Personalized Escalation of Consolidation Treatment Following Chemoradiotherapy and Immunotherapy in Stage III NSCLC in Stage III NSCLC

Study Overview
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Brief Summary
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The purpose of this study is to test whether or not number of circulating cancer cells detected in the blood can be decreased the by combining the standard treatment (durvalumab) with additional chemotherapy

Detailed Description
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Primary objective is to measure the change in the levels of circulating tumor DNA (ctDNA) in Cohort 1 (MRD+) due to the addition of platinum doublet chemotherapy in subjects with stage III unresectable disease with positive DNA treated with consolidation chemotherapy and immunotherapy. Secondary Objectives: To determine the proportion of subjects in Cohort 1 MRD+ for whom ctDNA becomes undetectable after chemotherapy To describe overall survival (OS) of subjects with baseline detectable ctDNA (Cohort 1 MRD+) vs baseline undetectable ctDNA (Cohort 2 MRD ) ·To describe progression free survival (PFS) between subjects with baseline detectable (Cohort 1 MRD+) vs baseline undetectable ctDNA (Cohort 2 MRD ) ·To describe the frequency and severity of toxicity of consolidation durvalumab plus chemotherapy

Official Title
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Personalized Escalation of Consolidation Treatment Following Chemoradiotherapy and Immunotherapy in Stage III NSCLC

Conditions
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Non Small Cell Lung Cancer, NSCLC, Stage III, Nsclc

Intervention / Treatment
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* Drug: Durvalumab
* Drug: Carboplatin
* Drug: Pemetrexed
* Drug: Paclitaxel
* Drug: Cisplatin
* Device: AVENIO ctDNA Surveillance Kit


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically documented NSCLC who present with locally advanced, unresectable (stage III) disease (Version 8 of American Joint Committee on Cancer (AJCC) Staging Manual) Must have received at least 2 doses of platinum based chemotherapy concurrent with ≥ 60 Gy definitive radiation therapy to all known tumor sites, and not have known progression of disease. Must have received, or be scheduled to receive, 2 prior doses of durvalumab Willing to potentially receive further consolidation chemotherapy with carboplatin and pemetrexed or carboplatin and paclitaxel as specified by the protocol, but not be currently intended to receive additional consolidation chemotherapy apart from this protocol Aged 18 years or older Weight > 30kg Life expectancy ≥ 12 weeks Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Absolute neutrophil count > 1.0 x 109/L (1000/mm3) Platelets > 75 x 109/L (100,000/mm3) Hemoglobin ≥ 9.0 g/dL (5.59 mmol/L) Measured creatinine clearance > 40 mL/min, by either 24 hour urine collection or the Cockcroft Gault formula Males: Mass(kg) x (140-Age) / 72 x serum creatinine (mg/dL) Females: Mass(kg) x (140-Age) x 0.85 / 72 x serum creatinine (mg/dL) 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. aspartate aminotransferase (AST) (SGOT)/Alanine Aminotransferase (ALT) (SGPT) ≤ 2.5 x institutional upper limit of normal (ULN) unless liver metastases are present, in which case it must be ≤ 5 x ULN Ability to understand and the willingness to sign the written IRB approved informed consent document. Exclusion Criteria: Involvement in the planning and/or conduct of the study Previous enrollment or randomization in the present study Participation in another clinical study with an investigational product (ie, non standard of care) during the last 4 weeks Mixed small cell and non small cell lung cancer histology Receiving or will receive sequential chemoradiation therapy for locally advanced NSCLC History of another primary malignancy and currently undergoing active treatment (ie, chemotherapy, hormonal therapy, biologics) Current or prior use of immunosuppressive medication within 14 days before enrollment, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Systemic steroid administration required to manage toxicities arising from radiation therapy delivered as part of the chemoradiation therapy for locally advanced NSCLC is allowed. Any unresolved toxicity CTCAE > Grade 2 from the prior chemoradiation 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) only after consultation with the Protocol Director / Principal Investigator. Any prior Grade ≥ 3 immune related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > Grade 1) that may limit subject from continuing durvalumab during the study Recent major surgery within 4 weeks prior to entry into the study (excluding the placement of vascular access) that would prevent administration of study drug. Active or prior documented autoimmune or inflammatory disorders which could limit the subjects ability to continue 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: Vitiligo or alopecia Hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement Chronic skin condition not requiring systemic therapy Those without active disease in the last 5 years may be included, but only after consultation with the study physician Celiac disease controlled by diet alone History of primary immunodeficiency History of organ transplant requiring therapeutic immunosuppression History of hypersensitivity to durvalumab, carboplatin, pemetrexed or paclitaxel Active infection including but not limited to: Tuberculosis Hepatitis B (HBV) [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. Hepatitis C (HCV). EXCEPTION: Subjects positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA 16 .Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. 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. 17. 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 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. 18. Female subjects who are pregnant or breast feeding; or subjects of reproductive potential of any gender who are not employing or who do not agree to employ an effective method of birth control prior to trial enrollment.

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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No

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 residual disease positive (MRD+)<br>Subjects with detectable ctDNA will receive 4 cycles of platinum doublet chemotherapy [carboplatin/pemetrexed] and durvalumab (1500 mg IV every 21 days, for 1 year), except subjects with squamous cell carcinoma histology will receive carboplatin/paclitaxel. Subjects will be evaluated with PET/CT and/or computed tomography (CT) thorax every 12 weeks.Following ctDNA evaluation, in the absence of progression or toxicity, subject will continue with durvalumab to complete 1 year of treatment as standard of care. | Drug: Durvalumab<br>* Cohort 1 (1500 mg IV every 21 days, for 1 year), •Cohort 2 (10mg/kg every 2 weeks for 1 year)<br>* Other names: MEDI4736;Drug: Carboplatin<br>* Target area under the curve (AUC) not to exceed 750mg on Day 1 of every 21-day cycle<br>* Other names: cis-diammine(cyclobutane-1,1-dicarboxylato)platinum;Drug: Pemetrexed<br>* 500mg/m2 on Day 1 of every 21-day cycle<br>* Other names: L-glutamic acid, N-(4-(2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo(2,3-d)pyrimidin-5-yl)ethyl)benzoyl);Drug: Paclitaxel<br>* 175mg/m2 on Day 1 of every 21-day cycle<br>* Other names: Praxel;Drug: Cisplatin<br>* Cisplatin (75mg/m2 per institution guidelines) may be substituted for Carboplatin<br>* Other names: platinum, diaminedichloro-, cis- (8CI);Device: AVENIO ctDNA Surveillance Kit<br>* Roche Sequencing and Life Science kit to detect minimal residue disease (MRD)<br>|
| Experimental: Cohort 2 minimal residual disease negative (MRD )<br>Subjects with undetectable ctDNA at study enrollment will receive standard of care durvalumab(10 mg/kg every 2 weeks, or equivalent, for 1 year). If subjects in Cohort 2 MRD progress prior to close of study, blood will be drawn for ctDNA testing. | Drug: Durvalumab<br>* Cohort 1 (1500 mg IV every 21 days, for 1 year), •Cohort 2 (10mg/kg every 2 weeks for 1 year)<br>* Other names: MEDI4736;Device: AVENIO ctDNA Surveillance Kit<br>* Roche Sequencing and Life Science kit to detect minimal residue disease (MRD)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in ctDNA Level Following Chemotherapy | Participants in Cohort 1 MRD+ will be assessed for ctDNA levels at baseline and end of treatment, expected to be 4 cycles of 3 weeks per cycle (defined as ctDNA evaluable set or ctDES). The outcome will be assessed as the number of participants with a ≥ 3 fold decrease in ctDNA level, a number without dispersion. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presence of Detectable ctDNA Following Chemotherapy | Participants in Cohort 1 MRD+ will be assessed for ctDNA levels at baseline and end of treatment, expected to be 4 cycles of 3 weeks per cycle. The outcome will be assessed as the number of participants with or without detectable ctDNA, a number without dispersion. | 12 weeks | 
| Overall Survival (OS) | Overall survival (OS) is defined as the period a participant remains alive after study registration until death due to any cause. Participants lost to follow up will be censored at last known date alive. The outcome will be reported as the number of participants in both cohorts remaining alive after 2 years, a number without dispersion. | 2 years | 
| Progression free survival (PFS) | Progression free survival (PFS) is defined as the period a participant remains alive without disease progression after study registration. Tumor status is assessed per the Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) by computed tomography (CT), positron emission tomography (PET) CT; and/or X rays. Participants lost to follow up will be censored at last known date alive. The outcome will be reported as the number of participants in both cohorts remaining alive without progression after 2 years, a number without dispersion. Complete Response (CR) = Disappearance of all lesions Partial Response (PR) = ≥30% decrease in the sum of the lesion diameters Overall Response (OR) = CR + PR Progressive disease (PD) = 20% increase in the sum of lesion diameters, and/or the appearance of 1+ new lesion(s) Stable disease (SD) = Small changes that do not meet any of the above criteria | 2 years | 
| Durvalumab related Adverse Events (Cohort 1 MRD+ only) | Adverse events will be collected for participants of Cohort 1 (MRD+) who initiate treatment with durvalumab through 30 days after the last dose of durvalumab. AE grade per the Common Terminology Criteria for Adverse Events (CTCAE v5) criteria and relationship to study treatment will be assessed. The outcome will be reported as the number of durvalumab related adverse events by grade that Cohort 1 MRD+ participants experienced. | 13 months |