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

Carcinoma, Non-Small-Cell Lung Clinical Trial

— PACIFIC-4  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03833154
• Other study ID #: D9103C00001
• Secondary ID: 2018-002572-41
• Status: Recruiting
• Phase: Phase 3
• Start date: March 6, 2019
• Est. completion date: April 4, 2028

Study information

• Verified date: June 2024
• Source: AstraZeneca
• Contact: AstraZeneca Clinical Study Information Center
• Phone: 1-877-240-9479
• Email: information.center[@]astrazeneca.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 690
• Est. completion date: April 4, 2028
• Est. primary completion date: March 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms

Intervention

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

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

Locations

Country	Name	City	State
Australia	Research Site	Blacktown
Australia	Research Site	Clayton
Australia	Research Site	Elizabeth Vale
Belgium	Research Site	Aalst
Belgium	Research Site	Charleroi
Belgium	Research Site	Edegem
Belgium	Research Site	Gent
Belgium	Research Site	Leuven
Belgium	Research Site	Sint-Niklaas
Brazil	Research Site	Barretos
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Recife
Brazil	Research Site	Rio de Janeiro
Brazil	Research Site	Sao Paulo
Brazil	Research Site	Volta Redonda
Canada	Research Site	Calgary	Alberta
Canada	Research Site	Edmonton	Alberta
Canada	Research Site	London	Ontario
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Toronto	Ontario
China	Research Site	Beijing
China	Research Site	Beijing
China	Research Site	Beijing
China	Research Site	Changchun
China	Research Site	Changsha
China	Research Site	Chengdu
China	Research Site	Fuzhou
China	Research Site	Hangzhou
China	Research Site	Hangzhou
China	Research Site	Hefei
China	Research Site	Jinan
China	Research Site	Nanjing
China	Research Site	Shanghai
China	Research Site	Shanghai
China	Research Site	Shanghai
China	Research Site	Shanghai
China	Research Site	Shenyang
China	Research Site	Suzhou
China	Research Site	Wenzhou
China	Research Site	Wuhan
China	Research Site	Wuhan
China	Research Site	Zhengzhou
France	Research Site	Bron
France	Research Site	Dijon
France	Research Site	Lyon Cedex 04
France	Research Site	Marseille
France	Research Site	Nantes
France	Research Site	Paris
France	Research Site	Pierre Benite
France	Research Site	Toulouse
France	Research Site	Villejuif
Germany	Research Site	Berlin
Germany	Research Site	Dresden
Germany	Research Site	Duisburg
Germany	Research Site	Düsseldorf
Germany	Research Site	Göttingen
Germany	Research Site	Halle
Germany	Research Site	Hannover
Germany	Research Site	Heidelberg
Germany	Research Site	Hemer
Germany	Research Site	Homburg
Germany	Research Site	Mainz
Germany	Research Site	München
Germany	Research Site	Regensburg
Germany	Research Site	Trier
Germany	Research Site	Würzburg
Greece	Research Site	Athens
Greece	Research Site	Athens
Greece	Research Site	Athens
Greece	Research Site	Thessaloniki
Israel	Research Site	Haifa
Israel	Research Site	Jerusalem
Israel	Research Site	Kfar Saba
Israel	Research Site	Petah Tikva
Israel	Research Site	Ramat Gan
Israel	Research Site	Tel Aviv
Italy	Research Site	Firenze
Italy	Research Site	Genova
Italy	Research Site	Milano
Italy	Research Site	Orbassano
Italy	Research Site	Padova
Italy	Research Site	Pavia
Italy	Research Site	Roma
Italy	Research Site	Rozzano
Japan	Research Site	Akashi-shi
Japan	Research Site	Bunkyo-ku
Japan	Research Site	Chuo-ku
Japan	Research Site	Fukuoka-shi
Japan	Research Site	Hirosaki-shi
Japan	Research Site	Hiroshima-shi
Japan	Research Site	Kashiwa
Japan	Research Site	Kobe-shi
Japan	Research Site	Kyoto-shi
Japan	Research Site	Niigata-shi
Japan	Research Site	Osaka-shi
Japan	Research Site	Sakai-shi
Japan	Research Site	Sapporo-shi
Japan	Research Site	Sunto-gun
Japan	Research Site	Toyoake-shi
Japan	Research Site	Yokohama-shi
Korea, Republic of	Research Site	Cheongju-si
Korea, Republic of	Research Site	Goyang-si
Korea, Republic of	Research Site	Gyeonggi-do
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Netherlands	Research Site	Amsterdam
Netherlands	Research Site	Groningen
Netherlands	Research Site	Harderwijk
Netherlands	Research Site	Maastricht
Netherlands	Research Site	Rotterdam
Netherlands	Research Site	Utrecht
Poland	Research Site	Bialystok
Poland	Research Site	Bydgoszcz
Poland	Research Site	Elblag
Poland	Research Site	Gdansk
Poland	Research Site	Katowice
Poland	Research Site	Lódz
Poland	Research Site	Siedlce
Poland	Research Site	Warszawa
Puerto Rico	Research Site	Hato Rey
Puerto Rico	Research Site	San Juan
Russian Federation	Research Site	Ekaterinburg
Russian Federation	Research Site	Kazan, Tatarstan
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Saint Petersburg
Russian Federation	Research Site	Saint-Petersburg
Russian Federation	Research Site	St. Petersburg
Russian Federation	Research Site	Ufa
Spain	Research Site	Badajoz
Spain	Research Site	Barcelona
Spain	Research Site	L'Hospitalet de Llobregat
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Malaga
Spain	Research Site	San Sebastián
Spain	Research Site	Santiago de Compostela
Spain	Research Site	Sevilla
Spain	Research Site	Sevilla
Spain	Research Site	Valencia
Spain	Research Site	Zaragoza
Turkey	Research Site	Ankara
Turkey	Research Site	Ankara
Turkey	Research Site	Istanbul
Turkey	Research Site	Izmir
Turkey	Research Site	Kocaeli
United Kingdom	Research Site	Birmingham
United Kingdom	Research Site	Leeds
United Kingdom	Research Site	London
United Kingdom	Research Site	Manchester
United Kingdom	Research Site	Middlesborough
United States	Research Site	Akron	Ohio
United States	Research Site	Albany	New York
United States	Research Site	Ann Arbor	Michigan
United States	Research Site	Annapolis	Maryland
United States	Research Site	Arroyo Grande	California
United States	Research Site	Atlanta	Georgia
United States	Research Site	Atlanta	Georgia
United States	Research Site	Austin	Texas
United States	Research Site	Baltimore	Maryland
United States	Research Site	Bay Pines	Florida
United States	Research Site	Bellingham	Washington
United States	Research Site	Berlin	Maryland
United States	Research Site	Boston	Massachusetts
United States	Research Site	Bronx	New York
United States	Research Site	Bronx	New York
United States	Research Site	Burlington	Vermont
United States	Research Site	Camden	New Jersey
United States	Research Site	Cedar Rapids	Iowa
United States	Research Site	Chandler	Arizona
United States	Research Site	Chapel Hill	North Carolina
United States	Research Site	Charleston	South Carolina
United States	Research Site	Chicago	Illinois
United States	Research Site	Chicago	Illinois
United States	Research Site	Chicago	Illinois
United States	Research Site	Cincinnati	Ohio
United States	Research Site	Cincinnati	Ohio
United States	Research Site	Cleveland	Ohio
United States	Research Site	Cleveland	Ohio
United States	Research Site	Columbus	Georgia
United States	Research Site	Dallas	Texas
United States	Research Site	Decatur	Illinois
United States	Research Site	Detroit	Michigan
United States	Research Site	Detroit	Michigan
United States	Research Site	Duarte	California
United States	Research Site	Duluth	Minnesota
United States	Research Site	Durham	North Carolina
United States	Research Site	East Brunswick	New Jersey
United States	Research Site	East Syracuse	New York
United States	Research Site	Elizabethtown	Kentucky
United States	Research Site	Elmhurst	Illinois
United States	Research Site	Eugene	Oregon
United States	Research Site	Flint	Michigan
United States	Research Site	Fort Wayne	Indiana
United States	Research Site	Geneva	Illinois
United States	Research Site	Goodyear	Arizona
United States	Research Site	Grand Forks	North Dakota
United States	Research Site	Houston	Texas
United States	Research Site	Iowa City	Iowa
United States	Research Site	Jacksonville	Florida
United States	Research Site	Kennewick	Washington
United States	Research Site	Kirkland	Washington
United States	Research Site	La Jolla	California
United States	Research Site	Las Vegas	Nevada
United States	Research Site	Lebanon	New Hampshire
United States	Research Site	Lexington	Kentucky
United States	Research Site	Lincoln	Nebraska
United States	Research Site	Long Beach	California
United States	Research Site	Los Angeles	California
United States	Research Site	Los Angeles	California
United States	Research Site	Louisville	Kentucky
United States	Research Site	Metairie	Louisiana
United States	Research Site	Miami Beach	Florida
United States	Research Site	Milwaukee	Wisconsin
United States	Research Site	Milwaukee	Wisconsin
United States	Research Site	Minneapolis	Minnesota
United States	Research Site	Morgantown	West Virginia
United States	Research Site	Napa	California
United States	Research Site	Naperville	Illinois
United States	Research Site	New Hyde Park	New York
United States	Research Site	New Orleans	Louisiana
United States	Research Site	New York	New York
United States	Research Site	New York	New York
United States	Research Site	Newark	Delaware
United States	Research Site	Newport Beach	California
United States	Research Site	Niles	Illinois
United States	Research Site	Omaha	Nebraska
United States	Research Site	Omaha	Nebraska
United States	Research Site	Orlando	Florida
United States	Research Site	Palm Springs	California
United States	Research Site	Paramus	New Jersey
United States	Research Site	Park Ridge	Illinois
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Phoenix	Arizona
United States	Research Site	Pittsburgh	Pennsylvania
United States	Research Site	Portland	Oregon
United States	Research Site	Portland	Oregon
United States	Research Site	Richmond	Virginia
United States	Research Site	Richmond	Virginia
United States	Research Site	Richmond	Virginia
United States	Research Site	Rochester	New York
United States	Research Site	Rochester	Minnesota
United States	Research Site	Rosedale	Maryland
United States	Research Site	Roseville	California
United States	Research Site	Royal Oak	Michigan
United States	Research Site	Sacramento	California
United States	Research Site	Saint Johnsbury	Vermont
United States	Research Site	Saint Louis	Missouri
United States	Research Site	Salisbury	Maryland
United States	Research Site	San Diego	California
United States	Research Site	Seattle	Washington
United States	Research Site	Sherman	Texas
United States	Research Site	Silver Spring	Maryland
United States	Research Site	Sioux Falls	South Dakota
United States	Research Site	South Portland	Maine
United States	Research Site	Spokane Valley	Washington
United States	Research Site	Springfield	Illinois
United States	Research Site	Stony Brook	New York
United States	Research Site	Syracuse	New York
United States	Research Site	Towson	Maryland
United States	Research Site	Tucson	Arizona
United States	Research Site	Tulsa	Oklahoma
United States	Research Site	Tuscaloosa	Alabama
United States	Research Site	Vancouver	Washington
United States	Research Site	Vero Beach	Florida
United States	Research Site	Voorhees	New Jersey
United States	Research Site	Warrenville	Illinois
United States	Research Site	Washington	District of Columbia
United States	Research Site	Watertown	South Dakota
United States	Research Site	Weston	Florida
United States	Research Site	Winston-Salem	North Carolina
United States	Research Site	Yuma	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  Canada,  China,  France,  Germany,  Greece,  Israel,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Poland,  Puerto Rico,  Russian Federation,  Spain,  Turkey,  United Kingdom, 

Outcome

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