A phase IB study of durvalumab with or without tremelimumab and platinum-doublet chemotherapy in advanced solid tumours: Canadian Cancer Trials Group Study IND226.

This multicenter phase Ib study aimed to establish a recommended phase II dose for durvalumab (Du) ± tremelimumab (Tr) in combination with standard platinum-doublet chemotherapy. Eligible patients were enrolled into one of six dose levels (DL) of Du ± Tr which included concomitant treatment with standard platinum-doublet regimens; (pemetrexed, gemcitabine, etoposide, (each with cisplatin or carboplatin) or nab-paclitaxel (with carboplatin)). Dose escalation was according to a Rolling Six type design. Both weight-based and fixed dosing of Du and Tr were explored. Du was continued until progression. Tr dosing was finite (up to 6 doses) with increasing dose and/or frequency by DL. 136 patients were enrolled. The majority of drug-related adverse events (AEs) were ≤ grade 2 and attributable to chemotherapy. AEs considered related to immunotherapy were mainly ≤ grade 2; the most frequent (occurring ≥10 %) were colitis/diarrhea, skin, and thyroid dysfunction. Seven patients had DLTs including pneumonitis, myocarditis, diarrhea, encephalitis, motor neuropathy, and enterocolitis. There were 2 treatment-related deaths. Tr and Du exposures did not appear affected by chemotherapy. Among the 73 non-small cell lung cancer (NSCLC) patients treated, the objective response rate was 51 % (95 %CI = 38.7-62.6 %) with a median progression-free and overall survival of 6.5 months (95 % CI = 5.5-9.4 months) and 19.8 months (95 % CI = 14.8 months - not yet reached) respectively. Anti-tumour activity was observed across PD-L1 subtypes. Du 1500 mg q3w and Tr 75 mg q3wx5 can be safely combined with platinum-doublet chemotherapy. Efficacy among NSCLC patients appears comparable to results from other immunotherapy and chemotherapy combination trials. NCT02537418.

Seamless Designs: Current Practice and Considerations for Early-Phase Drug Development in Oncology.

Traditionally, drug development has evaluated dose, safety, activity, and comparative benefit in a sequence of phases using trial designs and endpoints specifically devised for each phase. Innovations in drug development seek to consolidate the phases and rapidly expand accrual with "seamless" trial designs. Although consolidation and rapid accrual may yield efficiencies, widespread use of seamless first-in-human (FiH) trials without careful consideration of objectives, statistical analysis plans, or trial oversight raises concerns. A working group formed by the National Cancer Institute convened to consider and discuss opportunities and challenges for such trials as well as encourage responsible use of these designs. We reviewed all abstracts presented at American Society of Clinical Oncology annual meetings from 2010 to 2017 for FiH trials enrolling at least 100 patients. We identified 1786 early-phase trials enrolling 57 559 adult patients. Fifty-one of the trials (2.9%) investigated 50 investigational new drugs, were seamless, and accounted for 14.6% of the total patients. The seamless trials included a median of 3 (range = 1-13) expansion cohorts. The overall risk of clinically significant treatment-related adverse events (grade 3-4) was 49.1% (range = 0.0-100%), and seven studies reported at least one toxic death. Rapid expansion of FiH trials may lead to earlier drug approval and corresponding widespread patient access to active therapeutics. Nevertheless, seamless designs must adhere to established ethical, scientific, and statistical standards. Protocols should include prospectively planned analyses of efficacy in disease- or biomarker-defined cohorts of sufficient rigor to support accelerated approval.

Adjuvant chemotherapy for resected early-stage non-small cell lung cancer.

BACKGROUND: To evaluate the effects of administering chemotherapy following surgery, or following surgery plus radiotherapy (known as adjuvant chemotherapy) in patients with early stage non-small cell lung cancer (NSCLC),we performed two systematic reviews and meta-analyses of all randomised controlled trials using individual participant data. Results were first published in The Lancet in 2010. OBJECTIVES: To compare, in terms of overall survival, time to locoregional recurrence, time to distant recurrence and recurrence-free survival:A. Surgery versus surgery plus adjuvant chemotherapyB. Surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapyin patients with histologically diagnosed early stage NSCLC.(2)To investigate whether or not predefined patient subgroups benefit more or less from cisplatin-based chemotherapy in terms of survival. SEARCH METHODS: We supplemented MEDLINE and CANCERLIT searches (1995 to December 2013) with information from trial registers, handsearching relevant meeting proceedings and by discussion with trialists and organisations. SELECTION CRITERIA: We included trials of a) surgery versus surgery plus adjuvant chemotherapy; and b) surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapy, provided that they randomised NSCLC patients using a method which precluded prior knowledge of treatment assignment. DATA COLLECTION AND ANALYSIS: We carried out a quantitative meta-analysis using updated information from individual participants from all randomised trials. Data from all patients were sought from those responsible for the trial. We obtained updated individual participant data (IPD) on survival, and date of last follow-up, as well as details of treatment allocated, date of randomisation, age, sex, histological cell type, stage, and performance status. To avoid potential bias, we requested information for all randomised patients, including those excluded from the investigators' original analyses. We conducted all analyses on intention-to-treat on the endpoint of survival. For trials using cisplatin-based regimens, we carried out subgroup analyses by age, sex, histological cell type, tumour stage, and performance status. MAIN RESULTS: We identified 35 trials evaluating surgery plus adjuvant chemotherapy versus surgery alone. IPD were available for 26 of these trials and our analyses are based on 8447 participants (3323 deaths) in 34 trial comparisons. There was clear evidence of a benefit of adding chemotherapy after surgery (hazard ratio (HR)= 0.86, 95% confidence interval (CI)= 0.81 to 0.92, p< 0.0001), with an absolute increase in survival of 4% at five years.We identified 15 trials evaluating surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy alone. IPD were available for 12 of these trials and our analyses are based on 2660 participants (1909 deaths) in 13 trial comparisons. There was also evidence of a benefit of adding chemotherapy to surgery plus radiotherapy (HR= 0.88, 95% CI= 0.81 to 0.97, p= 0.009). This represents an absolute improvement in survival of 4% at five years.For both meta-analyses, we found similar benefits for recurrence outcomes and there was little variation in effect according to the type of chemotherapy, other trial characteristics or patient subgroup.We did not undertake analysis of the effects of adjuvant chemotherapy on quality of life and adverse events. Quality of life information was not routinely collected during the trials, but where toxicity was assessed and mentioned in the publications, it was thought to be manageable. We considered the risk of bias in the included trials to be low. AUTHORS' CONCLUSIONS: Results from 47 trial comparisons and 11,107 patients demonstrate the clear benefit of adjuvant chemotherapy for these patients, irrespective of whether chemotherapy was given in addition to surgery or surgery plus radiotherapy. This is the most up-to-date and complete systematic review and individual participant data (IPD) meta-analysis that has been carried out.

Design and conduct of early clinical studies of two or more targeted anticancer therapies: recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies.

The Methodology for the Development of Innovative Cancer Therapies (MDICT) task force considered aspects of the design and conduct of early (phase I and II) studies of combinations of molecular targeted agents during their 2012 meeting. The task force defined necessary non-clinical data, such as evidence of additive or synergistic effects in multiple molecularly credentialed and validated models, and appropriate pharmacodynamic marker development. A robust hypothesis was considered critical while non-clinical pharmacokinetic studies were also considered valuable. Clinical trials should include clear objectives that will prove or disprove the hypothesis. Predictive biomarkers/classifiers should be explored in phase I studies, rather than used to select patients. Trial design should be efficient and flexible rather than based on a strict progression from phase I to II to III; researchers could consider phase I studies with an expansion cohort, Phase I/II designs or phase II studies with a safety run in. Pharmacokinetics are recommended when interactions or overlapping toxicity is expected. Pharmacodynamic evaluations should be considered especially in a subset of patients closest to the recommended dose; an attempt should be made to validate surrogate tissues to enable inclusion for all patients. Schedule and or dose should be formally explored for e.g. with a randomised or an adaptive design. Data and knowledge sharing was strongly recommended, including the creation of formal or informal consortia of laboratories with individual expertise in pathway or target based models, collaboration between companies to ensure that agents which are 'best in class' are combined, and the development of databases which will be able to inform the development of future recommendations/guidelines.

Design and conduct of phase II studies of targeted anticancer therapy: recommendations from the task force on methodology for the development of innovative cancer therapies (MDICT).

The Methodology for the Development of Innovative Cancer Therapies (MDICT) task force considered aspects of the design and conduct of phase II studies for molecular targeted agents during their 2007 meeting. The task force recommended that multinomial endpoints and designs should be considered for phase II studies of targeted agents, that both single arm as well as randomised designs remain appropriate in certain settings, and that further assessment of novel endpoints (tumour growth kinetic assessment, biomarker or functional imaging) and designs (randomised discontinuation or Bayesian adaptive design) be encouraged. The MDICT cautioned on the use of small randomised trials which have a number of statistical pitfalls and dangers and strongly encouraged the complete reporting, including negative trials, in the scientific literature.

Endpoints and other considerations in phase I studies of targeted anticancer therapy: recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies (MDICT).

Oncology drug development has seen a paradigm shift in the past decade from traditional cytotoxic agents to molecular targeted therapies. Given the different mechanisms and toxicities of these agents, drug development methodology may also require novel approaches. To address emerging issues in oncology drug development the 'Methodology for the Development of Innovative Cancer Therapies' (MDICT) task force was established to provide a forum for academic leaders involved in cancer drug development to discuss methodological issues inherent to the study of targeted anticancer therapy. At the inaugural MDICT meeting in 2006, discussion focused on the most appropriate primary endpoints for first-in-man phase I studies of targeted anticancer agents and organisational issues of such studies. This report summarises the scientific reviews and discussions as well as the recommendations regarding phase I trial design formulated by the MDICT task force.

Quality of life analyses in a clinical trial of DPPE (tesmilifene) plus doxorubicin versus doxorubicin in patients with advanced or metastatic breast cancer: NCIC CTG Trial MA.19.

BACKGROUND: DPPE (tesmilifene) plus doxorubicin (DOX) demonstrated a significant improvement in survival versus DOX in a phase III clinical trial in advanced breast cancer. However, DPPE is associated with unusual toxicity in the form of hallucinations, nausea and vomiting which were anticipated to impact on short-term quality of life (QOL). METHODS: Standard National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) approaches were applied as the primary method to analyze the QOL data from this trial. This includes cross-sectional comparisons, together with a global test for the QOL response rate. Sensitivity analyses were also performed for selected QOL domains and items, using other types of summary measures and statistics. RESULTS: Two hundred seventy one patients (89% of randomized) submitted the baseline QOL questionnaires and were included in the QOL analysis. No statistically significant difference in QOL response between treatment arms was found for any domain or item except nausea and vomiting (P = 0.04). Cross-sectional comparisons showed statistically significant differences for some domains/items at specific assessment times with all differences favoring the DOX alone arm. Patients on DPPE/DOX arm were significantly worse in terms of average and median pain change scores. CONCLUSION: Different analyses yielded slightly different conclusions but, in general, the QOL analyses were concordant and showed that patients on DOX alone had fewer disease and treatment related adverse events and better QOL. Interestingly, the QOL response analysis also showed that aggressive premedication regimens appear to ameliorate potential negative effects of DPPE on emesis and nausea as measured by patient assessed QOL.