Clinical trial designs for evaluating and exploiting cancer evolution.

The evolution of drug-resistant cell subpopulations causes cancer treatment failure. Current preclinical evidence shows that it is possible to model herding of clonal evolution and collateral sensitivity where an initial treatment could favourably influence the response to a subsequent one. Novel therapy strategies exploiting this understanding are being considered, and clinical trial designs for steering cancer evolution are needed. Furthermore, preclinical evidence suggests that different subsets of drug-sensitive and resistant clones could compete between themselves for nutrients/blood supply, and clones that populate a tumour do so at the expense of other clones. Treatment paradigms based on this clinical application of exploiting cell-cell competition include intermittent dosing regimens or cycling different treatments before progression. This will require clinical trial designs different from the conventional practice of evaluating responses to individual therapy regimens. Next-generation sequencing to assess clonal dynamics longitudinally will improve current radiological assessment of clinical response/resistance and be incorporated into trials exploiting evolution. Furthermore, if understood, clonal evolution can be used to therapeutic advantage, improving patient outcomes based on a new generation of clinical trials.

A Phase I Trial of CT900, a Novel α-Folate Receptor-Mediated Thymidylate Synthase Inhibitor, in Patients with Solid Tumors with Expansion Cohorts in Patients with High-Grade Serous Ovarian Cancer.

PURPOSE: CT900 is a novel small molecule thymidylate synthase inhibitor that binds to α-folate receptor (α-FR) and thus is selectively taken up by α-FR-overexpressing tumors. PATIENTS AND METHODS: A 3+3 dose escalation design was used. During dose escalation, CT900 doses of 1-6 mg/m2 weekly and 2-12 mg/m2 every 2 weeks (q2Wk) intravenously were evaluated. Patients with high-grade serous ovarian cancer were enrolled in the expansion cohorts. RESULTS: 109 patients were enrolled: 42 patients in the dose escalation and 67 patients in the expansion cohorts. At the dose/schedule of 12 mg/m2/q2Wk (with and without dexamethasone, n = 40), the most common treatment-related adverse events were fatigue, nausea, diarrhea, cough, anemia, and pneumonitis, which were predominantly grade 1 and grade 2. Levels of CT900 more than 600 nmol/L needed for growth inhibition in preclinical models were achieved for >65 hours at a dose of 12 mg/m2. In the expansion cohorts, the overall response rate (ORR), was 14/64 (21.9%). Thirty-eight response-evaluable patients in the expansion cohorts receiving 12 mg/m2/q2Wk had tumor evaluable for quantification of α-FR. Patients with high or medium expression had an objective response rate of 9/25 (36%) compared with 1/13 (7.7%) in patients with negative/very low or low expression of α-FR. CONCLUSIONS: The dose of 12 mg/m2/q2Wk was declared the recommended phase II dose/schedule. At this dose/schedule, CT900 exhibited an acceptable side effect profile with clinical benefit in patients with high/medium α-FR expression and warrants further investigation.

Building on the anti-PD1/PD-L1 backbone: combination immunotherapy for cancer.

Introduction: Immunotherapy has revolutionized the treatment of cancer. Given this growing success, at the same time, there are significant limitations and unanswered questions concerning response rates, duration of therapy, why some patients respond and others do not, and if combining different immune-agents would overcome this lack of response, increase the chance of success and postpone acquired resistance. Areas covered: The comprehension of how to properly modulate the immune pathways, the molecular and the immunological bases of the disease, will be fundamental to guide the development of therapeutic interventions and combinations that will be more suitable for treatment of cancer patients. In this review, we discuss the strategies of immunotherapy combinations in order to develop more effective immunotherapy programs, with a particular focus on melanoma and renal cancer patients, as well as the combination of immunotherapy and chemotherapy. Expert Opinion: Given the complexity of immune activation, combinatorial approaches are needed, and due to the considerable variability in tumor biology across patients and tumor types, patient selection and biomarkers need to be further explored. In summary, combined therapies have shown promising success, but additional and continuous research to identify the safety, efficacy, optimal combination, dosage and timing are still required.

Current and emerging systemic therapies for cutaneous metastatic melanoma.

INTRODUCTION: Melanoma therapies have evolved rapidly, and initial successes have translated into survival gains for patients with advanced melanoma. Both targeted and immune-therapy now have evidence in earlier stage disease. There are many new agents and combinations of treatments in development as potential future treatment options. This highlights the need for a reflection on current treatment practice trends that are guiding the development of potential new therapies. AREAS COVERED: In this review, the authors discuss the evidence for currently approved therapies for cutaneous melanoma, including adjuvant therapy, potential new biomarkers, and emerging treatments with early phase clinical trial data. The authors have searched both the PubMed and clinicaltrials.gov databases for published clinical trials and discuss selected landmark trials of current therapies and of investigational treatment strategies with early evidence for the treatment of melanoma. EXPERT OPINION: Significant efficacy has been demonstrated with both immune checkpoint inhibitors and targeted therapies in treating advanced melanoma. A multitude of novel therapies are in development and there is need for instructive biomarker assessment to identify patients likely to respond or be refractory to current therapies, to identify mechanisms of resistance and to direct further treatment options to patients based on individual disease biology.

A study of 1088 consecutive cases of electrolyte abnormalities in oncology phase I trials.

BACKGROUND: The incidence and clinical significance of electrolyte abnormalities (EAs) in phase I clinical trials are unknown. The objective of this study is to evaluate the incidence and severity of EAs, graded according to CTCAE, v4.03, to identify variables associated with EAs and their prognostic significance in a phase I population. METHODS: A retrospective chart review was performed of 1088 cases in 82 phase I clinical trials consecutively treated from 2011 to 2015 at the Drug Development Unit of the Royal Marsden Hospital. Cox regression analysis was performed to examine the relationship between overall survival (OS) and baseline characteristics, treating the occurrence of grade III/IV EAs as a time-varying covariate. RESULTS: The most common emergent EAs (all grades) were as follows: hyponatraemia 62%, hypokalaemia 40%, hypophosphataemia 32%, hypomagnesaemia 17% and hypocalcaemia 12%. Grade III/IV EAs occurred in 19% of cases. Grade III/IV EAs occurred during the dose-limiting toxicity window in 8.46% of cases. Diarrhoea was associated with hypomagnesaemia at all grades (p < 0.001), hyponatraemia at all grades (p = 0.006) and with G3/G4 hypokalaemia (p = 0.02). Baseline hypoalbuminaemia and hyponatraemia were associated with a higher risk of developing other EAs during the trial in the univariate analysis. Patients who developed grade III/IV EAs during follow-up had an inferior median OS (26 weeks vs 37 weeks, hazard ratio = 1.61; p < 0.001). CONCLUSION: This is the first study to demonstrate the clinical significance of baseline hypoalbuminaemia and hyponatraemia, which are predictors of development of other EAs in phase I patients. Grade III/IV EAs are adverse prognostic factors of OS independent of serum albumin levels.

Efficacy of doxorubicin after progression on carboplatin and paclitaxel in advanced or recurrent endometrial cancer: a retrospective analysis of patients treated at the Brazilian National Cancer Institute (INCA).

The treatment of endometrial cancer (EC) is challenging. There is no standard of care for patients who progressed after carboplatin and paclitaxel (CT) and all available drugs show a small response and poor long-term survival in this scenario. The objective of this study was to evaluate the efficacy and toxicity profile of palliative doxorubicin after progression to CT therapy in advanced or recurrent EC. A retrospective review of the Brazilian National Cancer Institute database between 2009 and 2013 was performed, and all patients with recurrent and advanced EC treated with palliative doxorubicin after progression on CT were included. Progression-free survival (PFS), overall survival (OS), objective response rates as well as toxicity were evaluated. A total of 33 patients were enrolled, with a median age of 65.7 years. Objective responses were documented in 12.1% (3.0% of complete responses and 9.1% of partial responses). The median PFS was 4.4 months, and the median OS was 8.1 months for patients exposed to doxorubicin. The most common adverse event was anemia observed in 60.6% of patients. This retrospective study suggests that doxorubicin has a modest activity in patients with advanced or recurrent EC after treatment with CT.

Neutrophil-lymphocyte ratio kinetics in patients with advanced solid tumours on phase I trials of PD-1/PD-L1 inhibitors.

BACKGROUND: Although the neutrophil-lymphocyte ratio (NLR) is prognostic in many oncological settings, its significance in the immunotherapy era is unknown. Mechanistically, PD-1/PD-L1 inhibitors may alter NLR. We sought to characterise NLR kinetics in patients with advanced solid tumours treated with PD-1/PD-L1 inhibitors. METHODS: Electronic records of patients treated with PD-1/PD-L1 inhibitors on phase I trials across three sites were reviewed. A high NLR (hNLR) was predefined as >5. Univariate logistic regression models were used for toxicity, response analyses and Cox models for overall survival (OS) and progression-free survival analyses. Landmark analyses were performed (cycle two, three). Longitudinal analysis of NLR was performed utilising a mixed effect regression model. RESULTS: The median OS for patients with hNLR was 8.5 months and 19.4 for patients with low NLR, (hazard ratio [HR] = 1.85, 95% confidence interval [CI] 1.15-2.96, p = 0.01). On landmark analysis, hNLR was significantly associated with inferior OS at all time points with a similar magnitude of effect over time (p < 0.05). On multivariate analysis, NLR was associated with OS (HR 1.06, 95% CI 1.01-1.11, p = 0.01). NLR did not correlate with increased immune toxicity. Longitudinally, NLR correlated with response: NLR decreased by 0.09 (95% CI: -0.15 to -0.02; p = 0.01) per month in responders compared with non-responders. CONCLUSIONS: hNLR at baseline and during treatment is adversely prognostic in patients with advanced malignancies receiving PD-1/PD-L1 blockade. Importantly, NLR reduced over time in responders to immunotherapy. Taken together, these data suggest that baseline and longitudinal NLR may have utility as a unique biomarker to aid clinical decision-making in patients receiving immunotherapy.

A phase I study of mTOR inhibitor everolimus in association with cisplatin and radiotherapy for the treatment of locally advanced cervix cancer: PHOENIX I.

BACKGROUND: Cervix cancer (CC) represents the fourth most common cancer in women. Treatment involving cisplatin and radiotherapy has been the standard for locally advanced disease. Everolimus inhibits the aberrant activity of mTOR that is part of carcinogenesis in CC. Further everolimus inactivates the HPV E7 oncoprotein and inhibits its proliferation. Preclinical models have suggested that everolimus sensitizes tumoral cells and vasculature to cisplatin and radiotherapy. METHODS: In a 3 + 3 design, the trial aimed to treat three dose levels of at least three patients with daily doses of everolimus (2.5, 5 and 10 mg/day), cisplatin and radiotherapy delivered in a 9-week interval in CC patients, stage IIB, IIIA or IIIB. Patients received everolimus from day -7 up to the last day of brachytherapy. Primary objective was to evaluate safety, toxicity and the maximum-tolerated dose (MTD) of everolimus in association with cisplatin and radiotherapy. Pharmacokinetic (PK) parameters and response rates were analyzed as secondary objectives. RESULTS: Thirteen patients were enrolled, 6 at 2.5 mg, 3 at 5 mg and 4 at 10 mg. Four patients did not complete the planned schedule, 1 at 2.5 mg presented grade 4 acute renal failure interpreted as dose-limiting toxicity (DLT) and 3 at 10 mg: 1 with disease progression, and 2 with DLTs-1 grade 3 rash and 1 grade 4 neutropenia. PK results were characterized by dose-dependent increases in AUC and C max. CONCLUSIONS: The MTD of everolimus in combination with cisplatin and radiotherapy has been defined as 5 mg/day. The data regarding safety and response rates support further studies.