Early Trial Discontinuation Research Articles

Adjuvant polypeptide vaccines for high-risk uveal melanoma.

e21509 Background: Due to biologic differences, uveal melanoma patients are often excluded from clinical trials for cutaneous melanoma; however, many antigens are shared between the two melanoma subtypes. Thus, our vaccine trials at the University of Virginia (UVA) have allowed enrollment of high-risk uveal melanoma patients, who have substantial risk of relapse without FDA-approved adjuvant therapy available. For the present study, we hypothesized that the vaccines would be well-tolerated and immunogenic in this population. We examined the clinical, immunogenicity and safety outcomes of subjects with uveal melanoma enrolled in our adjuvant vaccine clinical studies. Methods: Patients were identified through participation in an adjuvant vaccine study at UVA between 2012-2022. Ten patients received the 6-Melanoma-Helper Peptide (6-MHP) vaccine through Mel-65 and Mel-66 clinical trials (NCT03617328 and NCT04364230) and one patient received the 12-peptide MELITAC vaccine through the Mel-58 clinical trial (NCT01585350). Clinical outcomes included relapse-free (RFS) and overall survival (OS) and trial toxicity reporting. Immunogenicity was assessed by ex vivo interferon-gamma ELISpot assay of peripheral T cells. OS and RFS were reported by Kaplan-Meier survival analysis and compared by log rank test between groups. Results: Of the 11 identified patients, nine were male (82%) and two were female (18%), with a median age of 64 years. All patients were high risk by molecular testing, the majority by Castle Bioscience DecisionDx-UM. Five were PRAME positive, five PRAME negative, and one not reported. In the cohort, three patients had uveal melanoma recurrence and one subject died from metastatic disease during the evaluation period. The 5-year RFS and OS were 71% (95% CI 43-100) and 80% (95% CI 52-100), respectively. Two patients experienced dose-limiting, grade 3 toxicities to the vaccine, requiring early trial discontinuation, including one grade 3 injection-site reaction and one grade 3 uveitis. Nine patients experienced grade 1-2 toxicities, mostly injection-site reactions and constitutional symptoms. Of nine patients with available immunogenicity data, five (55%) had direct antigen-mediated immune response to vaccine. Two patients’ responses are pending. Patients with immunogenic response had a non-significant trend toward better RFS and OS (both p = 0.22). The 3-year RFS and OS were 100% for subjects with T cell response and the RFS and OS were 50% (95% CI 13-100) for patients without T cell response. Two of the relapsed patients did not have an immune response to vaccine, and response data were not available for the third. Conclusions: Melanoma polypeptide vaccines are immunogenic and safe in patients with uveal melanoma. Our early data suggests the possibility of early benefit with direct antigen response, though longer follow up and further study will be needed to investigate these findings.

Early discontinuation and results reporting of robot-assisted surgery studies registered on ClinicalTrials.gov: a research on research study

ObjectivesIn this study, we aimed to investigate the characteristics of robot-assisted surgery studies registered on ClinicalTrials.gov and identify factors associated with early trial discontinuation and timely results reporting.DesignWe searched ClinicalTrials.gov...

Early Termination of Oncology Clinical Trials in the United States.

The aim of this study was to evaluate the rate of early trial discontinuation of oncology trials and reasons for early termination, to assess potential trends in rates of oncology trial termination, and to perform a comprehensive analysis of predictors of early termination. This study intends to inform efforts in improving efficiency of the oncology clinical trial enterprise. We conducted a cross-sectional study of interventional cancer clinical trials registered in ClinicalTrials.gov database from September 27, 2007 to June 30, 2015, with at least one site listed in the United States. We evaluated predictors of early trial termination using Fisher exact or χ2 tests and logistic regression. Of 8687 trials, 22.74% (n= 1975) were terminated trials. Rates of early trial termination appeared stable over the study. Statistically significant univariate predictors of early termination for any reason include cancer category, phase, funding source, location, and age. In multivariable analysis, trials spanning multiple cancer categories and international trials were less likely to terminate early whereas phase 2 trials and trials funded by academia/foundation were more likely to terminate early. The most common reason for early termination was "Other, Multiple Reasons, or Unknown" (36.9%), followed by accrual issues (34.5%). In multivariate analysis among all terminated trials, supportive care trials, phase 2 trials, and non-industry funded trials had significantly higher odds of trial discontinuation specifically due to poor accrual. In this national sample of cancer clinical trials, early trial discontinuation was common. Many factors influenced early trial termination with poor accrual being a common reason. Specific trial features are associated with differential likelihood of early trial termination for any reason and for early trial termination due to poor accrual.

Characteristic and Early Discontinuation of Obsessive-Compulsive Disorder Trials Registered on ClinicalTrials.gov.

Objective: This study aimed to analyze the characteristics and reasons of early discontinuation of obsessive-compulsive disorder (OCD) trials registered on ClinicalTrials.gov.Methods: OCD trials and relevant publications were searched on ClinicalTrials.gov and PubMed, respectively. The characteristics and details regarding the timely publication of trials were recorded. Cox regression analysis was used to explore factors associated with the early discontinuation of OCD trials.Results: The analysis included 298 OCD therapy trials. Most investigations recruited <100 patients and were more likely to involve adults. Of all OCD studies identified, 67.8% were randomized and 61.4% were blind (single- or double-blind). Universities and hospitals were recorded as the two primary locations in the majority of trials. A total of 155 trials (52%) were completed; however, only 29% of those were published. Of the published trials, >70% were published at least 1 year after completion. Behavioral therapy trials were the most common type of major treatment-aimed OCD trials (39%), followed by drug trials (35.1%) and device/procedure trials (24.7%). The univariate Cox regression analysis indicated that drug trials [hazard ratio (HR) = 2.56, 95% confidence interval (CI): 1.21–5.43], absence of collaborators (HR = 3.87, 95% CI: 1.62–9.26), and sponsorship by industry (HR = 3.97, 95% CI: 1.49–10.53) were risk factors for early discontinuation of OCD trials. Further multivariate Cox regression showed that drug trials (HR = 3.93, 95% CI: 1.71–9.08) and absence of collaborators (HR = 5.17, 95% CI: 1.97–13.54) were independent risk factors for early trial discontinuation of OCD trials. The sensitivity analysis confirmed these results. Non-drug trials (OR = 3.32, 95% CI: 1.21–9.11), absence of collaborators (OR = 3.25, 95% CI: 1.10–9.60), and non-blinded trials (OR = 5.23, 95% CI: 1.05–26.2) were independent risk factors for unreported results in registry.Conclusion: The diagnosis and prevention of OCD are rarely investigated in trials. Underreporting and delayed reporting remain major problems. The type of intervention and participation of collaborators are associated with early discontinuation of OCD trials.

Chronic Myeloid Leukemia Patients' Voice: Preliminary Results from the Italian Substudy of Enestpath (CAMN107AIC05), Exploring the Emotional Experience of Patients in the Context of Treatment-Free Remission

Introduction:ENESTPath, an ongoing phase 3 study in patients with chronic myeloid leukemia (CML) in chronic phase, was designed to determine the optimal duration of consolidation treatment with nilotinib 300 mg twice daily required to remain in treatment-free remission (TFR) without molecular relapse, 12 months after entering TFR. With TFR as a new goal of therapy in clinical practice, there is a need for individual approaches and counselling for patients when preparing for a possible treatment discontinuation.An ongoing Italian substudy of ENESTPath assesses patients' emotional experience during and after stopping nilotinib therapy. To have a comprehensive evaluation of patients' psycho-emotional outcomes, both quantitative (questionnaires) and qualitative (expressive writing and interviews) methods are used. Here, we present preliminary qualitative data on the emotional experience of patients who were either ineligible for randomization or relapsed during TFR phase.Methods:Patients in stable MR4 for >12 months (≥MR4 in 4 of 5 PCR assessments, including the last assessment, in the last 12 months) in the consolidation phase were randomized to stop nilotinib and enter TFR phase immediately or to continue on nilotinib for another year and then enter TFR phase. Patients with unstable MR4 in the consolidation phase had to discontinue the trial early without attempting randomization. Patients who were ineligible for randomization or those who relapsed during TFR phase (loss of MMR, or the confirmed loss of MR4) had qualitative interviews.In-depth unstructured qualitative interviews were conducted according to interpretative phenomenological analysis (IPA) to explore patients' emotional experience of “being ineligible for randomization” and “failing TFR.” Interviews were guided using open-ended questions and followed patients' narrative flow; the interviewer facilitated the narration. Patients were asked to describe the course of their disease and their involvement in the clinical trial, including the final moments before trial discontinuation. Interviews were audio recorded, transcribed verbatim, and analyzed according to IPA.Results:Of the 30 patients included in this substudy so far, 10 (male, n=8; mean disease duration, 9.5 years) were interviewed, including 7 ineligible for randomization and 3 relapsing in TFR. As the study is still ongoing, these numbers are not representative of the total study population. The remaining 20 patients were either in TFR, year 2 of consolidation, or yet to be interviewed. Enrollment for qualitative research respects the criterion of the most possible variety (eg, socio-demographic characteristics, duration of the disease).In total, four themes that describe patients' experience were identified: experience of early trial discontinuation for unstable response, linked to the view on stopping treatment; experience of the illness particularly focused on diagnosis; impossibility to talk about death and view on the drug as lifesaver; and impact of the disease and treatment on future plans (Table).Patients' experience of not being able to continue the trial due to unstable response reflected a slightly negative emotional experience, and they saw the idea of stopping treatment as something useful but demanding. Patients remembered the communication of the diagnosis as an unthinkable drama that is difficult to express and a shock. They perceived the disease as invisible and had difficulties in thinking or talking about death; however, they referred to the drug therapy as essential for life and survival. Finally, the disease was also perceived as something that undermines future plans (Table).Conclusions:These preliminary findings described how patients perceived early trial discontinuation, and the way they give sense to it appears to have a relationship with individual disease experience. This qualitative analysis helps in understanding patients' perspective, both in terms of getting access to the inner subjective experience of having CML and its strict relationship with the involvement in a trial or its cessation. The insights provided show that patients' perception of their disease, on TFR, and on failure to stop the therapy needs further analysis. There is a need to develop strategies to cope with patients' emotional experience and guarantee their psychoemotional wellbeing beyond the clinical setting. [Display omitted] DisclosuresCastagnetti:Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Bonifacio:Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cavazzini:Bristol-Meyers Squibb: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Incyte: Consultancy. Galimberti:Incyte: Speakers Bureau; Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau. Orlandi:Incyte: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Galimberti:Novartis: Employment. Haenig:Novartis: Employment. Supekar:Novartis: Employment. Baccarani:Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Incyte ARIAD: Consultancy, Honoraria, Speakers Bureau. Vegni:Novartis: Research Funding.

A randomized controlled trial of structured palliative care versus standard supportive care for patients enrolled in phase 1 clinical trials.

PurposePatients enrolled in Phase 1 clinical trials have typically exhausted standard therapies and often are choosing between a clinical trial and hospice care. Significant symptom burden can result in early trial discontinuation and confound trial outcomes. This study aimed to examine differences in study duration, symptom burden, adverse events (AE), and quality of life (QOL) between those receiving structured palliative care versus usual supportive care.Patients and methodsSixty‐eight patients enrolled in phase 1 clinical trials and 39 of their CGs were randomly assigned to receive structured palliative care or usual supportive care. Patient QOL was measured monthly using the Functional Assessment of Cancer Therapy and Memorial Symptom Assessment Scale. The Quality of Life in Life‐Threatening Illness–Family Care Version and Caregiver Reaction Assessment were used for CGs. AEs and use of palliative care resources were compared between arms.ResultsMean duration of the phase 1 study was 142 days in the palliative care arm versus 116 days in the usual care arm (p = 0.55). Although not statistically significant, patients in the palliative care arm experienced fewer AEs and better QOL, as did their CGs, compared to those receiving usual care.ConclusionsPhase 1 patients and their CGs have physical and psychosocial needs warranting palliative care services. Results suggest that structured palliative care is associated with the increased duration of the study and improved patient and CG QOL.

Clinical Predictors of Early Trial Discontinuation for Patients Participating in Phase I Clinical Trials in Oncology.

Simple SummaryAbout 20% of patients with cancer who participate in a phase I clinical trial discontinue the trial early. Early trial discontinuation is undesirable both for the wellbeing of the patient as well as for the trial efficiency and the development of new anticancer drugs. We investigated which clinical predictors at baseline were significantly associated with early trial discontinuation of patients with cancer who participated in phase I clinical trials. The clinical predictors which were identified in this study were hyponatremia, elevated alkaline phosphatase level, performance score of 1 or higher and opioid use. Hyponatremia especially, which was the strongest predictor, should be considered to be used as an additional eligibility criterion in order to reduce the early trial discontinuation of patients with cancer who participate in phase I clinical trials. Despite stringent eligibility criteria for trial participation, early discontinuation often occurs in phase I trials. To better identify patients unlikely to benefit from phase I trials, we investigated predictors for early trial discontinuation. Data from 415 patients with solid tumors who participated in 66 trials were pooled for the current analysis. Early trial discontinuation was defined as (i) trial discontinuation within 28 days after start of treatment or (ii) discontinuation before administration of the first dosage in eligible patients. Multilevel logistic regression analyses were conducted to identify predictors for early trial discontinuation. Eighty-two participants (20%) demonstrated early trial discontinuation. Baseline sodium level below the lower limit of normal (OR = 2.95, 95%CI = 1.27–6.84), elevated alkaline phosphatase level > 2.5 times the upper limit of normal (OR = 2.72, 95%CI = 1.49–4.99), performance score ≥ 1 (OR = 2.07, 95%CI = 1.03–4.19) and opioid use (OR = 1.82, 95%CI = 1.07–3.08) were independent predictors for early trial discontinuation. Almost 50% of the patients with hyponatremia and all four patients in whom all four predictors were present together discontinued the trial early. Hyponatremia, elevated alkaline phosphatase level, performance score ≥ 1 and opioid use were identified as significant predictors for early trial discontinuation. Hyponatremia was the strongest predictor and deserves consideration for inclusion in eligibility criteria for future trials.

Smartphone measurements of physical activity and fitness are associated with early trial discontinuation of patients in (hemato)oncology phase I/II clinical trials

BackgroundPatients, who discontinue early, do not benefit from phase I/II clinical trials (early-phase clinical trials (EPCT)). In this study, associations between objective smartphone measurements of physical activity and fitness and early trial discontinuation in patients with cancer participating in EPCT were investigated.MethodsBefore start of treatment, physical activity (steps/day) and physical fitness (meters walked in 6 min) were measured with a smartphone, and patient-reported physical function (PRO-PF) was assessed (EORTC QLQ-C30-PF). Early trial discontinuation was defined as discontinuation ≤ 28 days. Univariable logistic regression analyses were performed to study associations of physical activity, fitness, and function with early trial discontinuation. Optimal cutoff values of physical activity and fitness were assessed with ROCs, based on positive predictive values (PPV).ResultsMedian (interquartile range (IQR)) step count was 4263 (2548–6897) steps/day, mean ± standard deviation 6-min walking distance was 477 ± 120 m and median (IQR) PRO-PF score was 83 (67–95) points. Fourteen patients (12%) discontinued the trial early. Smartphone measurements of physical activity in units of 100 steps per day (odds ratio (OR) = 0.96, 95% CI = 0.94–0.99, p = 0.01), physical fitness (OR = 0.99, 95% CI = 0.98–0.99, p < 0.01), and PRO-PF (OR = 0.97, 95% CI = 0.94–1.00, p = 0.03) were associated with early trial discontinuation. Optimal cutoff values were < 900 steps for physical activity and < 285 m for physical fitness. PPV for early trial discontinuation was 100% in patients who walked both < 1500 steps per day and < 300 m in 6 min.ConclusionsObjective smartphone measurements of physical activity and fitness are associated with early trial discontinuation. However, cutoff values should be externally validated in a larger cohort before implementation in clinical practice.

A randomized, controlled trial of structured palliative care versus standard supportive care for patients enrolled on phase I clinical trials.

3634 Background: Phase 1 clinical trials are the first step in developing new cancer therapeutics. Patients enrolled in these studies have typically exhausted standard therapies and are at a point in their disease trajectory where they often are choosing between a phase 1 clinical trial and hospice care. These patients may have significant symptom burden, which can result in early trial discontinuation and confound phase 1 trial outcomes, including toxicity profiles, which may influence further drug development. This study aimed to determine the palliative care needs of patients enrolled on phase 1 clinical trials and their caregivers (CGs), along with differences in study duration, adverse event (AE) and symptom profiles, and quality of life (QOL) between those receiving structured palliative care vs usual supportive care. Methods: 68 patients enrolled on phase 1 clinical trials were randomly assigned to receive structured palliative care or usual supportive care. 39 of their CGs were enrolled and assigned to the same arm as the patient. Quality of life metrics were obtained monthly: the Functional Assessment of Cancer Therapy-General and Memorial Symptom Assessment Scale -Short Form for patients, and The Quality of Life in Life Threatening Illness - Family Carer Version and Caregiver Reaction Assessment for CGs. Palliative care resources utilized were assessed for those in the palliative care arm, and referrals to supportive care services assessed in those in the usual care arm. AEs recorded on the Phase 1 trials were evaluated &amp; compared between arms. Results: Mean duration on phase 1 study was 132 days in the palliative care arm vs 114 days in the usual care arm (p = 0.55). Total weighted AE rate (# of AE [x] AE grade per month) was 26.9 in the palliative care arm vs 34.0 in the usual care arm (p = 0.53). Patients in the palliative care arm experienced better QOL and lower symptom burden, as did their CGs, compared to those in the usual care arm. While the differences in outcomes were not statistically significant, all results favored structured palliative care. Conclusions: Phase 1 patients and their CGs have physical and psychosocial needs which warrant palliative care services. Preliminary results suggest structured palliative care is associated with increased duration on study (by nearly 3 weeks), improved patient and CG QOL, and reduced patient symptom and CG burden. A larger study is warranted to confirm these results and further develop the ideal palliative care intervention in these populations. Clinical trial information: NCT02543541 .

Budgeting of non-commercial clinical trials: development of a budget tool by a public funding agency

BackgroundInvestigator-led multicentre randomised trials are essential to generate evidence on the optimal use of medical interventions. These non-commercial trials are often hampered by underfunding, which may lead to difficulties in gathering a team with the necessary expertise, a delayed trial start, slow recruitment and even early trial discontinuation. As a new public funder of pragmatic clinical trials, the KCE Trials programme was committed to correctly pay all trial activities in order to assure timely delivery of high-quality trial results. As no appropriate trial budget tool was readily publicly available that took into account the costs for the sponsor as well as the costs for participating sites, we developed a tool to make the budgeting of a clinical trial efficient, transparent and fair across applicants.MethodsAll trial-related activities of the sponsor and sites were categorised, and cost drivers were identified. All elements were included in a spreadsheet tool allowing the sponsor team to calculate in detail the various activities of a clinical trial and to appreciate the budget impact of specific cost drivers, e.g. a delay in recruitment. Hourly fees by role were adapted from published data. Fixed amounts per activity were developed when appropriate.ResultsThis publicly available tool has already been used for 17 trials funded since the start of the KCE Trials programme in 2016, and it continues to be used and improved. This budget tool is used together with additional risk-reducing measures such as a multistep selection process with advance payments, a recruitment feasibility check by sponsor and funder, a close monitoring of study progress and a milestone-based payment schedule with the last payment made when the manuscript is submitted.ConclusionsThe budget tool helps the KCE Trials programme to answer relevant research questions in a timely way, within budget and with high quality, a necessary condition to achieve impact of this programme for patients, clinical practice and healthcare payers.

496P - Predictors for early trial discontinuation of patients with cancer participating in phase I clinical trials

BackgroundPatients with cancer who are refractory to standard treatments may participate in phase I clinical trials. Despite stringent eligibility criteria for trial participation, early discontinuation often occurs. These patients do not benefit from study treatment and may experience additional burden from participation, while adequate evaluation of novel treatment strategies is hampered. The aim of this study was to identify predictors for early discontinuation of phase I clinical trials. MethodsData from patients with solid tumors who participated in phase I trials in our center were pooled for the current analysis. Early trial discontinuation was defined as (i) trial discontinuation within 28 days after administration of the first dose of the investigated drug or (ii) discontinuation before administration of the first dose in patients who were found to be eligible. Based on the literature, the following potential predictors were examined: opioid use, number of metastatic sites, body mass index, ECOG/WHO performance status, comorbidity history of thromboembolism, hemoglobin level, platelet count, leukocytes, lymphocytes, absolute neutrophil count, serum sodium level, creatinine clearance, serum albumin level, serum alkaline phosphatase level, serum aspartate aminotransferase level (AST), serum lactate dehydrogenase level and. Multilevel logistic regression analyses were conducted and Odds ratio (OR) and 95% confidence interval (95%CI) were reported. ResultsData from 154 patients recruited in 8 phase I clinical trials were analyzed. Thirty-six (23%) participants discontinued the trial early. Baseline hyponatremia (OR=3.69, 95%CI=1.09-12.47) and an elevated AST level (OR=2.57, 95%CI=1.10-6.01) were independent predictors for early trial discontinuation. ConclusionsHyponatremia and an elevated serum AST level were identified as significant independent predictors for early trial discontinuation in patients with cancer participating in phase I clinical trials. These predictors will be further investigated in a prospective study, to determine their added value in minimizing early trial discontinuation of patients participating in phase I oncology trials. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Discontinuation of surgical versus nonsurgical clinical trials: an analysis of 88,498 trials

BackgroundIt has been previously reported that over 20% of surgical trials will be discontinued prematurely raising ethical and financial concerns. Previous studies have been limited in scope owing to the need for manual review of selected trials. To date, there has been no broad analysis comparing surgical and nonsurgical registered clinical trials. Materials and methodsClinicalTrials.gov was queried October 7, 2017 for all US trials from 2005 to 2017. Trials were assigned to surgical or nonsurgical groups by automated sorting. The sorting algorithm was validated by comparison with manual assignments made by blinded investigators. Comparisons were made between trial status, funding sources, and trial design. The reasons for discontinuation were examined and tabulated. ResultsThe database search yielded 82,719 nonsurgical and 5779 surgical trials after automatic assignment. The algorithm for assignments had an overall accuracy of 87.99% and a positive likelihood ratio of 6.09 and negative likelihood ratio of 0.093. Significant differences existed in trial status (nonsurgical versus surgical: completed: 55.51% versus 39.49%, P < 0.001 and discontinued: 11.07% versus 15.97%, P < 0.001). Discontinuation due to poor recruitment was more commonly cited by surgical trials (44.65% versus 34.74% P < 0.001). Industry funding predicted discontinuation for all trials (odds ratio 1.63 P < 0.001) and surgical trials independently (OR 1.25 P = 0.041). Patient enrollment, reporting results, and NIH funding were all protective against discontinuation. ConclusionsSurgical trials are more likely to prematurely discontinue than nonsurgical trials. Industry funding independently predicts trial discontinuation. Poor recruitment is a major cause of early trial discontinuation for all trials and is more pronounced in surgical trials.

Objective smartphone measurements of physical activity and fitness in patients with cancer.

132 Background: Optimal (study) treatment for patients with advanced cancer is influenced by their performance status (PS) before initiation of systemic therapy. An objective assessment of a patient’s physical function is difficult to make and is currently heavily depending on the estimation of their PS by the treating physician. Objectively measured physical activity (PA) and physical fitness (FIT) may be more predictive for survival and treatment tolerability than their PS. We hypothesize that an objective measurement may provide more accurate estimates of a patient’s physical function and thereby a better outcome of (study) treatment. Unfortunately, routine objective measurements are time consuming and costly. Therefore, we aimed to investigate the validity and reliability of smartphone measurements of PA and FIT in patients with cancer. Methods: At present, 56 ambulant patients with various types of cancer participated. Patients wore an accelerometer for 7, and an IPhone for 14 consecutive days to measure the mean number of steps per day. Patients performed a 6MWT twice with the use of an smartphone application in their home environment and once in a test environment in the hospital. To assess the validity, we calculated the intraclass correlation coefficient (ICC) between the accelerometer and the first week of the IPhone for PA, and between the 6MWT in the hospital and the home environment for FIT. To assess reliability, we calculated the ICC between the IPhone week 1 and 2 for PA, and between the first and second 6MWT in the home environment for FIT. Results: Validity was excellent for PA (ICC = 0.96,p &lt; 0.05) and low for FIT (ICC = 0.33,p &lt; 0.05). We found excellent reliability for PA (ICC 0.94,p &lt; 0.05) and FIT (ICC = 0.93,p &lt; 0.05). Conclusions: In this study we found that objective smartphone measurements of PA are valid and reliable. FIT assessments were reliable, but in its present form its validity was low. A prospective study has been initiated to investigate whether objectively measured PA and/or FIT, better predicts early trial discontinuation and survival than PS or patient-reported physical function.

Early Trial Discontinuation in Toxicity-Driven, Dose-Escalating, Phase I Cancer Trials: Occurrence, Outcomes and Predictive Factors

The selection of patients for phase I cancer trials remains challenging. Patients who dropout of the trial before completion need to be replaced and this can result in significant delays to trial completion. The objective of this study was to identify patients enrolled in phase I oncology trials who were unable to complete the minimum evaluation period of the trial, and to use these data to develop a predictive model of risk factors for patient replacement. We retrospectively reviewed all consecutive patients who were enrolled in dose-escalating phase I cancer trials at four medical centers in France between May 2003 and May 2013. Replacement was defined as trial discontinuation before 6 weeks, without the occurrence of dose-limiting toxicity. Using logistic regression and decision-tree analyses, we developed a predictive model to identify patients who were at high risk for replacement, and also their common risk factors. This model was designed to provide maximum specificity and a negative predictive value. Of 332 patients enrolled in the study, 16 had to be replaced (4.8 %). The median overall survival time was 45 days for the patients who were replaced versus 480 days for the patients who were not replaced (p < 0.0001). In the univariate analysis, the risk factors for replacement included Eastern Cooperative Oncology Group performance status (ECOG-PS) = 2 [odds ratio (OR) 11], Royal Marsden Score (RMS) = 3 (OR 29), and enrollment in a study investigating multiple agents (OR 7). Multivariate analysis retained PS ≥2 and RMS = 3 as independent predictive factors for replacement. The following two patient subgroups were identified: low risk of replacement (RMS ≤2 and PS ≤1) and high risk of replacement (RMS = 3 or PS ≥2). The rates of replacement were 8/312 (2.5 %) and 8/20 (40.0 %) for low- and high-risk patients, respectively, and the specificity and negative predictive values of our model were 96.2 and 97.5 %, respectively. Approximately 5 % of enrolled patients were replaced, and these patients experienced very poor outcomes. To minimize trial delays, enrolling patients who have an RMS = 3 or PS ≥2 should be avoided.

A Simple Scoring System for Identifying Relapsed/Refractory Lymphoma Patients Prematurely Withdrawn from Phase I Trials: The Gustave Roussy Experience

Abstract Background: Treating relapsed/refractory non-Hodgkin and Hodgkin lymphoma in fit young and elderly patients represents a considerable challenge for clinicians. Combined cytotoxic agents are rapidly ineffective, especially when relapse occurs after autologous stem cell transplantation (ASCT). Alternative regimens are often sparse. In the era of personalized medicine, phase I clinical trials offer an alternative therapeutic option through a multitude of immunotherapy and targeted drugs in development. Phase I trials aim to determine the recommended phase II dose (RP2D) through toxicity and pharmacokinetic assessments. Documenting signal of activity is also a major objective, underlying the importance of including patients susceptible to remain on study until first lymphoma response evaluation (usually 6 weeks, 2 cycles). We aimed to assess a simple scoring system that could identify patients who will discontinue phase I studies before 6 weeks. Patients and Methods: Data from all lymphoma patients treated within a phase I trial in Gustave Roussy (GR) Cancer Center were retrospectively collected. 83 consecutive patients were enrolled in 17 phase I trials at GR between January 2008 and May 2014. All patients had progressive lymphoma at time of enrollment, after a median of 3 prior therapeutic lines (range 1;13). 37 patients (45%) received an ASCT prior to phase I inclusion. Median age was 67 years (range: 23-92) and WHO performance status (PS) was 0 in 36 patients (43%), 1 in 43 patients (52%) and 2 in 4 patients (5%). Median time from lymphoma diagnosis to phase I inclusion was 47 months. Lymphoma histological subtypes were represented as follows: 21% Hodgkin lymphoma, 36% aggressive non-Hodgkin lymphoma (83% diffuse large B cell lymphoma, 17% T cell lymphoma), 24% indolent non-Hodgkin lymphoma (70% follicular lymphoma, 25% marginal zone lymphoma, 5% Waldenström macroglobulinemia) and 19% mantle cell lymphoma. Univariate analysis on this cohort allowed identifying simple factors significantly associated with overall survival (OS). A simple scoring system, predictive for OS was pre-established and validated through a multivariate analysis in 2 large cohorts of various hematological malignancies by our group. Statistical tests were conducted on this relapsed/refractory lymphoma cohort, to evaluate this score's OS and early study discontinuation predictive ability. Results: Within a median follow up of 19 months, median OS and progression free survival (PFS) were respectively 18 (CI95%: 12; 37) and 3 (CI95%: 1.7; 3.6) months. Best overall response rate (ORR) and disease control rate (DCR: objective response and stable disease rates) were respectively 18% and 61%. Thirty-four patients (41%) experienced grade 3 or 4 adverse events and 7 patients (8%) a dose limiting toxicity (DLT). WHO performance status (PS) &gt; 0 at inclusion, baseline albumin ≤ 35 g/l and baseline LDH ≥ 250 UI/L were significantly associated with poorer OS. The predefined GR prognostic score combined 2 simple variables, PS and baseline serum albumin (+1 if PS 0, +1 if albumin≤ 35 g/l). In our lymphoma cohort, patients with a GR score = 0 experienced significantly better OS compared to patients with a score = 1 and a score = 2 (37 months vs 17 months vs 9 months; p = 0.007). This simple score, distinguishes patients most likely to remain on study for more than 6 weeks, considered as the minimum required period for response and toxicity evaluation (classical DLT and targeted therapies associated long term toxicities). Among patients prematurely withdrawn from clinical trials, 91% had a GR score ≥ 1 (p=0,007). Main study discontinuation reason was progressive disease (77%), drug related toxicity was only responsible for study discontinuation in 13 % of cases. Conclusion: Our data demonstrate efficacy and safety of phase I clinical trials in lymphoma, thus offering an interesting alternative therapeutic option for fit young and elderly relapsed/refractory lymphoma patients. The GR simple score, can both help in selecting patients most likely to benefit from a phase I trial (better OS) and to determine the phase II recommended dose (reduced early trial discontinuation). Disclosures No relevant conflicts of interest to declare.

Prognostic Factors and Outcome of Patients with Hematological Malignancies in Phase I Trials: The Gustave Roussy Scoring System

▪Background: Phase I clinical trials are conducted to determine the recommended phase II dose through safety and pharmacokinetic assessments. Potential clinical benefit is also a key aim. To improve patient’s selection and identify patients most likely to benefit from these studies in hematological malignancies (HM), we designed and then validated in an independent cohort, a prognostic score based on simple variables.Patients and Methods: We retrospectively collected data from 82 consecutive patients enrolled in 14 phase I trials at Gustave Roussy (GR) between January 2008 and February 2012 (cohort 1). A simple scoring system was established through multivariate analysis (MVA) of multiple potential prognostic factors (age, gender, BMI, smoking status, comorbidities, histological subtype, WHO performance status (PS), prior autologous stem cell transplant, prior radiotherapy, LDH, serum albumin and protein levels). We then prospectively collected data from 88 consecutive patients treated in 17 phase I trials in the GR phase I department from February 2012 to May 2014, to validate this prognostic score on an independent cohort (cohort 2). Stratification was done according to histology given the heterogeneity of diseases.Results: All patients had progressive HM after a median of 2 prior systemic standard therapeutic lines in cohort 1. The distribution of HM was: acute myeloid leukemia (AML) 23%, indolent non Hodgkin lymphoma (iNHL) 22%, myelofibrosis (MF) 21%, aggressive non-Hodgkin lymphoma (aNHL) 16%, chronic lymphoid leukemia (CLL) 10%, Hodgkin lymphoma (HL) 6% and multiple myeloma (MM) 2%. Median age was 73 years (range: 27-93) and 56 patients (67%) had more than one comorbidity. Best overall response rate (ORR) and disease control rate (DCR: objective response and stable disease rates) were 20% and 64 % respectively. Within a median follow up of 26 months, median progression-free survival (PFS) and overall survival (OS) were respectively 5 (CI95%: 4; 8) and 17 months (CI95%: 12; 26). One toxicity-related death (2%) occurred. Thirty-seven patients (45%) experienced grade 3 or 4 adverse events (AE) and 9 patients (11%) a dose-limiting toxicity (DLT). MVA identified PS > 0 at inclusion, baseline albumin ≤ 35 g/l and histological subtype as prognostic factors for OS. We defined the GR score using this MVA data: +1 if PS > 0, +1 if albumin ≤ 35 g/l. Patients with a GR score = 0 experienced significantly better OS compared to patients with a score = 1 and a score = 2 (37 months versus 17 months versus 8 months; p = 0.003).Cohort 2 patients were characterized by a median age of 64 years (range: 23-84) and a similar comorbidity rate (61%). Distribution among hematological entities was: 22% iNHL, 21% AML, 19% aNHL, 14% MM, 13% HL, 7% MF and 5% CLL. Patients received a median of 3 systemic therapeutic lines prior to phase 1 inclusion. Best ORR and DCR were respectively 28% and 57%. Within a median follow up of 11 months, median PFS and OS were 3 (CI95%: 1.5; 5) and 20 months (CI95%: 12; NA) respectively. No toxicity-related death occurred. Forty-seven patients (53%) experienced grade 3 or 4 toxicity and 1 patient (1%) a dose-limiting toxicity. Pre-established GR score was predictive of OS in this validation cohort (p=0.033).Main study discontinuation reason was progressive disease (75% and 80% in cohorts 1 and 2, respectively). Drug related toxicity was responsible for study discontinuation in 9% and 14% of cases in cohorts 1 and 2 respectively.The GR score distinguishes patients most likely to remain on study for more than 6 weeks, considered as the minimum required period for response and toxicity evaluation (classical DLT and targeted therapies associated long term toxicities). Among patients who discontinued prematurely clinical trials, GR score was ≥ 1 in 88% and 89% of cases respectively in cohort 1 (Cochran-Armitage: p= 0.02 and p=0.06) and cohort 2 (p=0.036).Conclusion: Our data demonstrate safety and efficacy of phase I trials in a significant number of relapsed/refractory HM patients with a clinical benefit achieved in more than half of patients. Response rates are higher than previously reported in solid tumors (Arkenau HT et al. 2008), thus encouraging HM patients inclusions in phase I trials. The simple GR score based on PS and albumin offers a valuable selection tool enabling OS and early trial discontinuation prediction. DisclosuresNo relevant conflicts of interest to declare.

20 µg versus >20 µg estrogen combined oral contraceptives for contraception.

Concern about estrogen-related adverse effects has led to progressive reductions in the estrogen dose in combination oral contraceptives (COCs). However, reducing the amount of estrogen to improve safety could result in decreased contraceptive effectiveness and unacceptable changes in bleeding patterns. To test the hypothesis that COCs containing ≤ 20 μg ethinyl estradiol (EE) perform similarly as those containing > 20 μg in terms of contraceptive effectiveness, bleeding patterns, discontinuation, and side effects. In July 2013, we searched CENTRAL, MEDLINE, and POPLINE, and examined references of potentially eligible trials. We also searched for recent clinical trials using ClinicalTrials.gov and ICTRP. No new trials met the inclusion criteria. Previous searches included EMBASE. For the initial review, we wrote to oral contraceptive manufacturers to identify trials. English-language reports of randomized controlled trials were eligible that compare a COC containing ≤ 20 μg EE with a COC containing > 20 μg EE. We excluded studies where the interventions were designed to be administered for less than three consecutive cycles or to be used primarily as treatment for non-contraceptive conditions. Trials had to report on contraceptive effectiveness, bleeding patterns, trial discontinuation due to bleeding-related reasons or other side effects, or side effects to be included in the review. One author evaluated all titles and abstracts from literature searches to determine whether they met the inclusion criteria. Two authors independently extracted data from studies identified for inclusion. We wrote to the researchers when additional information was needed. Data were entered and analyzed with RevMan. No differences were found in contraceptive effectiveness for the 13 COC pairs for which this outcome was reported. Compared to the higher-estrogen pills, several COCs containing 20 μg EE resulted in higher rates of early trial discontinuation (overall and due to adverse events such as irregular bleeding) as well as increased risk of bleeding disturbances (both amenorrhea or infrequent bleeding and irregular, prolonged, frequent bleeding, or breakthrough bleeding or spotting). While COCs containing 20 μg EE may be theoretically safer, this review did not focus on the rare events required to assess this hypothesis. Data from existing randomized controlled trials are inadequate to detect possible differences in contraceptive effectiveness. Low-dose estrogen COCs resulted in higher rates of bleeding pattern disruptions. However, most trials compared COCs containing different progestin types, and changes in bleeding patterns could be related to progestin type as well as estrogen dose. Higher follow-up rates are essential for meaningful interpretation of results.

High prevalence of dhfr triple mutant and correlation with high rates of sulphadoxine-pyrimethamine treatment failures in vivo in Gabonese children

BackgroundDrug resistance contributes to the global malaria burden. Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) polymorphisms confer resistance to sulphadoxine-pyrimethamine (SP).MethodsThe study assessed the frequency of SP resistance-conferring polymorphisms in Plasmodium falciparum-positive samples from two clinical studies in Lambaréné. Their role on treatment responses and transmission potential was studied in an efficacy open-label clinical trial with a 28-day follow-up in 29 children under five with uncomplicated malaria.ResultsSP was well tolerated by all subjects in vivo. Three subjects were excluded from per-protocol analysis. PCR-corrected, 12/26 (46%) achieved an adequate clinical and parasitological response, 13/26 (50%) were late parasitological failures, while 1/26 (4%) had an early treatment failure, resulting in early trial discontinuation. Of 106 isolates, 98 (92%) carried the triple mutant dhfr haplotype. Three point mutations were found in dhps in a variety of haplotypic configurations. The 437G + 540E double mutant allele was found for the first time in Gabon.ConclusionsThere is a high prevalence of dhfr triple mutant with some dhps point mutations in Gabon, in line with treatment failures observed, and molecular markers of SP resistance should be closely monitored.Trial RegistrationClinicalTrials.gov: NCT00453856