Clinical trial NCT04093167: Study of CTDNA Response Adaptive Immuno-Chemotherapy in NSCLC
Official title: A Biomarker-Directed, Multi-Centre Phase II/III Study of CTDNA Response Adaptive Immuno-Chemotherapy in Non-Small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Non-Small Cell Lung Cancer
Lead sponsor: Canadian Cancer Trials Group
Sponsor class: NETWORK
Collaborators: name: Cancer Research Institute, New York City
name: Personal Genome Diagnostics
name: Mark Foundation for Cancer Research
First posted: 2019-09-17
Enrollment: 230
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Stage 1: Concordance rate between molecular response and radiologic response
timeFrame: 18 months
measure: Stage 2: Phase II Progression-Free Survival (PFS)
timeFrame: 3 years
measure: Stage 2: Phase III Overall Survival
timeFrame: 3 years
Secondary outcomes:
measure: Stage 1: Time to molecular response
timeFrame: 18 months
measure: Stage 1: Correlate molecular response to RECIST response based on changes in ctDNA levels
timeFrame: 18 months
measure: Stage 1: Correlate molecular response to progression-free survival based on changes in ctDNA levels
timeFrame: 18 months
measure: Stage 1: Correlate molecular response to overall survival based on changes in ctDNA levels
timeFrame: 18 months
measure: Stage 1: Explore the degree of ctDNA reduction with clinical outcomes assessed by measuring changes in ctDNA levels in plasma
timeFrame: 18 months
measure: Stage 2: Phase II - Feasibility defined as screening success greater than 30% of patients screened have persistent ctDNA post 6 weeks of pembrolizumab
timeFrame: 3 years
measure: Stage 2: Phase II - Feasibility defined as accrual reaching 50% of project accrual by month 18 post randomization
timeFrame: 3 years
measure: Stage 2: Phase II - Feasibility defined as acceptance of randomization defined as >/= 80% of consenting patients accept randomization
timeFrame: 3 years
measure: Stage 2: Phase II - clinical efficacy endpoints of best overall response rate post randomization
timeFrame: 3 years
measure: Stage 2: Phase II - Number and severity of adverse events assessed by CTCAE v5
timeFrame: 3 years
measure: Stage 2: Phase III - Clinical efficacy endpoints of best overall RECIST response rate post-randomization
timeFrame: 3 years
measure: Stage 2: Phase III - Clinical efficacy endpoints of response duration
timeFrame: 3 years
measure: Stage 2: Phase III - Clinical efficacy endpoints of progression-free survival
timeFrame: 3 years
measure: Stage 2: Phase III - Number and severity of adverse events assessed by CTCAE v5
timeFrame: 3 years
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: The Sidney Kimmel Comprehensive Cancer Centre
state: Maryland
city: Vancouver
country: Canada
facility: BCCA - Vancouver Cancer Centre
state: British Columbia
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre at Hamilton Health Sciences
state: Ontario
city: Kingston
country: Canada
facility: Kingston Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital Research Institute
state: Ontario
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
Study officials:
affiliation: Johns Hopkins University
name: Valsamo Anagnostou
role: STUDY_CHAIR
affiliation: Ottawa Hospital Research Institute
name: Sara Moore
role: STUDY_CHAIR
References: