Study of CTDNA Response Adaptive Immuno-Chemotherapy in NSCLC

Non-Small Cell Lung Cancer Clinical Trial

Official title:

A Biomarker-Directed, Multi-Centre Phase II/III Study of CTDNA Response Adaptive Immuno-Chemotherapy in Non-Small Cell Lung Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04093167
• Other study ID #: BR36
• Secondary ID: CRI-CCTG-002
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: May 26, 2020
• Est. completion date: July 30, 2027

Study information

• Verified date: January 2024
• Source: Canadian Cancer Trials Group
• Contact: Janet Dancey
• Phone: 613-533-6430
• Email: jdancey[@]ctg.queensu.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

BR36 will evaluate the potential clinical benefit of tailoring immunotherapy treatment based on ctDNA molecular response in non-small cell lung cancer.

Description:

BR36 is an international multi-centre, open-label, biomarker-directed, phase II/III trial of ctDNA response adaptive immuno-chemotherapy in patients with immune checkpoint and chemotherapy naïve metastatic non-small cell lung cancer with ≥50% PD-L1 TPS expression. This trial will test if adding chemotherapy to pembrolizumab for patients with persistent ctDNA on Liquid Biopsy drawn at 6 weeks of treatment will result in better progression-free and overall survival compared to patients who remain on pembrolizumab therapy until clinical progression with subsequent change in standard therapy.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 230
• Est. completion date: July 30, 2027
• Est. primary completion date: December 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically or cytologically confirmed metastatic NSCLC. Patients with stage III disease are eligible if they are not candidates for surgical resection or definitive chemoradiation. Patients with Large Cell Neuroendocrine Carcinoma (LCNEC) are not eligible.

• Confirmed EGFR and ALK mutation-negative disease based on testing consistent with local guidelines.

• Patients must have a PD-L1 test result from a certified laboratory indicating PD-L1 expression Tumour Proportion Score (TPS) = 50%. Patients with lower PD-L1 TPS scores treated with single agent pembrolizumab consistent with local guidelines and regulatory approvals may be eligible following discussion with CCTG.

• Patients must have received at least and not more than 2 cycles of the 200mg or 2mg/kg IV Q3W dose/schedule of pembrolizumab, or at least and not more than 1 cycle of 400mg or 4mg/kg IV Q6W dose/schedule of pembrolizumab as first-line systemic immunotherapy for advanced metastatic NSCLC at the time of screening.

• Prior chemotherapy or immunotherapy for non-metastatic disease (e.g. adjuvant and or neoadjuvant therapy) is allowed if at least 6 months have elapsed between the completion of prior therapy and start of pembrolizumab as first-line treatment for metastatic disease. Local therapy, e.g. palliative extra-cranial radiation, is allowed as long as a period of 2 weeks has passed since completion and screening as ctDNA levels may be altered by radiotherapy. There is no requirement for delay for patients who have received brain radiation.

• Patients must have recovered to = grade 1 from all reversible toxicity related to prior systemic or radiation therapy.

• Previous major surgery is permitted provided that surgery occurred at least 14 days prior to screening of ctDNA and 28 days prior to patient enrollment and that wound healing has occurred.

• Eligible and suitable to receive continued treatment with pembrolizumab OR the addition of chemotherapy to pembrolizumab. Patients should be clinically stable without evidence of clinical progression or symptomatic deterioration that requires change in cancer treatment. Reimbursement of pembrolizumab may not be uniform across all sites. In the event that the site/investigator is unable to provide access to the drug, the patient will not be eligible for this trial.

• Must be = 18 years of age.

• ECOG performance status 0-2.

• Clinically and/or radiologically documented and evaluable disease. Measurable disease as defined by RECIST is not required.

• Imaging investigations including CT of the chest, abdomen and pelvis and MRI/CT of the brain (if known brain metastases) or other scans as necessary to document all sites of disease must be done within 14 days prior to randomization to ensure patients do not have clinical progression requiring change in systemic treatment.

• Patients must have RECIST non-PD or clinically stable PD documented prior to enrollment that can continue on IO therapy if randomized to that arm.

• Detectable ctDNA on screening is required for subsequent enrollment and randomization.

• Adequate hematology and organ function to continue immunotherapy or receive standard platinum combination therapy (must be done prior to registration for ctDNA testing).

• White Blood Cells = 2.0 x 10^9/L (2000/µL)

• Absolute neutrophils = 1.5 x 10^9/L (1500/µL)

• Platelets = 100 x 10^9/L (100 x 10^3/µL)

• Bilirubin = 1.5 x ULN (upper limit of normal)*

• AST and/or ALT = 3 x ULN, < 5 x ULN for patients with liver metastases

• Serum creatinine or Creatinine clearance = 1.5 x ULN OR = 40 mL/min

• Patients must consent to the provision of, and investigator must agree to submit, a representative archival formalin-fixed paraffin block of tumour tissue for correlative analyses when tumour tissue is available.

• Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to registration to the trial to document their willingness to the collection of liquid biopsy (blood) samples for ctDNA analysis by CLIA central laboratory and for correlative analysis by a research central laboratory, and to subsequent enrollment and randomization to continued pembrolizumab or the addition of chemotherapy to pembrolizumab if ctDNA is detected.

• Patients must be accessible for treatment and follow-up. Investigators must assure themselves the patients enrolled on this trial will be available for complete documentation of the treatment, adverse events, collection of blood samples, response assessments and follow-up. Patients must agree to return to their primary care facility for response assessments as well as any adverse events which may occur through the course of the trial.

• In accordance with CCTG policy, protocol treatment is to begin within 5 working days of patient randomization.

• Women/men of childbearing potential must have agreed to use a highly effective contraceptive method. Women of childbearing potential will have a pregnancy test to determine eligibility as part of the Pre-Study Evaluation.

Exclusion Criteria:

• Patients with a prior malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the protocol treatment regimens are eligible for this trial.

• Patients with symptomatic central nervous system (CNS) metastases and/or CNS metastases requiring immunosuppressive doses of systemic corticosteroids (>10 mg/day prednisone equivalents). Patients with known central nervous system metastases who are asymptomatic and on a stable dose of corticosteroids = 10 mg/day prednisone equivalents are eligible.

• Patients who are not suitable candidates for treatment with pembrolizumab as a single agent or in combination with standard platinum combination chemotherapy according to the current guidance/indications described in the Product Monograph (Canada) or Drug Label (U.S.) and practice guidelines including but not limited to patients with active infection, autoimmune disease, conditions that require systemic immunosuppressive therapy (such as transplant patients) and patients with a history of severe immune-mediated adverse reactions, or known hypersensitivity to pembrolizumab or its components. Patients with pre-existing conditions such as colitis, hepatic impairment, respiratory or endocrine disorders (such as hypo or hyperthyroidism or diabetes mellitus), can be considered for enrollment to this study provided pembrolizumab is administered with caution and patients are closely monitored. Patients should not have contraindications to platinum combination chemotherapy.

• History of significant neurologic or psychiatric disorder that would impair the ability to obtain consent or limit compliance with study requirements.

• Concurrent treatment with other anti-cancer therapy or other investigational anti-cancer agents

• Pregnant or lactating women.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-Small Cell Lung Cancer

Intervention

Drug:
• Pembrolizumab
Per current Product Monograph/U.S. Drug Label and/or local guidelines.

Locations

Country	Name	City	State
Canada	Juravinski Cancer Centre at Hamilton Health Sciences	Hamilton	Ontario
Canada	Kingston Health Sciences Centre	Kingston	Ontario
Canada	Ottawa Hospital Research Institute	Ottawa	Ontario
Canada	University Health Network	Toronto	Ontario
Canada	BCCA - Vancouver Cancer Centre	Vancouver	British Columbia
United States	The Sidney Kimmel Comprehensive Cancer Centre	Baltimore	Maryland

Sponsors (4)

Lead Sponsor	Collaborator
Canadian Cancer Trials Group	Cancer Research Institute, New York City, Mark Foundation for Cancer Research, Personal Genome Diagnostics (PGDx)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Stage 1: Concordance rate between molecular response and radiologic response	Molecular response will be assessed by measuring changes in ctDNA levels in plasma	18 months
Primary	Stage 2: Phase II Progression-Free Survival (PFS)		3 years
Primary	Stage 2: Phase III Overall Survival		3 years
Secondary	Stage 1: Time to molecular response		18 months
Secondary	Stage 1: Correlate molecular response to RECIST response based on changes in ctDNA levels		18 months
Secondary	Stage 1: Correlate molecular response to progression-free survival based on changes in ctDNA levels		18 months
Secondary	Stage 1: Correlate molecular response to overall survival based on changes in ctDNA levels		18 months
Secondary	Stage 1: Explore the degree of ctDNA reduction with clinical outcomes assessed by measuring changes in ctDNA levels in plasma		18 months
Secondary	Stage 2: Phase II - Feasibility defined as screening success greater than 30% of patients screened have persistent ctDNA post 6 weeks of pembrolizumab		3 years
Secondary	Stage 2: Phase II - Feasibility defined as accrual reaching 50% of project accrual by month 18 post randomization		3 years
Secondary	Stage 2: Phase II - Feasibility defined as acceptance of randomization defined as >/= 80% of consenting patients accept randomization		3 years
Secondary	Stage 2: Phase II - clinical efficacy endpoints of best overall response rate post randomization		3 years
Secondary	Stage 2: Phase II - Number and severity of adverse events assessed by CTCAE v5		3 years
Secondary	Stage 2: Phase III - Clinical efficacy endpoints of best overall RECIST response rate post-randomization		3 years
Secondary	Stage 2: Phase III - Clinical efficacy endpoints of response duration		3 years
Secondary	Stage 2: Phase III - Clinical efficacy endpoints of progression-free survival		3 years
Secondary	Stage 2: Phase III - Number and severity of adverse events assessed by CTCAE v5		3 years