Randomized Discontinuation Design Research Articles

Sorafenib in Molecularly Selected Cancer Patients: Final Analysis of the MOST-Plus Sorafenib Cohort.

MOST-plus is a multicenter, randomized, open-label, adaptive Phase II trial evaluating the clinical benefit of targeted treatments matched to molecular alteration in advanced/metastatic solid tumors. Sorafenib was tested on patients with tumors harboring sorafenib-targeted genes. The MOST-plus trial used a randomized discontinuation design. After 12 weeks of sorafenib (400 mg, po BID), patients with progressive disease discontinued study, patients with objective response were proposed to continue sorafenib, whereas patients with stable disease (SD) were randomly assigned (1:1) to the maintenance or interruption of treatment. The primary endpoint was RECIST version 1.1 progression-free rate at 16 weeks after randomization (PFR-16w). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Statistical analyses used a sequential Bayesian approach with interim efficacy analyses. The enrolment could be stopped in the case of a 95% probability for the estimated PFR-16w to be higher in the maintenance than in the interruption arm (NCT02029001). 151 patients were included, of whom 35 had SD at 12 weeks of Sorafenib. For the 35 patients with SD on sorafenib, the PFR-16w was 65% [95% credibility interval 43.4-83.7] in the continuation arm and 25% [7.8-48.1] in the interruption arm. Median PFS and OS were improved in the maintenance versus the interruption arm (mPFS: 5.6 [95%CI 1.97-6.77] months versus 2.0 [95%CI 1.61-3.91] months (p = 0.0231) and mOS: 14.3 [95%CI 8.9-23.8] versus 8.0 months [95%CI 3.5-15.2] (p = 0.0857)). Sorafenib showed activity in progressive patients with solid tumors harboring somatic genomic alterations in sorafenib-targeted genes. Continuing sorafenib when SD is achieved improves PFR compared to interruption.

Design of placebo-controlled randomized trials of anticancer agents: Ethical considerations based on a review of published trials.

Limited information exists about the design of placebo-controlled cancer trials. Through a systematic review of trials published in 2013, we describe placebo use in randomized trials testing anticancer agents and analyze strategies that increase exposure to the experimental regimen. Trials were classified as add-on (placebo in combination with standard treatment) or placebo-only. Strategies to allow more than half of the participants to receive the experimental regimen were reviewed. The risk-benefit ratio of receiving the experimental agent was considered favorable if the difference in primary outcome was significant (p ≤ 0.05), neutral if there was no significant difference in the primary outcome and the experimental agent did not add substantial toxicity, and unfavorable otherwise. Eighty trials were included (32,694 participants). Most trials were add-on (69%). The risk-benefit outcome was favorable, neutral, and unfavorable to the experimental agent in 52%, 32%, and 16% of placebo-only trials and 25%, 53%, and 22%, respectively, of add-on trials. Four strategies increased exposure to the experimental regimen: one-way crossover (23%), uneven randomization (21%), three-arms (13%), and randomized discontinuation design (4%); these strategies were used more often in placebo-only trials. A minority of participants received placebo alone and strategies to increase experimental exposure were used commonly. Fewer than half of the studies had favorable outcomes, thus defending the use of placebo controls, when there is no established treatment. Strategies that increase patient exposure to experimental agents rather than placebo may expose them to non-beneficial, sometimes toxic, experimental agents.

Effects of antidepressant medicines on preventing relapse of unipolar depression: a pooled analysis of parametric survival curves.

Major depressive disorder is characterized by a high risk of relapse. We aimed to compare the prophylactic effects of different antidepressant medicines (ADMs). PubMed, Cochrane Central Register of Controlled Trials, Embase and the Web of Science were searched on 4 July 2019. A pooled analysis of parametric survival curves was performed using a Bayesian framework. The main outcomes were hazard ratios (HRs), relapse-free survival and mean relapse-free months. Forty randomized controlled trials were included. The 1-year relapse-free survival for ADM (76%) was significantly better than that for placebo (56%). Most of the relapse difference (86.5%) occurred in the first 6 months. Most HRs were not constant over time. Proof of benefit after 6 months of follow-up was not established partially because of small differences between the drug and placebo after 6 months. Almost all studies used an 'enriched' randomized discontinuation design, which may explain the high relapse rates in the first 6 months after randomization. The superiority of ADM v. placebo was mainly attributed to the difference in relapse rates that occurred in the first 6 months. Our analysis provided evidence that the prophylactic efficacy was not constant over time. A beneficial effect was observed, but the prevention of new episodes after 6 months was questionable. These findings may have implications for clinical practice.

YI02.03 Statistical Pitfalls in Clinical Trial Design

YI02.03 Statistical Pitfalls in Clinical Trial Design

3 Randomized Discontinuation Designs in Early Clinical Drug Screening – how to Adapt if the Drug Works too well? The Cabozantinib Experience

3 Randomized Discontinuation Designs in Early Clinical Drug Screening – how to Adapt if the Drug Works too well? The Cabozantinib Experience

A randomized phase II study of bicalutamide (BIC) followed by placebo or gamma secretase inhibitor RO4929097 (RO492) in men with rising PSA.

219 Background: Notch signaling is a key determinant of cell fate. RO492 is a selective γ-secretase inhibitor blocking cleavage of Notch. We hypothesize that anti-androgen therapy will lead to an enriched population of basal prostate cancer stem cells. Targeting Notch following anti-androgen treatment will lead to delay in re-growth of mature luminal PC cells. We are using a novel double blind, placebo controlled randomized discontinuation design to treat men with rising PSA. A non-castrating anti-androgen (BIC) was used to induce initial tumor regression Methods: Pts with rising PSA after primary therapy for PC, and no radiographic evidence of disease were enrolled in this ongoing study. All pts received BIC 50mg/day for 16 weeks (induction phase). Pts achieving a >50% (modified from 80% decrease after the first 8 pts) decrease in PSA were randomized to placebo or RO492 20mg orally 3 days on/ 4 days off per week (randomization phase). Primary endpoint is PSA progression (increase in PSA by 50% over nadir with minimum PSA rise of 2ng/mL) during randomization phase. Pts meeting primary endpoint could receive 12 months of RO492 and BIC (combination phase). Serum is collected for evaluation of soluble markers of gamma secretase inhibition. 29 pts/arm in randomization phase gives 90% power to detect a decrease in1 yr PFS from 80% to 45% with 5% alpha. Results: We report on the first 16 patients that have enrolled. Median pretreatment PSA was 6.3ng/ml (0.35 to 34). 9 of 16 pts on the induction phase came off study due to PSA progression, although 5 of 9 pts would have been randomized using the 50% PSA response criteria. 6 pts have been randomized to RO492 or placebo (1 pt not yet randomized) and 2 pts have proceeded to combination phase. Median PSA decrease during induction phase in 6 pts who went on to randomization was 86% (69–97). Overall decline in PSA in induction phase was 67% (7.3-99%). Placebo/RO492 has been well tolerated with 1 pt experiencing g1 fatigue, and 1 pt experiencing g1 nausea in the combination phase. 8/16 pts had g1 breast tenderness with BIC. Conclusions: In this ongoing randomized phase II trial, BIC decreased PSA by >50% in 12/16 pts. Placebo/RO492 is well tolerated. Enrollment continues with analysis of plasma correlates to be compared to clinical results.

Randomized controlled trials in schizophrenia: opportunities, limitations, and trial design alternatives

State-of-the art clinical trial design and methodology are enormously important for the advancement of the field. In contrast, the critical relevance of trial conduct and implementation have only more recently been the focus of discussion and research. Although randomized controlled trials are generally considered the gold standard for the assessment of pharmacologic and nonpharmacologic interventions in medicine, trials are vulnerable to complications and influences that can seriously compromise their success. Like interventions, trial design and conduct are also contextual. They need to be individualized and adapted to a number of relevant variables, such as setting, population, illness phase, interventions, patient and rater expectations and biases, and the overall aims of the investigation. While this means that there is no unified approach possible, certain general principles and guidelines require careful consideration. Knowledge of basic solutions and alternatives, and the recognition of the complex challenges that need to be addressed proactively can help to minimize unwanted outcomes, including trial failure and uninformative or falsely negative outcomes. Moreover, novel design alternatives need to be explored that target sample enrichment according to the study question and enhancement of precision in the measurement of relevant outcomes. We propose two novel design strategies that take advantage of the recently validated early antipsychotic response paradigm (that has also been observed with antidepressants and mood stabilizers). In the "early responder randomized discontinuation design" all patients are assigned to the active drug, and only those who had at least a minimal response at 2 weeks are enrolled in a double-blind, placebo-controlled discontinuation trial, enriching the placebo controlled trial portion with true drug responders. In the mirror image "early nonresponder randomized dose increase or augmentation design," early nonresponders at 2 weeks are assigned to staying on the medication or going either to a higher dose or an augmentation agent. It is hoped that through increased attention to the issues raised in this article and further refinement of trial methodology and conduct, the field will make much needed additional progress in the prevention and treatment of schizophrenia.

Discussions

We congratulate Trippa, Rosner, and Müller (2011, Biometrics, in press) on an intriguing and timely article. The randomized discontinuation design (RDD) has only recently been used in cancer clinical trials, and methodological understanding on how to best design such studies is limited. The authors’ approach to optimize RDD designs based on prior information and utility considerations is an important step forward. A noteworthy element is their use of a semimechanistic model to describe tumor growth. Mathematical models have provided considerable insight on the complex process of tumor evolution (Preziosi, 2003, Cancer Modelling and Simulation). Utilizing this knowledge should lead to better design, analysis, and decisions.

Randomized Phase II Trials: A Long-term Investment With Promising Returns

Given the multitude of novel anticancer drugs and the limited resources available to study them, phase II trials should identify drugs with the highest probability of succeeding in subsequent phase III trials. Currently, single-arm phase II trial results are interpreted relative to historical control subjects, introducing selection bias and confounding that may limit the validity of the conclusions. The rate of success (defined as a statistically significant difference between arms) in phase III oncology trials is only 40%, suggesting that current phase II trials are insufficiently informative. However, simulation studies suggest that randomized phase II trials would have lower error rates and greater predictive power for phase III results. Randomized phase II trials may also be more informative than single-arm phase II trials because of the hypotheses being tested, the variety of possible endpoints, and the opportunities for biomarker discovery. There are a wide variety of randomized phase II designs that can be used, including the randomized discontinuation design, the delayed-start design, adaptive (Bayesian) designs, selection designs, and phase II/III designs. The barriers to widespread adoption of randomized phase II trials include time to completion, sample size considerations, and ethical concerns, but none are insurmountable. We conclude that randomized phase II trials are a worthy investment considering finite patient and financial resources and should be the rule rather than the exception for evaluating novel therapies in oncology.

Target-specific, histology-independent, randomized discontinuation study of lapatinib in patients with HER2-amplified solid tumors

To explore the activity of lapatinib with a novel trial design focused on the drug target rather than on histology. Patients with HER2 amplified gastro-esophageal, bladder, ovarian, or uterine tumors were enrolled into a double-blinded randomized discontinuation study of lapatinib 1,500 mg PO daily. The planned sample size was 250 patients with HER2 amplified tumors, with the goal of randomizing 100 patients with stable disease (SD) at week 12 to either lapatinib or placebo. Patients responding after 12 weeks continued on lapatinib; those who progressed were discontinued from study. The primary objectives were response rate after 12 weeks and the percentage of patients who remained progression free 12 weeks after randomization to placebo versus lapatinib. Secondary objectives were duration of response and determination of the incidence of HER2 amplification in multiple tumor types. A total of 141 patients were screened and 32 patients with HER2 amplified tumors were enrolled. At week 12, 1 (3%) patient had a complete response, 9 (28%) had stable disease, 20 (63%) had progressive disease, and 2 (6%) were unknown. Only 7 patients with SD underwent randomization. The low response rate coupled with slow screening and enrollment led to early study closure. Basing trial eligibility on the presence of a genetic target, versus histologic classification, is challenging. While HER2 amplifications appear to be prevalent in select non-breast tumors, lapatinib monotherapy is associated with modest activity. The target-specific histology-independent randomized discontinuation design still merits consideration for targets clearly implicated in "oncogene addiction".

Comparison of Power Between Randomized Discontinuation Design and Upfront Randomization Design on Progression-Free Survival

Enrichment based on molecular characteristics has emerged as an important inclusion criterion in phase II trials of targeted anticancer agents. In this study, we evaluate a well-described method of population enrichment by tumor growth characteristics in the early development stage of targeted cytostatic agents. For some solid tumors, such as pancreatic carcinoma, using a time-to-event end point (eg, time to disease progression) to evaluate the efficacy of a cytostatic agent in a phase II trial is more relevant than clinical response by Response Evaluation Criteria in Solid Tumors. In this setting, we compared the power of the randomized discontinuation and upfront randomization designs under two previously proposed tumor growth models for treatment effect when the end point is time-to-event. By selecting patients with more homogeneous tumor growth characteristics, the randomized discontinuation design is more efficient than the upfront randomization design when treatment benefit is restricted to slow-growing tumors. Under a model where only a subset of patients expressing the molecular target are sensitive to the agent, the randomized discontinuation design is more powerful than the upfront randomization design when the treatment effect is small; and vice versa when the treatment effect is moderate to large. For selected targeted agents where a bioassay to select patients expressing the specific molecular target is not available, the randomized discontinuation design is a feasible alternative patient enrichment strategy in certain disease settings and provides a reasonable platform to evaluate drugs before phase III testing.

Phase II Trials in Journal of Clinical Oncology

Phase II Trials in <i>Journal of Clinical Oncology</i>

Target-specific randomized discontinuation trial design: a novel approach in molecular therapeutics

To describe a phase II study design to evaluate the activity of novel anti-cancer agents that focuses on molecular pathogenesis rather than tumor histology. We propose an enrichment design that enrolls patients across histologies expressing target X and incorporates randomized discontinuation of drug Y after an initial treatment period to evaluate for potential cystostatic activity. We are currently evaluating the activity of lapatinib in patients with HER-2 amplified solid tumors using the target-specific, histology-independent, randomized discontinuation design. Patients receive treatment with lapatinib for an initial 12-week period. After restaging, patients with disease progression are removed from study, patients achieving an objective response continue treatment, and patients with stable disease are randomized to continue lapatinib versus initiate treatment with placebo. The primary endpoints are to evaluate the objective response rate during the initial treatment period and to evaluate the proportion of patients progression-free 12 weeks post-randomization. The target-specific, histology-independent, randomized discontinuation design is an attractive alternative to the traditional phase II design for the development of "targeted" therapeutics.

Methodological aspects on new protocols in oncology

This review will summarize specific methodological aspects in targeted therapies like EPR (early progression rate) or RDD (randomized discontinuation design), along with Adaptive Design such as CRM (continual reassessment method, Eff-TOX (dose-finding based on efficacy-toxicity, PPD (predictive probability design) or ADTT (adaptive randomization for targeted therapy) methods.

A randomized discontinuation phase II study of sorafenib versus placebo in patients with non-small cell lung cancer who have failed at least two prior chemotherapy regimens: E2501

8014 Background: Sorafenib (S) is a raf kinase and angiogenesis inhibitor with activity in hepatoma and renal cell carcinoma. Given the activity of other angiogenic inhibitors in non-small cell lung cancer, we conducted this randomized, double blind, placebo (P) controlled Phase II study in third line and beyond disease (dx). We utilized a unique randomized discontinuation design in order to enrich for patients (pts) with slower growing dx, who theoretically might be more likely to derive benefit. Methods: Pts were required to have PS of 0–1; at least 2 prior chemotherapy regimens; and progressing dx. All pts received 400 mg of S orally twice daily for 2 cycles (2 months) (Step 1). Responding pts on Step 1 continued on S; progressing pts went off study, and pts with stable dx were randomized to P or S (Step 2). Pts randomized to P were allowed to cross over to S on progression (PD). The primary endpoint of this study was the proportion of pts having stable or responding dx 2 months after randomization. Ac...

Clarification Regarding “Phase II Trials Published in 2002: A Cross-Specialty Comparison Showing Significant Design Differences between Oncology Trials and Other Medical Specialties” and the Accompanying Commentary, “Phase II Cancer Trials: Out of Control?”

To the Editors: We would like to clarify our comments about the use of placebos in phase II cancer clinical trials, as discussed in the article by Michaelis and Ratain, “Phase II Trials Published in 2002: A Cross-Specialty Comparison Showing Significant Design Differences between Oncology Trials and Other Medical Specialties” (1), and the accompanying commentary, “Phase II Cancer Trials: Out of Control” by Chabner (2).In particular, the commentary addressed the “problematic” inclusion of a control group treated only with placebo as one arm of a randomized phase II evaluation of an experimental compound. Although many oncologists would find it difficult to offer such a trial to patients with progressive and potentially fatal disease, we both strongly endorse certain “innovative” trial designs that use placebos. Such designs might include either a limited period of placebo treatment versus initial therapy with experimental drug, a trial of a standard agent plus placebo versus the same standard agent plus an experimental agent, or a randomized discontinuation design in which all patients receive experimental drug, and, thereafter, stable patients receive either continued experimental drug or placebo, until disease progression. These and other designs might provide valuable information regarding the effect of the experimental drug on disease progression, and at the same time provide an opportunity to assess the effect of drug on biomarkers. In these and other trial designs, periods of placebo treatment are not likely to adversely affect patient outcomes compared with “standard” treatment. Other novel designs using placebos are certainly possible.

Problems With the Randomized Discontinuation Design

Problems With the Randomized Discontinuation Design

Phase II Clinical Trial Design: Methods in Translational Research from the Genitourinary Committee at the Eastern Cooperative Oncology Group

Given the increase in novel agents and difficulty with planning and completing many phase III studies, various phase II trial design options should be considered to more effectively guide phase III trial plans. The need for novel phase II trial designs has increased, given the number of novel molecular targeted therapies now available for testing, an abundance of cytostatic agents, and limited resources to conduct phase III studies for all interesting agents or combinations. This review will focus on options for phase II trial designs. We review randomized phase II designs with placebo control, randomized selection designs, and randomized discontinuation designs. As agents become available for testing in the clinic, the strengths and weaknesses of different phase II trial designs should be considered to optimize a trial development plan that guides phase III trial decisions more effectively.

A Phase II Study of GW786034 Using a Randomized Discontinuation Design in Patients with Locally Recurrent or Metastatic Clear-Cell Renal Cell Carcinoma

A Phase II Study of GW786034 Using a Randomized Discontinuation Design in Patients with Locally Recurrent or Metastatic Clear-Cell Renal Cell Carcinoma

Evaluation of Randomized Discontinuation Design

Single-arm phase II trials may not be appropriate for testing cytostatic agents. We evaluate two kinds of randomized designs for the early development of target-based cytostatic agents. We compared power of the randomized discontinuation and upfront randomization designs under two models for the treatment effect of targeted cytostatic agents. The randomized discontinuation design is not as efficient as upfront randomization if treatment has a fixed effect on tumor growth rate or if treatment benefit is restricted to slower-growing tumors. On the other hand, the randomized discontinuation design can be advantageous under a model where only a subset of patients, those expressing the molecular target, is sensitive to the agent. To achieve efficiency, the design parameters must be carefully structured to provide adequate enrichment of the randomly assigned patients. With careful planning, the randomized discontinuation designs can be useful in some settings in the early development of targeted agents where a reliable assay to select patients expressing the target is not available.