We're building a better ClinicalTrials.gov. Check it out and tell us what you think!
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Durvalumab vs Placebo With Stereotactic Body Radiation Therapy 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 (PACIFIC-4)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03833154
Recruitment Status : Recruiting
First Posted : February 6, 2019
Last Update Posted : December 19, 2022
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Study Description
Go to 
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
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.


Condition or disease Intervention/treatment Phase
Carcinoma, Non-Small-Cell Lung Drug: Durvalumab Other: Placebo Drug: Osimertinib (single-arm, open-label) Phase 3

Detailed Description:

Patients who are to receive SoC SBRT as definitive treatment of Stage I/II lymph node-negative NSCLC and confirmed to meet all eligibility criteria will be randomized 1:1 to Durvalumab or placebo.

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 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 4years-PFS. Key secondary objectives include safety, OS and efficacy of Osimertininb treatment with SBRT.

Study Design
Go to 
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 733 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double- Blind
Primary Purpose: Treatment
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
Actual Study Start Date : March 6, 2019
Estimated Primary Completion Date : March 31, 2026
Estimated Study Completion Date : April 4, 2028

Resource links provided by the National Library of Medicine


Arms and Interventions
Go to 
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Arm Intervention/treatment
Experimental: SoC SBRT + Durvalumab Therapy (Main Cohort)

SBRT - delivered in 3, 4, 5 or 8 fractions.

Durvalumab (PD-L1 monoclonal antibody) 1500 mg every 4 weeks [q4w] intravenously [iv] for up to 24 months or until progression or other discontinuation criteria are met.

 Drug: Durvalumab
Durvalumab 1500 mg every 4 weeks [q4w] intravenously [iv] for up to 24 months or until progression or other discontinuation criteria are met.
Other Name: MEDI4736
Placebo Comparator: SoC SBRT + Placebo Therapy (Main Cohort)

SBRT - delivered in 3, 4, 5 or 8 fractions.

Placebo (matching placebo for infusion every 4 weeks iv for up to 24 months or until progression or other discontinuation criteria are met.

 Other: Placebo
Matching placebo for infusion every 4 weeks iv for up to 24 months or until progression or other discontinuation criteria are met.
Experimental: SoC SBRT + Osimertinib Therapy (Osimertinib cohort, single-arm, separate cohort)

SBRT delivered in 3, 4, 5 or 8 fractions

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

 Drug: Osimertinib (single-arm, open-label)
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


Outcome Measures
Go to 
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :
  1. 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

  2. 4-year Progression-Free Survival (4y-PFS) by ICR according to RECIST 1.1 criteria [ Time Frame: from randomization up to 5 years ]
    Osimertinib Cohort


Secondary Outcome Measures :
  1. Progression-Free Survival (PFS) assessed by BICR per RECIST 1.1 in all randomised patients with Stage I/II NSCLC [ Time Frame: from randomization up to 6 years ]
    Main Cohort

  2. Overall Survival (OS) [ Time Frame: from randomization up to 7 years ]
    Main Cohort

  3. Lung cancer-specific mortality [ Time Frame: from randomization up to 7 years ]
    Main Cohort

  4. Maximum Plasma concentration (Cmax) [ Time Frame: 12 weeks after last dose ]
    Main Cohort

  5. Detection of ADA neutralising antibodies titers [ Time Frame: up to 6 months after last dose ]
    Main Cohort

  6. Health-related quality of life in patients treated with durvalumab with SoC SBRT compared to placebo with SoC SBRT using the EORTC QLQ-C30 [ Time Frame: from randomization up to 7 years ]
    Main Cohort

  7. Proportion of patients alive and progression free at 24 months from randomisation (PFS24) assessed by BICR according to RECIST 1.1 [ Time Frame: at 24 months following randomization ]
    Main Cohort

  8. Time to progression (TTP) assessed by BICR according to RECIST 1.1 [ Time Frame: from randomization up to 6 years ]
    Main Cohort

  9. Time to death or distant metastasis (TTDM) assessed by BICR according to RECIST 1.1 [ Time Frame: from randomization up to 6 years ]
    Main Cohort

  10. Time from randomisation to second progression (PFS2) as defined by local standard clinical practice [ Time Frame: from randomization up to 7 years ]
    Main Cohort

  11. Trough Concentration (Ctrough) [ Time Frame: up to 3 months after last dose ]
    Main Cohort

  12. 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 [ Time Frame: up to 3 months after last dose ]
    Main Cohort

  13. Assessment of AEs by CTCAE v 5.0 as measures of the safety, tolerability and compliance of osimertinib with SoC SBRT therapy [ Time Frame: Up to 35 days after last dose ]
    Osimertinib Cohort

  14. WHO performance status [ Time Frame: from randomization Up to 5 years ]
    Osimertinib Cohort

  15. ECG QT interval [ Time Frame: Up to 156 weeks of treatment or treatment discontinuation ]
    Osimertinib Cohort

  16. Overall Survival [ Time Frame: from randomization Up to 5 years ]
    Osimertinib Cohort

  17. Lung cancer mortality [ Time Frame: from randomization Up to 5 years ]
    Osimertinib Cohort

  18. Time To Progression (TTP) [ Time Frame: from randomization Up to 5 years ]
    Osimertinib Cohort

  19. Time to CNS progression [ Time Frame: from randomization Up to 5 years ]
    Osimertinib Cohort

  20. PFS2 [ Time Frame: from randomization up to 5 years ]
    Osimertinib Cohort

  21. Site(s) of disease progression [ Time Frame: from randomization up to 5 years ]
    Osimertinib Cohort

  22. PFS by ICR using RECIST 1.1 [ Time Frame: from randomization up to 5 years ]
    Osimertinib Cohort


Eligibility Criteria
Go to 
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Main 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. 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. World Health Organization (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 available tumor tissue sample
  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 currently receiving potent inducers of CYP3A4
  3. Patients with known or increased risk factor for QTc prolongation

  4. 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
    • 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
Contacts and Locations
Go to 
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03833154


Contacts
Layout table for location contacts
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Contact: Astrazeneca Cancer Study Locator Service 1-877-400-4656 AstraZeneca@emergingmed.com

Locations
Show Show 261 study locations
Sponsors and Collaborators
AstraZeneca
More Information
Go to 
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Layout table for additonal information
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03833154    
Other Study ID Numbers: D9103C00001
2018-002572-41 ( EudraCT Number )
First Posted: February 6, 2019    Key Record Dates
Last Update Posted: December 19, 2022
Last Verified: December 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
NSCLC
Early-Stage NSCLC
Lung cancer
Double- Blind
PD-L1
MEDI4736
Durvalumab
Osimertinib
 PFS
OS
Unresected lung cancer
Inoperable
Operable
SBRT
SABR
EGFR
Additional relevant MeSH terms:
Layout table for MeSH terms
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
 Bronchial Neoplasms
Durvalumab
Osimertinib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action