Study: TARGET Trial (Treatment Approaches in RCC Global Evaluation Trial)

Clinical Question:

During the hem/onc clinic rotation, on GU Malignancies Clinic day, you see a new patient –a 28 y/o Caucasian female recently diagnosed with Stg IV Renal Cell Carcinoma (local invasion, 2 LN nodes positive, one pulm nodule) who presents for consideration of systemic chemotherapy.

Study: TARGET Trial (Treatment approaches in RCC Global Evaluation trial) Escudier et al; Sorafenib in Advanced Clear cell Renal Cell Carcinoma. N Engl J Med. 2007 Jan 11;356(2):125-34

Study Type: phase III multi center randomized double blinded placebo controlled trial.

Description of Clinical Trials:

Phase I Trial: -assess the safety (pharmacovigilance), tolerability, pharmacokinetics, and pharmacodynamics of a drug. -also normally include dose-ranging, also called dose escalation, studies so that the appropriate dose for therapeutic use can be found. The tested range of doses will usually be a fraction of the dose that causes harm in preclinical models. -Single vs Multiple Ascending Dose Regimens: SAD vs MAD protocols. -usually small studies, N=20-50. -most often include healthy volunteers. -However, there are some circumstances when real patients are used, such as patients who have end-stage disease and lack other treatment options. Usually occurs in oncology and trials of immunomodulatory agents.

Phase II Trial: Once the initial safety of the study drug has been confirmed in Phase I trials, Phase II trials are performed to assess efficacy -usually larger pt population N=20-300. -When the development process for a new drug fails, this usually occurs during Phase II trials when the drug is discovered not to work as planned, or to have toxic effects. -Trial Design: Some are designed as case series while some are designed as RCT’s. However, phase II RCT have far fewer patients than the phase III trials. -May be subdivided into phase IIA(designed to study dosing requirements) vs Phase IIB(designed to study efficacy)

Phase III Trial: -randomized controlled multicenter trials on large patient groups. -Large studies: N=300-3000. -aimed at definitive assessment of drug efficacy where exp drug is compared to current standard of care. -most expensive, time-consuming and difficult trials to design and run. -some industry sponsored phase III’s are often done for “label expansion” --to show the drug works for additional types of patients/diseases beyond the original use for which the drug was approved for marketing. - It is typically expected that there be at least two successful Phase III trials, demonstrating a drug's safety and efficacy in order to obtain approval from the FDA.

Phase IV Trial: -also known as Post Marketing Surveillance Trials. -safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials. -Harmful effects discovered by Phase IV trials may result in a drug being no longer sold, or restricted to certain uses: recent examples involve the glitazones and cox-2 inhibitors.

BACK TO THE PAPER: Study Population: 903 patients recruited at 117 centers in 19 countries, age 18 or older from Nov 14 2003 to March 31 2005. Study Sponsors: Bayer and Onyx Pharmaceuticals. Cost of Sorafenib 120 pills=$5000.

Inclusion Criteria: 1. Histologically confirmed metastatic clear cell renal cell carcinoma which had progressed after one systemic treatment within the previous 8 months. 2. ECOG performance status of 0 or 1. 3. Intermediate to low risk status as defined by the MSKCC Prognostic score 4. Life expectancy of at least 12 weeks 5. Adequate bone marrow, liver, pancreatic and renal function 6. PT/PTT < 1.5 upper limits of normal.

Exclusion Criteria Brain Mets and previous exposure to VEGF pathway inhibitors.

Study Design and Validity: Fig 1 : 1. Were the patients randomized: Yes. 451 patients in treatment arm, 452 patients in placebo arm. 2. Was randomization concealed: Yes, double blind design 3. Were patients analyzed to groups in which they were randomized-Yes. Intention to treat analysis. 4. Were patients in treatment and control groups similar in respect to known prognostic risk factors?-Yes Table 1. 5. Were the outcome assessors aware of group allocation: NO- independent data and safety monitoring committee. 6. Were the groups treated equally apart from experimental treatment? Yes. Tumor evaluation performed within last 10 days of each cycle 7. Was follow-up sufficiently long and complete: yes, until disease progression or withdrawal from study due to adverse events. Median f/u was 6.6 months of both groups.

Continuous treatment with sorafenib at a dose of 400 mg po bid or placebo in double blind fashion. Dose reduction and escalation per protocol.

At first interim analysis, (11/03-04/05) cross over permitted from placebo to treatment group, essentially turning the RCT into a cohort study.

Desired Study Outcomes:

Primary Outcome: Overall survival from date of randomization until date of death.

Secondary Outcomes: 1. Progression – free survival from date of randomization until date of progression includes both radiological and clinical progression. * Valid outcome measure usually seen in oncology trials. 2. Best overall radiographic response rate/cycle measured within last 10 days of each cycle. All radiological response measured by CT or MRI using RECIST criteria.

Statistical Analysis 1. Study powered at 90% for duration of 29 months to detect a 33% difference in survival between the two groups once 540 patients had died with a two sided Type I error of 0.04. Calculated Study Size=856. Number of patients=903.

2. Given estimated median survival time of 12 months in placebo group 270 deaths (50%) were expected in 17 months, and therefore plan for first interim analysis.

Statistical Concepts: 1. O’Brien –Fleming Spending Function: one type of spending function used in interim analysis of clinical trials. Intuitively, if statistical analyses are done earlier in a trial, the magnitude of effect is amplified, and increased chance of bias with a higher rate of false positive results. Therefore the probability of a type I error is increased. The O’Brien-Fleming function uses a strict cut off at first and then relaxes this cut off over time Page 127: right hand column 2nd paragraph: threshold for significance at first analysis P=0.0005- if this threshold is reached, then less than 0.0005 chance that results are a function of design bias. At second analysis, P=0.0094 –more relaxed.

2. Hazard Ratios: comparison of two hazard rates-can be thought of as relative risks. Therefore, gives an estimate of magnitude of probability. However, does not provide any information on magnitude of actual difference. Results:

A. Overall survival: 1. During first analysis before cross over, 97/451 patients in sorafenib group and 123/452 patients in placebo group had died. 2. *** Fig 2a: Median overall survival in placebo group was 14.2 months but not yet reached in sorafenib group: hazard ratio:0.72 95%CI =0.54-0.94 P=0.02. 3. Fig 2b: median overall survival 19.3 months in sorafenib group, 15.9 months in placebo group( 6months after crossover permitted). The analyses did not reach pre-specified O’Brien-Fleming boundaries for statistical significance.

B. Progression Free survival: 1. **January 2005 independent protocol defined analysis of 769 patients: 384 in sorafenib group, 385 in placebo group. 147 events in sorafenib group: 38% patients: 117 radiologic progression, 23 deaths and 7 clinical progression*-not defined. 195 events in placebo group: 51 % patients: 164 radiologic progression , 23 deaths, 8 clinical progression. 2. Investigator assessed median progression free survival was 5.9 months in sorafenib( 136 events) and 2.8 months in placebo (211 events) group. **criteria for event selection not defined. 3. Sorafenib associated with 56% reduction in risk of progression (Hazard ratio of 0.44, 95% CI, 0.35-0.55) Fig 2c. 4. Fig 2d: investigator assessed for entire study population: 903 patients: at time of cross over: 49% reduction with risk of progression in sorafenib (Hazard ratio, 0.51, 95% CI, 0.43-0.60). 5. Fig 3 : sub group analysis noted benefit was independent of age, MSKCC score, previous use or nonuse of cytokine therapy, presence or absence of metastasis, and the time since diagnosis (<1.5 years or >1.5 years).

C. Overall Radiographic response: Table 2. 451 patients in sorafenib group:1 had a complete response. 333 had stable disease 452 patients in placebo: 0 complete response, 239 had stable disease.

D. Adverse Events: most common events were diarrhea, rash, fatigue, hand-foot skin reactions, alopecia and nausea- Grade 1 or 2 as defined by CTCAE -Table 3.

1. Cardiac: ischemia or infarction occurred in 12 patients in sorafenib group, 2 in placebo group. Hypertension also more frequent in sorafenib group.

2. Serious adverse events leading to hospitalization or death: 154 patients with 46 deaths in sorafenib group. 110 patients in placebo group with 25 deaths. Conclusions: -phase III trial of an innovative agent that demonstrates efficacy in advanced RCC where therapeutic options are limited. -Question benefit of drug given limited improvement in overall survival, and Cost. Since relatively new agent, no Quality adjusted life years data available yet. -Also must consider efficacy to toxicity analysis. -Caution for appropriate patient selection. -Now a category I NCCN Guideline recommendation in patients post cytokine therapy.

Can I apply these results to my patient? Yes, but after a thorough documented discussion of above concepts, including cost and limited overall survival benefit.