Clinical trial NCT06194448: To Evaluate the Efficacy/Safety of Osimertinib Prior to CRT and Maintenance of it With Stage III, Unresectable NSCLC With EGFR Mutations
Official title: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Lung Cancer
Keywords: EGFR +
Unresectable Non-small Cell Lung Cancer
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2024-01-08
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: 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.
Primary purpose: TREATMENT

Brief summary: 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).

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.

Eligibility criteria: 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. Patients with HBV are only eligible for inclusion if they meet all the following criteria:

   * Demonstrate absence of HCV co-infection or history of HCV co-infection
   * Demonstrate absence of HIV co-infection
   * Patients with active HBV infection are eligible if they are:

     * Receiving anti-viral treatment for at least 6 weeks prior to study treatment, HBV DNA is suppressed to \<100 IU/mL and transaminase levels are below ULN.

   Participants with a resolved or chronic HBV infection are eligible if they are:
   * Negative for HBsAg and positive for hepatitis B core antibody \[anti-HBc IgG or total anti-HBc Ab\]. In addition, patients must be receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment or
   * Positive for HBsAg, but for \> 6 months have had transaminases levels below ULN and HBV DNA levels below \<100 IU/mL (i.e., are in an inactive carrier state). In addition, patients must be receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment.
6. Patients with HIV are only eligible for inclusion if they meet all the following criteria:

   * Demonstrate absence of HBV/ HCV co-infection
   * Undetectable viral RNA load for 6 months
   * CD4+ count of \>350 cells/μL
   * No history of AIDS-defining opportunistic infection within the past 12 months
   * Stable for at least 4 weeks on the same anti-HIV medications
7. 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
8. 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.
9. Minimum life expectancy of \> 12 weeks at Day 1.
10. 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.
11. 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 and/or SoC CRT
12. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this CSP.
13. 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.

Note: If a patient declines to participate in optional genetic research, there will be no penalty or loss of benefit to the patient, and he/she will not be excluded from other aspects of the study.

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 and Grade 2 prior platinum-therapy related neuropathy. 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. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:

   * Absolute neutrophil count \<1.5 × 10\^9/L
   * Platelet count \<100 × 10\^9/L
   * Haemoglobin \<90 g/L
   * Alanine transferase \>2.5 times the upper limit of normal (ULN)
   * Aspartate transferase \>2.5 times ULN
   * Total bilirubin \>1.5 times ULN or \>3 times ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia)
   * Creatinine \>1.5 times ULN concurrent with creatinine clearance \<50 mL/min (measured or calculated by Cockcroft and Gault formula); confirmation of creatinine clearance is only required when creatinine is \>1.5 times ULN.
10. 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.
11. 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.
12. Prior exposure to EGFR-TKI therapy
13. 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.
14. 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).
15. History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib.
16. 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.
17. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
18. 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.
19. Previous enrolment in the present study. Rescreening of individuals who were screen failures is allowed.
20. For females only: Currently pregnant (confirmed with positive pregnancy test) or breastfeeding.
21. Patients should refrain from breastfeeding from enrolment throughout the study and until 6 weeks after last dose of study intervention.
22. 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.

Primary outcomes:
measure: PFS (Progression-Free Survival)
timeFrame: Assessed from date of first dose to progression (up to a maximum of approximately 4 years)
Secondary outcomes:
measure: ORR (Objective Response Rate)
timeFrame: Assessed during the induction phase of the study, scans are carried out at baseline and week 8 (plus or minus visit window).
measure: DCR (Disease Control Rate)
timeFrame: Assessed during the induction phase of the study, scans are carried out at baseline and week 8 (plus or minus visit window).
measure: OS (Overall Survival)
timeFrame: Assessed from first dose to end of study or death (up to a maximum of approximately 4 years)
measure: EFS (Event-Free Survival)
timeFrame: Assessed from first dose until a progression event or death (up to a maximum of approximately 4 years)
Other outcomes:
measure: AEs
timeFrame: from signing ICF to 28 days after last dose or end of study (up to a maximum of approximately 4 years)
Locations:
city: La Jolla
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Palo Alto
country: United States
facility: Research Site
state: California
city: Brooklyn
country: United States
facility: Research Site
state: New York
city: Pittsburgh
country: United States
facility: Research Site
state: Pennsylvania
city: Beijing Shi
country: China
facility: Research Site
city: Changsha
country: China
facility: Research Site
city: Guangzhou
country: China
facility: Research Site
city: Hangzhou
country: China
facility: Research Site
city: Harbin
country: China
facility: Research Site
city: Hefei
country: China
facility: Research Site
city: Jinan
country: China
facility: Research Site
city: Nanning
country: China
facility: Research Site
city: Shanghai
country: China
facility: Research Site
city: Shaoguan Shi
country: China
facility: Research Site
city: Tianjin Shi
country: China
facility: Research Site
city: Wuhan
country: China
facility: Research Site
city: Wuhan
country: China
facility: Research Site
city: Xi'an
country: China
facility: Research Site
city: Zhengzhou
country: China
facility: Research Site
city: Ahmedabad
country: India
facility: Research Site
city: Gurgaon
country: India
facility: Research Site
city: Mohali
country: India
facility: Research Site
city: Mumbai
country: India
facility: Research Site
city: New Delhi
country: India
facility: Research Site
city: Pune
country: India
facility: Research Site
city: Haifa
country: Israel
facility: Research Site
city: Jerusalem
country: Israel
facility: Research Site
city: Petach-Tikva
country: Israel
facility: Research Site
city: Tel Aviv
country: Israel
facility: Research Site
city: Cheongju-si
country: Korea, Republic of
facility: Research Site
city: Seongnam-si
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Suwon
country: Korea, Republic of
facility: Research Site
city: Badalona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Donostia-San Sebastian
country: Spain
facility: Research Site
city: Granada
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Hsinchu
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Tainan City
country: Taiwan
facility: Research Site
city: Tainan
country: Taiwan
facility: Research Site
city: Taipei City
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Bangkok
country: Thailand
facility: Research Site
city: Bangkok
country: Thailand
facility: Research Site
city: Chiang Rai
country: Thailand
facility: Research Site
city: Hat Yai
country: Thailand
facility: Research Site
city: Khlong Toey
country: Thailand
facility: Research Site
city: Khon Kaen
country: Thailand
facility: Research Site
city: Lampang
country: Thailand
facility: Research Site
city: Naimuang
country: Thailand
facility: Research Site
city: Rachathewi
country: Thailand
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Edirne
country: Turkey
facility: Research Site
city: Istanbul
country: Turkey
facility: Research Site
city: Istanbul
country: Turkey
facility: Research Site
city: Izmir
country: Turkey
facility: Research Site
city: Yenimahalle
country: Turkey
facility: Research Site
city: Yenimahalle
country: Turkey
facility: Research Site
city: Hanoi
country: Vietnam
facility: Research Site
city: Hanoi
country: Vietnam
facility: Research Site
city: Ho Chi Minh
country: Vietnam
facility: Research Site
Study officials:
References: