Edwin P. Rock

Approval Summary: Sunitinib for the Treatment of Imatinib Refractory or Intolerant Gastrointestinal Stromal Tumors and Advanced Renal Cell Carcinoma

Purpose: To describe the Food and Drug Administration (FDA) review and approval of sunitinib malate (Sutent). Sunitinib received regular approval for the treatment of gastrointestinal stromal tumor (GIST) after disease progression or intolerance to imatinib mesylate (Gleevec). Additionally, sunitinib received accelerated approval for the treatment of advanced renal cell carcinoma. Experimental Design: For the GIST indication, FDA reviewed data from a randomized, placebo-controlled trial with supportive evidence from a single-arm study. For the advanced renal cell carcinoma indication, FDA reviewed data from two single-arm studies of patients with cytokine-refractory metastatic renal cell carcinoma. Results: In patients with imatinib refractory or intolerant GIST, time-to-tumor progression of sunitinib-treated patients was superior to that of placebo-treated patients. Median time-to-tumor progression of sunitinib-treated patients was 27.3 weeks, compared with 6.4 weeks for placebo-treated patients (P < 0.0001). Partial responses were observed in 6.8% of sunitinib-treated patients. In patients with metastatic renal cell carcinoma, partial responses were observed in 25.5% (95% confidence interval, 17.5, 34.9) and 36.5% (95% confidence interval, 24.7, 49.6) of patients treated with sunitinib. Median response durations were 27.1 and 54 weeks. The most common adverse events attributed to sunitinib included diarrhea, mucositis, skin abnormalities, and altered taste. Reductions in left ventricular ejection fraction and severe hypertension were also more common in sunitinib-treated patients. Conclusions: On January 26, 2006, the FDA approved sunitinib for the treatment of patients with imatinib refractory or intolerant GIST. Accelerated approval was granted for the treatment of advanced renal cell carcinoma.

Patient-Reported Outcomes Assessment in Cancer Trials: Taking Stock, Moving Forward

To evaluate and improve the use of cancer trial end points that reflect the patients own perspective, the National Cancer Institute organized an international conference, Patient-Reported Outcomes Assessment in Cancer Trials (PROACT), in 2006. The 13 preceding articles in this special issue of the Journal were commissioned in preparation for or in response to the PROACT conference, which was cosponsored by the American Cancer Society. Drawing from these articles and also commentary from the conference itself, this concluding report takes stock of what has been learned to date about the successes and challenges in patient-reported outcome (PRO) assessment in phase III, phase II, and symptom management trials in cancer and identifies ways to improve the scientific soundness, feasibility, and policy relevance of PROs in trials. Building on this synthesis of lessons learned, this article discusses specific administrative policies and management procedures to improve PRO data collection, analysis, and dissemination of findings; opportunities afforded by recent methodologic and technologic advances in PRO data collection and analysis to enhance the scientific soundness and cost efficiency of PRO use in trials; and the importance of better understanding the usefulness of PRO data to the full spectrum of cancer decision makers, including patients and families, health providers, public and private payers, regulatory agencies, and standards-setting organizations.

Patient-Reported Outcomes Supporting Anticancer Product Approvals

In 2006, the US Food and Drug Administration (FDA) published draft guidance to provide recommendations for development, validation, implementation, and interpretation of patient-reported outcome (PRO) measures that can support treatment benefit claims in product labeling. Here, we summarize and discuss FDA approvals of anticancer products in the context of the draft guidance. We identified anticancer product approvals having efficacy claim(s) based at least in part on a PRO. In addition, we collated limitations of PRO instruments commonly submitted for regulatory review over the period from October 1, 2004 to September 30, 2006. From 1995 onward, nine indications were approved for seven anticancer products based at least in part on a PRO. In eight of nine approvals, PRO data supplemented other evidence of clinical benefit. In seven approvals, the PRO measured a single symptom or functional domain that was directly attributable to the treatment benefit observed in the disease. The FDAs draft PRO guidance describes principles that have been used in anticancer product approvals for more than a decade. PRO end points typically support treatment benefit claims that refer to a patients symptoms or ability to function. Single-item PROs may be acceptable. PRO data should be both internally consistent and aligned with other evidence of clinical benefit. The FDA encourages sponsors to consult with the FDA early in the process of PRO development.

Nutritional Approaches to Late Toxicities of Adjuvant Chemotherapy in Breast Cancer Survivors

Adjuvant chemotherapy of breast cancer reduces recurrence rates and prolongs survival at the cost of both acute and chronic toxicities. Breast cancer survivors who have received adjuvant chemotherapy may suffer from late effects of chemotherapy including congestive heart failure, neuropathy, premature menopause, and osteoporosis. Nutritional approaches to these problems are distinct in their orientation and success. Study of free radical scavengers for anthracycline-induced cardiomyopathy was born from known pathogenetic mechanisms of cardiotoxicity but has been universally disappointing thus far in clinical trials. Application of agents used for diabetic neuropathy suggests that evening primrose oil, alpha-lipoic acid, and capsaicin may all play a role in the empiric options available to patients with chemotherapy-induced neuropathy. Plant-derived preparations including black cohosh (Actaea racemosa), dong quai (Angelica sinensis), evening primrose (Oenothera biennis), and red clover (Trifolium pretense) are used by patients experiencing hot flashes due to premature menopause despite a paucity of clinical trial data demonstrating either safety or efficacy. Calcium and vitamin D are widely accepted as an effective means to retard bone loss leading to osteoporosis. Nutritional approaches to late effects of breast cancer chemotherapy offer the prospect of preventing or ameliorating these sequelae of treatment. However, except for vitamin D and calcium for prevention of bone loss, current clinical evidence supporting use of nutritional agents remains sparse.

Lenalidomide in Combination with Dexamethasone for the Treatment of Multiple Myeloma After One Prior Therapy

PURPOSE Lenalidomide (CC-5013, Revlimid; Celgene Corporation, Summit, NJ), a thalidomide analogue, was granted approval by the U.S. Food and Drug Administration (FDA) on June 29, 2006, for use in combination with dexamethasone in patients with multiple myeloma (MM) who have received at least one prior therapy. The FDA approved lenalidomide with a restricted distribution program, RevAssist. EXPERIMENTAL DESIGN In two randomized, double-blind, multicenter studies, the combination of lenalidomide and dexamethasone (LD) was compared with placebo and dexamethasone (PD) in patients with MM who had received at least one prior therapy. The primary endpoint was time to progression (TTP). RESULTS Following a prespecified interim analysis of TTP, an independent data-monitoring committee advised the sponsor to halt the two studies. For both studies, the interim analysis for efficacy revealed a statistically significant longer TTP with LD than with PD. The most clinically relevant grade 3 and 4 adverse events that occurred more frequently in the LD arm were neutropenia, thrombocytopenia, deep vein thrombosis, pulmonary embolism, and atrial fibrillation. Thrombotic or thromboembolic events, including deep vein thrombosis, pulmonary embolism, thrombosis, and intracranial venous sinus thrombosis were reported more frequently in patients treated with LD than with PD. CONCLUSIONS The FDA approved lenalidomide based on interim results from two multicenter, placebo-controlled, randomized trials comparing the combination of LD with PD that revealed a longer TTP with LD than with PD. The major toxicity observed during these trials was myelosuppression. The serious toxicities included thromboembolic events. Lenalidomide is only available under the RevAssist Program.

GCP Data Quality for Early Clinical Development

Good Clinical Practice (GCP) provides an internationally accepted standard to ensure subject safety and data quality in clinical trials. Much of GCP parallels ethical considerations that have accumulated in successive versions of the World Medical Associations Declaration of Helsinki. This document advocates for preservation of rights, safety, and well-being of human study participants. By contrast, GCP data quality provisions follow from evolution in the United States drug regulatory system during the 1960s. Evidence of fraudulent or otherwise biased data-gathering ultimately led to U.S. Food and Drug Administration (FDA) data integrity regulations that were subsequently embraced as GCP principles in the Declaration of Helsinki. This manuscript summarizes GCP data quality provisions and describes practices that clinical site investigators can adopt to comply with these principles and to prevent adverse audit findings in the event of a regulatory inspection. Clin Cancer Res; 16(6); 1756–63