Relationship between objective responses in phase I trials and potential efficacy of non-specific cytotoxic investigational new drugs.

BACKGROUND: Although the evaluation of new investigational drugs in phase I, II and III trials requires considerable time and patient resources, only a few of these drugs are ultimately established as anticancer drugs. MATERIALS AND METHODS: We collected papers of phase I trials by a Medline search using the key words 'Neoplasms/Drug Therapy in MeSH' and 'Phase I' for the period from 1976 to 1993. A drug was defined as 'effective' if a regimen including the drug produced positive results in at least one phase III trial. We analyzed the relationship between objective (complete and partial) responses in phase I trials and the effectiveness of agents in phase III trials. RESULTS: A total of 399 single-agent phase I trials of cytotoxic agents in adult patients with solid tumors were obtained. Further clinical investigation was not recommended in 36 trials (9%) because of severe toxicity. In the remaining 363 trials, 174 drugs were evaluated and the median number of trials for each drug was two (range one to nine). Objective responses were observed in 495 (4.1%) of 12 076 patients, 178 (49%) of 363 trials, and 115 (66%) of 174 drugs. Of the 174 drugs, 48 (28%) were considered to be effective. Percentages of effective drugs rose as the number of responders in phase I trials increased. Logistic regression analyses showed the number of responders to be significantly associated with drug effectiveness [odds ratio = 1.16 (1.06-1.27), P = 0.001 for 174 drugs; odds ratio = 1.16 (1.05-1.28), P = 0.0038 for 363 trials]. Although 10 active drugs failed to produce an objective response in phase I trials, seven of them produced a tumor regression of <50%, and three reportedly produced objective responses in phase I trials conducted before 1975. The numbers of responders among patients with lung, ovarian, breast or colorectal cancer, but not those among patients with lymphoma, melanoma, sarcoma or renal-cell carcinoma, were associated significantly with drug effectiveness against the respective tumors. CONCLUSIONS: Objective responses observed in phase I trials are important for determining the future development of an anticancer drug.     

Characteristics and outcome of pediatric patients enrolled in phase I oncology trials

PURPOSE: To describe the characteristics of pediatric subjects who enroll in phase I trials, to determine the associations between pre-enrollment characteristics and the risk for toxicity, and to analyze response and survival outcomes. EXPERIMENTAL DESIGN: Pre-enrollment characteristics and study outcomes were retrospectively analyzed for children with refractory solid tumors treated in one of 16 phase I trials with similar eligibility criteria at the National Cancer Institute between 1992 and 2005. RESULTS: The 262 subjects analyzed had received a median of two (range, 0-9) prior chemotherapy regimens, and were on one (range, 0-12) concomitant medication. The Eastern Cooperative Oncology Group performance status scores for subjects were 0 (29%), 1 (48%), and 2 (19%); 19% had received a prior stem cell transplantation and 73% had received prior radiation. Approximately 90% of subjects were evaluable for the primary trial endpoints (toxicity and pharmacokinetics). Seventeen percent of subjects experienced a dose-limiting toxicity (DLT), 5% discontinued the study drug because of toxicity, and a drug-related death occurred in one subject (0.4%). Variables associated with a higher risk for developing a DLT, by multiple logistic regression analysis, were drug dose and prior radiation, for myelosuppressive agents, and drug dose and performance status, for nonmyelosuppressive agents. The complete and partial response rate was 4%; however, 17% of subjects had stable disease (received three or more cycles). The median overall survival time from the time of enrollment was five months. CONCLUSIONS: Primary trial objectives are achieved in approximately 90% of subjects with the standard phase I trial design and eligibility criteria despite the intensification of frontline and salvage therapies in pediatric subjects with cancer.     

Progressive disease rate as a surrogate endpoint of phase II trials for non-small-cell lung cancer

Background: Although the potential activity of anticancer agents has been traditionally assessed by the response rate (RR) in phase II trials, there is an increasing need to identify alternative endpoints to evaluate the efficacy of novel types of antineoplastic agents such as cytostatic agents. However, none of the proposed alternatives have been validated.Design: RR, rate of progressive disease (PD), and median survival time (MST) were obtained from 44 treatment arms in 42 single-agent phase II trials for non-small-cell lung cancer (NSCLC). Correlations between these parameters and their significance in selection of promising drugs were evaluated.Results: The median (range) RR and PD rate per treatment arm were 17% (0%–40%) and 41% (8%–93%), respectively. The PD rate correlated more closely with MST (correlation coefficient (r) = 0.80, P < 0.001) than did the RR (r = 0.62, P < 0.001). The RR of active agents against NSCLC ranged broadly from 7% to 40%, whereas their PD rates were all 50% or less. In addition, all treatment arms with a PD rate over 50% had a poor MST of six months or shorter.Conclusions: The PD rate was potentially as good an endpoint as RR, and it may be a good candidate for the primary endpoint of phase II trials for novel types of anticancer agents.     

Response rate as an endpoint for evaluating new cytotoxic agents in phase II trials of non-small-cell lung cancer

Background: Response rate (RR) has been used as a defining endpoint of new-agent phase II trials for non-small-cell lung cancer (NSCLC). However, tumor responses to chemotherapy do not always result in prolonged survival of patients with this disease.Design: Single-agent phase II trials were identified by a MEDLINE search of the period from 1976 to 1995. Associations between RR, median survival time (MST) and characteristics of patients who entered the trial, including tumor extent, performance status and prior chemotherapy, were studied by using the logistic regression model.Results: A total of 183 treatment arms in 176 trials (including 10 randomized phase II trials) were identified. The overall RR in the 6768 evaluable patients was 11%. Eleven drugs, cisplatin, epirubicin, ifosfamide, edatrexate, irinotecan, vinorelbine, docetaxel, paclitaxel, etoposide, vindesine, and 254-S, produced a RR of more than 20%. An MST of eight months or longer was obtained with 12 drugs, but there were cases in which no objective responses were produced by these drugs. MST was correlated with RR (r = 0.504, P <; 0.0001), but ranged broadly at a given level of RR. Multiple linear regression analysis showed a significant correlation between RR and MST (regression coefficient = 0.60, P = 0.00003) after adjustment for other variables.Conclusions: RR was significantly correlated with MST in single-agent phase II trials for NSCLC, but there is room for further consideration of the endpoint of these trials.     

Treatment outcome and survival in participants of phase I oncology trials carried out from 2003 to 2006 at Institut Gustave Roussy.

BACKGROUND: The oncology community usually perceives phase I oncology trials as associated with poor or limited benefits and substantial risks. There is scarce data concerning outcome and survival of patients enrolled in current phase I oncology trials. PATIENTS AND METHODS: We reviewed all phase I oncology trials conducted by investigators from the Adult Phase I Unit at Institut Gustave Roussy from 2003 to 2006. We report data concerning patient demographics, treatment outcome, toxicity, survival and type of care after trial exit. RESULTS: We analyzed 10 trials involving 180 participants. The overall response rate was 7.2%. Disease control (objective response plus stable disease) was achieved in 48.2% of patients. The rate of toxic death was 0.5%. In all, 38% of patients had at least one episode of grade 3 or 4 toxic events. The median progression-free survival and the median overall survival (OS) were 2.3 and 8.7 months, respectively. On multivariate analysis, a time between diagnosis of disease and inclusion in the phase I trial > or =24 months and evidence of disease control were statistically significant predictors of improved OS. CONCLUSION: Current phase I oncology trials are safe and are associated with clinical benefit in a substantial proportion of patients.     

Evaluation of an information booklet for patients considering participation in phase I clinical trials in cancer

Phase I trials in cancer patients, although essential, are a difficult field of clinical research. A particularly challenging area for all members of the clinical research team is that concerned with information‐giving and informed consent leading to patient participation in the trial. An information booklet for patients was written in an attempt to address some of those issues, with the overall aim of improving the informed consent process and influencing patient decision‐making. Questions covered in the booklet include: What is a phase I trial? Who can take part? Are there any side‐effects or risks involved? What if I say no? The booklet was given to patients prior to consent. On the first day of receiving treatment they were given a questionnaire to evaluate the usefulness and acceptability of the booklet . The results showed the booklet to be generally well accepted by patients and the majority of them perceived the content and volume of information to be appropriate. The booklet did support patient decision‐making and the evaluation showed that the optimal time for patients to receive it was prior to the signing of a consent form. Minor amendments have been made to the booklet, which is now given routinely to all patients at the cancer centre who are considering participation in a phase I trial, and is a valuable addition to the informed consent process.     

Revisiting the definition of dose-limiting toxicities in paediatric oncology phase I clinical trials: An analysis from the Innovative Therapies for Children with Cancer Consortium

BackgroundDose-escalation trials aim to identify the maximum tolerated dose and, importantly, the recommended phase II dose (RP2D) and rely on the occurrence of dose-limiting toxicities (DLTs) during the first treatment cycle. Molecularly targeted agents (MTAs) often follow continuous and prolonged administrations, displaying a distinct toxicity profile compared to conventional chemotherapeutics, and classical DLT criteria might not be appropriate to evaluate MTAs' toxicity. We investigated this issue in children.MethodsThe Innovative Therapies for Children with Cancer Consortium (ITCC) phase I trials of novel anticancer agents between 2004 and 2015 were analysed. Data from investigational product, trial design, items defining DLT/RP2D were extracted. A survey on dose-escalation process, DLTs and RP2D definition was conducted among the ITCC clinical trials committee members.ResultsThirteen phase I trials with 15 dose-escalation cohorts were analysed. They explored 11 MTAs and 2 novel cytotoxics; 12 evaluated DLT during cycle 1. Definition of DLT was heterogeneous: Grade III–IV haematologic toxicities that were transient or asymptomatic and grade III–IV non-haematological toxicities manageable with adequate supportive care were often excluded, whereas some included dose intensity or grade II toxicities into DLT. None of the studies considered delayed toxicity into the RP2D definition.ConclusionDLTs should be homogeneously defined across trials, limiting the number of exceptions due to specific toxicities. Dose escalation should still be based on safety data from cycle 1, but delayed and overall toxicities, pharmacokinetic parameters and pharmacodynamic data should be considered to refine the final RP2D. The evaluation of long-term toxicity in the developing child cannot be adequately addressed in early trials.     

Patient motivations surrounding participation in phase I and phase II clinical trials of cancer chemotherapy

Successful advances in the treatment of advanced malignant diseases rely on recruitment of patients into clinical trials of novel agents. However, there is a genuine concern for the welfare of individual patients. The aim of this study was to examine motives of patients entering early clinical trials of novel cancer therapies. Questionnaire survey with both open- and close-ended questions. The patients were surveyed after they had given informed consent and before or during the first cycle of treatment. In all, 38 phase I/II trial patients participated and completed the survey. Obtaining possible health benefit was listed by 89% as being a 'very important' factor in their decision to participate, with only 17% giving reasons of helping future cancer patients and treatment. Other items cited as a 'very important' motivating factor were 'trust in the doctor' (66%), 'being treated by the latest treatment available' (66%), 'better standard of care and closer follow-up' (61%), and 'closer monitoring of patients in trials' (58%). Only 47% patients indicated that someone had explained to them about any 'reasonable' alternatives to the trial. In total, 71% strongly agreed that 'surviving for as long time as possible was the most important thing (for them)'. Nearly all (97%) indicated that they knew the purpose of the trial and had enough time to consider participation in the trial (100%). In this survey, most patients entering phase I and II clinical trials felt they understood the purpose of the research and had given truly informed consent. Despite this, most patients participated in the hope of therapeutic benefit, although this is known to be a rare outcome in this patient subset. Trialists should be aware, and take account of the expectations that participants place in trial drugs.     

Drug induced interstitial lung disease in oncology phase I trials

Interstitial lung disease is a serious drug‐related condition that can cause life threatening organ failure. The incidence and risk factors of drug‐induced interstitial lung disease (DILD) are unknown in oncology phase I trials. This study analyzed clinical information from 8906 patients with malignancies who were enrolled in 470 phase I trials sponsored by the Cancer Therapy Evaluation Program, National Cancer Institute, from 1988 to 2014. Logistic and Cox statistical analyses were utilized to determine clinical differences between patients who developed DILD and patients who did not. In this study, the overall incidence rate of patients with pulmonary toxicity was 2.7%. The overall incidence rate for DILD was 0.77%, whereas for grade 3 or 4 DILD it was 0.31%. Median time to occurrence of DILD was 1.4 months. The Cox hazard analysis indicated smaller body surface area and a combination of thoracic radiation with investigational drug regimens were significant risk factors for time to occurrence of interstitial lung disease. Investigators should carefully monitor for DILD in oncology patients enrolled in phase I trials with identified risk factors. A 6‐month observation period would be sufficient to detect the onset of most DILD in such patients.     

Multivariable analysis of prognostic factors for toxicity and survival for patients enrolled in phase I clinical trials

Background:Patients with advanced solid tumors may be includedin phase I clinical trials. In such studies, the benefit expected is generallylower than the likelihood of toxicity and may even be non-existent if thepatient's life expectancy is too short. This study was performed to identifyprognostic variables for toxicity and survival in patients who participate inphase I clinical trials. Patients and methods:One hundred fifty-four patients treated ona phase I clinical trial in our institute were evaluated retrospectively.Univariable and multivariable analyses of patients' characteristics wereundertaken to determine their effects on the probability of grade 3 and 4toxicity and on survival. Results:Grade 3 or 4 toxicity was experienced by 56 patients(36%): dosage level at entry (P < 0.001) and age over 65years (P = 0.03) were independently associated with the risk oftoxicity. Median overall survival was 5 months. The multivariable analysisidentified performance status 2 or 3 (P < 0.001) and lactatedehydrogenase levels greater than 600 UI (P < 0.001) asindependent adverse prognostic variables for overall survival. Using these twoparameters, we determined a prognostic index which allowed us to discriminatethree risk groups of patients with an observed median survival of 8.5, 4.5 and1.5 months, respectively. Conclusions:Subgroups with different survival expectancy can beidentified among patients who are eligible for phase I clinical trials. Ifconfirmed, the proposed prognostic model may be useful for therapeuticdecision making in palliative oncology.eased     

Therapeutic response and potential pitfalls in phase I clinical trials of anticancer agents conducted in Japan

The published reports of phase I clinical trials of anticancer agents conducted in Japan from 1981 to 1991 were reviewed. A total of 56 clinical studies that evaluated 38 different agents were reviewed. An average of five agents were studied each year. A total of 2200 patients had been recruited into the 56 clinical trials conducted during this period. A total of 91 patients (4.1%) responded to the treatment, with 23 showing a complete response (1.1%) and 48, a partial response (2.2%). In all, 62% of the responses were observed when patients were treated with doses ranging from 76% to 125% of the recommended doses for phase II studies. The response rates obtained for hematological malignancies were higher than those reported for other malignancies. The past status of phase I clinical trials in Japan can be summarized as follows. (1) A median of seven institutes participated in a single trial. The number of institutes participating correlated with the number of patients enrolled. However, too many institutes participated in a single phase I clinical trial in some studies. (2) The median duration of study for the clinical trials was 14 months. The duration of study was too long in some studies, considering the small number of patients enrolled. In conclusion, the methodology of phase I clinical trials of anticancer agents conducted in Japan should be improved in an efficient and scientific manner, especially for the testing of imported agents.     

Trends in the characteristics,dose-limiting toxicities and efficacy of phase I oncology trials: The Cancer Research UK experience

IntroductionPhase I oncology trials have evolved over the years, and these changes could have implications for future studies and patients.MethodsAdult trials sponsored by Cancer Research UK Centre for Drug Development between 1995 and 2013 were analysed. Forty-nine trials were divided into two groups based on the starting date for recruitment: 1995–2003 (24 trials, n = 603) and 2004–2013 (25 trials, n = 750) for comparative purposes.ResultsFrom 1995–2003 to 2004–2013, there was a shift towards studying non-cytotoxic agents that are administered orally. In later trials, patients tended to have better performance status, were older, had greater disease burden, and were more likely to have received prior treatment. In 2004–2013, wider variety of dose escalation designs were used, and studies were more likely to be multicentre, target/disease specific, conducted in first-/any-line setting and to require tumour biopsy. The overall incidence of dose-limiting toxicities (DLTs) was unchanged (10.9%; risk of death 0.4%), but DLTs such as neuropathy, stomatitis and thrombocytopaenia were less frequent in the more recent trials, while elevated liver enzymes were more frequent. Non-classical DLTs emerged in the later trials, including hypertension, hypophosphataemia, cardiac and ophthalmic toxicities. Disease control rate (DCR) increased from 27.9% (1995–2003) to 36.0% (2004–2013; P = 0.0033) due to higher rates of disease stabilisation.ConclusionChanges in trial designs, therapeutic agents, patient characteristics and DLTs were observed. Although the nature of DLTs changed, the incidence was similar in the two time periods and DCR improved, suggesting that the benefit-risk balance for patients participating in early-phase trials remains acceptable.     

Presentation and subsequent publication rates of phase I oncology clinical trials

BACKGROUND: Many trials submitted to scientific meetings are not reported in peer-reviewed journals. Results may vary substantially and the lack of final publication constitutes a form of reporting bias. The authors sought to determine the presentation and publication rates of Phase I trials submitted to a major oncology meeting and the factors impeding their subsequent publication. METHODS: The authors identified all Phase I studies submitted to the annual meeting of the American Society of Clinical Oncology in 1997, categorizing them as novel (agents not approved by the Food and Drug Administration at the time of submission) or nonnovel (at least one agent approved), and as industry sponsored or not. MEDLINE searches and an E-mailed questionnaire confirmed publication in peer-reviewed literature and the reasons for nonpublication. RESULTS: Approximately 54% of the 275 Phase I studies were selected for presentation. Abstracts reporting novel agents were more likely selected for presentation than those reporting nonnovel compounds (68% vs. 38%; P < 0.0001). Seventy-two percent of the presented abstracts were subsequently published, compared with 62% of those not presented (P = 0.08). The overall publication rate was 67% at 7.5 years. Presentation status was associated with time to publication (P = 0.01), with abstracts chosen for presentation being published sooner. The median time from presentation to publication was found to be 3.4 years. Lack of time and author relocation were the major obstacles to publication. CONCLUSIONS: The underreporting of final results of Phase I oncology trials remains a serious problem. In the future, investigators must commit to the publication of final results in a timely manner. Journals should provide mechanisms for rapid reporting of Phase I trials.     

Predictors of early treatment discontinuation in patients enrolled on Phase I oncology trials

Purpose

Patients who do not complete one cycle of therapy on Phase I trials for reasons other than dose limiting toxicity (DLT) are considered inevaluable for toxicity and must be replaced.

Methods

Individual records from patients enrolled to NCI-sponsored Phase I trials activated between 2000 and 2010 were used. Early discontinuation was defined as the failure to begin cycle 2 for reasons other than a DLT during cycle 1. A multinomial logistic regression with a 3-level nominal outcome (early discontinuation, DLT during cycle 1, and continuation to cycle 2) was used with continuation to cycle 2 serving as the reference category. The final model was used to create two risk scores. An independent external cohort was used to validate these models.

Results

Data from 3079 patients on 127 Phase I trials were analyzed. ECOG performance status (1, ≥ 2, two-sided P = .0315 and P = .0007), creatinine clearance (<60 ml/min, P = .0455), alkaline phosphatase (>2.5xULN, P = .0026), AST (>ULN, P = .0076), hemoglobin (<10 g/dL, P < .0001), albumin (< 3.5 g/dL, P < .0001), and platelets (<400x109/L, P = .0732) were predictors of early discontinuation. The c-index of the final model was 0.63.

Conclusion

Knowledge of risk factors for early treatment discontinuation in conjunction with clinical judgment can help guide Phase I patient selection.     

Phase I trials in cancer patients: participants' perceptions

There is controversy surrounding the ethics of performing phase I clinical trials with cancer patients and limited research concerning patients' attitudes when participating in such trials. The aim of this study was to determine how cancer patients perceive phase I clinical trials in reference to trial participation and trial information received. Cancer patients ( n = 28) were interviewed 2–4 weeks after consenting to participate, using a questionnaire which contained open and closed questions. Responses were analysed using non-parametric statistical tests. The results demonstrated that although the majority of patients participated in experimental treatment because it offered hope that they might be helped, their expectations from the new drug were realistic. Patients found that there were benefits related to participating in phase I trials and felt that the amount and quality of both nursing and medical care was superior in a phase I trial as compared to standard treatment in non-experimental settings. There were varying opinions among patients with regard to information giving by nursing and medical staff. It can be concluded that phase I trials employing cancer patients can be ethical.     

Factors associated with failure of oncology drugs in late-stage clinical development: A systematic review

BackgroundWe aimed to describe the reasons for failure of experimental anticancer drugs in late-stage clinical development.Material and methodsWe searched the PharmaProjects database (https://citeline.com/products/pharmaprojects/) for anticancer drugs discontinued between 01/01/2009 and 06/30/2014. Drug programs that reached phase III trials, but never gained Food and Drug Administration (FDA) approval were compared to 37 anti-cancer drugs achieving FDA approval in this time period.ResultsForty-two drugs fit our criteria for development failures. These failed drugs (49% targeted, 23% cytotoxics, and 28% other) were tested in 43 cancer indications (drug programs). Only 16% (7/43) of failed drug programs adopted a biomarker-driven rationale for patient selection versus 57% (21/37) of successful drug programs (P < 0.001). Phase II trial information was available in 32 of 43 failed drug programs and in 32 of 37 successful programs. Nine of the 32 trials (28%) of failed drugs versus 28 of 32 trials (87%) of successful drugs (P < 0.001) achieved proof of concept (single agent response rate (RR) ⩾20% or combination therapy showing a ⩾20% RR increase above the median historical RR without the experimental agent (with a minimal absolute increase of 5%) or a randomized phase II trial showing significance (P ⩽ 0.05) for its primary outcome). No pattern of study sites, trial design or funding characteristics emerged from the failed drug analysis.ConclusionFor drugs that reached Phase III, lack of a biomarker-driven strategy and failure to attain proof of concept in phase II are potential risk factors for later discontinuation, especially for targeted agents.