive days (800 to 1,000 mg/m2); cycles were repeated every 21 days. RESULTS Twenty-eight patients were enrolled and received 155 cycles of therapy (median, five cycles; range, one to 18 cycles). With irinotecan 60 mg/m2/d and capecitabine 2 x 800 mg/m2/d, grade 3 delayed diarrhea in combination with grade 2 nausea (despite maximal antiemetic support) and grade 3 anorexia and colitis, were the first-cycle dose-limiting toxicities in two of six patients, respectively. At the recommended doses (irinotecan 50 mg/m2/d; capecitabine 2 x 1,000 mg/m2/d), side effects were mostly mild to moderate and uniformly reversible. Pharmacokinetic analysis showed that there was no interaction between oral irinotecan and capecitabine, and that body-surface area was not significantly contributing to the observed pharmacokinetic variability. Confirmed partial responses were observed in two patients with gallbladder carcinoma and in one patient with melanoma. Disease stabilization was noted in 16 patients. CONCLUSION The recommended phase II doses for oral irinotecan and capecitabine are 50 mg/m2/d for 5 consecutive days, and 2 x 1,000 mg/m2/d for 14 consecutive days repeated every 3 weeks, respectively.

Intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours: Results from the expansion cohort of a phase I study

BACKGROUND Following the dose-escalation stage, this double-blind expansion stage of the phase I study evaluated the safety, pharmacodynamics, pharmacokinetics, anti-vascular effects and antitumour activity of aflibercept 4 mg/kg with irinotecan, 5-fluorouracil and leucovorin (LV5FU2). PATIENTS AND METHODS Patients with advanced solid tumours were randomised at cycle-1 to placebo or aflibercept (4 mg/kg) on day 1 then irinotecan-LV5FU2 on days 1 and 2. Subsequently, all patients received aflibercept with irinotecan-LV5FU2 every 2 weeks. Anti-vascular effects were assessed using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). RESULTS Twenty-seven patients were treated; 14 received placebo in cycle-1 followed by aflibercept in later cycles and 13 received aflibercept 4 mg/kg upfront. The median number of aflibercept cycles was 16 (range 1-44), 12 patients received ≥20 cycles. Most frequent grade 3/4 adverse events were neutropenia (37%), fatigue (33%) and hypertension (30%). No anti-aflibercept antibodies were detected. Four patients achieved partial responses and 17 had stable disease, lasting >3 months in 14 patients. Plasma levels of free over vascular endothelial growth factor-bound aflibercept were adequate, with steady-state achieved from cycle-3. Exploratory DCE-MRI showed no significant perfusion changes with aflibercept. CONCLUSION Aflibercept 4 mg/kg plus irinotecan-LV5FU2 every 2 weeks had acceptable toxicity and pharmacokinetics, and showed promising antitumour activity.

Abstract A73: A Phase I first-in-human (FIH) study of SAR566658, an anti CA6-antibody drug conjugate (ADC), in patients (Pts) with CA6-positive advanced solid tumors (STs) (NCT01156870).

Background: SAR566658 (SAR) is a maytansinoid-loaded ADC (huDS6-SPDB-DM4) targeting CA6, a specific glycol-epitope of MUC-1 over-expressed in solid tumors (pancreas 26%, ovary 55%, breast 30%, bladder 60%) and rarely in normal tissues. This FIH study was designed to assess the safety, dose limiting toxicities (DLTs)/recommended dose (RD) and pharmacokinetic following SAR administration in Pts with CA6-expressing STs. Trial is funded by Sanofi. Methods: This Phase I study explored escalating intravenous doses of SAR administered as single agent every 3 weeks (q3w). An accelerated dose escalation scheme was used for the two first dose levels (DL), followed by a standard 3+3 dose escalation scheme. Results: 34 heavily pretreated Pts were enrolled including: 11M/23F, median age 58 years (range, 32-77), ECOG-PS ≤1, with a variety of advanced STs including ovary (13), pancreas (10) and breast (4). A total of 114 cycles (cy), median 2, (range,1-14) of SAR was administered across 9 DLs ranging from 10 to 240 mg/m2. DLTs were observed at the highest DL of 240 mg/m2 and included grade (Gr) 3 diarrhea at cy1 in 1 Pt and Gr3 keratitis at cy2 in 2 Pts. Anticipated toxicity was cornea, peripheral neuropathy, hematological and pulmonary. So far the number of Pts with these toxicities are: keratitis (all Gr: 11 Pts, including 2 Pts with Gr3), peripheral neuropathy (5 Pts, no Gr≥3), neutropenia (Gr3, 2 Pts), interstitial pneumonitis (1 Pt). Other than late occurrence of reversible corneal adverse events (AE) at 150 mg/m2, no dose-dependent AE was observed. Exposure to SAR (Cmax and AUC) increased with no major deviation from dose proportionality over doses of 20 to 240 mg/m2. Clearance was roughly constant over the doses with a low to moderate total variability. SAR 190 mg/m2 fulfills the criteria for RD: no DLT and manageable ocular AE versus highest DL. Clinical benefit was observed at doses ≥120 mg/m2: 1 partial response (breast), 1 PR to be confirmed (ovary), 3 stable disease (SD)>6months and 11 SDs were noted. A significant decrease in tumor marker was noted in 1 Pt. Conclusions: SAR has a favorable safety profile and encouraging antitumor activity. SAR at 190mg/m2 q3w was selected as the RD and is being confirmed in an ongoing extension cohort. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A73. Citation Format: Valentina Boni, Olivier Rixe, Drew Rasco, Carlos Gomez-Roca, Emiliano Calvo, John C. Morris, Anthony W. Tolcher, Sylvie Assadourian, Helene Guillemin, Jean-Pierre Delord. A Phase I first-in-human (FIH) study of SAR566658, an anti CA6-antibody drug conjugate (ADC), in patients (Pts) with CA6-positive advanced solid tumors (STs) ([NCT01156870][1]). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A73. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01156870&atom=%2Fmolcanther%2F12%2F11_Supplement%2FA73.atom

Meta-analysis of anti-VEGF class adverse events from three double-blind (db), placebo (pbo)-controlled phase III trials with IV aflibercept (Afl)

561 Background: Three Db Pbo controlled studies were conducted with IV Afl in metastatic cancer patients [colorectal (CRC) Afl+FOLFIRI (WCGC 2011 abstract O-0024), lung (LC) Afl+docetaxel (WCLC 2011, abstract 511) and pancreatic (PC) Afl+gemcitabine (WCGC 2009 abstract O-0006)]. Each study used the same weekly Afl dose intensity (4 mg/kg q2w for CRC and PC; 6mg/kg q3w for LC). A safety meta-analysis of anti-VEGF class adverse events (AE) was performed on data from these studies. METHODS A fixed-effect logistic regression model was used, including study, treatment and study-by-treatment interaction factors as covariates to test the consistency of treatment effect across studies for each of the considered AE. When no evidence of heterogeneity of treatment effects was found across studies, relative risks (RR) and 95% confidence intervals (CI) were estimated. Summary incidences (% of patients [pts]) and RR are presented for NCI grade 3-4 events. RESULTS Safety data from total of 2,662 pts (Afl: 1,333; Pbo: 1,329) were included for analysis (Table). Among pts treated with Afl, 0.4 and 0.5% experienced grade 4 hypertension and nephrotic syndrome, respectively. CONCLUSIONS The addition of Afl to concurrent chemotherapies did not increase the risk of VTE. The risk of grade 3-4 anti-VEGF class AEs was increased when adding Afl to concurrent chemotherapies. This increased risk was statistically significant (**) only for hypertension, proteinuria and hemorrhage. Further analyses, when more data are available, should improve the precision of these results. Studies were sponsored by Sanofi NCT00561470 , NCT00532155 , and NCT00574275 . [Table: see text].