Lung Cancer
Conditions
Keywords
NSCLC, lung cancer, stage III, chemotherapy, immunotherapy, chemoradiation, ctDNA, circulating tumor DNA, MRD, minimum residual disease
Brief summary
CLEAR LUNG-III is a single-arm, phase II study evaluating a circulating tumor DNA (ctDNA)-guided treatment strategy in patients with unresectable stage III non-small cell lung cancer who have completed definitive chemoradiation and are receiving consolidation immunotherapy. Patients with persistent molecular residual disease (MRD) by tumor-informed ctDNA assay will receive consolidation chemotherapy intensification in addition to standard immunotherapy, with the goal of improving molecular response.
Interventions
Consolidation chemotherapy intensification in addition to standard immunotherapy. Carboplatin + pemetrexed for non-squamous histology - up to 3 cycles (9 weeks) Carboplatin + paclitaxel for squamous histology - up to 3 cycles (9 weeks) Durvalumab - for total of 1 year NOTE: Durvalumab administration begins at the same time as chemotherapy (can be started earlier if needed).
Sponsors
Anusha Chidharla, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Ability of participant to understand this study, and participant willingness to sign a written informed consent. 2. Stated willingness to comply with all study procedures / study intervention regimen and availability for the duration of the study 3. Males and females age ≥ 18 years 4. Histologically or cytologically confirmed unresectable Stage III NSCLC 5. Completion of definitive concurrent chemoradiation (CRT) within 6 weeks prior to enrollment/registration 6. MRD-positive status confirmed by a validated circulating tumor DNA (ctDNA) assay within 6 weeks following chemoradiation 7. Eastern Cooperative Oncology Groug (ECOG) Performance Status (PS): 0 - 2 (Appendix A) 8. Availability of archival tumor tissue for tumor-informed ctDNA assay, or eligibility for a validated plasma-only ctDNA panel if tumor tissue is unavailable. 9. Patients with a prior or concurrent malignancy are eligible provided the malignancy is not expected to interfere with study treatment, safety assessment, or interpretation of study endpoints, in the opinion of the treating investigator 10. Females of childbearing potential must have a negative serum or urine pregnancy test 48 hours prior to initiating treatment. 11. Females of child-bearing potential and males with partners of child-bearing potential must agree not to donate sperm, to practice sexual abstinence or to use the forms of contraception listed in Child-Bearing Potential/Pregnancy section for the duration of study participation and : * Females: for 6 months after the last dose of the study medication. * Males: for 3 months after the last dose of the study medication. 12. Adequate organ function, defined as follows: * Leukocytes \> 1.5 × 10⁹/L * Absolute Neutrophil Count (ANC) \> 1.5 × 10⁹/L Note: Patients with benign neutropenia may be eligible with ANC 1000-1500 if deemed safe by the treating physician. * Platelets \> 100 × 10⁹/L * Hemoglobin ≥ 9 g/dL * Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min (Cockcroft-Gault) * Total bilirubin ≤ 1.5 × ULN or direct bilirubin ≤ 1 × ULN * AST and ALT ≤ 2.5 × ULN (≤ 5 × ULN if liver metastases present)
Exclusion criteria
1. Prior neoadjuvant chemotherapy. 2. Concurrent or planned use of other anti-neoplastic or investigational agents during study participation. 3. Absence of post-chemoradiation ctDNA results 4. Radiographic evidence of disease progression on CT and/or PET/CT imaging within 6 weeks following completion of definitive concurrent chemoradiation 5. Presence of known sensitizing genomic alterations, including EGFR mutations or ALK rearrangements.. 6. Diagnosed with a psychiatric illness or is in a social situation that would limit compliance with study requirements 7. Currently pregnant or breastfeeding 8. Has a known allergic reaction to any excipient contained in the study drug formulation 9. Patients with a prior or concurrent malignancy are eligible provided the malignancy is not expected to interfere with study treatment, safety assessment, or interpretation of study endpoints, in the opinion of the treating investigator 10. Any condition, diagnosis, or physical exam finding that, in the opinion of the investigator, would pose excessive risk or interfere with study participation 11. Known history of autoimmune disease requiring systemic immunosuppression (if applicable to durvalumab safety profile) 12. Has not had ctDNA testing prior to study enrollment 13. Known history of interstitial lung disease or pneumonitis requiring steroids (if applicable) 14. Known active hepatitis B, hepatitis C, or HIV infection with uncontrolled viral load or clinically significant active disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MRD (ctDNA) Clearance | Approximately 12 weeks after initiation of consolidation chemotherapy (±14 days) | Treatment response, defined as MRD (ctDNA) clearance, measured as undetectable ctDNA at 12 weeks(±14 days), after initiation of chemotherapy plus durvalumab in patients with MRD-positive unresectable Stage III NSCLC after definitive chemoradiation. MRD clearance is a validated surrogate for recurrence risk and survival. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | Approximately 1 year | Disease Control Rate (DCR) is defined as the proportion of enrolled patients who achieve complete response (CR), partial response (PR), or stable disease (SD) as their best overall response, assessed by imaging per RECIST v1.1. |
| Progression-Free Survival (PFS) | Approximately 1 year | Progression Free Survival (PFS) will be defined as the time from initiation of treatment to first documented disease progression per RECIST v1.1 or death from any cause, whichever occurs first. PFS will be summarized using Kaplan-Meier methods, and the 1-year PFS rate with 95% confidence interval will be estimated. |
| Overall Survival (OS) | Approximately 1 year | Overall Survival (OS) is defined as the time from initiation of treatment to death from any cause. Patients who are alive at the time of analysis will be censored at the date of last known follow-up. OS will be summarized using Kaplan-Meier methods, and the 1-year OS rate with 95% confidence interval will be estimated. |
| Time to Radiographic Progression | Approximately 1 year | Interval between ctDNA detection and radiographic evidence of disease. Measured by serial ctDNA assessments and radiographic imaging per RECIST 1.1. Kaplan-Meier analysis will be used to estimate time-to-event endpoints. |
| Incidence of Adverse Events (AE) | Approximately 30 days (From start of intensification to 30 days post-treatment) | Frequency of Grade ≥3 treatment-related adverse events as assessed by CTCAE v 6.0. |
Contacts
CONTACTErin Mapson
PRINCIPAL_INVESTIGATORAnusha Chidharla, MD
The University of Kansas Cancer Center
Outcome results
None listed