Single-Blinded Trial Design Prevents Patients From Withdrawing Prematurely, Analysis Shows

Single-Blinded Trial Design Prevents Patients From Withdrawing Prematurely, Analysis Shows

BeyondSpring’s single-blinded trial design, in which patients are unaware of the treatment they receive, effectively prevented participants from prematurely withdrawing from the company’s DUBLIN-3 study due to dissatisfaction with their treatment allocation, an analysis shows.

The findings were presented in a poster, titled “Validation of a Single-Blinded (Patients Only) Study Design for the Prevention of Premature Patient Consent Withdrawal in the Immuno-Oncology Trial DUBLIN-3,” at the recent Society for Immunotherapy of Cancer 2019 Annual Meeting in National Harbor, Maryland.

Normally, cancer patients participating in clinical trials prefer to be treated with immunotherapy over chemotherapy. For that reason, in open-label studies in which participants are informed of the treatment they will receive during the trial, cancer patients often decide to withdraw from the study after being told that they will be treated with chemotherapy.

Premature patient withdrawal can have a negative impact on a study’s endpoints, as was the case in the open-label, JAVELIN Lung 200 Phase 3 trial (NCT02395172). The main goal of the study was to demonstrate that Bavencio (avelumab) improved the survival of patients with advanced non-small cell lung cancer (NSCLC) over standard-of-care chemotherapy with docetaxel.

According to investigators overseeing JAVELIN Lung 200, one of the reasons why the study failed to meet its primary goal was because of the high percentage of participants who decided to withdraw from the study after being informed that they would be treated with docetaxel.

BeyondSpring is currently carrying out a global, single-blinded Phase 3 trial called DUBLIN-3 (NCT02504489) to evaluate the effects of plinabulin, its lead anti-cancer therapy candidate, in combination with docetaxel as a second- and third-line treatment for people with advanced NSCLC who had previously received platinum-based chemotherapy.

The study is still recruiting patients from different sites across the U.S., Australia, and China. BeyondSpring is expecting to enroll up to 554 participants in DUBLIN-3, who will be divided into two regional sub-groups (Asia and non-Asia).

The goal of DUBLIN-3 is to demonstrate that patients receiving a combination of plinabulin and docetaxel live longer than those receiving docetaxel alone. The main difference in design between this study and JAVELIN Lung 200 is that BeyondSpring decided to use a single-blinded trial design to avoid premature patient withdrawal.

To validate the effectiveness of the study’s design choice, the company decided to analyze and compare the patient drop-out rates during the first interim analysis of DUBLIN-3 to those in JAVELIN Lung 200.

Findings from this analysis showed that the single-blinded trial design significantly reduced patient drop-out rates, with 1% of the participants enrolled in DUBLIN-3 and receiving docetaxel deciding to withdraw from the study prematurely compared to 8% of those in JAVELIN.

“The results from this analysis validate the effectiveness of a single-blinded (for patients only) study design for the prevention of premature patient drop-out from the chemotherapy comparator arm. Since premature patient drop out in the comparator arm is associated with negative trial outcome results, these observations may prove favorable in obtaining a positive outcome in DUBLIN-3. This finding may also be relevant for the design of future [immuno-oncology] trials,” Ramon Mohanlal, executive vice president of R&D, and chief medical officer of BeyondSpring, said in a press release.

“Following the first pre-planned interim analysis with Study 103 [DUBLIN-3] in the first quarter of 2019, the study continued without modifications. Our second interim analysis to evaluate overall survival is projected to be triggered late 2019,” Mohanlal said.

Plinabulin is a marine-derived small molecule meant to improve the activation of T-cells and accelerate the maturation of immune neutrophils, preventing a common chemo-associated side effect called neutropenia, or low neutrophil levels.

Previous Phase 2 trials assessing the effects of plinabulin in combination with docetaxel in people with advanced NSCLC showed that the combo therapy prolonged patient survival, reduced the incidence of neutropenia associated with docetaxel, and improved patients’ quality of life.

If data from DUBLIN-3 confirms these findings, the addition of plinabulin to docetaxel may become the new standard-of-care treatment for people with advanced NSCLC who failed to respond to first- and second-line therapies.