Comparison of performance of various tumour response criteria in assessment of regorafenib activity in advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib

PurposeTo compare performance of various tumour response criteria (TRCs) in assessment of regorafenib activity in patients with advanced gastrointestinal stromal tumour (GIST) with prior failure of imatinib and sunitinib.MethodsTwenty participants in a phase II trial received oral regorafenib (median duration 47 weeks; interquartile range (IQR) 24–88) with computed tomography (CT) imaging at baseline and every two months thereafter. Tumour response was prospectively determined on using Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, and retrospectively reassessed for comparison per RECIST 1.0, World Health Organization (WHO) and Choi criteria, using the same target lesions. Clinical benefit rate [CBR; complete or partial response (CR or PR) or stable disease (SD) ⩾ 16 weeks] and progression-free survival (PFS) were compared between various TRCs using kappa statistics. Performance of TRCs in predicting overall survival (OS) was compared by comparing OS in groups with progression-free intervals less than or greater than 20 weeks by each TRC using c-statistics.ResultsPR was more frequent by Choi (90%) than RECIST 1.1, RECIST 1.0 and WHO (20% each), however, CBR was similar between various TRCs (overall CBR 85–90%, 95–100% agreement between all TRC pairs). PFS per RECIST 1.0 was similar to RECIST 1.1 (median 44 weeks versus 58 weeks), and shorter for WHO (median 34 weeks) and Choi (median 24 weeks). With RECIST 1.1, RECIST 1.0 and WHO, there was moderate concordance between PFS and OS (c-statistics 0.596–0.679). Choi criteria had less favourable concordance (c-statistic 0.506).ConclusionsRECIST 1.1 and WHO performed somewhat better than Choi criteria as TRC for response evaluation in patients with advanced GIST after prior failure on imatinib and sunitinib.     

Masitinib in advanced gastrointestinal stromal tumor (GIST) after failure of imatinib: A randomized controlled open-label trial

BackgroundMasitinib is a highly selective tyrosine kinase inhibitor with activity against the main oncogenic drivers of gastrointestinal stromal tumor (GIST). Masitinib was evaluated in patients with advanced GIST after imatinib failure or intolerance.Patients and methodsProspective, multicenter, randomized, open-label trial. Patients with inoperable, advanced imatinib-resistant GIST were randomized (1 : 1) to receive masitinib (12 mg/kg/day) or sunitinib (50 mg/day 4-weeks-on/2-weeks-off) until progression, intolerance, or refusal. Primary efficacy analysis was noncomparative, testing whether masitinib attained a median progression-free survival (PFS) (blind centrally reviewed RECIST) threshold of >3 months according to the lower bound of the 90% unilateral confidence interval (CI). Secondary analyses on overall survival (OS) and PFS were comparative with results presented according to a two-sided 95% CI.ResultsForty-four patients were randomized to receive masitinib (n = 23) or sunitinib (n = 21). Median follow-up was 14 months. Patients receiving masitinib experienced less toxicity than those receiving sunitinib, with significantly lower occurrence of severe adverse events (52% versus 91%, respectively, P = 0.008). Median PFS (central RECIST) for the noncomparative primary analysis in the masitinib treatment arm was 3.71 months (90% CI 3.65). Secondary analyses showed that median OS was significantly longer for patients receiving masitinib followed by post-progression addition of sunitinib when compared against patients treated directly with sunitinib in second-line [hazard ratio (HR) = 0.27, 95% CI 0.09–0.85, P = 0.016]. This improvement was sustainable as evidenced by 26-month follow-up OS data (HR = 0.40, 95% CI 0.16–0.96, P = 0.033); an additional 12.4 months survival advantage being reported for the masitinib treatment arm. Risk of progression while under treatment with masitinib was in the same range as for sunitinib (HR = 1.1, 95% CI 0.6–2.2, P = 0.833).ConclusionsPrimary efficacy analysis ensured the masitinib treatment arm could satisfy a prespecified PFS threshold. Secondary efficacy analysis showed that masitinib followed by the standard of care generated a statistically significant survival benefit over standard of care. Encouraging median OS and safety data from this well-controlled and appropriately designed randomized trial indicate a positive benefit–risk ratio. Further development of masitinib in imatinib-resistant/intolerant patients with advanced GIST is warranted.     

Practical management of sunitinib toxicities in the treatment of pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors (pNETs) are infrequent malignancies which manifest in both functional (hormone-secreting) and more commonly non-functional (non-secreting) forms. The oral multitargeted tyrosine kinase inhibitor sunitinib and mammalian target of rapamycin (mTOR) inhibitor everolimus are approved as targeted therapies for patients with well-differentiated, non-resectable disease and evidence of disease progression. The recent approval of sunitinib for the management of advanced pNET is based on a continuous daily dosing (CDD) schedule that differs from the intermittent 4 weeks on/2 weeks off (4/2) schedule approved for sunitinib in advanced renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST). Therefore, although clinicians may be familiar with therapy management approaches for sunitinib in advanced RCC and GIST, there is less available experience for the management of patients with a CDD schedule. Here, we discuss the similarities and differences in the treatment of pNET with sunitinib compared with advanced RCC and GIST. In particular, we focus on the occurrence and management of sunitinib-related toxicity in patients with pNET by drawing on experience in these other malignancies. We aim to provide a relevant and useful guide for clinicians treating patients with pNET covering the management of events such as fatigue, mucositis, hand–foot syndrome, and hypertension.     

Adjuvant sunitinib in patients with high-risk renal cell carcinoma: safety,therapy management,and patient-reported outcomes in the S-TRAC trial

BackgroundAdjuvant sunitinib has significantly improved disease-free survival versus placebo in patients with renal cell carcinoma at high risk of recurrence post-nephrectomy (hazard ratio 0.76; 95% confidence interval, 0.59–0.98; two-sided P = 0.03). We report safety, therapy management, and patient-reported outcomes for patients receiving sunitinib and placebo in the S-TRAC trial.Patients and methodsPatients were stratified by the University of California, Los Angeles Integrated Staging System and Eastern Cooperative Oncology Group performance status score, and randomized (1 : 1) to receive sunitinib (50 mg/day) or placebo. Single dose reductions to 37.5 mg, dose delays, and dose interruptions were used to manage adverse events (AEs). Patients’ health-related quality of life, including key symptoms typically associated with sunitinib, were evaluated with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30).ResultsPatients maintained treatment for 9.5 (mean, SD 4.4) and 10.3 (mean, SD 3.7) months in the sunitinib and placebo arms, respectively. In the sunitinib arm, key AEs occurred ∼1 month (median) after start of treatment and resolved within ∼3.5 weeks (median). Many (40.6%) AEs leading to permanent discontinuation were grade 1/2, and most (87.2%) resolved or were resolving by 28 days after last treatment. Patients taking sunitinib showed a significantly lower EORTC QLQ-C30 overall health status score versus placebo, although this reduction was not clinically meaningful. Patients reported symptoms typically related to sunitinib treatment with diarrhea and loss of appetite showing clinically meaningful increases.ConclusionsIn S-TRAC, AEs were predictable, manageable, and reversible via dose interruptions, dose reductions, and/or standard supportive medical therapy. Patients on sunitinib did report increased symptoms and reduced HRQoL, but these changes were generally not clinically meaningful, apart from appetite loss and diarrhea, and were expected in the context of known sunitinib effects.Clinical trial registrationClinicalTrials.gov, NCT00375674.     

Comparison of RECIST and Choi criteria for computed tomographic response evaluation in patients with advanced gastrointestinal stromal tumor treated with sunitinib

BackgroundControversies exist about computed tomography (CT) response evaluation criteria for patients with gastrointestinal stromal tumor (GIST).Patients and methodsFifty-one patients with advanced GIST treated second line with sunitinib were evaluated with contrast-enhanced CT every 3 months. Response was rated according to RECIST and Choi criteria. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan–Meier analysis.ResultsAccording to RECIST, patients were categorized as complete response (CR; n = 0; 0%), partial remission (PR; n = 1; 2.0%), stable disease (SD; n = 37; 72.5%), and progressive disease (PD; n = 13; 25.5%) at 3 months. When Choi criteria were applied responses were CR (n = 0; 0%), PR (n = 16; 31.4%), SD (n = 21; 41.1%), and PD (n = 14; 27.5%). Despite these discrepancies, patients rated as SD with RECIST and PR as well as SD according to Choi criteria displayed similar PFS (41.3, 40.7, and 41.3 weeks, respectively) and OS (100.4, 91.6, and 108.0 weeks, respectively). Patients with PD had significantly shorter PFS (10.1 weeks for both criteria) and OS (29.1 weeks for RECIST; 28.9 weeks for Choi) regardless of the response classification applied.ConclusionIn contrast to absence of progression, discrimination of PR from SD with Choi criteria was of no predictive value.     

Efficacy and toxicity of sunitinib in patients with metastatic renal cell carcinoma with renal insufficiency

BackgroundPatients with metastatic renal cell carcinoma (mRCC) with renal insufficiency are generally excluded from clinical trials, despite their increasing numbers. Thus, we evaluated the efficacy and toxicity of sunitinib in such patients.Patients and methodsKorean patients with mRCC with renal insufficiency who had received sunitinib as first-line treatment between January 2008 and May 2012 were included. Patient characteristics, clinical outcomes and toxicities were evaluated. Overall survival (OS) and progression-free survival (PFS) were determined according to the degree of renal impairment.ResultsThe median age of the 34 patients evaluated was 66 years, 90% had an Eastern Cooperative Oncology Group performance status of 0 or 1 and the median glomerular filtration rate was 46.5 mL min⁻¹·1.73 m⁻² (range, 21.1–59.5). The starting sunitinib dose was 37.5 and 50 mg for 12 and 22 patients, respectively. A 4-weeks-on–2-weeks-off regimen was followed for 31 patients; a 2-weeks-on–2-weeks-off regimen, for one patient; and a daily regimen, for two patients. The best response was partial response in eight patients and stable disease in 12. Median OS and PFS times were 26.3 months (95% confidence interval [CI]: 17.1–35.3) and 12.2 months (95% CI: 10.2–13.2), respectively. Common non-haematologic adverse events (AEs) were stomatitis, rash, general oedema and fatigue. The most common AEs of ⩾grade 3 severity were fatigue, neutropenia and thrombocytopenia.ConclusionsIn patients with mRCC with renal insufficiency, sunitinib was efficacious and did not cause increased toxicity. Thus, clinicians should not hesitate to treat patients with mRCC with renal insufficiency with sunitinib.     

Sorafenib and sunitinib for elderly patients with renal cell carcinoma

BackgroundSunitinib and sorafenib are small-molecule tyrosine kinase inhibitors with known antitumor activity in advanced renal cell carcinoma.Materials and MethodsWe retrospectively assess the response and tolerance of elderly patients with renal cell carcinoma to these two agents. Data of patients aged ≥ 70 years receiving sorafenib or sunitinib at the Centre Léon Bérard were analyzed. Forty-eight patients received sorafenib or sunitinib as a first line treatment, 8 received sorafenib followed by sunitinib and 4 received the reverse sequence. Objective responses (ORs), stable disease (SD), toxicity, overall survival (OS) and progression-free survival (PFS) were reported.ResultsSorafenib and sunitinib achieved similar OR + SD rates (79% vs. 71% respectively). Median PFS was 6 months in first-line sorafenib treated patients and 5 months in the sunitinib group. Median OS was 16 months in first-line sorafenib-treated patients and 15 months in the sunitinib group. In patients receiving sorafenib followed by sunitinib, median PFS was 11.5 months, and median OS was 13.1 months. With the reverse sequence, median PFS was 8.1 months and median OS was 15 months. Treatment modifications were more frequent in sunitinib-treated patients, in first or second line (75% vs. 50%). Limitations are the retrospective design of the study and the small number of patients.ConclusionFirst-line sunitinib and sorafenib seem equally efficient in elderly patients treated for advanced renal carcinomas, but sunitinib is less well tolerated. Sequential treatment with sorafenib followed by sunitinib seems to be better tolerated. These results should be confirmed in a larger prospective study.     

Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors

BackgroundHSP90 inhibition leads to proteosomal degradation of activated KIT and has in vitro activity against gastrointestinal stromal tumors (GIST). BIIB021 is an oral non-ansamycin HSP90 inhibitor. We carried out a phase II study of BIIB021 in patients with GIST refractory to imatinib and sunitinib.Patients and methodsThe primary end-point was metabolic partial response (mPR) as assessed by fluorodeoxyglucose positron emission tomography (FDG-PET). The secondary end-points were pharmacokinetic assessments of BIIB021 and pharmacodynamic assessments of HSP70. Twenty-three patients were treated on two schedules: 12 pts received 600 mg twice a week (BIW) and 11 patients received 400 mg three times a week (TIW). All had prior imatinib and sunitinib but stopped >14 days before starting BIIB021.ResultsThe median age was 59 years (33–88 years), 61% male, 44% Eastern Cooperative Oncology Group 1 (ECOG1). The best response was PR by FDG-PET for five patients (3/12 at 600 mg BIW and 2/9 at 400 TIW) for an overall response rate of 22%. The response duration was 25–138 days. Adverse events (AEs) were mild to moderate. The mean C_max was 1.5 µmol and the mean AUC was 2.9 µmol h. C_max >1.5 µmol was associated with a decrease in standardized uptake value (SUV_max). HSP70 increased substantially following treatment.ConclusionsThis study met its primary end-point. BIIB021 leads to objective responses in refractory GIST patients. Pharmacodynamic studies confirmed HSP90 inhibition. Further evaluation of BIIB021 in GIST is warranted.     

Sorafenib as third- or fourth-line treatment of advanced gastrointestinal stromal tumour and pretreatment including both imatinib and sunitinib,and nilotinib: A retrospective analysis

BackgroundTyrosine kinase inhibitors (TKI) improve the outcome of patients with advanced gastrointestinal stromal tumour (GIST), but treatment failure is frequent, and prognosis then bleak. Smaller trials in this setting suggested activity for sorafenib, a multikinase inhibitor of receptor tyrosine kinases and RAF serine/threonine kinases.Patients and methodsWe retrospectively evaluated the efficacy of sorafenib, starting dose 400 mg twice daily, in a large community-based cohort of 124 patients treated in 12 European and one United States (U.S.) cancer centre. All but one patient had a WHO performance score 0–2. All had failed both imatinib and sunitinib, 68 patients nilotinib and 26 had failed investigational therapy, too.ResultsTwelve (10%) patients responded to sorafenib and 70 (57%) patients achieved disease stabilisation. Sorafenib was moderately tolerated, and toxicity reported in 56% of the patients. Rash, hand-foot-syndrome and diarrhea occurred frequently. Sorafenib dosage was reduced in a third of patients, but this did not have an impact on progression-free survival (PFS) (p = 0.15). Median PFS was 6.4 months (95% confidence interval [CI], 4.6–8.0 months) and median overall survival (OS) 13.5 months (95% CI, 10.0–21.0 months). Patients with a good performance status and those who responded to sorafenib had a significant better PFS.ConclusionWe conclude that sorafenib is active in GIST resistant to imatinib, sunitinib and nilotinib. These results warrant further investigation of sorafenib or similar molecules in GIST.     

A phase I–II study of everolimus (RAD001) in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors

Background: Imatinib is standard therapy for advanced gastrointestinal stromal tumors (GIST), but most patients develop resistance. This phase I–II study assessed the safety and efficacy of coadministering everolimus with imatinib in imatinib-resistant GIST.Patients and methods: In phase I, patients received imatinib (600/800 mg/day) combined with weekly (20 mg) or daily (2.5/5.0 mg) everolimus to determine the optimal dose. In phase II, patients were divided into two strata (progression on imatinib only; progression after imatinib and sunitinib/other tyrosine kinase inhibitor) and received everolimus 2.5 mg plus imatinib 600 mg/day. Primary end point was 4-month progression-free survival (PFS).Results: Combination treatment was well tolerated. Common adverse events were diarrhea, nausea, fatigue, and anemia. In phase II strata 1 and 2, 4 of 23 (17%) and 13 of 35 (37%) assessable patients, respectively, were progression free at 4 months; median PFS was 1.9 and 3.5 months, and median overall survival was 14.9 and 10.7 months, respectively. In stratum 1, 36% had stable disease (SD) and 54% progressive disease (PD), while in stratum 2, 2% had partial response, 43% SD, and 32% PD.Conclusion: Predetermined efficacy criteria were met in both strata. The combination of everolimus and imatinib after failure on imatinib and sunitinib merits further investigation in GIST.     

A phase I study of daily afatinib,an irreversible ErbB family blocker,in combination with weekly paclitaxel in patients with advanced solid tumours

BackgroundThis phase I study evaluated afatinib, an irreversible ErbB family blocker, plus paclitaxel in patients with advanced solid tumours likely to express human epidermal growth factor receptor (HER1/EGFR) or HER2.MethodsOral afatinib was combined with intravenous paclitaxel (80 mg/m²; days 1, 8 and 15 every four weeks) starting at 20 mg once daily and escalated to 40 and 50 mg in successive cohorts of ⩾3 patients. The primary objective was to determine the maximum tolerated dose (MTD) of afatinib combined with paclitaxel. Secondary objectives included safety, pharmacokinetics and antitumour activity.ResultsSixteen patients were treated. Dose-limiting toxicities with afatinib 50 mg were fatigue and mucositis. The MTD was determined as afatinib 40 mg with paclitaxel 80 mg/m², which proved tolerable with repeated dosing. Frequent adverse events (AEs) included diarrhoea (94%), fatigue (81%), rash/acne (81%), decreased appetite (69%) and inflammation of mucosal membranes (69%); no grade 4 treatment-related AEs were observed. Five (31%) confirmed partial responses were observed in patients with non-small cell lung cancer (n = 3), oesophageal cancer and cholangiocarcinoma; eight (50%) patients remained on study for ⩾6 months. Pharmacokinetic parameters of afatinib and paclitaxel were similar for single administration or in combination.ConclusionsThe MTD and recommended phase II dose of once-daily afatinib combined with paclitaxel 80 mg/m² (days 1, 8 and 15 every four weeks) was 40 mg. AEs at or below this dose were generally manageable with repeated dosing. No pharmacokinetic interactions were observed. This combination demonstrated promising antitumour activity.Trial registrationClinicalTrials.gov, NCT00809133.     

Sunitinib objective response in metastatic renal cell carcinoma: Analysis of 1059 patients treated on clinical trials

BackgroundRetrospective analyses were performed in patients with metastatic renal cell carcinoma (mRCC) to characterise the objective response (OR) rate to sunitinib and differentiate pretreatment features and outcomes of patients with early (response by ⩽12 weeks) versus late response, and responders versus non-responders.MethodsData were pooled from 1059 patients in six trials. Median progression-free survival (PFS) and overall survival (OS) were estimated by Brookmeyer and Crowley method and compared between groups by log-rank test. Baseline characteristics were compared by Fisher-exact, t-, or Wilcoxon rank-sum tests. Associations between characteristics and survival were investigated by Cox proportional regression analysis.Results398 patients (38%) had confirmed OR (12 complete responses); 26%, 61%, 79% and 86% responded by 6, 12, 18 and 24 weeks, respectively. Median (range) time to tumour response (TTR) was 10.6 (2.7–94.4) weeks and was similar in treatment-naïve and cytokine-refractory patients. Median response duration in early and late responders was 52.0 and 55.0 weeks, respectively. Median PFS in early versus late responders was 13.8 versus 20.2 months (P = 0.001); however, median OS did not significantly differ (37.8 versus 40.8 months; P = 0.144). Early responders had more lung metastases (P < 0.01), but baseline characteristics were otherwise mostly similar. Median PFS (16.3 versus 5.3 months) and OS (40.1 versus 14.5 months) were longer in responders versus non-responders (both P < 0.001); responders had more favourable prognostic factors.ConclusionsOR occurred in 38% of sunitinib-treated mRCC patients. Sixty-one percent of responses occurred by 12 weeks of therapy, and responders had favourable pretreatment features and significantly longer survival.     

Phase II study of pazopanib as second-line treatment after sunitinib in patients with metastatic renal cell carcinoma: A Southern China Urology Cancer Consortium Trial

This multicentre, single arm, phase II study was aimed to assess the efficacy and safety of pazopanib as second-line treatment after failure of sunitinib in patients with metastatic renal cell carcinoma (mRCC) and explore biomarkers for pazopanib response. Patients received pazopanib 800 mg per day. The primary end-point was progression-free survival (PFS). Secondary end-points included objective response rate (ORR), overall survival (OS) and safety. Serum proteins (Delta-like ligand (DLL4), Notch1, hypoxia inducible factor-1α (HIF-1α), HIF-2α, vascular endothelial growth factor A (VEGFA) and platelet-derived growth factor receptor β (PDGFRB)) levels were measured using enzyme-linked immunosorbent assay (ELISA). 86 patients with clear cell mRCC were enrolled from December 2009 to March 2012 from three centres in Southern China. Of 85 evaluable patients, the median PFS was 5.6 months (95% confidence interval (CI), 4.1–6.7 months) by independent review. No complete response (CR) was observed in all patients. 13 (15.3%; 95% confidence interval [CI], 11.2–23.9%) patients achieved partial responses (PR) (ORR 15.3%). Median OS was 18.1 months (95% CI, 13.2–19.8 months). The most common adverse events (AEs) were mild to moderate and clinically manageable, including hypertension (37.6%), diarrhoea (36.5%), increased AST (51.8%), and anaemia (60%). AEs resulted in dose reduction in 24.7% of patients. Multivariable analysis showed that higher baseline levels of DLL4 and VEGFA and lower baseline level of HIF-2α were associated with shorter PFS; only lower baseline level of HIF-2α was correlated with shorter OS. The lower expression level of DLL4 after pazopanib treatment was associated with higher response rate probability. In conclusion, pazopanib was clinically active and well tolerated as second-line treatment after sunitinib in mRCC patients. Baseline levels of serum DLL4, VEGFA and HIF-2α may have potential utility as biomarkers of clinical efficacy in this setting (chiCTR-TRC-13004016).     

Phase 1 dose-escalation study of oral tyrosine kinase inhibitor masitinib in advanced and/or metastatic solid cancers

BackgroundMasitinib is a tyrosine kinase inhibitor with a pre-clinical profile suggesting greater affinity and selectivity in vitro for the wild-type c-Kit receptor and its juxtamembrane mutation than imatinib.MethodsThis dose-escalation study was conducted in patients with advanced and/or metastatic cancer to determine the maximum tolerated dose (MTD) for orally administered masitinib over a 12-week period. Secondary objectives were a clinical assessment of masitinib’s activity in cancer patients and establishment of a pharmacokinetic profile.ResultsForty patients with various solid tumours (predominantly GIST, 19 patients) were treated with masitinib at doses ranging between 0.7 and 17.2 mg/kg/day. Although the MTD was not formally reached, an acceptable dose for chronic use was identified at 12 mg/kg/day. Treatment-related AEs were frequent (38/40 patients), however, the majority were grade 1 or 2 and demonstrated dose dependency at higher concentrations. Pharmacokinetic results showed a linear, dose-dependent increase of C_max and AUC. One of two GIST patients with imatinib intolerance had a partial response at 11.1 mg/kg/day. About 29% of the imatinib-resistant GIST population and 38% of the overall population had stable disease.ConclusionsThe safety profile of masitinib at 12 mg/kg/day b.i.d. for the treatment of solid cancers appears favourable and compatible with a long-term regimen. Tumour control rate in imatinib-resistant patients was encouraging, hence, the activity of masitinib in c-Kit expressing tumours, such as GIST, warrants further exploration as first-line anticancer therapy as well as for imatinib-resistant patients.     

A phase I/II study of lenalidomide in combination with sunitinib in patients with advanced or metastatic renal cell carcinoma

BackgroundThis phase I/II study was conducted to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide plus sunitinib in metastatic renal cell carcinoma (RCC) patients.Patients and methodsPatients with histologically confirmed, metastatic RCC were treated with 10 mg/day lenalidomide plus 37.5 mg/day sunitinib, orally in 21-day cycles. Doses were escalated to determine the MTD in phase I, with additional patients planned at this dose in phase II. Primary end points were MTD and response rate.ResultsSixteen patients received a median of 2, 3, and 5 cycles in cohort 1 [lenalidomide 10 mg (days 1–21) and sunitinib 37.5 mg (days 1–21)], cohort 2 [lenalidomide 10 mg (days 1–21) and sunitinib 37.5 mg (days 1–14)], and cohort 3 [lenalidomide 15 mg (days 1–21) and sunitinib 37.5 mg (days 1–14)], respectively. Median treatment durations were 41, 63, and 97 days for lenalidomide; and 41, 57, and 97.5 days for sunitinib. The MTD was found to be continuous dosing of lenalidomide 10 mg/day plus sunitinib 37.5 mg/day for 14 of 21 days. Dose-limiting toxicities included neutropenia, leukopenia, thrombocytopenia, asthenia, atrial fibrillation, and increased transaminases. The most frequent grade 3–4 treatment-emergent adverse events were hematologic, including neutropenia and leukopenia. One patient achieved partial response, and seven had stable disease of which three were confirmed at subsequent tumor assessments. B cells and several T-cell subsets were modulated versus baseline.ConclusionThe dose schedules of lenalidomide and sunitinib evaluated in this study were not well tolerated; cumulative toxicity precluded enrollment at the MTD.     

Evaluation of the safety of C-1311 (SYMADEX) administered in a phase 1 dose escalation trial as a weekly infusion for 3 consecutive weeks in patients with advanced solid tumours

PurposeC-1311 is a member of the novel imidazoacridinone family of anticancer agents. This phase 1 trial was designed to investigate the safety, tolerability and preliminary anti-tumour activity of C-1311.Patients and methodsThis was a phase 1, inter-subject dose escalating and pharmacokinetic study of intravenous (IV) C-1311, administered weekly during 3 consecutive weeks followed by 1 week rest (constituting 1 cycle) in subjects with advanced solid tumours.ResultsTwenty-two (22) patients were treated with C-1311, the highest dose given was 640 mg/m². All subjects experienced one or more treatment-related adverse events (AEs). The most frequently observed treatment-related AEs were neutropaenia and nausea (50% each), followed by vomiting (27%), anaemia (23%), asthenia (23%) and diarrhoea (18%). Most treatment-related AEs were of Common Terminology Criteria for Adverse Events (CTCAE) grades 1–2, except for the blood and lymphatic system disorders, which were primarily of grades 3–4. The recommended dose (RD) of C-1311 administered as once weekly IV infusions for 3 weeks every 4 weeks is 480 mg/m², with the dose limiting toxicity (DLT) being grade 4 neutropaenia lasting more than 7 days. Treatment at this dose offers a predictable safety profile and excellent tolerability.ConclusionThe safety profile and preliminary anti-tumour efficacy of C-1311, observed in this broad-phase dose-finding study, warrants further evaluation of the compound.     

A multi-centre Canadian pilot study of metronomic temozolomide combined with radiotherapy for newly diagnosed paediatric brainstem glioma

PurposeSurvival rates for paediatric diffuse intrinsic brainstem glioma (DIBSG) are dismal. Metronomic dosing of temozolomide (TMZ) combined with standard radiotherapy may improve survival by increasing the therapeutic index and anti-angiogenic effect of TMZ. This study aimed to evaluate the safety and efficacy of this regimen in paediatric DIBSG patients.MethodsChildren aged 18 years or younger with newly diagnosed DIBSG were treated with standard radiotherapy and concomitant metronomic TMZ at 85 mg/m²/day for 6 weeks, followed by metronomic TMZ monotherapy at the same dose. Treatment was continued until tumour progression or unacceptable toxicity occurred. Primary endpoints included overall survival and toxicities. For patients who consented, plasma and urine samples were collected at diagnosis, post-induction and prior to each course of maintenance therapy for the quantification of angiogenesis markers.ResultsFifteen eligible patients were enrolled, with a median age of 6.4 years. The most common toxicities were myelosuppression, most notably prolonged lymphopaenia and thrombocytopaenia. The only dose-limiting toxicity was thrombocytopaenia. Intratumoural haemorrhage was confirmed in one patient. Median time to progression was 5.13 months (95% CI = 6.4, 10.8) and median overall survival (OS) was 9.8 months (95% CI = 6.4, 10.8). Six-months OS was 80% ± 10.3%, with a 1-year OS of 20% ± 10.3%. Serum levels of both VEGF and endoglin tended to decrease during the first two cycles of therapy.ConclusionChemoradiotherapy with metronomic dosing of TMZ showed similar toxicity to previous TMZ regimens, and does not appear to improve survival in paediatric DIBSG.     

A prospective randomised phase-II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer: A study of the CESAR Central European Society for Anticancer Drug Research–EWIV

BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours and is still associated with a poor prognosis in advanced disease. To improve the standard therapy with gemcitabine, we initiated a prospective randomised phase-II trial with gemcitabine (GEM) versus gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. The rational of adding sunitinib was its putative antiangiogenic mechanism of action.MethodsA total of 106 eligible patients with locally advanced, unresectable or metastatic PDAC without previous system therapy were randomised to receive GEM at a dosage of 1.000 mg/m² d1, 8, 15 q28 versus a combination of SUNGEM at a dosage of GEM 1.000 mg/m² d1 + 8 and sunitinib 50 mg p.o. d1–14, q21d. The primary end-point was progression free survival (PFS), secondary end-points were overall survival (OS), toxicity and overall response rate (ORR).ResultsThe confirmatory analysis of PFS was based on the intend-to-treat (ITT) population (N = 106). The median PFS was 13.3 weeks (95% confidence interval (95%-CI): 10.4–18.1 weeks) for GEM and 11.6 weeks for SUNGEM (95%-CI: 7.0–18.0 weeks; p = 0.78 one-sided log-rank). The ORR was 6.1% (95%-CI: 0.7–20.2%) for GEM and for 7.1% (95%-CI: 0.9–23.5%) for SUNGEM (p = 0.87). The median time to progression (TTP) was 14.0 weeks (95%-CI: 12.4–22.3 weeks) for GEM and 18.0 weeks (95%-CI: 11.3–19.3 weeks) for SUNGEM (p = 0.60; two-sided log-rank). The median OS was 36.7 weeks (95%-CI: 20.6–49.0 weeks) for the GEM arm and 30.4 weeks (95%-CI: 18.1–37.6 weeks) for the SUNGEM (p = 0.78, one-sided log-rank). In regard to toxicities, suspected SAEs were reported in 53.7% in the GEM arm and 71.2% in the SUNGEM arm. Grade 3 and 4 neutropenia was statistically significantly higher in the SUNGEM arm with 48.1% versus 27.8% in the GEM arm (p = 0.045, two sided log-rank).ConclusionsThe combination SUNGEM was not sufficient superior in locally advanced or metastatic PDAC compared to GEM alone in regard to efficacy but was associated with more toxicity.