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The Oncologist, Vol. 9, No. 1, 8–12, February 2004
© 2004 AlphaMed Press

FDA COMMENTARY

FDA Drug Approval Summaries: Oxaliplatin

Amna Ibrahim, Steven Hirschfeld, Martin H. Cohen, Donna J. Griebel, Grant A. Williams, Richard Pazdur

Division of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland, USA

Correspondence: Amna Ibrahim, M.D., Food and Drug Administration, HFD-150, 5600 Fishers Lane, Rockville, Maryland 20857, USA. Telephone: 301-594-2473; Fax: 301-594-0499; e-mail: IbrahimA{at}cder.fda.gov


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Prescribing Oxaliplatin
 Accelerated Approval Clinical...
 Discussion
 Endnote
 References
 
After completing this course, the reader will be able to:

  1. Describe the safe and effective use of oxaliplatin in patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed during or within 6 months of completion of first-line therapy with the combination of bolus 5-FU/LV and irinotecan.
  2. List the major common toxicities of oxaliplatin.
  3. Discuss the limitations of the results of the reviewed trial.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Prescribing Oxaliplatin
 Accelerated Approval Clinical...
 Discussion
 Endnote
 References
 
The purpose of this report is to summarize information on oxaliplatin, a drug recently approved by the U.S. Food and Drug Administration. Information provided includes regulatory history, study design, efficacy and safety results, and pertinent literature references.

A single, multicenter, randomized trial, enrolling 463 patients with metastatic colorectal carcinoma whose disease had recurred or progressed during or within 6 months of completion of therapy with the combination of bolus 5-fluorouracil (FU)/leucovorin (LV) and irinotecan, was submitted. Study arms included infusional 5-FU/LV alone (arm A), oxaliplatin alone (arm B), and the combination of oxaliplatin and infusional 5-FU/LV(arm C). Oxaliplatin, at a dose of 85 mg/m2, was administered to patients in arms B and C intravenously over 2 hours in 250–500 ml of dextrose 5% in water (D5W) on day 1 only. A 200-mg/m2 dose of LV was administered simultaneously to arm C patients, in a separate bag using a Y-line, or alone to arm A patients, by i.v. infusion, over 2 hours. 5-FU was then administered to arms A and C patients, first as a bolus injection over 2–4 minutes at a dose of 400 mg/m2, then as a continuous infusion in 500 ml of D5W over 22 hours at a dose of 600 mg/m2. LV was repeated on day 2 of the cycle (arms A and C) followed by a 400-mg/m2 5-FU bolus and a 600-mg/m2 22-hour infusion. Treatment was repeated every 2 weeks.

Response rate was the prespecified end point for accelerated approval. Time to progression (TTP) was a secondary end point. The prespecified primary comparison was between the 5-FU/LV regimen and the 5-FU/LV/ oxaliplatin combination regimen. The three arms were well balanced for patient prognostic factors.

There were no complete responders. The partial response rates were 0%, 1%, and 9% for the 5-FU/LV, oxaliplatin, and oxaliplatin plus 5-FU/LV treatments, respectively (p = 0.0002, arm C versus arm A). The median times to radiographic tumor progression, based on available radiographs, were 2.7 months, 1.6 months, and 4.6 months, respectively (p < 0.0001, arm C versus arm A).

Common adverse events associated with the combination treatment included peripheral neuropathy, fatigue, diarrhea, nausea, vomiting, stomatitis, and abdominal pain. Neutropenia was the major hematologic toxicity. Adverse events were similar in men and women and in patients <65 and >=65 years of age, but older patients may have been more susceptible to dehydration, diarrhea, hypokalemia, and fatigue.

Oxaliplatin in combination with infusional 5-FU/LV was approved for the treatment of patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed during or within 6 months of completion of first-line therapy with the combination of bolus 5-FU/LV and irinotecan. Approval was based on response rate and on an interim analysis of TTP. No results are available, at this time, that demonstrate a clinical benefit, such as improvement in disease-related symptoms or survival.

Key Words. Oxaliplatin • Metastatic colorectal cancer • Second-line treatment


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Prescribing Oxaliplatin
 Accelerated Approval Clinical...
 Discussion
 Endnote
 References
 
Oxaliplatin (EloxatinTM; Sanofi Synthelabo Inc.; New York, NY) (Fig. 1Go) is a platinum (II) analog similar to the approved drugs cisplatin and carboplatin. Its mechanism of action involves the formation of DNA adducts and inhibition of DNA synthesis. Oxaliplatin has been evaluated, both in vitro and in vivo, alone and in combination with 5-fluorouracil (FU), in several tumor models including human breast, colon, and mammary tumors. The oxaliplatin/5-FU combination consistently has demonstrated greater activity than that which is seen with either drug alone.



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  		Figure 1. Chemical structure of oxaliplatin. Molecular weight: 397.3; Molecular formula: C8H14N2O4Pt.

 
A New Drug Application (NDA) for a first-line indication in metastatic colorectal cancer was submitted to the U.S. Food and Drug Administration (FDA) in February 1999. The NDA comprised two multicenter, randomized, controlled clinical trials. In one study, 200 patients were randomized to receive either oxaliplatin followed by 5-FU and leucovorin (LV) daily for 5 days as a chronomodulated infusion [1] or the same regimen without oxaliplatin. In the second study, 420 patients were randomized to receive either the FOLFOX 4 regimen, consisting of oxaliplatin and 5-FU/LV (Table 1Go and Fig. 2Go), or 5-FU/LV alone. The primary end points were response rate (first study) and progression-free survival (second study).


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  		Table 1. Schedule and regimen of the three treatment arms
 


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  		Figure 2. Treatment schema.

 
The application was presented to the Oncologic Drugs Advisory Committee in March 2000. The Committee noted that, although oxaliplatin demonstrated antitumor activity, no survival benefit was observed. As other treatment regimens had produced survival benefit in first-line metastatic colorectal cancer treatment, the committee recommended non-approval.

Subsequent meetings between the FDA and the sponsor produced a plan for a study comparing oxaliplatin with infusional 5-FU/LV (the de Gramont regimen) [2] and with a combination of oxaliplatin and infusional 5-FU/LV as second-line therapy for colorectal cancer. An infusional 5-FU regimen was chosen because of evidence that infusional 5-FU treatment might induce objective responses in patients who had previously progressed on i.v. bolus 5-FU [3] and because of the different toxicity spectrums of infusional versus bolus 5-FU [4]. That study was granted "Fast Track" designation, meaning that, in addition to scheduled meetings, the sponsor had the option to submit the data for an NDA application in sections over time.

Review of data from the above study, summarized below, led to accelerated approval of oxaliplatin on August 14, 2002 for use in combination with infusional 5-FU/LV in the treatment of patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed during or within 6 months of completion of first-line therapy with the combination of bolus 5-FU/LV and irinotecan. Approval was based on response rate and on an interim analysis of time to progression (TTP). No results are available, at this time, that demonstrate a clinical benefit, such as improvement of disease-related symptoms or survival.


   PRESCRIBING OXALIPLATIN
Top
 Learning Objectives
 Abstract
 Introduction
 Prescribing Oxaliplatin
Accelerated Approval Clinical...
 Discussion
 Endnote
 References
 
The recommended dose of oxaliplatin in combination with infusional 5-FU/LV is 85 mg/m2 i.v. over 2 hours in 250–500 ml of dextrose 5% in water (D5W). LV, 200 mg/m2, is administered by an i.v. infusion simultaneously over 2 hours in a separate bag using a Y-line. 5-FU follows the oxaliplatin and LV, first as a bolus injection over 2–4 minutes at a dose of 400 mg/m2, and then as a continuous infusion in 500 ml of D5W over 22 hours at a dose of 600 mg/m2. LV is repeated on day 2 of the cycle without oxaliplatin. The 5-FU 400-mg/m2 bolus and 600-mg/m2 22-hour infusion are repeated on day 2, after completion of the day 2 LV infusion (Fig. 2Go). The cycle is repeated every 2 weeks (Table 1Go and Fig. 2Go). See full prescribing details in the package insert [5].


   ACCELERATED APPROVAL CLINICAL TRIAL
Top
 Learning Objectives
 Abstract
 Introduction
 Prescribing Oxaliplatin
 Accelerated Approval Clinical...
Discussion
 Endnote
 References
 
Methods
A single, large, multicenter, randomized trial enrolled 463 patients with metastatic colorectal carcinoma. Response rate was the prespecified end point for potential accelerated approval. TTP was a secondary end point. The prespecified primary comparison was between the 5-FU/LV regimen and the 5-FU/LV/oxaliplatin combination regimen (arm A versus arm C). The null hypothesis was tested at a two-tailed level of p = 0.05, using the log-rank test. The three arms were well balanced for prognostic factors. The treatment could have been continued for up to 1 year. However, a maximum number of 18 cycles (16 on the oxaliplatin combination arm) were actually administered.

Response Rate
Responses were evaluated using the Response Evaluation Criteria in Solid Tumors [6]. An independent consulting group reviewed the radiological studies. That group’s response assessment, based on radiographic measurements, was prespecified in the analysis plan as the basis for the primary analysis of response rate. The independent reviewer was blinded to the treatment arm of the patients and the investigator’s assessments of response (including investigator choice of target lesions). The FDA subsequently conducted an independent response rate review. The results of the FDA analysis of response rate are summarized in Table 2Go.


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  		Table 2. Analysis of response rate
 
TTP
TTP evaluation was submitted in two separate analyses, one based on investigator data (counting radiographic and clinical progression as well as death as events) and the other limited to radiographic data for progressive disease as assessed by an independent radiology group. The latter was the prespecified primary analysis of TTP. With approximately 50% of the potential TTP events recorded, a longer TTP of almost 2 months was noted for the oxaliplatin combination arm compared with the 5-FU and LV control arm by both the sponsor and FDA analyses (Table 3Go). This analysis excluded 82 (18%) patients by censoring them at baseline. Twenty-five of those patients had radiographic assessments performed beyond baseline by the investigator, but those radiographs were either not submitted for independent radiologist review or were not deemed evaluable by the radiologist. The other censored patients did not have any radiographic assessments beyond baseline. An exploratory analysis was performed incorporating the radiographic progression data from the investigator analysis, when available, where data were unavailable from the independent review. Twelve percent of patients were censored at baseline by this method. The difference in TTP remained at 2 months in the exploratory analysis, giving support to the improvement in TTP as evaluated in the independent analysis.


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  		Table 3. FDA analysis of radiographic TTP*
 
Safety
Common adverse events associated with the combination treatment included peripheral neuropathy, fatigue, diarrhea, nausea, vomiting, stomatitis, and abdominal pain (Table 4Go). Neutropenia was the major hematologic toxicity. The diarrhea and myelosuppression normally associated with 5-FU/LV treatment were accentuated by oxaliplatin. Adverse events were similar in men and women and in patients <65 and >=65 years of age, but older patients may have been more susceptible to dehydration, diarrhea, hypokalemia, and fatigue.


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  		Table 4. Adverse event experience (>=5% of all patients and with >=1% NCI grade 3/4 events)
 
Acute (lasting fewer than 14 days) or persistent (14 days or greater) neuropathies, often exacerbated by exposure to cold (temperature, objects, or liquids) were associated with oxaliplatin. An acute syndrome of pharyngolaryngeal dysesthesia characterized by dysphagia or dyspnea also occurred. The majority of neurotoxic events were reversible. In any given cycle, at least 30% of patients had a neurotoxic event. Having an event in one cycle was not predictive of subsequent events, although there were patients who had events with every cycle. The population of patients having an event varied, so that over the course of the study about 75% of all patients had at least one neurotoxic event.

The mean number of acute neurotoxic events per patient was three with a range of 1–12. Of the patients that had neurotoxic events, the acute events tended to occur in the earlier cycles. Persistent events and high-grade events occurred during any cycle, with the net result that proportionately more patients had persistent events during the later cycles.


   DISCUSSION
Top
 Learning Objectives
 Abstract
 Introduction
 Prescribing Oxaliplatin
 Accelerated Approval Clinical...
 Discussion
Endnote
 References
 
A small but statistically significant improvement in tumor response rate was observed in the combination arm of oxaliplatin, infusional 5-FU, and LV in a population that has no other treatment options. An interim analysis of radiographic TTP, with approximately 50% of events, revealed that TTP was longer in the combination arm. This improvement in response rate and the interim analysis showing a longer radiographic TTP were the bases of approval for oxaliplatin.

The trial results demonstrate that the efficacy of single-agent oxaliplatin is similar to that of infusional 5-FU/LV, and that oxaliplatin should not be used alone in this patient population, except in clinical trials. Caution should be exercised in choosing the regimen if bolus 5-FU is used together with oxaliplatin due to excessive toxicities [7]. One arm of the North Central Cancer Treatment Group study 9741 using bolus 5-FU and oxaliplatin was also closed early due to toxicity.


   ENDNOTE
Top
 Learning Objectives
 Abstract
 Introduction
 Prescribing Oxaliplatin
 Accelerated Approval Clinical...
 Discussion
 Endnote
References
 
The views expressed are the result of independent work and do not necessarily represent the views and findings of the U.S. FDA.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Prescribing Oxaliplatin
 Accelerated Approval Clinical...
 Discussion
 Endnote
 References
 

  1. Levi F, Misset JL, Brienza S et al. A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid, and oxaliplatin using an ambulatory multichannel programmable pump. High antitumor effectiveness against metastatic colorectal cancer. Cancer 1992;69:893–900.[CrossRef][Medline]
  2. de Gramont A, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938–2947.[Abstract/Free Full Text]
  3. Goldberg RM. Is repeated treatment with a 5-fluorouracil-based regimen useful in colorectal cancer? Semin Oncol 1998;25(suppl 11):21–28.
  4. Thrall MM, Wood P, King V et al. Investigation of the comparative toxicity of 5-FU bolus versus 5-FU continuous infusion circadian chemotherapy with concurrent radiation therapy in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2000;46:873–881.[CrossRef][Medline]
  5. EloxatinTM (oxaliplatin for injection) Prescribing Information [package insert]. New York, NY: Sanofi Synthelabo Inc.
  6. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–216.[Abstract/Free Full Text]
  7. Zori Comba A, Blajman C, Richardet E et al. A randomised phase II study of oxaliplatin alone versus oxaliplatin combined with 5-fluorouracil and folinic acid (Mayo Clinic regimen) in previously untreated metastatic colorectal cancer patients. Eur J Cancer 2001;37:1006–1013.
Received May 19, 2003; accepted for publication October 27, 2003.




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