Clinical trial NCT03833154: Durvalumab With Stereotactic Body Radiation Therapy (SBRT) vs Placebo With SBRT in Early Stage Unresected Non-small Cell Lung Cancer (NSCLC) Patients/ Osimertinib Following SBRT in Patients With Early Stage Unresected NSCLC Harboring an EGFR Mutation
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: NSCLC
Early-Stage NSCLC
Lung cancer
Double- Blind
PD-L1
MEDI4736
Durvalumab
Osimertinib
PFS
OS
Unresected lung cancer
Medically Inoperable
Operable with Patient refusal
SBRT
SABR
EGFR
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2019-02-06
Enrollment: 724
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: 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
timeFrame: from randomization up to 6 years
measure: 4-year Progression-Free Survival (4y-PFS) by ICR according to RECIST 1.1 criteria
timeFrame: from treatment start up to 5 years
Secondary outcomes:
measure: Progression-Free Survival (PFS) assessed by BICR per RECIST 1.1 in all randomised patients with Stage I/II NSCLC
timeFrame: from randomization up to 6 years
measure: Overall Survival (OS)
timeFrame: from randomization up to 7 years
measure: Concentration of durvalumab in serum such as peak concentration and trough
timeFrame: 12 weeks after last dose
measure: Detection of ADA neutralising antibodies titers
timeFrame: up to 6 months after last dose
measure: Health-related quality of life in patients treated with durvalumab with SoC SBRT compared to placebo with SoC SBRT using the EORTC QLQ-C30
timeFrame: from randomization up to 7 years
measure: Proportion of patients alive and progression free at 24 months from randomisation (PFS24) assessed by BICR according to RECIST 1.1
timeFrame: at 24 months following randomization
measure: Time to progression (TTP) assessed by BICR according to RECIST 1.1
timeFrame: from randomization up to 6 years
measure: Time to death or distant metastasis (TTDM) assessed by BICR according to RECIST 1.1
timeFrame: from randomization up to 6 years
measure: Time from randomisation to second progression (PFS2) as defined by local standard clinical practice
timeFrame: from randomization up to 7 years
measure: 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
timeFrame: up to 3 months after last dose
measure: Assessment of AEs by CTCAE v 5.0 as measures of the safety, tolerability and compliance of osimertinib with SoC SBRT therapy
timeFrame: Up to 35 days after last dose
measure: WHO performance status
timeFrame: from treatment start up to 5 years
measure: ECG QT interval
timeFrame: Up to 156 weeks of treatment or treatment discontinuation
measure: Overall Survival
timeFrame: from treatment start up to 5 years
measure: Time To Progression (TTP)
timeFrame: from treatment start up to 5 years
measure: Time to CNS progression
timeFrame: from treatment start up to 5 years
measure: PFS2
timeFrame: from treatment start up to 5 years
measure: Site(s) of disease progression
timeFrame: from treatment start up to 5 years
measure: PFS by ICR using RECIST 1.1
timeFrame: from treatment start up to 5 years
Other outcomes:
measure: Lung cancer mortality
timeFrame: from treatment start up to 5 years
measure: Lung Cancer Mortality
timeFrame: from randomization Up to 5 years
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References: