Thomas R. Geldart

A Randomised Phase 2 Study of AZD2014 Versus Everolimus in Patients with VEGF-Refractory Metastatic Clear Cell Renal Cancer

BACKGROUND Everolimus is a mammalian target of rapamycin (mTOR) inhibitor used in vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma (mRCC). It acts on only part of the mTOR complex (TORC1 alone). In vitro data support the use of mTOR inhibitors with broader activity (TORC1 and TORC2). OBJECTIVE The purpose of this study was to determine whether combined TORC1 and TORC2 inhibition with AZD2014 has superior activity to everolimus in VEGF-refractory clear cell mRCC. DESIGN, SETTING, AND PARTICIPANTS Patients with measurable mRCC and VEGF-refractory disease were eligible for this trial. INTERVENTION Starting in February 2013, patients were randomised (1:1) to AZD2014 (50 mg twice daily) or everolimus (10 mg once daily) until progression of disease at 10 centres across the United Kingdom. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Progression-free survival (PFS) was the primary end point and was compared using the stratified log-rank test. Secondary end points included tolerability, response rates, overall survival (OS), and pharmacokinetics (PK) analysis. The study was planned to recruit 120 patients. RESULTS AND LIMITATIONS Recruitment into the trial was stopped early (June 2014) due to lack of efficacy of AZD2014. At that point, 49 patients were randomised (26 to AZD2014 and 23 to everolimus). The PFS for AZD2014 and everolimus was 1.8 and 4.6 mo, respectively (hazard ratio: 2.8 [95% confidence interval (CI), 1.2-6.5]; p=0.01). Progression of disease as the best response to therapy was 69% for AZD2014 and 13% for everolimus (p<0.001). Grade 3-4 adverse events (AEs) occurred in 35% of AZD2014 and 48% of everolimus patients (p=0.3). Only 4% of patients stopped AZD2014 due to AEs. PK analysis suggested concentrations of AZD2014 were compatible with the therapeutic range. Final stratified OS hazard ratio at the time of trial closure (January 2015) was 3.1 (95% CI, 1.1-8.4; p<0.02). CONCLUSIONS The PFS and OS of AZD2014 were inferior to everolimus in this setting despite acceptable AE and PK profiles. PATIENT SUMMARY There is a strong rationale for testing mTOR inhibitors with a broader spectrum of activity than everolimus in metastatic clear cell renal cell carcinoma. AZD2014 is such an agent, but in this study, it was inferior to everolimus despite its attractive toxicity profile.

SUCCINCT: An open-label, single-arm, non-randomised, phase 2 trial of Gemcitabine and Cisplatin chemotherapy in combination with Sunitinib as first-line treatment for patients with advanced urothelial carcinoma.

Gemcitabine and cisplatin chemotherapy (GC regimen) represents a standard treatment for advanced urothelial carcinoma. We performed an open-label, single-arm, non-randomised, phase 2 trial evaluating the addition of sunitinib to standard GC chemotherapy (SGC regimen). Overall, 63 treatment-naïve participants were recruited and received up to six 21-d cycles of cisplatin 70 mg/m2 (intravenously [IV], day 1) and gemcitabine 1000 mg/m2 (IV, days 1 and 8) combined with sunitinib 37.5 mg (orally, days 2–15). Following review of toxicity after the first six patients, the sunitinib dose was reduced to 25 mg for all patients. Overall response rate was 64%, with response noted in 37 of 58 patients. At 6 mo, 30 of 58 assessable patients (52%; 90% confidence interval [CI], 40–63%) were progression free. Median overall survival was 12 mo (95% CI, 9–15) and was heavily influenced by Bajorin prognostic group. Grade 3–4 toxicities were predominantly haematologic and limited the deliverability of the triple SGC regimen. The trial did not meet its prespecified primary end point of >60% patients progression free at 6 mo. Cumulative myelosuppression led to treatment delays of gemcitabine and cisplatin and dose reduction and/or withdrawal of sunitinib in the majority of cases. The triple-drug combination was not well tolerated. Phase 3 evaluation of the triple SGC regimen in advanced transitional cell carcinoma is not recommended. Patient summary The addition of sunitinib to standard cisplatin and gemcitabine chemotherapy was poorly tolerated and did not improve outcomes in advanced urothelial carcinoma. Treatment delivery was limited by myelotoxicity.

Serum total hCGβ level is an independent prognostic factor in transitional cell carcinoma of the urothelial tract

Background:Serum total human chorionic gonadotrophin β subunit (hCGβ) level might have prognostic value in urothelial transitional cell carcinoma (TCC) but has not been investigated for independence from other prognostic variables.Methods:We utilised a clinical database of patients receiving chemotherapy between 2005 and 2011 for urothelial TCC and an independent cohort of radical cystectomy patients for validation purposes. Prognostic variables were tested by univariate Kaplan–Meier analyses and log-rank tests. Statistically significant variables were then assessed by multivariate Cox regression. Total hCGβ level was dichotomised at < vs ⩾2 IU l−1.Results:A total of 235 chemotherapy patients were eligible. For neoadjuvant chemotherapy, established prognostic factors including low ECOG performance status, normal haemoglobin, lower T stage and suitability for cisplatin-based chemotherapy were associated with favourable survival in univariate analyses. In addition, low hCGβ level was favourable when assessed either before (median survival not reached vs 1.86 years, P=0.001) or on completion of chemotherapy (4.27 vs 0.42 years, P=0.000002). This was confirmed in multivariate analyses and in patients receiving first- and second-line palliative chemotherapy, and in a radical cystectomy validation set.Conclusions:Serum total hCGβ level is an independent prognostic factor in patients receiving chemotherapy for urothelial TCC in both curative and palliative settings.

A randomized, double-blind phase II study evaluating cediranib versus cediranib and saracatinib in patients with relapsed metastatic clear-cell renal cancer (COSAK)

BACKGROUND Preclinical work suggests SRC proteins have a role in the development of resistance to vascular endothelial growth factor (VEGF) targeted therapy in metastatic clear-cell renal cancer (mRCC). This hypothesis was tested in this trial using the SRC inhibitor saracatinib and the VEGF inhibitor cediranib. PATIENTS AND METHODS Patients with disease progression after ≥1 VEGF-targeted therapy were eligible to participate in this double-blind, randomized (1:1) phase II study. The study compared the combination cediranib 30 mg once daily (o.d.) and saracatinib 175 mg o.d. (CS) (n = 69) or cediranib 45 mg o.d. and placebo o.d

COAST (Cisplatin ototoxicity attenuated by aspirin trial): A phase II double-blind, randomised controlled trial to establish if aspirin reduces cisplatin induced hearing-loss

Background Cisplatin is one of the most ototoxic chemotherapy drugs, resulting in a permanent and irreversible hearing loss in up to 50% of patients. Cisplatin and gentamicin are thought to damage hearing through a common mechanism, involving reactive oxygen species in the inner ear. Aspirin has been shown to minimise gentamicin-induced ototoxicity. We, therefore, tested the hypothesis that aspirin could also reduce ototoxicity from cisplatin-based chemotherapy. Methods A total of 94 patients receiving cisplatin-based chemotherapy for multiple cancer types were recruited into a phase II, double-blind, placebo-controlled trial and randomised in a ratio of 1:1 to receive aspirin 975 mg tid and omeprazole 20 mg od, or matched placebos from the day before, to 2 days after, their cisplatin dose(s), for each treatment cycle. Patients underwent pure tone audiometry before and at 7 and 90 days after their final cisplatin dose. The primary end-point was combined hearing loss (cHL), the summed hearing loss at 6 kHz and 8 kHz, in both ears. Results Although aspirin was well tolerated, it did not protect hearing in patients receiving cisplatin (p-value = 0.233, 20% one-sided level of significance). In the aspirin arm, patients demonstrated mean cHL of 49 dB (standard deviation [SD] 61.41) following cisplatin compared with placebo patients who demonstrated mean cHL of 36 dB (SD 50.85). Women had greater average hearing loss than men, and patients treated for head and neck malignancy experienced the greatest cHL. Conclusions Aspirin did not protect from cisplatin-related ototoxicity. Cisplatin and gentamicin may therefore have distinct ototoxic mechanisms, or cisplatin-induced ototoxicity may be refractory to the aspirin regimen used here.

854PTREATMENT OUTCOME AND PATTERNS OF RELAPSE FOLLOWING ADJUVANT CARBOPLATIN FOR STAGE 1 SEMINOMA: RESULTS FROM A 17 YEAR UK EXPERIENCE

ABSTRACT Aim: The prognosis for stage 1 seminoma is excellent with a cure rate approaching 100%, but without adjuvant therapy, approximately 15-20% of patients may relapse and require salvage treatment. The TE19 trial confirmed the efficacy of a single dose of adjuvant carboplatin (AUC 7) in reducing recurrence rate. This study reviews our regional experience, with a focus on the presentation, management and outcome of relapsed patients. Methods: A retrospective clinical database was constructed for patients who have received one cycle of adjuvant carboplatin (AUC 7) between 1996 and 2013 for stage 1 seminoma. Tumour characteristics, clinical outcomes and patient relapse were evaluated. Results: 518 patients were eligible for inclusion. All patients underwent nuclear medicine measurement of GFR. Median age of diagnosis was 38 (range 18 – 73). Median tumour size was 32mm (range 4 – 110) and 57% had rete testis invasion. Median time from orchidectomy to chemotherapy was 44.5 days (range 10 – 174). 18 patients (3.5%) presented with bilateral disease or developed a contralateral germ cell tumour during follow up; median 94 months (range 0 – 265). With a median follow up of 43.2 months (range 0 – 199), 22 patients (4.2%) have relapsed. Median time to relapse was 22.4 months (range 11 – 108) with the majority of patients (13/518; 2.5%) relapsing within 2 years. Relapse beyond 4 years was very uncommon (4/518: Conclusions: This is, to our knowledge, the biggest non-trial series describing the clinical outcome and relapse data of patients with stage 1 seminoma treated with a single cycle of adjuvant carboplatin chemotherapy. Our results confirm the excellent prognosis for these patients with outcomes similar to those of prospective clinical trials. Disclosure: All authors have declared no conflicts of interest.