A Phase III, Randomized, Placebo-controlled, Double-blind, Multi-center, International Study of Durvalumab With Stereotactic Body Radiation Therapy (SBRT) for the Treatment of Patients With Unresected Stage I/II, Lymph-node Negative Non-small Cell Lung Cancer (PACIFIC-4/RTOG-3515) Osimertinib Following SBRT, a Single Arm Cohort for Patients With Unresected Stage I/II, Lymph Node Negative NSCLC Harboring a Sensitizing EGFR Mutation
Overview
- Phase
- Phase 3
- Intervention
- Durvalumab
- Conditions
- Carcinoma, Non-Small-Cell Lung
- Sponsor
- AstraZeneca
- Enrollment
- 724
- Locations
- 211
- Primary Endpoint
- Progression-Free Survival (PFS) assessed by Blinded Independent Central Review (BICR) according to RECIST 1.1 in subpopulation of patients with Stage I/II NSCLC
- Status
- Active, not recruiting
- Last Updated
- 9 days ago
Overview
Brief Summary
This is a Phase III, randomized, placebo-controlled, double-blind, multi-center study assessing the efficacy and safety of durvalumab with SoC SBRT versus placebo with SoC SBRT in patients with unresected clinical Stage I/II lymph node-negative (T1 to T3N0M0) NSCLC.
An additional cohort will assess Osimertinib following SBRT in patients with early stage unresected T1 to T3N0M0 NSCLC harbouring an EGFR mutation.
Detailed Description
Patients with Stage I/II lymph node negative NSCLC and confirmed to meet all eligibility criteria will be randomized 1:1 to receive either Durvalumab + SoC SBRT or placebo + SoC SBRT. The primary objective of main cohort is to assess the efficacy of Durvalumab with SoC SBRT compared to placebo with SoC SBRT in terms of PFS. Key secondary is to assess the efficacy of Durvalumab with SoC SBRT compared to placebo with SoC SBRT in terms of Overall Survival (OS). In addition, a study cohort with a sufficient number of patients harboring an EGFR-TKI sensitizing mutation, will receive Osimertinib treatment after completion of SoC SBRT as definitive treatment of Stage I/II lymph node-negative NSCLC. The primary objective of Osimertinib cohort is to assess efficacy of Osimertinib following SoC SBRT in terms of 4-year PFS. Key secondary objectives include safety, OS and efficacy of Osimertininb treatment with SBRT.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Main Cohort Key Inclusion Criteria:
- •Age ≥18 years
- •Planned SoC SBRT as definitive treatment
- •World Health Organization (WHO)/ECOG PS of 0, 1 or 2
- •Life expectancy of at least 12 weeks
- •Body weight \>30 kg
- •Submission of tumor tissue sample if available
- •Adequate organ and marrow function required
- •Patients with central or peripheral lesions are eligible
- •Staging studies must be done during screening (PET-CT within 10 weeks)
Exclusion Criteria
- •Mixed small cell and non-small cell cancer
- •History of allogeneic organ transplantation
- •History of another primary malignancy with exceptions
- •History of active primary immunodeficiency
- •Epidermal growth factor receptor local testing is strongly recommended prior to enrollment. Patients with a tumor harboring an EGFRm per local testing will be excluded from the main cohort
- •Prior exposure to immune-mediated therapy with exceptions
- •Osimertinib Cohort Key Inclusion Criteria
- •Age ≥18 years
- •Planned SoC SBRT as definitive treatment
- •WHO/ECOG PS of 0, 1, or 2
Arms & Interventions
SoC SBRT + Durvalumab Therapy (Main Cohort)
SBRT Durvalumab (PD-L1 monoclonal antibody) 1500 mg every 4 weeks \[q4w\] intravenously \[iv\] for up to 26 cycles or until progression or other discontinuation criteria are met.
Intervention: Durvalumab
SoC SBRT + Placebo Therapy (Main Cohort)
SBRT Placebo (matching placebo for infusion) every 4 weeks iv for up to 26 cycles or until progression or other discontinuation criteria are met.
Intervention: Placebo
SoC SBRT + Osimertinib Therapy (Osimertinib cohort, single-arm, open-label separate cohort)
SBRT Osimertinib 80mg every day \[qd\] for oral administration up to 36 months or until progression. Osimertinib treatment should start within 7 to 14 days after completion of SBRT
Intervention: (Osimertinib cohort, single-arm, open-label separate cohort)
Outcomes
Primary Outcomes
Progression-Free Survival (PFS) assessed by Blinded Independent Central Review (BICR) according to RECIST 1.1 in subpopulation of patients with Stage I/II NSCLC
Time Frame: from randomization up to 6 years
Main Cohort
4-year Progression-Free Survival (4y-PFS) by ICR according to RECIST 1.1 criteria
Time Frame: from treatment start up to 5 years
Osimertinib Cohort
Secondary Outcomes
- Progression-Free Survival (PFS) assessed by BICR per RECIST 1.1 in all randomised patients with Stage I/II NSCLC(from randomization up to 6 years)
- Overall Survival (OS)(from randomization up to 7 years)
- Concentration of durvalumab in serum such as peak concentration and trough(12 weeks after last dose)
- Detection of ADA neutralising antibodies titers(up to 6 months after last dose)
- Assessment of AEs by CTCAE v 5.0 as measures of the safety, tolerability and compliance of osimertinib with SoC SBRT therapy(Up to 35 days after last dose)
- Health-related quality of life in patients treated with durvalumab with SoC SBRT compared to placebo with SoC SBRT using the EORTC QLQ-C30(from randomization up to 7 years)
- Proportion of patients alive and progression free at 24 months from randomisation (PFS24) assessed by BICR according to RECIST 1.1(at 24 months following randomization)
- Time to progression (TTP) assessed by BICR according to RECIST 1.1(from randomization up to 6 years)
- Time to death or distant metastasis (TTDM) assessed by BICR according to RECIST 1.1(from randomization up to 6 years)
- Time from randomisation to second progression (PFS2) as defined by local standard clinical practice(from randomization up to 7 years)
- Assessment of AEs by CTCAE v 5.0 as measures of the safety and tolerability of Durvalumab with SoC SBRT compared to placebo with SoC SBRT(up to 3 months after last dose)
- WHO performance status(from treatment start up to 5 years)
- ECG QT interval(Up to 156 weeks of treatment or treatment discontinuation)
- Overall Survival(from treatment start up to 5 years)
- Time To Progression (TTP)(from treatment start up to 5 years)
- Time to CNS progression(from treatment start up to 5 years)
- PFS2(from treatment start up to 5 years)
- Site(s) of disease progression(from treatment start up to 5 years)
- PFS by ICR using RECIST 1.1(from treatment start up to 5 years)