Objectives for a Clinical Trial

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There is concordance of opinion amongst physicians, clinical scientists and regulatory health authorities on the value of multicentre, randomised, controlled clinical trials, with adequate statistical power and preferably double-blinded, to determine the true effects of an intervention with therapeutic intent. To evaluate treatment of a complex syndrome such as cachexia, rather than a distinct or singular abnormality, those design features may be considered requisite. Restrictive protocol eligibility criteria and stratification on prognostic factors must be used to limit the impact of various co-morbidities, concomitant medications, patient histories and physicians' treatment patterns and skills. Patients with eating disorders, infections, maldigestion, malabsorption or diarrhoea, adrenal or thyroid diseases should be excluded. Efforts to limit disparities among the patients may reduce confounding variables but also will limit the validity of generalisations about the results from the 'sample' studied to the wider population with cancer cachexia. End-points should be assessed frequently so that time-to-

event estimates may be as precise as possible.

In some situations, prospective, controlled trials could be unethical because some patients would need to be allocated to study groups hypothesised to be less beneficial than other groups. Early-phase clinical studies that precede evidence of clinical efficacy must be based upon strong evidence from animal and laboratory studies that demonstrate the predicted effects with acceptable toxicity. By adding the experimental treatment or placebo to the standard treatment for the disease, all randomised patients can receive ethical and appropriate medical care while the potential added benefit of the investigational treatment can be evaluated objectively. The potential adverse effects and/or interactions of the combined therapies must be assessed.

Treatment of cancer cachexia with the anti-TNF-a monoclonal antibody infliximab is being investigated in a multicenter, randomised, doubleblind, and placebo-controlled study. The therapeutic goals of anti-TNF-a treatment in patients with cancer cachexia are to inhibit the systemic inflammatory response and catabolic processes, with intent to improve patients' physical functioning, nutritional health and overall quality of life. Thereby, ultimately and most importantly, survival may be prolonged, and with such quality as to be worth prolonging.

Cancer cachexia involves systemic manifestations and multiorgan, multisystem pathological consequences of TNF-a produced by the tumour and by activated immune cells throughout the patient. This implies widely distributed and/or high levels of TNF-a in metabolically (catabolical-ly) active tissues, and intra/peri-tumoral. The doses and schedule of infliximab will define the pharmacokinetic profile in a metabolically dysreg-ulated population of patients with cancer cachexia. The pharmacokinetic, pharmacodynamic and clinical results may suggest an effective dose and schedule of anti-TNF therapy.

Adult patients with previously untreated, surgically unresectable, locally advanced or metastatic adenocarcinoma of the pancreas, who have experienced involuntary weight loss of > 10% compared to their stable weight before illness, or loss of 5% body weight within 90 days, are being treated.

Weight loss should be documented, if possible, not only self-reported. The overall goals are to evaluate the safety and efficacy for treating cachexia when infliximab is administered concomitantly with standard gemcitabine chemotherapy, and to provide a basis for the selection of a functional (or performance) end-point, representative of clinical benefit in the context of a debilitating syndrome of wasting.

The primary objective of the study is to evaluate the effects of treatment on a critical hallmark of cachexia, the patients' loss of lean body mass. Lean body mass is a biologically rational endpoint and logical target measure for the efficacy assessment of anti-TNF-a therapy. Loss of meta-bolically active lean tissue, including skeletal/respiratory muscle, is associated with worsened performance status, a higher incidence of infections and toxicities due to chemotherapy, progressive impairment of function, dependence on care-givers, and markedly decreased survival time. Clinical evidence of preservation of lean body mass in these cancer patients would provide proof of the concept that blocking the actions of TNF-a systemically with infliximab can inhibit the prote-olytic pathways of cachexia.

Major secondary objectives of the study are to evaluate the safety of infliximab in a concomitant regimen with gemcitabine, time to tumour progression, survival, quality of life and tumour response. Additionally, this study will evaluate the feasibility and value of a basic physical performance end-point, the 6-minute walk test (American Thoracic Society guideline) [81], as a measure of clinical benefit.

The potential impact on the underlying cancer of combining anti-TNF-a antibody with chemotherapy is not known. Could the anti-tumour activity of the chemotherapy be impaired by interference with its mechanism of action or by alteration of its metabolism and pharmacokinet-ics? If possible, reliable and appropriate animal models should be used in experiments to test for interactions. Researchers must understand the biochemical pathways of the anti-tumour chemotherapy and any plausible biological rationale for interference by the anti-cytokine immunotherapy. Thus, in this study the time to tumour progression is monitored closely as both a measure of efficacy and of safety. An independent, unblinded, safety monitoring committee oversees the study and regularly reviews safety data. The committee consists of two medical oncologists, a bioethicist and a statistician. Should there be unexpected evidence of accelerated progression of cancer, or exacerbation of complications in patients treated with gem-citabine plus infliximab, compared to patients treated with gemcitabine plus placebo, the active combination regimen could be considered unsafe. Conversely, evidence of longer median time to tumour progression in the patients treated with the active combination would support the hypothesis that blocking the effector functions of endogenous TNF-a with antibody may inhibit the tumour growth.

Until completion of the study and analyses of all the results, the primary and major secondary end-points are considered of equal importance. Evaluated together, they should provide decisive knowledge of the biological effects and clinical benefit of infliximab added to standard chemotherapy in pancreas cancer patients (Fig. 2,3).

Fig. 2. Inter-related outcomes or endpoints that contribute to overall assessment of benefit to a cancer patient

Clinical Benefit

BIA = Bioelectric Impedence Analysis

6MWT = 6-minute Walk Test

Borg = Borg Dyspnoea Scale

FAACT = Nutritional Health Questionnaire

FACIT-F = Fatigue Questionnaire

BPI = Brief Pain Inventory

SF-36 = Medical Outcomes Study Questionnaire

BIA

6MWT

Borg

FAACT

FACIT-F

BPI-1

BIA = Bioelectric Impedence Analysis

6MWT = 6-minute Walk Test

Borg = Borg Dyspnoea Scale

FAACT = Nutritional Health Questionnaire

FACIT-F = Fatigue Questionnaire

BPI = Brief Pain Inventory

SF-36 = Medical Outcomes Study Questionnaire

Fig. 3. Multiple methods and instruments used to assess clinical benefit. PRO, patients reported outcomes

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