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

Official 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.

Eligibility Requirements

• Minimum Age: 18 Years
• Maximum Age: 130 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: QUADRUPLE
• Enrollment: 724 participants

Study Arms

• SoC SBRT + Durvalumab Therapy (Main Cohort) (EXPERIMENTAL)
  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.
• SoC SBRT + Placebo Therapy (Main Cohort) (PLACEBO_COMPARATOR)
  SBRT Placebo (matching placebo for infusion) every 4 weeks iv for up to 26 cycles or until progression or other discontinuation criteria are met.
• SoC SBRT + Osimertinib Therapy (Osimertinib cohort, single-arm, open-label separate cohort) (EXPERIMENTAL)
  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

Interventions

• DRUG: Durvalumab — Durvalumab 1500 mg every 4 weeks \[q4w\] intravenously \[iv\] for up to 26 cycles or until progression or other discontinuation criteria are met.
• OTHER: Placebo — Matching placebo for infusion every 4 weeks iv for up to 26 cycles or until progression or other discontinuation criteria are met.
• DRUG: (Osimertinib cohort, single-arm, open-label separate cohort) — Osimertinib 80 mg every day \[qd\] orally for up to 36 months or until progression or other discontinuation criteria are met. Osimertinib treatment should start from 7 to 14 days after completion of SBRT

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 (from randomization up to 6 years)
• 4-year Progression-Free Survival (4y-PFS) by ICR according to RECIST 1.1 criteria (from treatment start up to 5 years)

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)
• 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)

Eligibility Criteria

Main Cohort Key Inclusion Criteria:

1. Age ≥18 years
2. Planned SoC SBRT as definitive treatment
3. World Health Organization (WHO)/ECOG PS of 0, 1 or 2
4. Life expectancy of at least 12 weeks
5. Body weight \>30 kg
6. Submission of tumor tissue sample if available
7. Adequate organ and marrow function required
8. Patients with central or peripheral lesions are eligible
9. Staging studies must be done during screening (PET-CT within 10 weeks)
10. Patients with a history of metachronous NSCLC and synchronous lesions are eligible with some exceptions

Main Cohort Key Exclusion Criteria:

1. Mixed small cell and non-small cell cancer
2. History of allogeneic organ transplantation
3. History of another primary malignancy with exceptions
4. History of active primary immunodeficiency
5. 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
6. Prior exposure to immune-mediated therapy with exceptions

Osimertinib Cohort Key Inclusion Criteria

1. Age ≥18 years
2. Planned SoC SBRT as definitive treatment
3. WHO/ECOG PS of 0, 1, or 2
4. Patients with central or peripheral lesions are eligible
5. Patients with a history of metachronous NSCLC and synchronous lesions are eligible with some exceptions
6. Staging studies must be done during screening (PET-CT within 10 weeks)
7. Submission of tumor tissue sample if available
8. Confirmation by local laboratory that the tumor harbors one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R)
9. Adequate bone marrow reserve or organ function required
10. Female patients should be using highly effective contraceptive measures
11. Male patients should be asked to use barrier contraceptives (ie, condoms) during sex with all partners during the trial and avoid procreation

Osimertinib Cohort Key Exclusion Criteria

1. Mixed small cell and non-small cell cancer
2. Patients with known or increased risk factor for QTc prolongation
3. Treatment with any of the following:

   * Preoperative or adjuvant platinum-based or other chemotherapy for the disease under investigation
   * Prior treatment with neoadjuvant or adjuvant EGFR TKI
   * Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4
4. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of osimertinib
5. Any of the following cardiac criteria

   * Mean resting corrected QT interval \>470 msec, obtained from 3 ECGs
   * Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG.
   * Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, or unexplained -sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval
   * Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD

Trial Locations

• Research Site, Tuscaloosa, Alabama, United States
• Research Site, Chandler, Arizona, United States
• Research Site, Phoenix, Arizona, United States
• Research Site, Tucson, Arizona, United States
• Research Site, Duarte, California, United States
• Research Site, Long Beach, California, United States
• Research Site, Los Angeles, California, United States
• Research Site, San Diego, California, United States
• Research Site, Newark, Delaware, United States
• Research Site, Washington D.C., District of Columbia, United States
• ...and 10 more locations

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