Adjuvant Durvalumab for Early Stage NSCLC Patients With ctDNA Minimal Residual Disease

Study Overview
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Brief Summary
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In this study circulating tumor DNA (ctDNA) blood testing is used to detect the residual blood cancer. If residual cancer using this blood test is detected there may be at higher risk of having the cancer return. The study is going to test whether or not the number of circulating cancer cells detected in the blood can be reduced by administration durvalumab after the standard treatment if you are tested positive for the residual cancer.

Detailed Description
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Primary Objective: The primary objective of this study is to measure the change in ctDNA from trial enrollment to after 2 cycles of adjuvant durvalumab in subjects with stage I to III NSCLC who had positive ctDNA following definitive treatment with surgery or radiation and completion of adjuvant standard of care chemotherapy. Secondary Objectives To compare disease free survival (DFS) To compare overall survival (OS) To evaluate the frequency and severity of toxicity To evaluate the severity of toxicity

Official Title
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Adjuvant Durvalumab for Early comStage NSCLC Patients With ctDNA Minimal Residual Disease

Conditions
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Non-small Cell Lung Cancer, Non-small Cell Lung Cancer Stage I, Non-small Cell Lung Cancer Stage II, Non-small Cell Lung Cancer Stage III

Intervention / Treatment
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* Device: AVENIO ctDNA Surveillance Kit
* Drug: Durvalumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: * Pathologically (histologically or cytologically proven) NSCLC. Tumors with any component of small cell lung cancer are not allowed. Must NOT be known positive for EGFR TKI sensitizing mutation (Exon 19 deletion or L858R mutation), or ALK/ ROS1 rearrangement. Exception: EGFR mutant NSCLC with PD-L1 expression of 1% or higher is allowed if not planned to receive adjuvant EGFR TKI). AJCC 8th edition clinical or pathological stage IA2 to IIIC disease. Stage IA1 tumors are excluded unless recurrent with radiographic solid component -or- pathologic invasive component of > 10 mm. Received therapy with surgery and/or definitive (curative intent) radiation. Note: May have received chemotherapy. Completed all intended therapy (surgery, radiation, and/or chemotherapy) - AND- no more than 32 weeks has elapsed after the last day of this therapy No known residual disease after intended therapy, for example: No positive margins after surgery without adjuvant radiotherapy No disease recurrence (in the investigator's assessment) Pre-treatment tumor tissue or tumor DNA sample is believed to be available for analysis Not received immunotherapy (PD-1, PD-L1, or CTLA-4 antibodies) or be intended to receive immunotherapy, apart from this study. Not received another systemic anti-cancer investigational product during the 4 weeks prior to enrollment. Aged 18 years or older ECOG Performance Status of 0 or 1 (Appendix B) Life expectancy ≥ 12 weeks Acceptable laboratory parameters: Absolute neutrophil count > 1.0 x 109/L Platelets > 75 x 109/L Hemoglobin ≥ 9.0 g/dL Creatinine ≤ 1.5 x ULN, OR creatinine clearance > 40 mL/min, by either 24 hour urine collection or the Cockcroft Gault formula Serum bilirubin ≤ 1.5 x upper limit of normal (ULN). This will not apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of evidence of hemolysis or hepatic pathology) who will be allowed in consultation with their physician. AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal (ULN) Ability to understand and the willingness to sign the written IRB approved informed consent document. Women of childbearing potential or their male partner must agree to use a highly effective method of contraception from enrollment until 8 months after final study therapy. (see section 4.6.1) Exclusion Criteria: Involvement in the planning and/or conduct of the study Previous enrollment or randomization in the present study History of Grade 3 or higher pneumonitis from prior radiation; patients with grade 2 radiation pneumonitis may be considered for enrollment with permission from the Protocol Director or Co-Director. History of another primary malignancy and currently undergoing active treatment Exception: May participate if receiving adjuvant endocrine therapy for breast or prostate cancer. Expected to require ongoing chronic treatment with immunosuppressive medication after enrollment. Exceptions: intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, not to exceed 10 mg/day of prednisone equivalent Any unresolved toxicity CTCAE > Grade 2 from prior therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. Subjects with Grade > 2 neuropathy will be evaluated on a case by case basis after consultation with the Protocol Director / Principal Investigator Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by treatment with durvalumab may be included (ie, hearing loss) with permission from the Protocol Director / Co-Director. Active or prior documented autoimmune or inflammatory disorders which could limit the subjects ability to receive durvalumab on the study (including inflammatory bowel disease [eg, 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 may be taken in to considerations as exceptions to this criterion: a. Vitiligo or alopecia b .Hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement c. Chronic skin condition not requiring systemic therapy d. Those without active disease in the last 5 years may be included with permission from the Protocol Director / Co-Director. e. Celiac disease controlled by diet alone History of primary immunodeficiency History of organ transplant requiring therapeutic immunosuppression Active infection including but not limited to: Known Tuberculosis Known Hepatitis B [known positive results for HBV surface antigen (HBsAg) within 2 months prior to enrollment]. EXCEPTION: Subjects with a past or resolved HBV infection, defined as the presence of hepatitis B core antibody (anti HBc) and absence of HBsAg are eligible. Known Hepatitis C (HCV) EXCEPTION: Subjects positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA Known HIV infection Receipt of live attenuated vaccine within 30 days prior to enrollment. Note: Subjects, if enrolled, should not receive live vaccine while receiving the investigational product (IP), and through 30 days after the last dose of IP. Uncontrolled intercurrent illness, including but not limited to clinically significant: Ongoing or active Grade 3 or higher infection Symptomatic congestive heart failure Uncontrolled hypertension Unstable angina pectoris Cardiac arrhythmia Interstitial lung disease Serious chronic gastrointestinal conditions associated with diarrhea Psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the subject to give written informed consent. Female subjects who are pregnant or breast feeding. Any other medical condition that, in the investigator's opinion, makes the subject unsuitable for enrollment and study procedures.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 minimal residue disease positive(MRD+)<br>Subjects with detectable ctDNA (MRD+) will receive up to 12 cycles of durvalumab (1500mg dose by intravenous (by vein) injection every 28 days). ctDNA will be re checked following 2 cycles (8 weeks) of durvalumab and compared to baseline levels. In the absence of progression or toxicity after 2 cycles, subject will continue with durvalumab to complete 1 year of treatment about 10 additional cycles). Subjects will be monitored for secondary endpoints of progression free survival (PFS) and overall survival (OS). | Device: AVENIO ctDNA Surveillance Kit<br>* Roche Sequencing and Life Science kit to detect minimal residue disease (MRD)<br>* Other names: The AVENIO ctDNA Surveillance Kit;Drug: Durvalumab<br>* 1500mg intravenous dose or 20mg/kg if weight is 30kg or less, manufactured by AstraZeneca<br>* Other names: MEDI4736;|
| Active Comparator: Cohort 2 minimal residue disease negative (MRD-)<br>Subjects with undetectable ctDNA (MRD) will receive Standard of care and no treatment | Device: AVENIO ctDNA Surveillance Kit<br>* Roche Sequencing and Life Science kit to detect minimal residue disease (MRD)<br>* Other names: The AVENIO ctDNA Surveillance Kit;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Decrease in ctDNA Level | Change in minimal residual disease (MRD) will be assessed on the basis of reduction of circulating tumor DNA (ctDNA) in the blood of participants in Cohort 1 MRD+ only. ctDNA is an indicator of MRD. The outcome will be reported as the number of participants who have a ≥ 3-fold drop in ctDNA levels after 2 cycles of durvalumab treatment, a number without dispersion. | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presence or absence of detectable ctDNA | Circulating tumor DNA (ctDNA) in the blood is an indicator of minimal residual disease (MRD), a risk factor for future relapse or progression. The outcome will be reported as the number of Cohort 1 MRD+ participants for whom, following 2 cycles of durvalumab, ctDNA was detected, not detected, or unable to be determined, each a number without dispersion. Available data for Cohort 2 MRD- participants will also be reported for the 8-week timepoint. | 8 weeks | 
| Overall survival (OS) | Overall survival (OS) defined as the duration from study registration until death due to any cause. The outcome will be reported as the number of participants in each cohort known to be alive at 12 months after study registration, a number without dispersion. | 12 months | 
| Disease-free survival (DFS) | Disease-free survival (DFS) is defined as the number of participants remaining alive without disease progression (DP), symptomatic deterioration, or death due to any cause. DP is assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria, as follows. Complete Response (CR) = Disappearance of all target lesions Partial Response (PR) = ≥ 30% decrease in the sum of the longest diameter of target lesions Progressive disease (PD) = 20% increase in the sum of the diameters of target lesions (must be > 5 mm), unequivocal progression of non-target lesions, and/or the appearance of one or more new lesion(s) Stable disease (SD) = Small changes that do not meet any of the above criteria The outcome will be reported as the number of participants who meet the criteria for DFS, a number without dispersion. | 8 weeks | 
| Related Adverse Events | Related adverse events (AEs) are deleterious events determined to be possibly, probably, or definitely-related to durvalumab treatment. The outcome will be reported as the number of related AEs experienced by the participants in Cohort 1 MRD+ only (ie, durvalumab treatment cohort), a number without dispersion. | 12 months |