National Cancer Institute Cancer Therapy Evaluation Program Research Articles

Abstract B036: Trends in disparities in clinical trial accrual: An analysis of National Cancer Institute (NCI)-sponsored early phase clinical trials over the last 22 years

Abstract Using the NCI Cancer Therapy Evaluation Program (CTEP)-sponsored early phase oncology clinical trials database, we evaluated trends in disparities in patient enrollment over the last 22 years. Counts and percentages of enrolled patients were calculated directly from the full population of patients enrolled to CTEP-sponsored Phase 1, 2, and 1/2 trials during 2000-22. Trends in enrollment were assessed based on single-year data, four-year periods, and using a three-year rolling average. Analyses of patient residential ZIP code were restricted to patients residing and enrolled at institutions within the United States. Geographical data corresponding to patient ZIP codes was obtained using the zipcodeR package, including geographical region and median household income corresponding to each ZIP, and distance between patient residential and enrolling institution ZIPs. A total of 14,877 patients were enrolled in CTEP-sponsored early phase trials evaluated during 2000-22, with 14,342 residing and enrolled within the US. The proportion of patients aged 40-64 at enrollment decreased from 59.8% in 2000-03 to 47.5% in 2020-22, with corresponding increases in ages 65-74 (24.2% to 32.9%) and 75-84 (5.9% to 12.3%). There were fluctuations in gender, most likely based on the specific agents being studied in clinical trials enrolling at a given time. In 2020-22, 72.9% of the population was non-Hispanic white when compared to 2000-03 when enrollment of non-Hispanic whites was 83.7%. Hispanic/Latino population enrollment increased from 4.2% in years 2000-03 to 6.9% in years 2020-22. Asian/Pacific Islander population increased from 2.5% in 2000-03 to 5.4% in 2020-22. Enrollment of non-Hispanic Black patients increased slightly over the last 20 years (6.3% to 7.1%), as did the proportion with unknown or unspecified race/ethnicity (3.3% to 7.6%). Trial enrollment trends by geographic regions revealed that enrollment in South and West overall increased (29.1% to 40.9%; 7.9% to 18.2%), Northeast representation remained static (23.9% to 20.8%) and Midwest representation decreased (24.4% to 19.4%) from 2000-03 to 2020-22. Most early phase participants in our database were from localities with a moderate median household income ($52,200 - $156,600; 51.9% to 59.4%), with an increase in representation from low-income localities (income < $52,000; 31.1% to 37.7%) over the last 22 years. We observed an overall increase in patients enrolling within a 50-mile radius of their residence over the 22-year period (46.5% to 64.5%) and an overall decrease in patients traveling over 200 miles to enroll in clinical trials (16.1% to 8.3%). We also examined trends in disparities during the COVID-19 pandemic and saw no significant differences in trial enrollment by race/ethnicity and gender when compared to pre-pandemic enrollment. Disparities in patients enrolled in early-phase clinical trials have marginally improved over the span of two decades, and outreach and inclusion efforts for enrollment of underrepresented patients should be continued to sustain these observed trends. Citation Format: Maria Farooq, Elad Sharon, Naoko Takebe, Ana F. Best, Shanda Finnigan. Trends in disparities in clinical trial accrual: An analysis of National Cancer Institute (NCI)-sponsored early phase clinical trials over the last 22 years [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B036.

Enrollment of adolescent and young adult patients newly diagnosed with cancer in NCI CTEP-sponsored clinical trials before and after launch of the NCI National Clinical Trials Network.

Participation of adolescents and young adults (AYAs) in oncology clinical trials is important to ensure adequate opportunities for AYA patients to contribute to, and benefit from, advances in cancer treatment. Accrual data for National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) cooperative group-led treatment trials were examined to assess enrollment of newly diagnosed AYA patients (15-39 years) during the period 2004-2019, with particular interest in comparing enrollment before launch of the NCI National Clinical Trials Network (NCTN) to after. All phase 2, 2/3, and 3 trials activated during the period between January 1, 2004, and December 31, 2019, were identified (n=1568) and reduced to a set of 304 that met predetermined criteria to focus on cooperative group-led trials that involved therapy for newly diagnosed cancer and had age eligibility overlapping the AYA range. The proportion of AYA patients relative to total accrual, along with 95% bootstrapped CI was calculated for patients enrolled pre-NCTN and post-NCTN. AYA accrual comprised 9.5% (95% CI, 7.6-11.8) pre-NCTN compared with 14.0% (95% CI, 9.9-18.3) post-NCTN. The mean difference in proportions post-NCTN compared with pre-NCTN was 4.4% (0.7%-8.3%). These results indicate an increase in AYA participation in trials conducted within the NCTN relative to the pre-NCTN period. This suggests an awareness and utilization of NCTN trials for AYAs with cancer.

Major adverse cardiac events (MACE) with immune checkpoint inhibitor (ICI)-based therapies for cancer: A pooled analysis of investigational clinical trials sponsored by the National Cancer Institute Cancer Therapy Evaluation Program (NCI-CTEP) in the United States and Canada.

2508 Background: MACE due to ICIs are infrequent immune-related adverse events (irAEs) that comprise a spectrum of cardiac toxicities with variable manifestations. ICI-related MACE can lead to significant morbidity and mortality, hence the need to better define presentations of MACE and their association with non-cardiac irAEs in ICI-treated patients. Methods: We conducted a retrospective pooled analysis of MACE captured in the serious adverse events reporting database of the NCI-CTEP for NCI-sponsored investigational clinical trials between 6/2015-12/2019. Patients (pts) were eligible if they had been treated with anti-programmed cell death protein-1/programmed death-ligand 1 (anti-PD-[L]1) alone or in combination with additional anti-cancer therapies. Results: A total of 6,925 pts received anti-PD-(L)1-based therapies; 48% (n = 3354) were treated with single-agent anti-PD-(L)1 therapy. Of 6925 pts, 0.6% (n = 40) qualified as ICI-related MACE. Myocarditis accounted for 45% (n = 18/40) of total ICI-MACE. Approximately 77.5% (n = 31/40) of MACE were ≥ grade 3. Multi-system organ involvement with other non-cardiac irAEs was seen in 65% (n = 26/40). Most pts with myocarditis (83%, n = 15/18) had one or more non-cardiac irAEs associated; non-cardiac irAEs were observed in 50% (n = 11/22) of non-myocarditis MACE. Incidence of MACE was higher with anti-PD-(L)1 + targeted therapies vs. anti-PD-(L)1 + anti-CTLA-4 (2.1% vs. 0.09%, p = 0.08). Most of these were non-myocarditis MACE. There was a significantly higher incidence of myocarditis with anti-PD-(L)1-based combinations vs. single-agent anti-PD-(L)1 therapies (0.39%, n = 13/3341 vs. 0.14%, n = 5/3566, p = 0.04. Most pts with myocarditis had been treated with anti-PD-1-based combinations (72%, n = 13/18); the most common combination being anti-PD1+ anti-CTLA-4 (92%, n = 12/13). Pts with myocarditis presented after a median of 2 ICI doses and after a median of 35 days from the initial ICI administration. In pts with myocarditis, a concurrent or preceding history of myositis was present in 53% (n = 8/15). Deaths related to myocarditis were identified in 22.5% (n = 4/18). All four patients who died had concurrent myositis, with three having concurrent transaminitis. Conclusions: Our results represent the first report of a comprehensive pooled analysis of ICI-MACE obtained from NCI CTEP-sponsored investigational clinical trials. Based on our results, increasing patient and prescriber awareness in understanding patterns of ICI-MACE and associated non-cardiac irAEs should be emphasized. Furthermore, better characterization of the risk and patterns of non-myocarditis MACE with the use of anti-PD(L)-1 ICIs concurrently with non-ICI-based anti-cancer therapies is needed.

National Cancer Institute support for targeted alpha-emitter therapy.

Radiopharmaceutical targeted therapy (RPT) has been studied for decades; however, recent clinical trials demonstrating efficacy have helped renewed interest in the modality. This article reviews National Cancer Institute (NCI)'s support of RPT through communication via workshops and interest groups, through funding extramural programs in academia and small business, and through intramural research, including preclinical and clinical studies. NCI has co-organized workshops and organized interest groups on RPT and RPT dosimetry to encourage the community and facilitate rigorous preclinical and clinical studies. NCI has been supporting RPT research through various mechanisms. Research has been funded through peer-reviewed NCI Research and Program Grants (RPG) and NCI Small Business Innovation Research (SBIR) Development Center, which funds small business-initiated projects, some of which have led to clinical trials. The NCI Cancer Therapy Evaluation Program (CTEP)'s Radiopharmaceutical Development Initiative supports RPT in NCI-funded clinical trials, including Imaging and Radiation Oncology Core (IROC) expertise in imaging QA and dosimetry procedures. Preclinical targeted a-emitter therapy (TAT) research at the NCI's intramural program is ongoing, building on foundational work dating back to the 1980s. Ongoing "bench-to-bedside" efforts leverage the unique infrastructure of the National Institutes of Health's (NIH) Clinical Center. Given the great potential of RPT, our goal is to continue to encourage its development that will generate the high-quality evidence needed to bring this multidisciplinary treatment to patients.

National Cancer Institute (NCI) implementation of the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (Friends) broadening clinical trials eligibility criteria.

6518 Background: The 2017 ASCO/Friends eligibility criteria guidelines recommend inclusiveness to promote generalizable trial results and clear rationale for necessary exclusion. These guidelines focused on brain metastases, minimum age for enrollment, HIV infection, and organ dysfunction and prior and concurrent malignancies. In September 2018, the NCI Cancer Therapy Evaluation Program (CTEP) implemented modernized protocol template language to operationalize these criteria. We evaluated utilization of the new language among CTEP-sponsored treatment trials. Methods: We evaluated protocols first approved by CTEP between 11/01/2018 and 4/30/2020. The most recent approved protocol version was evaluated for consistency with the new template language for brain metastases, HIV infection, prior or concurrent malignancies, minimum age, and cardiac, liver and kidney function. If a particular criterion was not relevant for a trial, it was not included in the analysis. We did not score age in pediatric or adult-specific trials (e.g. prostate). Results: 122 trials (71% early and 29% late phase) were identified and included in the analysis. Compliance with the new criteria language ranged from a high of 87.7% for liver function to a low of 11.5% for “new or progressive brain metastases” (table). Modernized criteria language was lacking in nearly 46% of trials in the use of concurrent or prior malignancy criteria and 31% of trials for the cardiac criteria. Of the 87 trials for non-localized disease or non-brain tumor trials, 64.4% did not address brain metastases, leaving it to investigator discretion. Thus, 75.9% of trials could theoretically enroll patients with brain metastases. Only 6 trials were considered relevant for patients < 18 years old; 50% were consistent with the age criterion (not shown in table). Conclusions: Implementing ASCO/Friends eligibility criteria requires focused reviews during protocol development to ensure compliance. CTEP is using these findings to continue to improve its protocol review processes to broaden eligibility in clinical trials. Maximizing opportunities for diverse populations to participate in trials is a priority for the National Cancer Institute and CTEP will continue efforts to achieve this goal.[Table: see text]

Phase 0 Radiopharmaceutical-Agent Clinical Development.

The evaluation of antibody-targeted or peptide-targeted radiopharmaceuticals as monotherapy or in oncological drug combinations requires programmatic collaboration within the National Cancer Institute (NCI) clinical trial enterprise. Phase 0 trials provide a flexible research platform for the study of radiopharmaceutical–drug pharmacokinetics, radiation dosimetry, biomarkers of DNA damage response modulation, and pharmacodynamic benchmarks predictive of therapeutic success. In this article, we discuss a phase 0 clinical development approach for human antibody-targeted or peptide-targeted radiopharmaceutical–agent combinations. We expect that early-phase radiopharmaceutical–agent combination trials will become a more tactical and more prevalent part of radiopharmaceutical clinical development in the near-term future for the NCI Cancer Therapy Evaluation Program.

Financial Toxicity Encountered in Therapeutic Radiopharmaceutical Clinical Development for Ovarian Cancer.

Financial toxicity or the debt a cancer survivor incurs from the costs of their medical cancer care is an understudied aspect in the clinical development of experimental therapeutic agents. The United States National Cancer Institute (NCI) Cancer Therapy Evaluation Program studies experimental therapeutic agents like radiopharmaceuticals in both early and late phase trials, which provide opportunities to comprehend more clearly the possible sources of financial toxicity incurred by cancer survivors. We reviewed the academic scholarship describing fiscal and social costs involved in the development of therapeutic radiopharmaceuticals. Because many ovarian cancer survivors outlive their disease through initial and, perhaps, multiple treatment courses, these women and their treatments provide context for our discussion on financial toxicity. 16 (27%) of 60 articles discuss financial toxicity incurred by women with ovarian cancer; none described financial toxicity associated with regulatory agency-approved or experimental therapeutic radiopharmaceuticals. Fiscal costs of radiopharmaceutical dose and schedule and social costs of individual productivity loss or asset expenditure arose as primary financial toxicities. The development of radiopharmaceuticals for women with ovarian cancer remains a high priority for the NCI Cancer Therapy Evaluation Program. Weighing radiopharmaceutical clinical benefit against measures of financial toxicity is challenging and warrants further study in prospective radiopharmaceutical clinical trials.

Clinical Outcome Assessments Toolbox for Radiopharmaceuticals.

For nearly 40 years, the U.S. National Cancer Institute (NCI) has funded health-related quality-of-life (HRQOL) and symptom management in oncology clinical trials as a method for including a cancer patient's experience during and after treatment. The NCI's planned scope for HRQOL, symptom and patient-reported outcomes management research is explained as it pertains to radiopharmaceutical clinical development. An effort already underway to support protocol authoring via an NCI Cancer Therapy Evaluation Program (CTEP) Centralized Protocol Writing Service (CPWS) is described as this service aids incorporation of HRQOL, symptom and patient-reported outcomes management research into sponsored protocols.

Dietary and Serum Lycopene Levels in Prostate Cancer Patients Undergoing Intensity-Modulated Radiation Therapy

Tomato products, good sources of lycopene, may lower the incidence of prostate cancer, but data on the effectiveness of lycopene supplementation during radiation therapy are lacking. This study aimed to evaluate the tolerance and acceptance of three different amounts (4, 8, or 12 oz) of tomato juice (TJ) and their effect on serum lycopene during radiotherapy in 20 men with localized prostate cancer. Participants were randomized into a control group or one of three intervention groups who consumed TJ daily during treatment. Dietary lycopene intake was estimated using the National Cancer Institute (NCI) Diet History Questionnaire, and gastrointestinal tolerance of TJ was evaluated using the NCI Cancer Therapy Evaluation Program: Common Toxicity Criteria v 2.0. Serum and TJ lycopene levels were measured by liquid chromatography-mass spectrometry. TJ was well tolerated without any gastrointestinal side effects, and increased serum lycopene levels were observed in the 8 and 12 oz groups from baseline to endpoint. No correlation between serum and dietary lycopene was detected. Despite no reported change in dietary intake, non-significant weight loss was observed in the control group but not the intervention group participants. A significant positive correlation between serum lycopene, weight, and body mass index, and a negative correlation between serum lycopene and piror nutritional supplement use was detected. Weight change should be monitored and evaluated during treatment. Larger clinical trials are needed to validate the use of TJ to increase serum/dietary lycopene intake and correlate with side effects during radiotherapy in men with prostate cancer.

Adult participation in oncology clinical trials by indication, race, and age.

e17586 Background: According to the National Cancer Institute (NCI), approximately 3 percent of adult cancer patients participate in clinical trials despite the NCCN guidelines frequently recommending clinical trials as standard of care in many circumstances (Mooney, 2010). In a large analysis of NCI Cancer Therapy Evaluation Program (CTEP) trials, 40 percent of trials failed to achieve minimum enrollment, including 3 of 5 phase III trials (Cheng, 2010). Additionally, concerns about unequal access to clinical trials led Congress to enact the National Institutes of Health (NIH) Revitalization Act 20 years ago (June 10, 1993). Using data from Ipsos’ Tandem Oncology Monitor, a robust, nationwide system that collects actual prescriptions and clinical trial participation by indication from 500 oncologists and hematologists from the United States, we evaluated current participation and ethnic diversity in clinical trials. Methods: We assessed adult clinical trial participation from October 2011 to September 2012. Age, ethnicity and practice type were also collected to identify descriptive trends. Results: With regards to indication, clinical trial participation ranged from 1 percent (prostate, renal cell and head and neck) to 12 percent (thyroid) averaging between 2 and 3 percent. We observed a decline in first-line metastatic melanoma participation between pre- and post- vemurafenib/ipilimumab approval (9%-pre versus 2%-post). Patient diversity results are included in the Table. Conclusions: Despite efforts to increase oncology clinical trial participation, we have observed overall low clinical trial participation. Additionally, we observed better trial participation in the youngest age groups and minor differences between ethnic categories. Continued focus on increasing trial participation and patient diversity is still needed. [Table: see text]

Similar efficacy for phase I trials in comparison with DTIC for advanced malignant melanoma

After ipilimumab, vemurafenib, and interleukin-2, standard of care chemotherapy for melanoma remains dacarbazine (response rate ∼9%). Despite this, many physicians hesitate to refer patients to phase I protocols given a perceived lack of clinical benefit and potential for harm. To better understand the validity of these perceptions, the experience of all patients with melanoma treated on phase I trials sponsored by the National Cancer Institute-Cancer Therapy Evaluation Program (NCI-CTEP) from 1995 to 2011 were analyzed and compared with the pooled results of six contemporary phase III trials of dacarbazine. A total of 937 patients with melanoma were treated in 148 CTEP phase I trials. The majority were men with a median of two prior therapies (46% receiving prior dacarbazine). Response and clinical benefit rates in these trials were not clinically different from those of dacarbazine (phase I: 6.3 and 26.8% vs. dacarbazine: 8.8 and 27.9%) although grades 3 and 4 toxicity was significantly higher (54 vs. 28%). Efficacy and toxicity were generally consistent within phase I subgroups (targeted agents, immunotherapies, or chemotherapeutics) though targeted therapy was associated with a lower response rate, immunotherapy with lower clinical benefit rate, and chemotherapy with higher incidence of grade 4 toxicity. Thus, the perception of limited efficacy of phase I trials for patients with melanoma was disproven, whereas the perception of toxicity was observed. However, this difference in toxicity may have been largely because of the nature of phase I vs. phase III trials (i.e. more heavily pretreated) and because of the phase I trials often being multiagent as opposed to dacarbazine alone.

Clinical Trial Development as a Predictor of Accrual Performance—Response

We thank Schoen for her comments and insights into accrual performance. The primary purpose of our research was to reveal the relationship between development time of National Cancer Institute Cancer Therapy Evaluation Program (NCI-CTEP)-supported trials and a standard accrual milestone that was

Predicting Accrual Achievement: Monitoring Accrual Milestones of NCI-CTEP–Sponsored Clinical Trials

The need to increase the number oncology clinical trials with sufficient enrollments is a well-known issue, particularly for trials targeting therapeutic applications. It is critical to identify early predictors of eventual study accrual achievement. All nonpediatric phase I, I/II, II, and III therapeutic studies supported by the National Cancer Institute Cancer Therapy Evaluation Program (NCI-CTEP) between 2000 and 2007 (n = 764) were analyzed for accrual performance. Accrual achievement is defined as those enrolling 100% or more of the stated minimum accrual goal at the time of trial closure. Two accrual milestones were analyzed per trial: time to first patient enrollment and expected time to accrual goal. Multivariate logistic regression analysis was used to calculate the OR with respect to the likelihood of clinical trial accrual achievement. A total of 81.5% (n = 623) of the trials did not achieve the projected accrual goals within the anticipated accruing period. Furthermore, 37.2% (n = 284) of trials failed to achieve the minimum projected accrual at study closure regardless of time the trial was open. Trials that accrue the first enrollment beyond 2 months (n = 379, 49.6%) are significantly less likely to achieve the accrual performance than those trials that enroll patients under 2 months (OR: 0.637, 95% CI: 0.464-0.875, P = 0.005). Of the studies that are open beyond the anticipated enrollment period (n = 603), those do not achieve at least 60.0% of the projected minimum accrual (n = 391, 64.8%) have a significantly less likelihood of achieving final accruals by study closure (OR: 0.190, 95% CI: 0.055-0.652, P = 0.008). The time to first patient enrollment and expected time to accrual goal are shown to be valid measures to evaluate the likelihood of achieving the minimum projected accrual.

The Novel, Investigational NEDD8-Activating Enzyme Inhibitor MLN4924 In Adult Patients with Acute Myeloid Leukemia (AML) or High-Grade Myelodysplastic Syndromes (MDS): A Phase 1 Study

AbstractAbstract 658 Background:NEDD8-activating enzyme (NAE) regulates the NEDD8 conjugation pathway, and is required for the activity of the cullin-RING E3 ligases (CRLs). CRLs control the timed degradation of several substrates involved in cell-cycle regulation, signal transduction, DNA replication, and stress response, including proteins important for the survival of AML cells. We evaluated the preclinical anti-leukemic activity of MLN4924, a novel, investigational, first-in-class small molecule inhibitor of NAE, and based on the activity of MLN4924 in preclinical AML models (Swords RT et al, Blood 2010) we conducted a phase 1 study to evaluate the safety and tolerability of this agent in patients with AML and advanced MDS. Methods:The primary objectives of this study were to evaluate the safety and tolerability of MLN4924, to establish the maximum tolerated dose (MTD), and to determine the recommended phase 2 dose of MLN4924 in patients with AML and high-grade MDS. Secondary objectives included a preliminary assessment of efficacy, and analysis of pharmacokinetics and pharmacodynamics (via NAE-regulated proteins in peripheral blood mononuclear cells). Patients aged ≥18 years, with ECOG performance status 0–2, who had AML or high-grade MDS, and who were not candidates for potentially curative therapy, were eligible. MLN4924 was administered as a 60-minute IV infusion on days 1, 3, and 5 of a 21-day cycle for up to 12 months or until documented disease progression. Dose escalation was commenced at 25 mg/m2 and proceeded using a standard 3+3′ escalation method until the MTD was established. Response assessment was based on recently published guidelines (Döhner H et al, Blood 2010) and adverse events (AEs) were graded per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events v3.0 (NCI Cancer Therapy Evaluation Program, 2006). Results:To date, 15 patients (9 males, 6 females; 14 AML, 1 high-grade MDS) have been enrolled and treated, including 3, 4, 3, 3, and 2 at dose levels of 25, 33, 44, 59, and 78 mg/m2, respectively. Median age was 62.3 years (range 29.3–84.0 years). By cytogenetics, 1 (7%), 5 (33%), and 7 (47%) patients had good-, intermediate-, and poor-risk disease (not available in 2). Prior antineoplastic therapies included cytarabine (n=7), azacitidine, daunorubicin (n=3 each), decitabine, etoposide, gemtuzumab, idarubicin, and mitoxantrone (n=2 each). To date, 3 patients have received ≥8 cycles; 6 remain on treatment. Two dose-limiting toxicities have been reported at the 78 mg/m2 dose level: one patient with multi-organ failure in Cycle 2, and one with reversible elevation of alanine aminotransferase in Cycle 1. The most common AEs were pneumonia (n=6), atelectasis, constipation, diarrhea, and febrile neutropenia (each n=4); most common grade ≥3 AEs were febrile neutropenia (n=4), elevated aspartate aminotransferase, and pneumonia (each n=3). Three patients have achieved a complete response (CR) to date. A 29-year-old woman with relapsed AML following allogeneic stem cell transplantation achieved a CR after cycle 1 at 25 mg/m2 before developing progressive disease at an extramedullary site during cycle 8. An 82-year-old man with history of high-risk MDS, which was unresponsive to azacitidine, that evolved into AML had a partial response in cycle 8 and a CR with incomplete recovery of blood counts (CRi) in cycle 10 at 33 mg/m2; the patient is currently in cycle 12 and has become transfusion-independent. A 71-year-old man with de-novo AML refractory to standard cytarabine plus daunorubicin induction achieved a CRi during cycle 1 at 44 mg/m2; although this was not maintained, the patient continued to benefit from treatment and is currently in cycle 11 with reduced transfusion dependence. Pharmacodynamic data are available for 9 patients; 7 show evidence of target inhibition in peripheral blood by changes in NAE-regulated proteins. Conclusion:The preliminary findings of this study indicate that the novel mechanism of action of MLN4924 through NAE inhibition results in observed activity in patients with relapsed or refractory AML, and suggest the successful translation of preclinical research in AML models into the clinic. Enrollment continues in expanded cohorts of AML and MDS patients at 59 mg/m2. Updated efficacy and safety data will be presented, together with data on MLN4924 pharmacokinetics and pharmacodynamics. Disclosures:Off Label Use: Investigational agent in clinical development for the treatment of acute myeloid leukemia or myelodysplastic syndromes. Erba:Millennium Pharmaceuticals, Inc.: Research Funding. DeAngelo:Deminimus: Consultancy. Smith:Millennium Pharmaceuticals, Inc.: Employment. Pickard:Millennium Pharmaceuticals, Inc.: Employment. Dezube:Millennium Pharmaceuticals: Employment, Equity Ownership. Giles:Millennium Pharmaceuticals, Inc.: Research Funding. Medeiros:Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding.

Phase III clinical trial development: a process of chutes and ladders.

The Institute of Medicine report on cooperative groups and the National Cancer Institute (NCI) report from the Operational Efficiency Working Group both recommend changes to the processes for opening a clinical trial. This article provides evidence for the need for such changes by completing the first comprehensive review of all the time and steps required to open a phase III oncology clinical trial and discusses the effect of time to protocol activation on subject accrual. The Dilts and Sandler method was used at four cancer centers, two cooperative groups, and the NCI Cancer Therapy Evaluation Program. Accrual data were also collected. Opening a phase III cooperative group therapeutic trial requires 769 steps, 36 approvals, and a median of approximately 2.5 years from formal concept review to study opening. Time to activation at one group ranged from 435 to 1,604 days, and time to open at one cancer center ranged from 21 to 836 days. At centers, group trials are significantly more likely to have zero accruals (38.8%) than nongroup trials (20.6%; P < 0.0001). Of the closed NCI Cancer Therapy Evaluation Program-approved phase III clinical trials from 2000 to 2007, 39.1% resulted in <21 accruals. The length, variability, and low accrual results demonstrate the need for the NCI clinical trials system to be reengineered. Improvements will be of only limited effectiveness if done in isolation; there is a need to return to the collaborative spirit with all parties creating an efficient and effective system. Recommendations put forth by the Institute of Medicine and Operational Efficiency Working Group reports, if implemented, will aid this renewal.

Early indicators of accrual success: Time-to-first-patient and accrual performance at an anticipated enrollment milestone-A study of NCI-CTEP-sponsored clinical trials.

6001 Background: This research investigates whether indicators of time from trial opening to first enrollment and accrual performance may predict ultimate successful trial accrual. Methods: National Cancer Institute Cancer Therapy Evaluation Program (NCI-CTEP) Sponsored trials for all therapeutic, nonpediatric phase I, I/II, II, and III trials activated and closed to accrual from 2000 to 2007 were investigated (n = 764). Two indicators were evaluated. The first indicator was months from opening of the trial to first patient enrolled. The second indicator was the accrual performance, computed as the percentage of actual accrual compared to the minimum accrual goal, evaluated at the anticipated time to achieve the minimum goal. For example, if a trial had a minimum accrual goal of 150 and was anticipated to accrue 15 pts/month, the anticipated time is 10 months. Multivariable logistic regression analysis was used to calculate unadjusted and adjusted odds ratios, controlling for study size, cancer incidence, and cancer mortality. Results: Trials that enrolled the first patient beyond the first two months of study activation were statistically significantly less likely to achieve the minimum accrual goal regardless of the time they remain open (odds ratio:0.616; 95% CI:0.464-0.875). Almost half of all trials (n = 379, 49.6%) enroll the first patient outside this window. Overall, 18.5% (n = 141) of CTEP-approved oncology trials achieve their minimum accrual goal within their anticipated time. Of the trials that remained open after this time (n = 603, 78.9%), trials that did not enroll a least 60% of their minimum goal within the anticipated period were statistically significantly less likely to achieve this minimum accrual goal by study closure, regardless of the time to closure (odds ratio:0.190; 95% CI: 0.055- 0.652). Conclusions: Early indicators in accrual performance can be used to identify trials that are highly likely to close without achieving their intended accrual goal. Time to first patient and accrual performance at anticipated trial enrollment time appear to be two such predictors. No significant financial relationships to disclose.

An Overview of the Optimal Planning, Design, and Conduct of Phase I Studies of New Therapeutics

Phase I clinical trials represent the first step in bringing promising new treatments from the laboratory to the clinic. Although the importance of phase I clinical trials is widely recognized, there is currently no consensus among the scientific, medical, and statistical communities on how best to do these studies in humans. With the advent of targeted therapies, it has become evident that we need to tailor the design of phase I studies for the particular drug class under investigation and any endpoints that are being defined. The National Cancer Institute (NCI) Investigational Drug Steering Committee (IDSC) provides broad external scientific and clinical input on the design and prioritization of early-phase clinical trials with agents for which the NCI Cancer Therapy Evaluation Program (CTEP) holds an Investigational New Drug (IND) application through the U.S. Food and Drug Administration (FDA). The IDSC has formed a number of task forces and working groups, including the Clinical Trial Design Task Force and the Biomarker Working Group, many with membership from within the IDSC as well as external experts, including participants from academia, the pharmaceutical industry, and regulatory authorities. The Clinical Trials Design Taskforce sponsored a Phase I Workshop with the primary goal being to develop consensus recommendations for the optimal design of phase I studies. The primary focus included (1) efficient trial designs, (2) phase I drug combinations, and (3) appropriate statistical and correlative endpoints. In this CCR Focus series, articles summarize key aspects and recommendations on phase I studies (including combination trials), such as design, use of biomarkers, the European Union and Japanese perspectives on design, requirements for first-in-human and other phase I studies, and ensuring regulatory and International Conference on Harmonization (ICH) compliance. A final article summarizes recommendations for the design and conduct of phase II studies.

A sense of urgency: Evaluating the link between clinical trial development time and the accrual performance of CTEP-sponsored studies

CRA6509 Background: Post-activation barriers to oncology clinical trial accruals are well documented; however, potential barriers prior to trial opening are not. We investigate one such barrier: trial development time. Methods: National Cancer Institute Cancer Therapy Evaluation Program (NCI-CTEP) sponsored trials for all therapeutic, non-pediatric phase I,I/II, II, and III studies activated in an eight year period (2000–2007) were investigated (n=553). Successful trials were those achieving 100% of minimum accrual goal. Time to open a study was the calendar time from initial CTEP submission to trialactivation. Multivariable logistic regression analysis was used tocalculate unadjusted and adjusted odds ratios, controlling for study phase and size of expected accruals. Results: 40.0 percent (n=221) of CTEP-approved oncology trials failed to achieve minimum accrual goals, with 49.2 percent (n=30) of phase III trials failing to achieve at least 25 percent of accrual goals. A total of 8,723 patients (17.0% of accruals) accrued to those studies that were unable to achieve the projected minimum accrual goal. Trials requiring 9–12 months development were significantly more likely to achieve accrual goals (odds ratio, 1.94; 95% CI, 1.06 to 3.52, P=0.031) than trials requiring the median time (15–18 months); trials that exceeded 27 months of development time were significantly less likely of achieving accrual goals (odds ratio, 0.14; 95% CI, 0.04 to 0.54, P=0.004). Conclusions: A large percentage of oncology clinical trials do not achieve minimum projected accruals. Trial development time appears to be one important predictor of the likelihood of successfully achieving the minimum accrual goals. [Table: see text] No significant financial relationships to disclose.

Effect of 9–11 on U.S. national cancer clinical trials accrual and lack of effect of National Cancer Institute budget increases

6551 Background: During the past decade, a variety of initiatives have been implemented to improve the accrual of cancer patients on clinical trials. In the U.S., these have included comprehensive reviews and recommendations by the two most recent National Cancer Institute (NCI) administrations, reorganization of the clinical trials infrastructure at the NCI, and campaigns by the NCI Cooperative Groups and their Coalition. During the past six years, additional funds were allocated to this effort as part of the doubling of the NCI budget. The impact of these efforts on national cancer treatment clinical trials was evaluated, with emphasis on age groups. Methods: Accrual data from NCI-sponsored treatment trials conducted between 1997 and 2006 were obtained from the NCI Cancer Therapy Evaluation Program. Entries were analyzed by patient age, gender, race, type of cancer treated, and calendar year of trial entry. Results: Overall, national cancer treatment trial entries declined after 9–11–2001 and in 2003 reached the lowest levels since 1997. As of 2005 accrual recovered to pre 9–11 levels only in 15–29 and &gt;60 year-olds, with the former demonstrating the greatest gain ( Table ). Entries among &lt;15 and 30–49 year- olds declined steadily since 1997 with no evidence for recovery as of 2005 ( Table ). Overall, the estimated proportion of the nation's cancer patients entered onto national treatment trials remains below 3%. Conclusions: Despite continued national and local efforts to increase the participation of cancer patients on clinical trials, accompanied by significant increases in the NIH and NCI budgets, there is little evidence of a beneficial impact. The effect of 9–11 has yet to be overcome, except in young and elderly adults, in whom specific, targeted initiatives appear to have been successful. The latter approaches may be useful to apply to other age groups, particularly in view of the recent cuts in the cooperative group budgets and current mandated decreases in study accruals. No significant financial relationships to disclose. [Table: see text]