Comparing three regularization methods to avoid extreme allocation probability in response-adaptive randomization

<p>We examine three variations of the regularization methods for response-adaptive randomization (RAR) and compare their operating characteristics. A power transformation (PT) is applied to refine the randomization probability. The clip method is used to bound the randomization probability within specified limits. A burn-in period of equal randomization (ER) can be added before adaptive randomization (AR). For each method, more patients are assigned to the superior arm and overall response rate increase as the scheme approximates simple AR, while statistical power increases as it approximates ER. We evaluate the performance of the three methods by varying the tuning parameter to control the extent of AR to achieve the same statistical power. When there is no early stopping rule, PT method generally performed the best in yielding higher proportion to the superior arm and higher overall response rate, but with larger variability. The burn-in method showed smallest variability compared with the clip method and the PT method. With the efficacy early stopping rule, all three methods performed more similarly. The PT and clip methods are better than the burn-in method in achieving higher proportion randomized to the superior arm and higher overall response rate but burn-in method required fewer patients in the trial. By carefully choosing the method and the tuning parameter, RAR methods can be tailored to strike a balance between achieving the desired statistical power and enhancing the overall response rate.</p

PIK3CA, RAS (KRAS, NRAS), and BRAF mutations.

<p>PIK3CA, RAS (KRAS, NRAS), and BRAF mutations.</p

Simultaneous <i>PIK3CA</i> and <i>KRAS</i> mutations.

<p>Wild-type <i>KRAS</i> (blue bar) and mutant <i>KRAS</i> (red bar) in: A. All tumor types (tested, n = 367); B. All cancers excluding colorectal cancers (tested, n = 270); C. Colorectal cancers (tested, n = 97); D. Ovarian cancers (tested, n = 46).</p

Simultaneous <i>PIK3CA</i> and <i>RAS</i> (<i>KRAS, NRAS</i>) or <i>BRAF</i> mutations.

<p>Wild-type <i>RAS</i> (<i>KRAS, NRAS</i>) or <i>BRAF</i> (blue bar) and mutant <i>RAS</i> (<i>KRAS, NRAS</i>) or <i>BRAF</i> (red bar) in: A. All tumor types (tested, n = 436); B. All cancers excluding colorectal cancers (tested, n = 332); C. Colorectal cancers (tested, n = 104); D. Ovarian cancers (tested, n = 50).</p

Proportion (numbers) of mutation types.

<p>A. <i>PIK3CA</i> mutations (n = 54). B. <i>KRAS</i> mutations (n = 69). C. <i>NRAS</i> mutations (n = 19). D. <i>BRAF</i> mutations (n = 31).</p

Real Time <i>RT-PCR</i> detection of <i>TUSC2</i> gene expression in patients receiving DC-<i>TUSC2</i>.

1<p>Specimens not available.</p

Consort style flowchart of participants through the study.

<p>Consort style flowchart of participants through the study.</p

DC-<i>TUSC2</i> metabolic tumor response in a metastatic lung cancer patient.

<p>The patient is a 54 year old female with a large cell neuroendocrine carcinoma. She had received six prior chemotherapy regimens. Prior to entry in the protocol, two hepatic metastases were progressing on gemcitabine. The patient also had a metastasis in the head of the pancreas and a peripancreatic lymph node (arrows). A. Pretreatment PET scan. The dose of Fluorodeoxyglucose(18F) was 8.8mCi B. Post-treatment PET scan performed 20 days following the fourth dose of DC-<i>TUSC2</i>. The dose of Fluorodeoxyglucose(18F) was 9.0mCi. All scans were performed within a 60 to 90 minute window after injection.</p

Baseline Characteristics of Patients.

<p>Abbreviations: ECOG, Eastern Cooperative Oncology Group; NOS, not otherwise specified.</p