Oncology Phase Research Articles

Impact of the 2010 Consensus Recommendations of the Clinical Trial Design Task Force of the NCI Investigational Drug Steering Committee.

Oncology phase III trials have a high failure rate, leading to high development costs. The Clinical Trials Design Task Force of the Investigational Drug Steering Committee of the NCI Cancer Therapy and Evaluation Program developed Recommendations regarding the design of phase II trials. We report here on the results of a Concordance Group review charged with documenting whether concordance rates improved after the publication of the Recommendations. One hundred and fifty-five trials were reviewed. Letter of Intents (LOI) from the post-Recommendation period were more likely to be randomized (44% vs. 34%) and biomarker selected (19% vs. 10%). Single-arm studies using time-to-event endpoints (benchmarked against historical data) were similar, as was the type of tumor. There was a significant improvement in the rate of concordance, with 74% of LOIs scored as concordant compared with 58% before the Recommendations (P = 0.042). This included a marked decrease in the use of single-arm designs to evaluate the activity of drug combinations (19% vs. 5%, P = 0.009). There were areas for which clarification was warranted, including the need for protocols to include further development plans, the use of realistic benchmarks, the careful evaluation of historical controls, and the use of a standard treatment option as a control. Ongoing critical evaluation of current trial design methodology and the development of new Guidelines when appropriate will continue to improve drug development ensuring that safe and effective cancer therapeutics are made available to our patients as quickly and efficiently as possible.

Description of the types and content of phase 1 clinical trial consent conversations in practice.

All agree that informed consent is a process, but past research has focused content analyses on post-consent or on one conversation in the consent series. Our aim was to identify and describe the content of different types of consent conversations. We conducted a secondary analysis of 38 adult oncology phase 1 consent conversations, which were audio-recorded, transcribed, coded, and qualitatively analyzed for type and content. Four types of consent conversations were identified: (1) priming, (2) patient-centered options, (3) trial centered, and (4) decision made. The analysis provided a robust description of the content discussed in each type of conversation. Two themes, supportive care and prognosis, were rarely mentioned. Four themes clustered in the patient-centered (type 2) conversations: affirmation of honesty, comfort, progression, and offer of supportive care. We identified and described four types of consent conversations. Our novel findings include (1) four different types of conversations with one (priming) not mentioned before and (2) a change of focus from describing the content of one phase 1 consent conversation to describing the content of different types. These in-depth descriptions provide the foundation for future research to determine whether the four types of conversations occur in sequence, thus describing the structure of the consent process and providing the basis for coaching interventions to alert physicians to the appropriate content for each type of conversation. A switch from a focus on one conversation to the types of conversations in the process may better align the consent conversations with the iterative process of shared decision making.

Comparison of adult oncology phase 1 trials to pediatric oncology phase 1 trials of targeted therapies.

2581 Background: Intractable aggressive cancers continue to take the lives of children, adolescents and young adults at the prime of their lives. The prior era of drug development wherein pediatric...

A Bayesian three-parameter logistic model for early- and late-onset DLTs in oncology Phase I studies

ABSTRACTWe introduce a three-parameter logistic model to analyze the dose limiting toxicity (DLT) as a time-to-event endpoint in oncology Phase I trials. In the proposed model, patients are allowed to stay on trial without the constraint of a maximum follow-up time. Our model accommodates late-onset DLT as well as early-onset DLT, by both of which the dose recommendation is informed. A Bayesian approach is used to incorporate prior knowledge of the test treatment into dose recommendation. Simulation examples show that our proposed model has good operating characteristics in assessing the maximum tolerated dose (MTD).

Capecitabine, oxaliplatin and irinotecan in combination, with bevacizumab (COI-B regimen) as first-line treatment of patients with advanced colorectal cancer. An Italian Trials of Medical Oncology phase II study

BackgroundA dose-finding phase I/II trial that evaluated the maximum tolerated doses of a combination of three drugs with irinotecan, oxaliplatin and capecitabine (COI regimen) has been conducted in patients with metastatic colorectal cancer (mCRC). In this study the safety and activity of the combination of COI regimen plus bevacizumab (COI-B) were assessed. MethodsPatients judged to be unresectable for metastatic disease, were enrolled in a phase II, open-label study and treated with the combination of bevacizumab (5mg/kg on day 1) and COI regimen (irinotecan 180mg/mq on day 1, oxaliplatin 85mg/mq on day 2, capecitabine 2000mg d2–6; q14) as first-line treatment. Induction treatment was administered for a maximum of 8 cycles, followed by maintenance treatment with bevacizumab (7.5mg/kg on d1, q21) until progression. ResultsFifty-one patients were enrolled in six Italian centres. The primary end-point of overall response rate was met, reaching the value of 62% in the per-protocol population and 57% in the intent-to-treat population, patients with stable disease were also taken into account, the clinical benefit rate was 94%. In the intention-to-treat population, median progression-free and overall survivals were 10.3 and 22months, respectively. Toxicity was different from 5-fluorouracil-based triplet regimens, with 31% of severe diarrhoea, but a low incidence of grade 3/4 neutropenia (6%) and mucositis (4%). ConclusionsOur results show the feasibility and promising activity of the combination of capecitabine, oxaliplatin, irinotecan and bevacizumab.

Clinical and molecular characterization of refractory BRAF mutant metastatic colorectal carcinoma (mCRC): Vall d’Hebron Institute of Oncology phase I program cohort.

587 Background: BRAF mutation (mt) occurs in 5-8% of mCRC and its role as a negative prognostic factor is well known. The up-front detection of BRAF mt is not standardized beyond the boundaries of research. However, since novel emerging specific therapies are increasingly available in clinical trials, the prior determination of this mutation is now warranted. Methods: From 07/2010 to 01/2014, 581 patients (pts) with advanced refractory mCRCunderwent genetic tumor profiling as part of the VHIO Phase I Trial Molecular Prescreening Program. BRAF mt was determined by Sanger sequencing or multiplex PCR and mass detection (MassARRAY, Sequenom) of 268 frequent hotspots in 25 oncogenes including, KRAS, NRAS, and PIK3CA. PTEN status was also assessed by immunohistochemistry. Results: 581 samples were analyzed detecting BRAF mt in 56 (9.6%). In the BRAF mt population, median age was 61 years (45-80) and 54% had right-sided CRC. Metastatic sites were found at: liver 61%; peritoneum 52%; lung 39%. Median number of standard treatment was 4 (0-8) including cetuximab and/or panitumumab in 73%. BRAF V600E mutation was detected in 53 samples whereas V600K, D594V and D594G were seen in one sample each. PTEN was analyzed in 44.6% of samples resulting in low expression (H-score <50) in 56%. Other co-existing mutations were PIK3KCA H1047R, PIK3CA E545K, NRAS G12V, GNAS R201C and EGFR S768I. 22 pts were enrolled at least in one phase I trial with drugs targeting either BRAF alone (n=12) or combined with anti-EGFR (n=5), MEK (n=2), PI3K (n=1) inhibitors or double MEK/PI3K inhibition (n=2). Partial responses (PR) were seen in 3 pts (2 with BRAF inhibitor and EGFR inhibitor and 1 with BRAF inhibitor as a single agent). Conclusions: BRAF mt mCRC pts in our institution have a similar pattern to other series reported. Notably, PTEN low expression was present in almost half of the samples analyzed and other co-existent mutations in the ERK and PI3K pathways were detected. This observation, coupled with the clinical outcome observed with single agent BRAF inhibition in this population, suggests that these patients may derive greater benefit from dual BRAF and either EGFR, MEK or PI3K inhibition.

Impact of informative censoring on the Kaplan-Meier estimate of progression-free survival in phase II clinical trials.

Informative censoring in a progression-free survival (PFS) analysis arises when patients are censored for initiation of an effective anticancer treatment before the protocol-defined progression, and these patients are at a different risk for treatment failure than those who continue on therapy. This may cause bias in the estimated PFS when using the Kaplan-Meier method for analysis. Although there are several articles that discuss this issue from a theoretical perspective or in randomized phase III studies, there are little data to demonstrate the magnitude of the bias on the estimated quantities from a phase II trial. This article describes the issues by using two oncology phase II trials as examples, evaluates the impact of the bias using simulations, and provides recommendations. The two trials were selected because they demonstrate two different reasons for censoring. Simulations show that the magnitude of the bias depends primarily on the proportion of patients who are informatively censored and secondarily on the hazard ratio between the group of patients who remain on study and the group of patients who are informatively censored. Recommendations include using an alternative end point, which includes inadequate response and initial signs of clinical progression as treatment failure, and a competing risk analysis for studies in which competing events preclude or modify the probability of observing the primary event of interest. If informative censoring cannot be avoided, then all patients should be observed until progression, and sensitivity analyses should be used as appropriate.

Low Adequacy Between Severe Adverse Events Reporting in Oncology Phase III Trials and Expectations of the Eortc Members

ABSTRACT Aim: Reports of randomized controlled trials (RCTs) published in oncology literature are generally poorly conform to the 2004 Consolidated Standards of Reporting Trials (CONSORT ) extension for harms. We assessed the consistency in between expectations of a panel of EORTC experts regarding reporting of AEs and the actual quality of publication of RCTs. Methods: Reporting of severe-AEs, AEs related outcomes and composite AEs outcomes were reviewed in 325 oncology RCTs reports published between 2007 and 2011. An online survey was sent to the network of EORTC investigators to evaluate their expectation concerning the AE reporting. Then we compared AE reporting in phase III reports with EORTC member expectations. The characteristics of the article associated with better quality in AEs related outcomes reporting were also investigated. Results: A total of 211 EORTC members have responded to the survey. Among them, 99% thought that all lethal AEs (LAEs) should be reported and 95% thought that all AE leading to withdrawal should also be reported. Clearly described LAEs were found in 190 out of 325 RCTs (58%) and AEs leading to withdrawal were correctly reported in 53 out of 325 RCTs (16%). LAEs were more correctly reported in North-America / Intercontinental trials (p = 0.0004) and in trials testing a molecular targeted therapy (p = 0.016). AEs leading to withdrawals were more correctly reported in RCTs funded by industry (p = 0,001). Composite AEs such as “dermatologic AEs” or “neurologic AEs” were used in 95 out of 325 RCTs (29%); 25% of them were clearly described. Conclusions: There are important discrepancies between the expectations of EORTC network investigators and the reporting quality of AE reporting in oncology phase III reports. Recommendations able to improve the reporting of severe-AE reporting in oncology phase III reports are discussed. Disclosure: All authors have declared no conflicts of interest.

Distress among caregivers of phase I trial participants: a cross-sectional study.

The number of patients with cancer enrolling in phase I trials is expected to increase as these trials incorporate patient selection and exhibit greater efficacy in the era of targeted therapies. Despite the fact that people with advanced cancer often require a caregiver, little is known about the experience of caregivers of people enrolling in oncology phase I clinical trials. We conducted a cross-sectional study assessing the distress and emotion regulation of caregivers of phase I trial participants to inform the design of future interventions targeting the unique needs of this population. Caregivers of oncology patients were approached at the patient's phase I clinical trial screening visit. Caregiver participants completed a one-time survey incorporating validated instruments to comprehensively assess distress and emotion regulation. Basic demographic information about both the caregiver and patient was collected. Caregivers exhibited greater distress than population norms. Emotion regulation was also moderately impaired. Respondents identified positive aspects of caregiving despite exhibiting moderate distress. Enrollment of a patient in a phase I clinical trial is a time of stress for their caregivers. This pilot study demonstrates the feasibility of engaging caregivers of phase I trial participants and the need to better support them through this component of their caregiving experience.

Time-to-event continual reassessment method incorporating treatment cycle information with application to an oncology phase I trial.

Delayed dose limiting toxicities (i.e. beyond first cycle of treatment) is a challenge for phase I trials. The time-to-event continual reassessment method (TITE-CRM) is a Bayesian dose-finding design to address the issue of long observation time and early patient drop-out. It uses a weighted binomial likelihood with weights assigned to observations by the unknown time-to-toxicity distribution, and is open to accrual continually. To avoid dosing at overly toxic levels while retaining accuracy and efficiency for DLT evaluation that involves multiple cycles, we propose an adaptive weight function by incorporating cyclical data of the experimental treatment with parameters updated continually. This provides a reasonable estimate for the time-to-toxicity distribution by accounting for inter-cycle variability and maintains the statistical properties of consistency and coherence. A case study of a First-in-Human trial in cancer for an experimental biologic is presented using the proposed design. Design calibrations for the clinical and statistical parameters are conducted to ensure good operating characteristics. Simulation results show that the proposed TITE-CRM design with adaptive weight function yields significantly shorter trial duration, does not expose patients to additional risk, is competitive against the existing weighting methods, and possesses some desirable properties.

The current design of oncology phase I clinical trials: progressing from algorithms to statistical models.

In this article we examine how phase I trial designs for anti-cancer agents have developed over the past few decades. We review the use of algorithmic, relatively non- statistical designs, and then describe nonparametric and parametric statistically-driven designs that have better operating characteristics than algorithmic designs. We then follow with a description of how the original parametric design, known as the continual reassessment method (CRM), has been generalized and expanded to create designs for many complex settings that occur in early-phase oncology trials. We conclude with a discussion of outstanding issues and controversies that continue to exist with phase I trial designs.

Suggestions from adolescents, young adults, and parents for improving informed consent in phase 1 pediatric oncology trials

Informed consent for a pediatric oncology phase 1 trial is a delicate process, and is made more complex by the difficulty of the information and the requirement for parental consent, and patient assent when applicable. This analysis identifies suggestions for improving the informed consent process received from parents and adolescent and young adult patients (aged 14 years-21 years) who had the option of participating in a phase 1 pediatric oncology trial. A total of 57 parents and 20 patients completed interviews as part of a multisite, prospective, descriptive study. These transcribed interviews were studied using established content analysis methods. Parent and patient responses contained 220 suggestions and 54 suggestions, respectively. A total of 21 unique suggestions for improvement emerged in 3 main themes: 1) provision of more information; 2) structure and presentation of the informed consent process, and 3) suggestions for physicians conducting the process. Common suggestions included providing more specific information about the trial, allowing more time for decision-making, and using different methods to deliver information. Participants involved in the informed consent process for a phase 1 trial provided specific recommendations to research teams to enhance the process. Physician/investigators should be informed of these recommendations and develop and test interventions incorporating them.

11th International Congress on Targeted Anticancer Therapies

Paris, France, 4–6 March 2013 The Targeted Anticancer Therapies (TAT) conference provides a forum for in-depth discussion of emerging targeted agents for the treatment of cancer. TAT conferences are characterized by focus on emerging innovative agents with a cancer-specific molecular target, gathering the world‘s leading oncology Phase I investigators. They attract a mix of professionals with different backgrounds and roles in academia, industry and governmental agencies, all having a profound interest in the development of innovative cancer therapies. More than 500 delegates registered in 2013. Moreover, this year was organized, as part of the TAT congress, the first ‘TAT biotech event‘. New R&D initiatives often known as ‘open innovation‘ are emerging to bring medicines to patients faster by facilitating public- and private-sector partnerships and collaborations, to solve common challenges encountered during the drug discovery and development process. We strongly believe that disruptive innovative antic...

Dose finding when the target dose is on a plateau of a dose–response curve: comparison of fully sequential designs

Consider the problem of estimating a dose with a certain response rate. Many multistage dose-finding designs for this problem were originally developed for oncology studies where the mean dose-response is strictly increasing in dose. In non-oncology phase II dose-finding studies, the dose-response curve often plateaus in the range of interest, and there are several doses with the mean response equal to the target. In this case, it is usually of interest to find the lowest of these doses because higher doses might have higher adverse event rates. It is often desirable to compare the response rate at the estimated target dose with a placebo and/or active control. We investigate which of the several known dose-finding methods developed for oncology phase I trials is the most suitable when the dose-response curve plateaus. Some of the designs tend to spread the allocation among the doses on the plateau. Others, such as the continual reassessment method and the t-statistic design, concentrate allocation at one of the doses with the t-statistic design selecting the lowest dose on the plateau more frequently.

Trends, Outcomes, and Characteristics of Pediatric Oncology Phase I and II Studies: A Systematic Review

Tremendous improvement in the overall survival of pediatric cancer patients has occurred over the past 40 years, but this may be slowing down. Continued progress depends on the development of new drugs and their prompt evaluation in clinical trials. Because of a perceived increase due to a greater number of drugs in development in adult oncology clinical trials, we examined recent trends and outcomes of early-phase clinical trials conducted in pediatric oncology. We conducted a literature review using PubMed and examined articles between January 2005 and December 2010. Inclusion criteria consisted of (1) reports published in English, (2) trials conducted exclusively in the United States or Canada, and (3) enrollment of patients under the age of 22 years. Excluded were trials evaluating radiation therapy, stem cell transplantation, supportive care, and therapies for non-oncologic diseases. We identified 75 early-phase trials, 64 drug and 11 immunotherapy, involving 2,286 patients below the age of 22 years. Complete or partial responses were observed for 5 % (phase I) and 19 % (phase II) of patients. Study-associated deaths occurred in 5 % (phase I) and 20 % (phase II) of patients. Progressive disease accounted for the vast majority of these deaths, followed by infection. Only two of the 43 phase I and none of the 11 phase II studies were sponsored solely by industry. Time to complete enrollment was 29 ± 14 and 49 ± 20 months for pediatric phase I and II drug studies, respectively. Pediatric early-phase drug trials demonstrated efficacy with low toxic death rates. Pediatric trials, including immunotherapy trials, showed less industrial support and longer phase II enrollment times than adult trials. Between 1990 and 2010, adult trials increased linearly, while growth in pediatric trials was flat. Only three of the drugs approved by the FDA between 2000 and 2010 were also approved for pediatrics. Published pediatric oncology early-phase trials have not shown the same linear increase as adult trials. We have identified differences in sponsorship and longer enrollment times for phase II trials.

Oncology phase II clinical trials in 2011: Summary description and comparison to phase II trials in other subspecialties.

e17568 Background: Phase II clinical trials in oncology have previously been reported to differ significantly in design compared to trials in other subspecialties. The purpose of this study is to provide a summary description of Phase II oncology clinical trials published in 2011, and to identify persistent major cross-specialty differences in clinical trial design. Methods: Records identified through a computerized literature search on PUBMED were reviewed manually using pre-defined criteria to identify abstracts of Phase II clinical trials published in 2011. The abstracts were classified according to variables including subspecialty, use of control group (active and/or placebo), randomization, blinding, and study conclusions. Trials with positive outcomes were defined as those in which the conclusion indicated that the intervention was safe and effective/worthy of further investigation. Statistical analysis was performed using the chi-squared test. Results: A total of 1,500 abstracts of Phase II clinical trials were identified, of which the majority (75%) describe trials on interventions for neoplastic diseases. Among oncology trials, the largest proportion of abstracts described trials evaluating intervention for hematologic neoplasms (16%), followed by upper and lower gastrointestinal (15%), lung (13%) and breast (11%) cancers. Compared to trials in other subspecialties, oncology trials are significantly less likely to include the use of randomization (17% vs 66%, p < 0.0001), blinding (3% vs 44%, p < 0.0001), and control (13% vs 70%, p < 0.0001). The majority of the abstracts reported positive outcomes (66% for oncology; 74% for the other subspecialties). Among oncology trials, trials utilizing a control group are less likely to report positive outcomes than those without a control group (53% vs 67%, p = 0.002). Conclusions: Major differences in design still exist between Phase II trials in oncology and other subspecialties. Only a minority of oncology trials report the use of randomization, blinding, or control groups. Whether the growing interest in randomized Phase II oncology trials will translate into a larger proportion of such trials in the future remains to be seen.

Assessment of Audit Methodologies for Bias Evaluation of Tumor Progression in Oncology Clinical Trials

As progression-free survival (PFS) has become increasingly used as the primary endpoint in oncology phase III trials, the U.S. Food and Drug Administration (FDA) has generally required a complete-case blinded independent central review (BICR) of PFS to assess and reduce potential bias in the investigator or local site evaluation. However, recent publications and FDA analyses have shown a high correlation between local site evaluation and BICR assessments of the PFS treatment effect, which questions whether complete-case BICR is necessary. One potential alternative is to use BICR as an audit tool to detect evaluation bias in the local site evaluation. In this article, the performance characteristics of two audit methods proposed in the literature are evaluated on 26 prospective, randomized phase III registration trials in nonhematologic malignancies. The results support that a BICR audit to assess potential bias in the local site evaluation is a feasible approach. However, implementation and logistical challenges need further consideration and discussion.

Evaluation of Blinded Independent Central Review of Tumor Progression in Oncology Clinical Trials: A Meta-analysis

Use of blinded independent central review (BICR) has become more common in oncology phase 3 trials as progression-free survival (PFS) has been increasingly used as an endpoint for regulatory approval. Since PFS is primarily a radiographic endpoint, BICR has been implemented to assess and reduce potential bias in the local evaluation (LE) of PFS. Recent publications note an agreement between LE and BICR of the ultimate reported PFS treatment effect, which questions the need for costly and time-consuming complete-case BICR of PFS. A meta-analysis was conducted to systematically evaluate the relationship between BICR- and LE-assessed PFS based on FDA's regulatory experience from 2005 to present. Our results support the claim that a complete review of all radiographs by BICR may not be necessary for oncology trials, and alternative methods should be explored to evaluate bias. One potential alternative is to use BICR as an audit tool to detect evaluation bias in LE assessments.

Evaluation of Patient Enrollment in Oncology Phase I Clinical Trials

For anticancer drug development, it is crucial that patients participate in early-phase clinical trials. The main aim of this study was to gain insight into the motivations and other variables influencing patients in their decision to participate in phase I oncology trials. Over a period of 25 months, all patients who were informed about (specific) phase I trials in our cancer center were retrospectively included in this study. Data on providing informed consent and final phase I enrollment were collected. In total, 365 patients, with a median age of 59 years and a median World Health Organization performance status score of 1, were evaluated. The majority of patients (71%) were pretreated with systemic therapy, with a median of two lines. After specific study information had been given, 145 patients (40%) declined informed consent, 54% of them mainly because of low expectations regarding treatment benefits and concerns about potential side effects. Patients who had received previous systemic therapy consented more frequently than others. After initial consent, 61 patients (17%) still did not receive study treatment, mostly because of secondary withdrawal of consent or rapid clinical deterioration prior to first dosing. After specific referral to our hospital for participation in early clinical trials, only 44% of all patients who were informed about a specific phase I trial eventually participated. Reasons for both participation and nonparticipation were diverse. Patient participation rates could be improved by forming an experienced and dedicated study team.

Outcome of patients (pts) with relapsed, advanced upper gastrointestinal (GI) carcinoma treated in a specialist oncology phase I unit.

45 Background: Conventional chemotherapy in advanced upper GI cancer after progression on first line therapy yields low response rates and no clear survival benefit. In this context, some pts are offered experimental treatments, including participation in Phase I clinical trials. Methods: Baseline pt and tumour characteristics, toxicity, response and outcome data of pts with upper GI cancers consecutively treated within the Drug Development Unit, Royal Marsden Hospital, from 2005 to 2009, were documented. Results: Ninety-six pts (median age 59 years [range 24-77]; male/female ratio 3.6, median of 2 [range 0-4] prior lines of chemotherapy) with oesophageal (42%), gastric (14.5%), pancreatic (26%) and oesphagogastric junction (7%) carcinomas were treated in 30 Phase I trials; of these, 36% participated in studies containing conventional cytotoxic chemotherapies. The overall response rate by RECIST was 11% with a disease control rate of 49%. The overall clinical benefit rate (i.e. no disease progression at 6 months) was 14%, respectively. In all pts, the median progression free survival (PFS) and overall survival (OS) were 7.0 weeks (95% CI: 5.6-8.4) and 19 weeks (95% CI: 17-21), respectively; these were not superior in pts who received chemotherapy-containing regimens (p=0.364, p=0.897). Pts with CBR ≥6 months a median OS of 55 weeks (95% CI: 46-64); 59% of them were treated with single-agent molecular targeting agents. Grade 3 or 4 toxicities were observed in 37 pts (39%) and led to trial discontinuation in nine (9%); no toxicity-related death occurred in these pts. In the multivariate analysis of baseline factors, serum albumin (<35 g/dl, HR 2.0 [95%CI: 1.3-3.2] p=0.002) and serum lactate dehydrogenase (LDH) (>192 umol/l, HR 1.7 [95% CI: 1.1-2.6], p=0.016) were prognostic of OS. Conclusions: Phase I clinical trials should be considered a valid option in pts with advanced upper GI cancers with disease relapse after first-line chemotherapy In our experience the risk of toxicity is low/moderate and there is the potential for clinical benefit.