Xavier Paoletti

Randomised proof-of-concept phase II trial comparing targeted therapy based on tumour molecular profiling vs conventional therapy in patients with refractory cancer: results of the feasibility part of the SHIVA trial

Background:The SHIVA trial is a multicentric randomised proof-of-concept phase II trial comparing molecularly targeted therapy based on tumour molecular profiling vs conventional therapy in patients with any type of refractory cancer. Results of the feasibility study on the first 100 enrolled patients are presented.Methods:Adult patients with any type of metastatic cancer who failed standard therapy were eligible for the study. The molecular profile was performed on a mandatory biopsy, and included mutations and gene copy number alteration analyses using high-throughput technologies, as well as the determination of oestrogen, progesterone, and androgen receptors by immunohistochemistry (IHC).Results:Biopsy was safely performed in 95 of the first 100 included patients. Median time between the biopsy and the therapeutic decision taken during a weekly molecular biology board was 26 days. Mutations, gene copy number alterations, and IHC analyses were successful in 63 (66%), 65 (68%), and 87 (92%) patients, respectively. A druggable molecular abnormality was present in 38 patients (40%).Conclusions:The establishment of a comprehensive tumour molecular profile was safe, feasible, and compatible with clinical practice in refractory cancer patients.

Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma

BackgroundnPembrolizumab and nivolumab are immune checkpoint inhibitors targeting PD-1 that have recently been approved in pretreated recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients. In the clinic, some patients seem not only not to benefit from anti-PD-L1/PD-1 agents but rather to experience an acceleration of tumor growth kinetics (TGK).nnnPatients and methodsnWe retrospectively compared TGK on immunotherapy and TGK on last treatment in patients with R/M HNSCC treated with PD-1/PD-L1 inhibitors in four French centers. The TGK ratio (TGKR, ratio of the slope of tumor growth before treatment and the slope of tumor growth on treatment) was calculated. Hyperprogression was defined as a TGKR ≥ 2.nnnResultsnFrom September 2012 to September 2015, 34 patients were identified. Patterns of recurrence included exclusive loco-regional recurrence in 14 patients, exclusive distant metastases in 11 patients, and both in 9 patients. No pseudo-progression was observed. Hyperprogression was observed in 10 patients (29%), including 9 patients with at least a locoregional recurrence, and only 1 patient with exclusively distant metastases. Hyperprogression significantly correlated with a regional recurrence (TGKR ≥ 2: 90% versus TGKR < 2: 37%, Pu2009=u20090.008), but not with local or distant recurrence. Hyperprogression was associated with a shorter progression-free survival (PFS) according to RECIST (Pu2009=u20090.003) and irRECIST (Pu2009=u20090.02), but not with overall survival (Pu2009=u20090.77).nnnConclusionsnHyperprogression was observed in 29% of patients with R/M HNSCC treated with anti-PD-L1/PD-1 agents and correlated with a shorter PFS. It occurred in 39% of patients with at least a locoregional recurrence and 9% of patients with exclusively distant metastases. No pseudo-progressions were reported. Mechanisms and causality of hyperprogression should further be assessed through prospective controlled studies.

Breast cancer risk in relation to abortion: Results from the EPIC study

The role of spontaneous and induced abortion on breast cancer risk is examined among 267,361 women recruited into the European Prospective Investigation into Cancer and nutrition between 1992 and 2000. The data were collected from 20 centers, across 9 countries, and included information on a total of 4,805 women with breast cancer, of whom 1,657 reported having ever had any type of abortion. Overall, the relative risk of breast cancer in women who reported ever having had a spontaneous abortion was not significantly elevated when compared with women who reported never having had such an abortion (RR = 1.07, 95% CI = 0.99–1.14). However, there was some evidence of a slight increase in the risk of breast cancer among women who reported having had 2 or more spontaneous abortions (1.20, 1.07–1.35). The relative risk of breast cancer among women who reported ever having had an induced abortion when compared to women who reported never having had an induced abortion was 0.95 (0.87–1.03). Overall, the findings provide further unbiased evidence of the lack of an adverse effect of induced abortion on breast cancer risk.

Induced and spontaneous abortion and breast cancer risk: Results from the E3N cohort study

Recent reviews reach conflicting conclusions on breast cancer risk after spontaneous or induced abortion. E3N is a large‐scale cohort study collecting detailed information on environmental and reproductive factors. We investigated the relation between breast cancer and a history of induced and/or spontaneous abortion, using the data from the 100,000 women aged 40–65 at entrance in 1990. Among them, over 2,600 new invasive breast cancers had been diagnosed by June 2000. Multivariate analysis, adjusted for known potential confounders, showed no association between a history of induced abortion and breast cancer risk either in the whole population (relative risk [RR] = 0.91, 95% confidence interval [CI] 0.82–0.99) or in subgroups defined by parity or by menopausal status. Overall, the association between spontaneous abortion and breast cancer was not significant (RR = 1.05, 95% CI 0.95–1.15). However, there is a suggestion of increased risk with increased number of miscarriages (RR = 1.20, 95% CI 0.92–1.56 after 3 or more). Moreover, an interaction with menopausal status was observed. In premenopause, the risk decreased with increasing number of spontaneous abortions, whereas it increased in postmenopause. Among nulliparous and parous women, the relative risk estimates were respectively equal to 1.16 (95% CI 1.04–1.30, p trend < 0.0008) and 1.14 (95% CI 1.01–1.28, p trend = 0.005). Premenopausal breast cancer, on the other hand, appeared to be less frequent in women who had had repeated miscarriages. We conclude that there is no relationship between breast cancer and induced abortion but that an association with spontaneous abortion is possible and may depend on menopausal status.

An explorative study to assess the association between health-related quality of life and the recommended phase II dose in a phase I trial: idarubicin-loaded beads for chemoembolisation of hepatocellular carcinoma

Objectives The objective of this study was to explore the association between health-related quality of life (HRQoL) and the recommended phase 2 dose in a phase I clinical trial according to the Time to HRQoL deterioration approach (TTD). Setting This is a phase I dose-escalation trial of transarterial chemoembolisation (TACE) with idarubicin-loaded beads performed in cirrhotic patients with hepatocellular carcinoma. Patients had to complete the EORTC QLQ-C30 HRQoL questionnaire at baseline and at days 15, 30 and 60 after TACE. Participants Patients aged ≥18u2005years with HCC unsuitable for curative treatments were evaluated for the study (N=21). Primary and secondary outcome measurements The primary objective was to determine the maximum tolerated dose (MTD) of idarubicin loaded after a single TACE session. MTD was defined as the dose level closest to that causing dose-limiting toxicity in 20% of patients. HRQoL was the secondary end point. Results Between March 2010 and March 2011, 9, 6 and 6 patients were included at idarubicin dose levels of 5, 10 and 15u2005mg, respectively. Calculated MTD of idarubicin was 10u2005mg. At the 10u2005mg idarubicin dose, patients presented a longer TTD than at 5u2005mg, for global health status (HR=0.91 (95% CI 0.18 to 4.72)), physical functioning (HR=0.38 (0.04 to 3.22)), fatigue (HR=0.67 (0.18 to 2.56)) and pain (HR=0.47 (0.05 to 4.24)). Conclusions These HRQoL results were consistent with the estimated MTD, with a median TTD for global health status of 41u2005days (21 to NA) at 5u2005mg, 23u2005days (20 to NA) at 10u2005mg and 25u2005days (17 to NA) at 15u2005mg. These results show the importance of studying HRQoL in phase I trials. Trial registration number NCT01040559; Post-results.

A Poisson approach to the validation of failure time surrogate endpoints in individual patient data meta-analyses:

Surrogate endpoints are often used in clinical trials instead of well-established hard endpoints for practical convenience. The meta-analytic approach relies on two measures of surrogacy: one at the individual level and one at the trial level. In the survival data setting, a two-step model based on copulas is commonly used. We present a new approach which employs a bivariate survival model with an individual random effect shared between the two endpoints and correlated treatment-by-trial interactions. We fit this model using auxiliary mixed Poisson models. We study via simulations the operating characteristics of this mixed Poisson approach as compared to the two-step copula approach. We illustrate the application of the methods on two individual patient data meta-analyses in gastric cancer, in the advanced setting (4069 patients from 20 randomized trials) and in the adjuvant setting (3288 patients from 14 randomized trials).

Design and statistical principles of the SHIVA trial.

Most molecularly targeted agents (MTAs) are expected to work in subgroups of cancer patients characterized by the presence of molecular alterations in the tumor cells. However, clinical development is generally carried out according to tumor type. The SHIVA randomized trial on the contrary has been set up to investigate which of tumor biology or tumor location and histology is the most important to select treatment in patients with cancer refractory to standard of care. Statistical principles, specificities, strengths and limitations of this trial that evaluates an omic-based algorithm to select the targeted agent are reviewed. In particular, the need for a randomized trial where the various steps to build the algorithm are explicitly described and standardized is emphasized. The impact of an algorithm that would be partly misspecified (i.e., that would lead to correct treatment selection for some tumor molecular profile but not for all) is quantified.

A proposal for a new PhD level curriculum on quantitative methods for drug development

This paper provides an overview of “Improving Design, Evaluation and Analysis of early drug development Studies” (IDEAS), a European Commission–funded network bringing together leading academic institutions and small‐ to large‐sized pharmaceutical companies to train a cohort of graduate‐level medical statisticians. The network is composed of a diverse mix of public and private sector partners spread across Europe, which will host 14 early‐stage researchers for 36 months. IDEAS training activities are composed of a well‐rounded mixture of specialist methodological components and generic transferable skills. Particular attention is paid to fostering collaborations between researchers and supervisors, which span academia and the private sector. Within this paper, we review existing medical statistics programmes (MSc and PhD) and highlight the training they provide on skills relevant to drug development. Motivated by this review and our experiences with the IDEAS project, we propose a concept for a joint, harmonised European PhD programme to train statisticians in quantitative methods for drug development.

Randomized dose-escalation designs for drug combination cancer trials with immunotherapy

ABSTRACT This work considers Phase I cancer dual-agent dose-escalation clinical trials in which one of the compounds is an immunotherapy. The distinguishing feature of trials considered is that the dose of one agent, referred to as a standard of care, is fixed and another agent is dose-escalated. Conventionally, the goal of a Phase I trial is to find the maximum tolerated combination (MTC). However, in trials involving an immunotherapy, it is also essential to test whether a difference in toxicities associated with the MTC and the standard of care alone is present. This information can give useful insights about the interaction of the compounds and can provide a quantification of the additional toxicity burden and therapeutic index. We show that both, testing for difference between toxicity risks and selecting MTC can be achieved using a Bayesian model-based dose-escalation design with two modifications. Firstly, the standard of care administrated alone is included in the trial as a control arm and each patient is randomized between the control arm and one of the combinations selected by a model-based design. Secondly, a flexible model is used to allow for toxicities at the MTC and the control arm to be modeled directly. We compare the performance of two-parameter and four-parameter logistic models with and without randomization to a current standard of such trials: a one-parameter model. It is found that at the cost of a small reduction in the proportion of correct selections in some scenarios, randomization provides a significant improvement in the ability to test for a difference in the toxicity risks. It also allows a better fitting of the combination-toxicity curve that leads to more reliable recommendations of the combination(s) to be studied in subsequent phases.

Outcomes and prognostic factors for relapsed or refractory lymphoma patients in phase I clinical trials

SummaryBackground Although safety and prognostic factors for overall survival (OS) have been extensively studied in Phase I clinical trials on patients with solid tumours, data on lymphoma trials are scarce. Here, we investigated safety, outcomes and prognostic factors in relapsed or refractory lymphoma patients included in a series of Phase I trials. Method and patients All consecutive adult patients with recurrent/refractory lymphoma enrolled in 26 Phase I trials at a single cancer centre in France between January 2008 and June 2016 were retrospectively assessed. Results 133 patients (males: 65%) were included in the analysis. The median (range) age was 65 (23–86). Aggressive non-Hodgkin, indolent non-Hodgkin and Hodgkin types accounted for 64%, 25% and 11% of the patients, respectively. The patients had received a median (range) of 3 (1–13) lines of treatment prior to trial entry. The median [95% confidence interval] progression-free survival and OS times were 3.0 [1.8–3.6] and 17.8 [12.7–30.4] months, respectively. High-grade toxicity (grade 3 or higher, according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events classification) was experienced by 56 of the 133 patients (42%) and was related to the investigational drug in 44 of these cases (79%). No toxicity-related deaths occurred. Dose-limiting toxicity (DLT) was encountered in 11 (9%) of the 116 evaluable patients. High-grade toxicity occurred during the DLT period for 34 of the 56 patients (61%) and after the DLT period in the remaining 22 (39%). The main prognostic factors for poor OS were the histological type (i.e. tumour aggressiveness), an elevated serum LDH level, and a low serum albumin level. Early withdrawal from a trial was correlated with the performance status score, the histological type and the serum LDH level. The overall objective response and disease control rates were 24% and 57%, respectively. Conclusion Performance status, LDH, albumin and histological type (tumour aggressiveness) appear to be the most relevant prognostic factors for enrolling Phase I participants with relapsed or refractory lymphoma. 39% of the patients experienced a first high-grade toxic event after the dose-limiting toxicity period, suggesting that the conventional concept of dose-limiting toxicity (designed for chemotherapy) should be redefined in the era of modern cancer therapies.