Radiation during Osimertinib Treatment: a Safety and Efficacy Cohort Study (ROSE)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AIO-Studien-gGmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

14 Dec 2021 → ongoing

Decision date (initial)

2024-06-21

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca GmbH

External identifiers

EU CT number

2022-503028-29-01

ClinicalTrials.gov

NCT05089916

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To assess the safety of osimertinib treatment continuation during irradiation therapy for palliation or oligoprogressive disease by assessment of grade 3-5 AEs during and after concomitant osimertinib and irradiation of tumor sites.

Secondary objectives 4

1. To assess the efficacy of osimertinib treatment continuation during irradiation therapy for palliation or oligoprogressive disease.
2. To investigate Quality of Life during and after irradiation therapy and concomitant osimertinib
3. Exploratory objectives To investigate types of irradiation (conventional vs. stereotactic) and target volumes used.
4. To explore blood- and tissue-based biomarkers in this setting.

Conditions and MedDRA coding

Patients with stage IV EGFR-mutation positive NSCLC target population will comprise 3 parallel cohorts: 1. Irradiation of bone, solid organ (non-lung, non-brain) or soft-tissue metastases 2. Irradiation of brain metastases (initial lesion size < 3 cm) 3. Irradiation of lung lesions (primary tumor or pulmonary metastases, lesion size < 5 cm)

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Provision of written informed consent prior to any study specific procedures, including screening evaluations that are not SOC.
2. Age ≥ 18 years at time of study entry.
3. Histologically confirmed NSCLC
4. Ongoing or planned osimertinib treatment according to marketing authorization (first line treatment of tumor positive for an activating EGFR mutation, or later line treatment of tumor positive for EGFR T790M mutation, assessed according to local standard. First line therapy is defined as therapy used to treat advanced disease. Each subsequent line of therapy is preceded by disease progression. A switch of an agent within a regimen in order to manage toxicity does not define the start of a new line of therapy. Experimental therapies when given as separate regimen are considered as separate line of therapy. Maintenance therapy following platinum doublet-based chemotherapy is not considered as a separate regimen of therapy.)
5. Clinical indication for radiotherapy of one or more lesions, for instance for local symptom control of primary tumor or metastasis, for oligoprogressive metastasis, or for disease control with conventional or stereotactic strategy. Radiotherapy of metastatic sites can be for bone, solid organ or soft-tissue lesions; initial size of brain metastases should be < 3 cm. Lung lesions should be no more than 5 cm.
6. ECOG performance status 0-2
7. Life expectancy ≥12 weeks
8. Female subjects should be using highly effective contraceptive measures, and must have a negative pregnancy test and not be breast-feeding prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: • Post-menopausal defined as aged 50 years or more and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments • Women under 50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range for the institution. • Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
9. Male subjects who are sexually active with WOCBP should be willing to use highly effective contraception. Men who are azoospermic do not require contraception.
10. The patient is willing and able to comply with the protocol for the duration of the study, including hospital visits for treatment and scheduled follow-up visits and examinations.
11. Negative COVID-19 test within 1 week prior to starting irradiation if clinically required by current regional COVID-19 outbreak situation.

Exclusion criteria 23

1. Concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study, or during the follow-up period of an interventional study.
2. Treatment with an investigational drug within 5 half-lives of the compound or 3 months, whichever is greater
3. Previous enrolment in the present study
4. Any chemotherapy, biologic or hormonal cancer therapy other than EGFR-TKIs used concurrently or within 4 weeks prior to study enrolment, or checkpoint inhibitors within 130 days prior to study enrolment. Hormonal therapy for non-cancer-related conditions is acceptable
5. Any unresolved toxicities from prior therapy greater than grade I which in the investigator's opinion would jeopardise compliance with the protocol or worsen during irradiation
6. Cardiac side-effects of osimertinib not sufficiently improved by dose reduction as suggested by the label/ Fachinformation
7. In patients with indication for radiotherapy of lung lesions: past medical history of ILD/pneumonitis, radiation pneumonitis grade 2 or greater (CTCAE V5.0) or requiring steroid treatment, or any evidence of clinically active ILD, in particular IPF
8. Major surgery (as defined by the Investigator) within 4 weeks prior to starting the study; patients must have recovered from effects of preceding major surgery.
9. Congenital long QT syndrome
10. Any of the following cardiac criteria: Mean resting QTc >470 msec obtained from 3 ECGs, using the screening clinic ECG machine derived QTc value; Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG; Patient with any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, electrolyte abnormalities
11. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: Absolute neutrophil count <1.5 x 10^9/L; Platelet count <100 x 10^9/L; Hb <90 g/L (9 g/dL); ALT >2.5 times >5 times ULN nin absence or presence of liver metastases resp.; AST >2.5 times or >5 times ULN in absence and presence of liver metastases resp.; Total bilirubin >1.5 times ULN if no liver metastases or >3 times ULN in the presence of documented Gilbert's Syndrome/liver metastases; Serum creatinine >1.5 times ULN concurrent with creatinine clearance <50 mL/min —confirmation of creatinine clearance is only required when creatinine is >1.5 times ULN
12. Any evidence of severe or uncontrolled systemic diseases, also uncontrolled hypertension & active bleeding diatheses, which according to the investigator makes the patient undesirable, or active infection
13. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease
14. History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib.
15. 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
16. Active infection will include any patients receiving treatment for infection
17. Clinical suspicion of COVID-19
18. Participants with HBV infection are eligible only if they demonstrated absence of HCV co-infection or history of HCV co-infection and absence of HIV infection Participants 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 [antiHBc IgG]. 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 <100 IU/mL. In addition, patients must be receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment. Participants with HIV infection are only eligible if they have 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 and Stable for at least 4 weeks on the same anti-HIV medications.
19. 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.
20. Currently receiving medications or herbal that are strong inducers of CYP3A4 (at least 3 week prior)
21. Women who are pregnant or breast-feeding
22. Male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 4 months after the last dose of osimertinib
23. Patients who are unable to consent [§ 40 Abs. 1 S. 3 Nr. 3a AMG]

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Safety and tolerability (Frequency, time of onset and severity of Adverse Events, grading according to CTCAE V5.0), including pneumonitis, interstitial lung disease, radiation pneumonitis, radionecrosis, radiation alveolitis, radiation fibrosis - lung, pulmonary radiation injury and cardiac failure (congestive heart failure - CHF) as adverse events of special interest.
2. Pneumonitis. A consensus definition of pneumonitis based on symptoms, clinical examination, imaging and pulmonary function testing, as well as any available bronchoscopy results, will be used. In the absence of bronchoscopy, pharyngeal wash should be used to exclude viral infections. Care should be taken to differentiate between drug-induced and radiation-induced pneumonitis, by taking into account the localization and time of onset relative to treatment
3. Radionecrosis: A consensus definition of radionecrosis based on imaging and clinical consultation will be used

Secondary endpoints 8

1. Progression-free survival (PFS), calculated as PFS1, PFS2, PFS3, PFS0 to assess osimertinib treatment continued beyond several progression events entailing radiotherapy, and prior to first radiotherapy
2. Time to treatment failure (TTF)
3. Local tumor control
4. Overall survival (OS)
5. Quality of Life assessed by EORTC QLQ-C30
6. Optional tumor tissue analysis (pre-study FFPE sample) and biomarker correlation with patient baseline characteristics and outcomes
7. Target volume of irradiation
8. Type of irradiation (conventional, stereotactic)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AIO-Studien-gGmbH

Sponsor organisation

AIO-Studien-gGmbH

Address

Kuno-Fischer-Straße 8, Charlottenburg Charlottenburg

City

Berlin

Postcode

14057

Country

Germany

Scientific contact point

Organisation

AIO-Studien-gGmbH

Contact name

Prof. Dr. Amanda Tufman

Public contact point

Organisation

AIO-Studien-gGmbH

Contact name

Katrin Krause

Locations

1 EU/EEA country · 10 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications