Final results from GCIG/ENGOT/AGO-OVAR 12, a randomised placebo-controlled phase III trial of nintedanib combined with chemotherapy for newly diagnosed advanced ovarian cancer.

AGO-OVAR 12 investigated the effect of adding the oral triple angiokinase inhibitor nintedanib to standard front-line chemotherapy for advanced ovarian cancer. At the primary analysis, nintedanib demonstrated significantly improved progression-free survival (PFS; primary endpoint) compared with placebo. We report final results, including overall survival (OS). Patients with primary debulked International Federation of Gynaecology and Obstetrics (FIGO) stage IIB-IV newly diagnosed ovarian cancer were randomised 2:1 to receive carboplatin (area under the curve 5 or 6) plus paclitaxel (175 mg/m2 ) on day 1 every 3 weeks for six cycles combined with either nintedanib 200 mg or placebo twice daily on days 2-21 every 3 weeks for up to 120 weeks. Between December 2009 and July 2011, 1,366 patients were randomised (911 to nintedanib, 455 to placebo). Disease was considered as high risk (FIGO stage III with >1 cm residuum, or any stage IV) in 39%. At the final analysis, 605 patients (44%) had died. There was no difference in OS (hazard ratio 0.99, 95% confidence interval [CI] 0.83-1.17, p = 0.86; median 62.0 months with nintedanib vs. 62.8 months with placebo). Subgroup analyses according to stratification factors, clinical characteristics and risk status showed no OS difference between treatments. The previously reported PFS improvement seen with nintedanib did not translate into an OS benefit in the nonhigh-risk subgroup. Updated PFS results were consistent with the primary analysis (hazard ratio 0.86, 95% CI 0.75-0.98; p = 0.029) favouring nintedanib. The safety profile was consistent with previous reports.

Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Angiogenesis is a target in the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase inhibitor of VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, has shown activity in phase 2 trials in this setting. We investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer. METHODS: In this double-blind phase 3 trial, chemotherapy-naive patients (aged 18 years or older) with International Federation of Gynecology and Obstetrics (FIGO) IIB-IV ovarian cancer and upfront debulking surgery were stratified by postoperative resection status, FIGO stage, and planned carboplatin dose. Patients were randomly assigned (2:1) via an interactive voice or web-based response system to receive six cycles of carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m(2)) in addition to either 200 mg of nintedanib (nintedanib group) or placebo (placebo group) twice daily on days 2-21 of every 3-week cycle for up to 120 weeks. Patients, investigators, and independent radiological reviewers were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01015118. FINDINGS: Between Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366 randomly assigned by nine study groups in 22 countries: 911 to the nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients in the nintedanib group experienced disease progression or death compared with 266 (58%) of 455 in the placebo group. Median progression-free survival was significantly longer in the nintedanib group than in the placebo group (17·2 months [95% CI 16·6-19·9] vs 16·6 months [13·9-19·1]; hazard ratio 0·84 [95% CI 0·72-0·98]; p=0·024). The most common adverse events were gastrointestinal (diarrhoea: nintedanib group 191 [21%] of 902 grade 3 and three [<1%] grade 4 vs placebo group nine [2%] of 450 grade 3 only) and haematological (neutropenia: nintedanib group 180 [20%] grade 3 and 200 (22%) grade 4 vs placebo group 90 [20%] grade 3 and 72 [16%] grade 4; thrombocytopenia: 105 [12%] and 55 [6%] vs 21 [5%] and eight [2%]; anaemia: 108 [12%] and 13 [1%] vs 26 [6%] and five [1%]). Serious adverse events were reported in 376 (42%) of 902 patients in the nintedanib group and 155 (34%) of 450 in the placebo group. 29 (3%) of 902 patients in the nintedanib group experienced serious adverse events associated with death compared with 16 (4%) of 450 in the placebo group, including 12 (1%) in the nintedanib group and six (1%) in the placebo group with a malignant neoplasm progression classified as an adverse event by the investigator. Drug-related adverse events leading to death occurred in three patients in the nintedanib group (one without diagnosis of cause; one due to non-drug-related sepsis associated with drug-related diarrhoea and renal failure; and one due to peritonitis) and in one patient in the placebo group (cause unknown). INTERPRETATION: Nintedanib in combination with carboplatin and paclitaxel is an active first-line treatment that significantly increases progression-free survival for women with advanced ovarian cancer, but is associated with more gastrointestinal adverse events. Future studies should focus on improving patient selection and optimisation of tolerability. FUNDING: Boehringer Ingelheim.

Randomized phase II study of nintedanib in metastatic castration-resistant prostate cancer postdocetaxel.

This open-label, phase II trial assessed the efficacy and safety of two doses of nintedanib, a triple angiokinase inhibitor targeting vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor signaling, in patients with metastatic castration-resistant prostate cancer (mCRPC) following progression on docetaxel-based regimens. Patients were randomized to nintedanib 150 mg (arm A, n=40) or 250 mg (arm B, n=41) twice daily for 6 months unless disease progression or adverse events (AEs) led to discontinuation. The primary endpoint was the prostate-specific antigen (PSA) response rate (confirmed PSA decline of ≥20% from baseline). Eighty-one patients were enrolled. The PSA response rate was 0% (0/32) in arm A versus 11.1% (4/36) in arm B (P=0.12); 5.6% of patients (2/36) in arm B showed a PSA reduction of at least 50%. In arm B, the rate of PSA increase was significantly decelerated on treatment versus before treatment (P=0.002). The median progression-free survival was 73.5 and 76.0 days for arm A and arm B, respectively (P=0.3). AEs included gastrointestinal disorders, asthenia, hypertension, and reversible elevated transaminases. The incidence of drug-related serious AEs (no drug-related deaths) was 20.0% (arm A) and 24.4% (arm B). The primary endpoint was not met. Nintedanib (250 mg) showed only modest activity with manageable AEs in patients with mCRPC post-docetaxel.

Prolonged response of relapsed high grade serous ovarian carcinoma to the oral angiokinase inhibitor nintedanib in a patient with a germline BRCA1 mutation.

► Nintedanib is an anti-angiogenic agent that has demonstrated activity in relapsed ovarian cancer. ► Our patient had prolonged response to nintedanib, allowing her to have potentially curative surgery 6 years after her diagnosis. ► The relationship between angiogenesis and BRCA mutation is worth exploring in ovarian cancer.

Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer.

PURPOSE: Inhibiting angiogenesis is one of the most promising avenues for new therapies for ovarian cancer. We investigated the efficacy and safety of a novel agent, BIBF 1120, a triple angiokinase inhibitor, after chemotherapy for relapsed disease. PATIENTS AND METHODS: We conducted a randomized, double-blind, controlled phase II trial in 83 patients who had just completed chemotherapy for relapsed ovarian cancer, with evidence of response, but at high risk of further early recurrence. The patients were randomly assigned to receive maintenance therapy using BIBF 1120 250 mg or placebo, twice per day, continuously for 36 weeks. End points were progression-free survival (PFS), toxicity, and overall survival. RESULTS: Thirty-six-week PFS rates were 16.3% and 5.0% in the BIBF 1120 and placebo groups, respectively (hazard ratio, 0.65; 95% CI, 0.42 to 1.02; P = .06). Four patients continued on BIBF 1120, including two patients for another year or more. The proportion of patients with any grade 3 or 4 adverse events was similar between the groups (34.9% for BIBF 1120 v 27.5% for placebo; P = .49; mostly grade 3). However, more patients on BIBF 1120 experienced diarrhea, nausea, or vomiting (mainly grade 1 or 2 and no grade 4). There was a higher rate of grade 3 or 4 hepatotoxicity in patients on BIBF 1120 (51.2%) compared with patients on placebo (7.5%; P < .001), but this was rarely of clinical significance, and patients continued with the trial treatment. A single-level dose reduction to 150 mg was made in 15 patients, all on active drug. CONCLUSION: BIBF 1120 is well tolerated and associated with a potential improvement in PFS. The observed treatment effect is sufficient to justify further study within a large phase III trial.

Phase II trial of weekly alternating sequential BIBF 1120 and afatinib for advanced colorectal cancer.

AIM: The feasibility of an alternating regimen of BIBF 1120, a potent, oral, triple angiokinase inhibitor, and afatinib (BIBW 2992), a potent ErbB family blocker, was explored in patients with advanced pretreated colorectal cancer (CRC). PATIENTS AND METHODS: Patients received repeated courses of alternating 7-day treatment periods, first with BIBF 1120 250 mg twice daily and then afatinib 50 mg once daily. The primary endpoint was the objective response rate; the incidence/severity of adverse events (AEs) and pharmacokinetics (PK) were determined. RESULTS: Forty-six patients (≥4 prior lines, most anti-VEGF and/or -EGFR pretreated) received BIBF 1120 and afatinib. No objective responses were observed; the best response was stable disease in 20 patients (43.5%). Seven patients (15.2%) remained progression-free for ≥16 weeks. Median progression-free survival was 1.9 months; median overall survival was 5.5 months. The most frequent drug-related AEs were diarrhoea (80.4%), asthenia (47.8%), nausea (43.5%) and rash (41.3%). PK assessments did not show obvious alterations for either drug. CONCLUSION: Weekly alternating administration of BIBF 1120 and afatinib is feasible; however, its efficacy was limited in this highly palliative patient population.

Prolactin stimulates proliferation of the glucose-dependent beta-cell line INS-1 via different IRS-proteins.

CONTEXT: Prolactin is one of the most potent growth stimulating growth hormones of pancreatic beta cells. OBJECTIVE: We investigated the role of prolactin on the proliferation of the beta-cell line INS-1. DESIGN: In particular, we investigated the involvement of intracellular signal transduction molecules in prolactin-dependent upregulation of INS-1 growth. SETTING: The effect of prolactin on the growth of INS-1 cells was assessed in vitro under various feeding conditions. MAIN OUTCOME MEASURES: Cell proliferation was measured in the pancreatic beta-cell line INS-1 using 3H-thymidine incorporation. The activation of mitogenic signaling proteins was assessed by co-immunoprecipitation, immunoblot analysis and in proliferation assays using specific protein inhibitors. RESULTS: Prolactin (0.5-2 nM) increased INS-1 cell proliferation in the presence of 3-24 mM glucose up to 48 fold, having a maximum in the presence of physiological glucose concentrations (6 mM). Prolactin activated the JAK2/STAT5 pathway and phosphatidylinositol-3'-kinase (PI3'K) in the presence of all the glucose concentrations used (3-15 mM). At low glucose concentrations (3 mM), PI3'K activation occurred through IRS-2 phosphorylation whereas, in the presence of physiological glucose concentration IRS4 and at high glucose concentrations (15 mM), IRS-1 triggered a proliferative effect. PI3'K activation was essential for prolactin and glucose stimulated INS-1 cell proliferation. Co-stimulation with different growth factors (IGF-I, growth hormone) in addition to prolactin and glucose had no additive effects. CONCLUSION: These results define prolactin as an important hormone. mediating glucose-dependent pancreatic beta-cell proliferation primarily by the activation of PI3'K-dependent signaling pathways.