SCION: SABR and Checkpoint Inhibition of NSCLC

NCT ID: NCT04944173

Last Updated: 2024-09-03

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE2
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-08-11
• Study Completion Date: 2027-06-30

Brief Summary

The SCION Trial is a clinical trial in patients with early stage non-small cell lung cancer. The purpose of the trial is to investigate whether it is safe and effective to combine standard radiation treatment with a drug called durvalumab, a type of immunotherapy. In addition, the study will use a blood test to look for cancer cell DNA to determine how long treatment with durvalumab should last. Both the use of durvalumab and the use of the blood test are new strategies for managing early stage non-small cell lung cancer.

Detailed Description

PURPOSE The intent of the study is to determine whether disease control in early non-small cell lung cancer (NSCLC) achieved by stereotactic ablative body radiotherapy (SABR) can be augmented locally, regionally, and distantly by safely combining it with durvalumab. Moreover, the study will assess whether patients who are likeliest to benefit from extended treatment with durvalumab can be predicted by assaying for molecular residual disease (MRD) after initial treatment using the AVENIO assay for circulating tumor DNA (ctDNA).

HYPOTHESIS Combining SABR and Durvalumab in patients with T1-2 N0 M0 NSCLC reduces the overall relapse rate at 18 months by 50% compared with historical controls treated with SABR alone, from 19.3% to 9.7%.

OBJECTIVES Primary

• To determine the overall relapse rate at 18 months in patients with T1-2 N0 M0 NSCLC treated with SABR and Durvalumab.

Secondary

• To determine rates of Local Relapse, Regional Nodal Relapse, Distant Relapse, and Second Primary Lung Cancer in patients with T1-2 N0 M0 NSCLC treated with SABR and Durvalumab.
• To determine rates of Overall Survival, Cause-Specific Survival, and Relapse Free Survival in patients with T1-2 N0 M0 NSCLC treated with SABR and Durvalumab
• To determine rates of pneumonitis, immune-related toxicity, adverse events, serious adverse events in patients with T1-2 N0 M0 NSCLC treated with SABR and Durvalumab.
• To determine the rate of MRD detection using the AVENIO ctDNA assay in patients with T1-2 N0 M0 NSCLC treated with SABR and Durvalumab.
• To compare clinical outcomes between patients with detectable versus undetectable MRD using the AVENIO ctDNA assay following treatment with SABR and Durvalumab.
• To compare clinical outcomes between patients with detectable MRD using the AVENIO ctDNA assay following treatment with SABR and Durvalumab who receive extended Durvalumab versus no further therapy.

STUDY DESIGN Subjects who meet the eligibility criteria will be candidates for enrolment. All subjects will receive one infusion of Durvalumab every 4 weeks for four cycles (4 weeks = 1 cycle), with SABR delivered concurrently with cycle 2. Subjects will be assessed at baseline using the AVENIO assay initially on tumor tissue. This will allow the subsequent evaluation for molecular residual disease (MRD) following cycle 4 to be tumor-informed, and ultrasensitive. Subjects with no detectable ctDNA at the MRD assessment will receive no further therapy. Subjects with detectable ctDNA at the MRD assessment will be randomized to receive either no further therapy or 8 additional cycles of q4w Durvalumab. Safety will be evaluated by recording the occurrence of adverse events, serious adverse events, and laboratory abnormalities, with special attention to pneumonitis and immune-related toxicity.

Future research will be enabled through the collection of biospecimens. Subjects will separately consent to the optional collection of these biospecimens. Blood samples collected for this purpose at multiple timepoints (0, 4, 12, 24 months) will be archived in a biorepository created for this study operated by the BC Cancer Tumour Tissue Repository (Victoria, BC). Stool samples collected for this purpose at multiple timepoints (0, 4, and 12 months) will be archived in the Oncomicrobiome Repository (Montreal, QC).

Conditions

Non Small Cell Lung Cancer; Carcinoma, Non-Small-Cell Lung; Non-small Cell Lung Cancer Stage I; Lung Cancer; Lung Cancer Stage I; Lung Adenocarcinoma, Stage I; Lung Squamous Cell Carcinoma Stage I

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

MRD Negative

All subjects will receive four cycles of durvalumab with SABR concurrent at cycle 2, then will be evaluated for MRD. Subjects in this arm have no detectable ctDNA at MRD landmark and will receive no further therapy.

Group Type: EXPERIMENTAL

Durvalumab

Intervention Type: DRUG

Subjects will receive durvalumab 1500mg IV every four weeks for four cycles, undergo assessment for residual disease, then a subset of subjects will receive an additional eight cycles of durvalumab.

Stereotactic Body Radiotherapy

Intervention Type: RADIATION

Subjects will receive stereotactic radiation therapy concurrent with cycle 2 of durvalumab to a dose of 48Gy in four fractions. Fractionation may be modified for central tumors.

Circulating Tumor DNA assay

Intervention Type: DIAGNOSTIC_TEST

After four cycles of durvalumab, subjects will be evaluated at the MRD Landmark for residual ctDNA to determine subsequent treatment assignment.

MRD Positive, no further therapy

All subjects will receive four cycles of durvalumab with SABR concurrent at cycle 2, then will be evaluated for MRD. Subjects in this arm have detectable ctDNA at MRD landmark and are randomized to no further therapy.

Group Type: EXPERIMENTAL

Durvalumab

Intervention Type: DRUG

Subjects will receive durvalumab 1500mg IV every four weeks for four cycles, undergo assessment for residual disease, then a subset of subjects will receive an additional eight cycles of durvalumab.

Stereotactic Body Radiotherapy

Intervention Type: RADIATION

Subjects will receive stereotactic radiation therapy concurrent with cycle 2 of durvalumab to a dose of 48Gy in four fractions. Fractionation may be modified for central tumors.

Circulating Tumor DNA assay

Intervention Type: DIAGNOSTIC_TEST

After four cycles of durvalumab, subjects will be evaluated at the MRD Landmark for residual ctDNA to determine subsequent treatment assignment.

MRD Positive, consolidation durvalumab

All subjects will receive four cycles of durvalumab with SABR concurrent at cycle 2, then will be evaluated for MRD. Subjects in this arm have detectable ctDNA at MRD landmark and are randomized to eight additional cycles of durvalumab

Group Type: EXPERIMENTAL

Durvalumab

Intervention Type: DRUG

Subjects will receive durvalumab 1500mg IV every four weeks for four cycles, undergo assessment for residual disease, then a subset of subjects will receive an additional eight cycles of durvalumab.

Stereotactic Body Radiotherapy

Intervention Type: RADIATION

Subjects will receive stereotactic radiation therapy concurrent with cycle 2 of durvalumab to a dose of 48Gy in four fractions. Fractionation may be modified for central tumors.

Circulating Tumor DNA assay

Intervention Type: DIAGNOSTIC_TEST

After four cycles of durvalumab, subjects will be evaluated at the MRD Landmark for residual ctDNA to determine subsequent treatment assignment.

Interventions

Durvalumab

Subjects will receive durvalumab 1500mg IV every four weeks for four cycles, undergo assessment for residual disease, then a subset of subjects will receive an additional eight cycles of durvalumab.

Intervention Type: DRUG

Stereotactic Body Radiotherapy

Subjects will receive stereotactic radiation therapy concurrent with cycle 2 of durvalumab to a dose of 48Gy in four fractions. Fractionation may be modified for central tumors.

Intervention Type: RADIATION

Circulating Tumor DNA assay

After four cycles of durvalumab, subjects will be evaluated at the MRD Landmark for residual ctDNA to determine subsequent treatment assignment.

Intervention Type: DIAGNOSTIC_TEST

Other Intervention Names

MEDI4736; Imfinzi; Stereotactic Radiation; Stereotactic Radiation Therapy; AVENIO ctDNA surveillance assay; MRD Landmark assay

Eligibility Criteria

Inclusion Criteria

1. Subjects must be competent, >18yo at time of study entry, and capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.

2. Patients with histological diagnosis of NSCLC, all histological sub-types are eligible

3. Body weight >30kg

4. ECOG Performance status (PS) 0-2.

5. Tumor stage T1-2 (≤5cm) N0 M0 (8th Edition of the TNM Classification for Lung Cancer) based on CT chest/abdomen, FDG-PET within 12 weeks of enrolment, and, where performed, EBUS-guided biopsy of hilar or mediastinal nodes within 8 weeks of enrolment.

6. Subject deemed medically inoperable, or subject deemed operable but declines surgery following surgical assessment.

7. Peripheral (outside a 2cm radius proximal bronchial tree) and central (within 2cm, but neither abuts nor invades proximal bronchial tree) tumors permitted.

8. Screening laboratory values for organ function must meet the following criteria within 14 days prior to cycle 1 day 1:

• Bone Marrow: Absolute neutrophils ≥ 1.5 x 10^9/L; Platelets ≥ 100 x 10^9/L; Hemoglobin ≥ 90 g/L
• Kidney: Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:

Males:

Creatinine CL (mL/min) = Weight (kg) x (140 - Age)

÷ 72 x serum creatinine (mg/dL)

Females:

Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85

÷ 72 x serum creatinine (mg/dL)

• Liver: AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal
• serum bilirubin ≤ 1.5 X ULN
• Cardiac: LVEF ≥ 50%

9. No prior chemotherapy or planned adjuvant chemotherapy is allowed

10. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

• Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
• Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).

11. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

12. Must have a life expectancy of at least 12 weeks.

1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.

2. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician.

11. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.

12. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug

13. Previous radiotherapy to the chest or mediastinum. Subjects who have had previous breast radiotherapy may be eligible at the discretion of the Sponsor.

14. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP.

15. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent

16. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart).

17. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:

1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)

2. Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent

3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)

18. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy.

19. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

20. Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment arm assignment.

21. Patients who have received prior anti-PD-1, anti PD-L1 or anti CTLA-4:

1. Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy.

2. All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study.

3. Must not have experienced a ≥Grade 3 immune related AE or an immune-related neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE: Patients with endocrine AE of ≤Grade 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.

4. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day.

Exclusion Criteria

1. Any patient with malignancy which cannot be reliably defined on the treatment planning CT scan due to adjacent opacification from effusion, consolidation, or atelectasis.

2. History of allogenic organ transplantation.

3. History of active primary immunodeficiency

4. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:

1. Patients with vitiligo or alopecia

2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement

3. Any chronic skin condition that does not require systemic therapy

4. Patients without active disease in the last 5 years may be included but only after consultation with the study physician

5. Patients with celiac disease controlled by diet alone

5. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.

6. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C and HIV. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

7. History of another primary malignancy except for:

1. Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence

2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease

3. Adequately treated carcinoma in situ without evidence of disease

8. Participation in another clinical study with an investigational product during the last 2 months

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: collaborator

Ozmosis Research Inc.

INDUSTRY

Sponsor Role: collaborator

University of British Columbia

OTHER

Sponsor Role: lead

Responsible Party

Islam Mohamed

Clinical Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Islam Mohamed, MD

Role: PRINCIPAL_INVESTIGATOR

BC Cancer

Locations

BC Cancer--Kelowna

Kelowna, British Columbia, Canada

BC Cancer--Surrey

Surrey, British Columbia, Canada

BC Cancer--Vancouver

Vancouver, British Columbia, Canada

BC Cancer--Victoria

Victoria, British Columbia, Canada

Juravinski Cancer Centre

Hamilton, Ontario, Canada

Countries

Canada

Other Identifiers

OZM-119

Identifier Type: OTHER

Identifier Source: secondary_id

H21-00994

Identifier Type: -

Identifier Source: org_study_id