A Global, Multicenter, Randomized, Double-blinded, Phase 3 Study of Docetaxel + Plinabulin Compared to Docetaxel + Placebo in Patients With Advanced or Metastatic Non-squamous Non-Small Cell Lung Cancer With EGFR, ALK, ROS, and RET Wild Type After Progressing on Prior Immunotherapy (Anti-PD-1/L1 Antibody) and Platinum-based Chemotherapy (DUBLIN-4)
Overview
- Phase
- Phase 3
- Status
- Not yet recruiting
- Enrollment
- 442
- Primary Endpoint
- Overall Survival (OS)
Overview
Brief Summary
This is a global, multicenter, randomized, double-blind, placebo-controlled Phase 3 study evaluating docetaxel plus plinabulin versus docetaxel plus placebo in participants with advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) without EGFR, ALK, ROS1, or RET alterations who have experienced disease progression after prior anti-PD-1/PD-L1 immunotherapy and platinum-based chemotherapy. Approximately 442 participants will be randomized 1:1 to receive docetaxel (75 mg/m² IV on Day 1 of each 21-day cycle) in combination with plinabulin (30 mg/m² IV on Days 1 and 8) or matching placebo. Treatment will continue until disease progression, unacceptable toxicity, death, withdrawal of consent, or sponsor/investigator decision. Tumor assessments will be performed regularly per RECIST v1.1, and participants will be followed for survival after treatment discontinuation. The primary objective is to compare overall survival between treatment arms; secondary objectives include evaluation of progression-free survival, objective response rate, duration of response, disease control, incidence of Grade 4 neutropenia, quality of life, and safety/tolerability.
Detailed Description
Participants with advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) who have progressed following prior anti-PD-1/PD-L1 immunotherapy and platinum-based chemotherapy have limited treatment options and docetaxel remains a commonly used standard therapy in this setting. Plinabulin is a first-in-class small molecule with a distinct mechanism that may enhance anti-tumor activity and may mitigate chemotherapy-associated neutropenia. This study (DUBLIN-4) is designed to evaluate whether the addition of plinabulin to docetaxel improves clinical outcomes compared with docetaxel alone in this post-immunotherapy and post-platinum population without EGFR, ALK, ROS1, or RET alterations.
This is a global, multicenter, randomized, double-blind, placebo-controlled Phase 3 study. Participants will be randomized in a 1:1 ratio to receive docetaxel in combination with plinabulin or matching placebo. Randomization will be stratified by geographic region (Asian countries vs Western countries), current line of therapy (2nd vs 3rd line), and prior progression-free survival duration on PD-1/PD-L1 inhibitor therapy (≥6 months vs <6 months).
Efficacy will be evaluated using standard radiographic tumor assessments and response criteria, with additional evaluation of clinically relevant outcomes in this treatment setting, including overall survival, progression-free survival, and objective response. Safety will be assessed throughout the study by monitoring adverse events, laboratory parameters, and other routine clinical assessments. The study also includes evaluation of patient-reported quality of life and the incidence of severe neutropenia as an important tolerability endpoint for docetaxel-based treatment.
Participants who discontinue study treatment will enter follow-up, including a safety follow-up after treatment discontinuation and ongoing survival follow-up. Sparse pharmacokinetic samples will be collected to support population pharmacokinetic analyses of plinabulin.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Males and females 18 years of age or older at the time of signing the ICF
- •Willing and able to sign an ICF;
- •Non-squamous NSCLC with EGFR, ALK, ROS and RET wild type who have been diagnosed by histopathological and/or cytological examination as being ineligible for surgical treatment and have locally advanced (stage IIIb) or metastatic (stage IV) diseases, or have recurrent and progressive disease after local treatment (if there are multiple tumor components, classify the main cell type):
- •Developed disease progression after treatment with PD-1/L1 inhibitors and platinum-based chemotherapy in advanced non-squamous NSCLC with EGFR, ALK, ROS and RET wild type
- •Treatment progression with anti-PD-1/L1 inhibitors and platinum-based chemotherapy administered either concurrently or sequentially as part of the same first-line treatment plan, or as two separate prior lines of systemic therapy, (does not count preoperative and adjuvant therapy) is defined to meet all of the following criteria:
- •Demonstrated disease progression after anti-PD-1/L1 and platinum-based chemotherapy concurrently or sequentially as defined by RECIST v1.1
- •Once disease progression is confirmed, the initial date of disease progression documentation will be considered the date of disease progression. The disease progression to the first administration of the IMP should not exceed 60 days
- •Achieved PFS of anti- PD-1/L1 treatment for at least 3 months
- •ECOG performance status of 0 to 1
- •All AEs from any previous systemic therapy, surgery or radiotherapy must have been resolved to CTCAE v5.0 Grade ≤1 or baseline
Exclusion Criteria
- •Administration of chemotherapy, immunotherapy, biotherapy, targeted, or radiation therapy or investigational agent (therapeutic or diagnostic) within 3 weeks prior to the first dose of IMP. Major surgery, other than diagnostic surgery, within 4 weeks before first IMP administration is exclusionary
- •Receipt of more than two prior lines of systemic anticancer therapy for locally advanced or metastatic non-small cell lung cancer. Neoadjuvant and adjuvant systemic therapies are not counted as prior lines of therapy
- •Any of the following cardiac criteria experienced currently or within the last 6 months:
- •Congestive heart failure (New York Heart Association ≥Class 2)
- •Any clinically significant abnormalities (as assessed by the investigator) in rhythm, conduction, or morphology of resting ECGs, eg, complete left bundle branch block or third-degree heart block
- •Acute coronary syndrome
- •Clinically significant uncontrolled cardiac arrhythmia
- •Any of the following cardiac criteria experienced currently:
- •Mean QTC interval corrected (Friderica) \>470 ms
- •Left ventricular ejection fraction \<50% or the lower limit of normal (per institutional standard)
Arms & Interventions
Docetaxel + Plinabulin
Participants will receive docetaxel IV infusion on Day 1 of each 21-day cycle plus plinabulin IV infusion on Days 1 and 8. Treatment continues until disease progression, unacceptable toxicity, death, withdrawal, or sponsor/investigator decision.
Intervention: Plinabulin (Drug)
Docetaxel + Plinabulin
Participants will receive docetaxel IV infusion on Day 1 of each 21-day cycle plus plinabulin IV infusion on Days 1 and 8. Treatment continues until disease progression, unacceptable toxicity, death, withdrawal, or sponsor/investigator decision.
Intervention: Docetaxel (Drug)
Docetaxel + Placebo
Participants will receive docetaxel IV infusion on Day 1 of each 21-day cycle plus matching placebo IV infusion on Days 1 and 8. Treatment continues until disease progression, unacceptable toxicity, death, withdrawal, or sponsor/investigator decision.
Intervention: Docetaxel (Drug)
Docetaxel + Placebo
Participants will receive docetaxel IV infusion on Day 1 of each 21-day cycle plus matching placebo IV infusion on Days 1 and 8. Treatment continues until disease progression, unacceptable toxicity, death, withdrawal, or sponsor/investigator decision.
Intervention: Placebo (matching plinabulin placebo) (Drug)
Outcomes
Primary Outcomes
Overall Survival (OS)
Time Frame: Approximately 2 years after study initiation.
OS is defined as the time from randomization to death from any cause
Secondary Outcomes
- Progression-Free Survival (PFS)(Approximately 2 years after study initiation.)
- Objective Response Rate (ORR)(Approximately 2 years after study initiation.)
- Incidence of Grade 4 Neutropenia (Cycle 1 Day 8 ANC)(At Day 8 of Cycle 1 (approximately 1 week after the first dose; each treatment cycle is 21 days).)
- Overall Survival (OS) Rate at Month 24(24 months after randomization.)
- Overall Survival (OS) Rate at Month 36(36 months after randomization.)
- Duration of Response (DoR)(Approximately 2 years after study initiation.)
- Disease Control Rate (DCR)(Approximately 2 years after study initiation.)
- Incidence of New Brain Metastases(Approximately 2 years after study initiation.)
- Quality of Life (QoL) - EORTC QLQ-LC13(Approximately 2 years after study initiation.)
- Incidence and Severity of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)(Approximately 2 years after study initiation.)