Radiation during Osimertinib Treatment: a Safety and Efficacy Cohort Study

Phase 2

Active, not recruiting

Conditions: 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)

Interventions: Drug: Osimertinib
Radiation: Radiotherapy

Registration Number: 2022-503028-29-01

Lead Sponsor: AIO-Studien-gGmbH

Brief Summary: 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.

Detailed Description: Many patients with advanced lung cancer require palliative irradiation of metastases to relieve symptoms and prevent local complications. In addition, guidelines recommend local treatment (including radiation) for oligoprogression during TKI treatment. Clinicians are faced with the decision whether to continue TKI therapy during irradiation, a practice for which there is little data, or to interrupt the oral treatment for the duration of radiation, which may lead to progression of non-irradiated lesions. For erlotinib and gefitinib there is some data indicating that cranial irradiation as well as stereotactic body irradiation may be carried out safely without discontinuing or interrupting the TKI treatment. Although some small case series report on a PFS benefit with irradiation during osimertinib treatment, there is very limited data on the safety of osimertinib during irradiation, and no evidence-based recommendations around stopping osimertinib for irradiation.

The hypothesis is that osimertinib can be continued without interruption during irradiation of individual tumor lesions in the setting of oligoprogressive NSCLC, or for local symptom control of primary tumor or metastasis.

Recruitment & Eligibility

Status: Ongoing, recruitment ended

Sex: Not specified

Target Recruitment: 40

Inclusion Criteria

Provision of written informed consent prior to any study specific procedures, including screening evaluations that are not SOC.

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.

Negative COVID-19 test within 1 week prior to starting irradiation if clinically required by current regional COVID-19 outbreak situation.

Age ≥ 18 years at time of study entry.

Histologically confirmed NSCLC

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.)

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.

ECOG performance status 0-2

Life expectancy ≥12 weeks

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

Male subjects who are sexually active with WOCBP should be willing to use highly effective contraception. Men who are azoospermic do not require contraception.

Exclusion Criteria

Concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study, or during the follow-up period of an interventional study.

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

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

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

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

History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib.

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

Active infection will include any patients receiving treatment for infection

Clinical suspicion of COVID-19

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.

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.

Treatment with an investigational drug within 5 half-lives of the compound or 3 months, whichever is greater

Currently receiving medications or herbal that are strong inducers of CYP3A4 (at least 3 week prior)

Women who are pregnant or breast-feeding

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

Patients who are unable to consent [§ 40 Abs. 1 S. 3 Nr. 3a AMG]

Previous enrolment in the present study

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

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

Cardiac side-effects of osimertinib not sufficiently improved by dose reduction as suggested by the label/ Fachinformation

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

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.

Congenital long QT syndrome

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Osimertinib plus Radiation	Radiotherapy	Osimertinib 80 mg Radiation as per SOC
Osimertinib plus Radiation	Osimertinib	Osimertinib 80 mg Radiation as per SOC

Primary Outcome Measures

Name	Time	Method
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.		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.
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		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
Radionecrosis: A consensus definition of radionecrosis based on imaging and clinical consultation will be used		Radionecrosis: A consensus definition of radionecrosis based on imaging and clinical consultation will be used

Secondary Outcome Measures

Name	Time	Method
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		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
Time to treatment failure (TTF)		Time to treatment failure (TTF)
Local tumor control		Local tumor control
Overall survival (OS)		Overall survival (OS)
Quality of Life assessed by EORTC QLQ-C30		Quality of Life assessed by EORTC QLQ-C30
Optional tumor tissue analysis (pre-study FFPE sample) and biomarker correlation with patient baseline characteristics and outcomes		Optional tumor tissue analysis (pre-study FFPE sample) and biomarker correlation with patient baseline characteristics and outcomes
Target volume of irradiation		Target volume of irradiation
Type of irradiation (conventional, stereotactic)		Type of irradiation (conventional, stereotactic)

Trial Locations

Locations (10): Lungenklinik Hemer Deutscher Gemeinschafts-Diakonieverband GmbH
🇩🇪
Hemer, Germany
Vinzenz Von Paul Kliniken gGmbH
🇩🇪
Stuttgart, Germany
Klinikum der Universitaet Muenchen AöR
🇩🇪
Munich, Germany
Universitaetsklinikum Regensburg AöR
🇩🇪
Regensburg, Germany
Charite Universitaetsmedizin Berlin KöR
🇩🇪
Berlin, Germany
Klinikum Nuernberg
🇩🇪
Nuremberg, Germany
Justus-Liebig-Universitaet Giessen
🇩🇪
Giessen, Germany
Universitaetsklinikum Frankfurt AöR
🇩🇪
Frankfurt Am Main, Germany
Kliniken der Stadt Koeln gGmbH
🇩🇪
Cologne, Germany
Klinikum Wuerzburg Mitte gGmbH
🇩🇪
Wuerzburg, Germany
Lungenklinik Hemer Deutscher Gemeinschafts-Diakonieverband GmbH
🇩🇪Hemer, Germany
Karsten Schulmann
Site contact
0
1@1