Challenges Facing Early Phase Trials Sponsored by the National Cancer Institute: An Analysis of Corrective Action Plans to Improve Accrual

Massett, Holly A.; Mishkin, Grace; Rubinstein, Larry; Ivy, S. Percy; Denicoff, Andrea; Godwin, Elizabeth; DiPiazza, Kate; Bolognese, J; Zwiebel, James A.; Abrams, Jeffrey S.

doi:10.1158/1078-0432.ccr-16-0338

Cited by 30 publications

(24 citation statements)

References 27 publications

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“…Similarly, even for nonaccelerated programs, the inclusion of robust pharmacokinetics can be helpful to inform the need for further dose refinement (26). Although the inclusion of pharmacokinetics sampling was not mentioned specially as a reason for slow study accrual in the review by Massett and colleagues (31), to reduce both patient and operational burden, appropriate sampling schedules, which coincide with scheduled patient visits, should be encouraged, as the knowledge gathered from such evaluations can be essential to guide and refine dosing and inform future drug development.…”

Section: Discussionmentioning

confidence: 99%

Lessons Learned: Dose Selection of Small Molecule–Targeted Oncology Drugs

Bullock

Rahman

Liu

2016

Clinical Cancer Research

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Evaluation of dose plays a critical role in a successful oncology development program. Typically for oncology agents, the first-in-man phase I dose-escalation trials are conducted to determine a maximum tolerated dose (MTD). This MTD is taken forward into subsequent trials to establish the safety and efficacy of the drug product. Although this approach was appropriate historically for cytotoxics, the application of MTD as the recommend phase II dose has been problematic for the newer small molecule-targeted oncology agents. Promising alternative approaches using dose and exposure exploration, including lessons learned from recent targeted oncology agent development and approvals, are summarized and discussed.

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Section: Discussionmentioning

confidence: 99%

Lessons Learned: Dose Selection of Small Molecule–Targeted Oncology Drugs

Bullock

Rahman

Liu

2016

Clinical Cancer Research

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“…Such oral drugs held additional appeal for patients with mCRPC, whose only available option at that time was intravenous chemotherapy. Notably, as reported by Massett et al [9], the National Cancer Institute recognized competing trials as a reason for slow accrual in phase II studies. They proposed to invest in earlier accrual planning as a better strategy for future trials.…”

Section: Investigator's Assessmentmentioning

confidence: 91%

Phase II, Multicenter, Randomized Trial of Docetaxel plus Prednisone with or Without Cediranib in Men with Chemotherapy-Naive Metastatic Castrate-Resistant Prostate Cancer

et al. 2019

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Lessons Learned The negative results are consistent with the negative results of large phase III trials in which docetaxel plus antiangiogenic agents were used in patients with metastatic castrate‐resistant prostate cancer (mCRPC). The negative data underscore that, despite a sound biological rationale and supportive early‐phase clinical results, adding antiangiogenic agents to docetaxel for mCRPC is a great challenge. Background Inhibition of vascular endothelial growth factor (VEGF) signaling abrogates tumor‐induced angiogenesis to constrain tumor growth, and can be exploited therapeutically by using cediranib, an oral tyrosine kinase inhibitor of VEGF receptor signaling. Our preliminary phase I trial data showed that adding cediranib to docetaxel plus prednisone (DP) was safe and feasible, with early evidence for efficacy in patients with metastatic castrate‐resistant prostate cancer (mCRPC). Methods This multicenter phase II trial assessed whether adding cediranib to DP improves efficacy of DP in patients with mCRPC. Chemotherapy‐naive patients with mCRPC were randomly assigned to receive either docetaxel (75 mg/m2 intravenously every 3 weeks) with prednisone (5 mg twice daily) plus cediranib (30 mg once daily; the DP+C arm) or DP only (the DP arm). The primary endpoint was to compare 6‐month progression‐free survival (PFS) rate between the two arms. Secondary endpoints included 6‐month overall survival (OS), objective tumor and prostate‐specific antigen (PSA) response rates, biomarkers, and adverse events. Results The 6‐month PFS rate in a total of 58 patients was only numerically higher in the DP+C arm (61%) compared with the DP arm (57%). Similarly, the 6‐month OS rate, objective tumor and PSA response rates, and biomarkers were not significantly different between the two arms. Increased baseline levels of interleukin 6 (IL‐6), however, were significantly associated with increased risk of progression. Neutropenia was the only grade 4 toxicity (38% in the DP+C arm vs. 18% in the DP arm). Conclusion Combining cediranib with docetaxel + prednisone failed to demonstrate superior efficacy, compared with docetaxel + prednisone, and added toxicity. Our data do not support pursuing the combination further in patients with mCRPC.

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“…In this issue of Clinical Cancer Research, Massett and colleagues (1) describe the many challenges facing accrual to early-phase clinical trials sponsored by the NCI (Bethesda, MD), analyze proposed ways to increase accrual, and assess the utility of corrective action plans (CAP) to improve accrual.…”

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confidence: 99%

“…The letter includes an accrual summary and a request for a CAP, providing explanation for slow accrual and proposing means of improvement to achieve enrollment goals. Massett and colleagues (1) reported that CAP requests were made for 46% of CTEP IND-holding studies active from August 2011 through February 2013, indicating that a significant number of trials did not accrue as planned. Safety and toxicity were primary concerns cited for slow accrual to phase I trials.…”

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confidence: 99%

“…Utilization of a common IRB allows for trials to open efficiently and at multiple sites. Promoting clinical trial awareness (internally and externally) was frequently cited in CAPs as a means to increase accrual (1). At Carolinas HealthCare Systems' Levine Cancer Institute (Charlotte, NC), trials are placed on tumorspecific pathways accessible to physicians across 25 locations.…”

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confidence: 99%

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Who's Eligible Anyway? Risk Modeling for Clinical Trial Accrual

Mileham¹,

Kim²

2016

Clinical Cancer Research

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Accrual continues to be a challenge for oncology clinical trials. Interventions to enhance accrual after study activation exist, including corrective action plans for NCI-sponsored trials. Clinical trials would benefit from a proactive approach rather than a reactive approach. Accrual strategy planning early in trial development is suggested. Clin Cancer Res; 22(22); 5397-9. ©2016 AACRSee related article by Massett et al., p. 5408.

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Challenges Facing Early Phase Trials Sponsored by the National Cancer Institute: An Analysis of Corrective Action Plans to Improve Accrual

Abstract: Accruing patients in a timely manner represents a significant challenge to early phase cancer clinical trials. The NCI

Cited by 30 publications

References 27 publications

Lessons Learned: Dose Selection of Small Molecule–Targeted Oncology Drugs

Lessons Learned: Dose Selection of Small Molecule–Targeted Oncology Drugs

Phase II, Multicenter, Randomized Trial of Docetaxel plus Prednisone with or Without Cediranib in Men with Chemotherapy-Naive Metastatic Castrate-Resistant Prostate Cancer

Who's Eligible Anyway? Risk Modeling for Clinical Trial Accrual

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