Speeding up the evaluation of new agents in cancer

Abstract

Despite both the increase in basic biologic knowledge and the fact that many new agents have reached various stages of development during the last 10 years, the number of new treatments that have been approved for patients has not increased as expected. We propose the multi-arm, multi-stage trial design as a way to evaluate treatments faster and more efficiently than current standard trial designs. By using intermediate outcomes and testing a number of new agents (and combinations) simultaneously, the new design requires fewer patients. Three trials using this methodology are presented.

Figures

Figure 1

Hypothetical randomized trial showing a multi-arm, two-stage design. Arm 1 is the control arm and arms 2–5 are the experimental arms. At the end of stage I, each experimental arm is compared against the control arm in a pairwise manner using the intermediate outcome measure (in this case, progression-free survival). At the end of stage II, each experimental arm that has passed stage I is compared with the control arm on the primary outcome measure for the trial (primary comparison; in this case overall survival). However, secondary comparisons of experimental versus control for each arm that did not pass stage I are also performed (these comparisons will, of course, have fewer patients and events).

Figure 2

Where do multi-arm multi-stage (MAMS) trials fit into the phase 1, 2, and 3 setup? A) The traditional approach. Three new agents, R1, R2, and R3, enter and pass three single-agent single-arm phase 2 trials and also three separate single-arm combination phase 2 trials. The three combination therapies are finally compared with the control therapy in three separate randomized phase 3 trials. In this model, a total of 2100 patients are required. B) In the MAMS design, the single-agent single-arm phase 2 trials are followed by a single MAMS trial of all combination therapies. The MAMS model required 1300 patients in total, a saving of 800 patients. C = control arm; R1 = experimental arm R1; R2 = experimental arm R2; R3 = experimental arm R3. In these models, we assume that single-agent studies would be carried out before combination therapy studies and that phase 2 studies require only a small number of centers. Consequently, phase 2 studies of different agents may be carried out concurrently. We also assume that phase 3 trials require larger numbers of patients and a network of centers that can run only one trial in a particular group of patients at a time, and, therefore, phase 3 trials of different agents must be carried out sequentially. The MAMS design rolls the phase 2 assessment of the activity of combination therapy into the same trial as the phase 3 assessment of effectiveness.

Figure 3

Two multi-arm multi-stage trials. A) Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial with six arms (A–F). B) Gynecologic Oncology Group/International Collaborative Ovarian Neoplasm Studies (GOG-182/ICON5) trial with five arms (I–V).

Figure 4

Five Stages of the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial. IDMC  = Independent Data Monitoring Committee; FFS  = failure-free survival; HR  = hazard ratio, where 0 ≤ d ≤ c ≤ b ≤ a ≤ 5.

Figure 5

Stopping guidelines on the hazard ratio scale for the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial. CI = confidence interval; HR = hazard ratio; Stop = stopping of accrual (rather than termination of follow up).