To Evaluate the Efficacy/Safety of Osimertinib Prior to CRT and Maintenance of it With Stage III, Unresectable NSCLC With EGFR Mutations (NEOLA)

A Phase II, Open-label, Single-arm Study of Osimertinib as Induction Therapy Prior to CRT and Maintenance Osimertinib in Patients With Epidermal Growth Factor Receptor (EGFR) Mutation-positive, Stage III, Unresectable Non-small Cell Lung Cancer (NEOLA)

The purpose of this study is to measure efficacy and safety of osimertinib as induction therapy prior to curative intent CRT and maintenance osimertinib in adult patients with Stage III, unresectable NSCLC with common EGFR mutations (exon 19 deletion or L858R).

Study Overview

• Status: Not yet recruiting
• Conditions: Lung Cancer
• Intervention / Treatment: Drug: Osimertinib; Drug: Cisplatin or Carboplatin; Pemetrexed or Paclitaxel; Drug: Radiation

Detailed Description

The study duration will be approximately 2 years for recruitment and 2 years of follow-up from the last patient's initiation into the study.

The induction treatment with osimertinib will be up to 8 weeks, followed by 6 weeks of CRT treatment and osimertinib maintenance treatment until PD or death.

The visit frequency will be every 2 weeks to 4 weeks during the induction treatment period, every 3 weeks during the CRT period (every 3 weeks for chemotherapy and daily visits for RT)), and every 12 weeks during the osimertinib maintenance treatment period.

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: AstraZeneca Clinical Study Information Center; Phone Number: 1-877-240-9479; Email: information.center@astrazeneca.com

Study Locations

• China
  • Beijing Shi, China, 100021
    • Research Site
  • Changsha, China, 410013
    • Research Site
  • Guangzhou, China, 510060
    • Research Site
  • Hangzhou, China, 310022
    • Research Site
  • Harbin, China, 150081
    • Research Site
  • Hefei, China, 230001
    • Research Site
  • Jinan, China, 250117
    • Research Site
  • Nanning, China, 530021
    • Research Site
  • Shanghai, China, 200032
    • Research Site
  • Shaoguan Shi, China, 512025
    • Research Site
  • Tianjin Shi, China, 300060
    • Research Site
  • Wuhan, China, 430022
    • Research Site
  • Wuhan, China, 430071
    • Research Site
  • Xi'an, China, 710061
    • Research Site
  • Zhengzhou, China, 450052
    • Research Site
• India
  • Gurgaon, India, 122001
    • Research Site
  • Mohali, India, 160055
    • Research Site
  • Mumbai, India, 400012
    • Research Site
  • New Delhi, India, 110085
    • Research Site
  • Pune, India, 411004
    • Research Site
• Israel
  • Haifa, Israel, 31096
    • Research Site
  • Jerusalem, Israel, 91031
    • Research Site
  • Petach-Tikva, Israel, 4941492
    • Research Site
  • Tel Aviv, Israel, 62748
    • Research Site
• Korea, Republic of
  • Cheongju-si, Korea, Republic of, 28644
    • Research Site
  • Seongnam-si, Korea, Republic of, 13620
    • Research Site
  • Seoul, Korea, Republic of, 03722
    • Research Site
  • Seoul, Korea, Republic of, 03080
    • Research Site
  • Seoul, Korea, Republic of, 06351
    • Research Site
  • Suwon, Korea, Republic of, 16247
    • Research Site
• Spain
  • Badalona, Spain, 08916
    • Research Site
  • Barcelona, Spain, 08003
    • Research Site
  • Barcelona, Spain, 08907
    • Research Site
  • Donostia-San Sebastian, Spain, 20014
    • Research Site
  • Granada, Spain, 18016
    • Research Site
  • Madrid, Spain, 28050
    • Research Site
  • Madrid, Spain, 28007
    • Research Site
  • Valencia, Spain, 46026
    • Research Site
• Taiwan
  • Hsinchu, Taiwan, 300
    • Research Site
  • Taichung, Taiwan, 402
    • Research Site
  • Tainan, Taiwan, 704
    • Research Site
  • Tainan City, Taiwan, 73657
    • Research Site
  • Taipei, Taiwan, 10002
    • Research Site
  • Taipei, Taiwan, 11259
    • Research Site
  • Taipei City, Taiwan, 11217
    • Research Site
• Thailand
  • Bangkok, Thailand, 10210
    • Research Site
  • Bangkok, Thailand, 10330
    • Research Site
  • Chiang Rai, Thailand, 57000
    • Research Site
  • Hat Yai, Thailand, 90110
    • Research Site
  • Khlong Toey, Thailand, 10110
    • Research Site
  • Khon Kaen, Thailand, 40002
    • Research Site
  • Lampang, Thailand, 52000
    • Research Site
  • Naimuang, Thailand, 30000
    • Research Site
  • Rachathewi, Thailand, 10400
    • Research Site
• Turkey
  • Ankara, Turkey, 06010
    • Research Site
  • Ankara, Turkey, 06830
    • Research Site
  • Edirne, Turkey, 22030
    • Research Site
  • Istanbul, Turkey, 34722
    • Research Site
  • Istanbul, Turkey, 34214
    • Research Site
  • Izmir, Turkey, 35575
    • Research Site
  • Yenimahalle, Turkey, 06170
    • Research Site
  • Yenimahalle, Turkey, 06560
    • Research Site
• United States
  • California
    • La Jolla, California, United States, 92093
      • Research Site
    • Los Angeles, California, United States, 90095
      • Research Site
    • Palo Alto, California, United States, 94304
      • Research Site
  • New York
    • Brooklyn, New York, United States, 11220
      • Research Site
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • Research Site
• Vietnam
  • Hanoi, Vietnam, 100000
    • Research Site
  • Hanoi, Vietnam, 123
    • Research Site
  • Ho Chi Minh, Vietnam, 700000
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients must be 18 or the legal age of consent in the jurisdiction in which the study is taking place, at the time of signing the informed consent form.
2. Patients with histologically documented NSCLC of predominantly non-squamous, squamous, and adenosquamous pathology who present with locally advanced, unresectable (Stage III) disease (according to Version 8 of the IASLC Staging Manual in Thoracic Oncology). It is recommended but not required that except for overt cT4 disease, nodal status N2, or N3 should have been proven by biopsy, via endobronchial ultrasound, mediastinoscopy, thoracoscopy, or in absence of biopsy, should have been confirmed with whole body 18FDG PET plus contrast-enhanced CT in addition to or in combination with PET.
3. Patient who are eligible for and - planning to undergo CCRT or SCRT treatment.
4. Patients who had recurred from Stage I/II/III after complete surgery or had gross incomplete resections can be included if they didn't receive treatment with any chemotherapy, radiation therapy, immunotherapy, targeted therapy, or investigational agents.
5. Availability of the EGFRm test results confirming that the tumour harbours one of the two common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations including de novo T790M
6. WHO performance status of 0 or 1 with no deterioration over the previous 2 weeks prior to baseline at screening and prior to first dose.
7. Minimum life expectancy of > 12 weeks at Day 1.
8. At least one lesion that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15 mm) with CT or MRI and is suitable for accurate repeated measurements.
9. Adequate organ and bone marrow function
10. Male and/or female. Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
11. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this CSP.
12. Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional genomics initiative research that supports the Genomic Initiative

Exclusion Criteria:

1. Any presence of small cell and mixed small-cell and non-small cell histology.
2. Past medical history of ILD/pneumonitis, drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD/pneumonitis.
3. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment with the exception of alopecia. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the investigator may be included after consultation with the AstraZeneca medical monitor (eg, hearing loss).
4. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol, or active infection (eg, patients receiving treatment for infection, including HCV, HIV, and tuberculosis) or active uncontrolled HBV infection.
5. 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.
6. History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥ 2 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include adequately resected non-melanoma skin cancer and curatively treated in situ disease. Patients who have received RT with overlapping fields (eg, cured breast cancer) should be excluded.

7. Patient meets any of the following cardiac criteria:

   1. Mean resting QTc > 470 msec, obtained from 3 ECGs, using the screening clinic ECG machine-derived QTc value.
   2. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, third degree heart block and second-degree heart block. Patients with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted based on the investigator judgement with cardiologist consultation recommended.
   3. History of QT prolongation associated with other medications that required discontinuation of that medication.
8. Congenital long QT syndrome, family history of long QT syndrome, unexplained sudden death under 40 years of age in first-degree relatives or patients with any factors that increase the risk of QTc prolongation/arrhythmic events such as electrolyte abnormalities, heart failure or any concomitant medication known to prolong the QT interval and cause TdP.
9. Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers of CYP3A4 (at least 3-week prior to dosing). All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4.
10. Prior treatment with any chemotherapy, radiation therapy, immunotherapy or investigational agents for locally advanced, unresectable Stage III NSCLC. Prior surgical resection (ie, Stage I, II, or III) with no systemic treatment with residual disease or a recurrence is permitted.
11. Prior exposure to EGFR-TKI therapy
12. Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study.
13. Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 weeks (unless the safety profile is known prior to first dose of study intervention), or concurrent enrolment in another clinical study (unless the study is observational [noninterventional], or the patient is in the followup period of an interventional study).
14. History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib.
15. History of hypersensitivity to active or inactive excipients of the chemotherapy regimen of choice (pemetrexed or paclitaxel; cisplatin or carboplatin) or RT or drugs with a similar chemical structure or class to the chemotherapy.
16. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
17. Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.
18. Previous enrolment in the present study. Rescreening of individuals who were screen failures is allowed.
19. For females only: Currently pregnant (confirmed with positive pregnancy test) or breastfeeding.
20. Patients should refrain from breastfeeding from enrolment throughout the study and until 6 weeks after last dose of study intervention.

21. In addition, the following are considered criteria for exclusion from the exploratory genetic research:

    • Prior allogeneic bone marrow transplant.
    • Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample collection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Open-Label Osimertinib Induction Treatment; Patients will receive open-label osimertinib induction treatment for 8 weeks (± 1 week window to account for patient variability and CRT scheduling), followed by CRT treatment for 6 weeks (± 1 week) and then osimertinib maintenance treatment until RECIST 1.1-defined radiological progression by investigator unless there is evidence of unacceptable toxicity or if the patient requests to stop the study treatment.

Drug: Osimertinib; 80 mg daily (or 40 mg daily for dose reduction); Other Names: Tagrisso, AZD9291; Drug: Cisplatin or Carboplatin; Pemetrexed or Paclitaxel; Pemetrexed (500 mg/m2 to be administered on Day 1 of every 3-week cycle for 2 cycles) or Paclitaxel (175 mg/m2 on Day 1 of every 3-week cycle for 2 cycles) PLUS Cisplatin (75 mg/m2) or Carboplatin (AUC5) to be administered on Day 1 of every 3--week cycle for 2 cycles; Drug: Radiation; Patients must have received a total dose of radiation of 60 Gy ± 10% (54 to 66 Gy) as part of the chemoradiation therapy. It is recommended but not required that patients have a: Mean lung dose < 20 Gy and/or V20 < 35%; Mean oesophagus dose < 34 Gy; Heart V50 < 25%, V30 < 50%, and V45 < 35%

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS (Progression-Free Survival)	PFS is defined as the time from date of first dose until progression per RECIST 1.1 as assessed by the investigator at the local site, or death due to any cause.	Assessed from date of first dose to progression (up to a maximum of approximately 4 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR (Objective Response Rate)	ORR is defined as the proportion of patients who have a CR or PR, as determined by the investigator at local site per RECIST 1.1.	Assessed during the induction phase of the study, scans are carried out at baseline and week 8 (plus or minus visit window).
DCR (Disease Control Rate)	DCR is defined as the percentage of subjects who have a best overall response of CR or PR or SD (at 8 weeks) as determined by the investigator at the local site per RECIST 1.1.	Assessed during the induction phase of the study, scans are carried out at baseline and week 8 (plus or minus visit window).
OS (Overall Survival)	OS is defined as time from date of first dose until the date of death due to any cause.	Assessed from first dose to end of study or death (up to a maximum of approximately 4 years)
EFS (Event-Free Survival)	EFS is defined as time from date of first dose until any of the following events: progression of disease that precludes CRT or completion of CRT, progression during or after CRT, or death due to any cause.	Assessed from first dose until a progression event or death (up to a maximum of approximately 4 years)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
AEs	To assess the safety of osimertinib used as an induction therapy prior to CRT and maintenance osimertinib treatment by assessment of AEs in patients with unresectable EGFRm NSCLC	from signing ICF to 28 days after last dose or end of study (up to a maximum of approximately 4 years)

Collaborators and Investigators

• Sponsor: AstraZeneca

Study record dates

Study Major Dates

• Study Start (Estimated): April 25, 2024
• Primary Completion (Estimated): April 28, 2027
• Study Completion (Estimated): March 31, 2028

Study Registration Dates

• First Submitted: December 20, 2023
• First Submitted That Met QC Criteria: January 5, 2024
• First Posted (Actual): January 8, 2024

Study Record Updates

• Last Update Posted (Actual): April 12, 2024
• Last Update Submitted That Met QC Criteria: April 11, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: EGFR +; Unresectable Non-small Cell Lung Cancer
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Protein Kinase Inhibitors; Folic Acid Antagonists; Tyrosine Kinase Inhibitors; Carboplatin; Paclitaxel; Osimertinib; Pemetrexed
• Other Study ID Numbers: D516AC00003; 2023-507798-16-00 (Other Identifier: EMA- EU CT number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual participant-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing 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 refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No