CIrculating Tumour DNA in Lung Cancer (CITaDeL): Optimizing Sensitivity and Clinical Utility (CITaDeL)

This is a prospective observation study in patients with non-small cell lung cancer (NSCLC) starting either cytotoxic chemotherapy or radiation therapy. It will assess changes in circulating tumor DNA (ctDNA) in the days following the initiation of treatment, as well as longitudinal monitoring, to assess the dynamics and value of ctDNA in stage III-IV NSCLC.

Study Overview

• Status: Completed
• Conditions: Lung Neoplasms; Lung Cancer; Non Small Cell Lung Cancer; Neoplasm of Lung
• Intervention / Treatment: Other: Circulating tumour DNA (ctDNA)

Detailed Description

The study consists of three cohorts of patients initiating a new treatment for their NSCLC. The cohorts of (1) patients starting concurrent chemotherapy and radiation for stage III NSCLC (2) patients with advanced NSCLC starting cytotoxic chemotherapy (with or without pembrolizumab) (3) patients with advanced NSCLC starting palliative radiation therapy. This study aims to study the changes in ctDNA levels following a new treatment in lung cancer patients and to explore if the diagnostic utility of ctDNA testing is improved immediately following treatment when tumour cells are actively dying. It will also examine the changes in ctDNA levels and mutational analysis longitudinally.

• Study Type: Observational
• Enrollment (Actual): 40

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • London Regional Cancer Program

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients receiving treatment at the London Regional Cancer Program in London, Ontario, Canada.

Description

Inclusion Criteria:

• Histologically diagnosed NSCLC
• Age 18 or older
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-3
• Patients must be able to provide informed consent
• Patients must meet the criteria above AND fulfill the criteria below for entry into one of the 3 cohorts

Cohort 1

1. Stage III NSCLC as per the American Joint Committee on Cancer 8th edition (AJCC 8th ed.)
2. Appropriate to undergo concurrent chemotherapy and radiation
3. Planned radiation dose must be between 54 and 66 Gy
4. Chemotherapy regimen must include a platinum agent plus one of the following doublet agents: etoposide, pemetrexed, paclitaxel, vinorelbine, docetaxel, gemcitabine or vincristine
5. Day 1 platinum dose must be ≥ carboplatin 1.6 AUC or cisplatin 30 mg/m2
6. No prior system chemotherapy (induction) for their stage III NSCLC, any adjuvant chemotherapy given for resected disease must have been at least 100 days prior to enrollment

Cohort 2

1. Stage IV NSCLC or stage III NSCLC, as per the AJCC 8th ed.
2. Planning to start systemic cytotoxic chemotherapy, without concurrent radiation
3. Previous treatment with tyrosine kinase inhibitors or immunotherapy (PD-1, PD-L1, CTLA4 directed antibodies) is allowed as long as no cytotoxic chemotherapy was given concurrently
4. Previous palliative radiation is permitted, but must have been completed at least at least 21 days prior to the initiation of treatment
5. Chemotherapy regimen must include a platinum agent plus one of the following doublet agents: etoposide, pemetrexed, paclitaxel, vinorelbine, docetaxel, gemcitabine or vincristine
6. Day 1 platinum dose must be ≥ carboplatin 1.6 AUC or cisplatin 30 mg/m2
7. If cytotoxic chemotherapy was previously given for adjuvant or stage III NSCLC it must have been at least 100 days prior to enrollment

Cohort 3

1. Patients with advanced NSCLC set to undergo palliative radiation to the primary or regional or distant metastatic lesion(s), including intracranial lesions
2. Radiation dose scheduling must be 2.5 to 4.0 Gy on days 1 through 3 for extracranial treatment, ideally 40 Gy in 15 fractions, 20 Gy in 5 fractions, or 30 Gy in 10 fractions.
3. Radiation dose for brain lesions must be 6 to 9 Gy per dose, ideally 30 to 35 Gy in 5 daily fractions or 27 Gy in 3 fractions on alternating days
4. No plans for concurrent chemotherapy to be given
5. Five patients in cohort 3 will receive radiation to the primary tumor and five patients will receive radiation to brain lesions

Exclusion Criteria:

• Any other malignancy in the last five years other than adequately treated non-melanoma skin cancer

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Cohort 1; Stage III NSCLC as per the American Joint Committee on Cancer 8th edition (AJCC 8th ed.); Appropriate to undergo concurrent chemotherapy and radiation; Planned radiation dose must be between 54 and 66 Gy; Chemotherapy regimen must include a platinum agent plus one of the following doublet agents: etoposide, pemetrexed, paclitaxel, vinorelbine, docetaxel, gemcitabine or vincristine; Day 1 platinum dose must be ≥ carboplatin 1.6 AUC or cisplatin 30 mg/m2; No prior system chemotherapy (induction) for their stage III NSCLC, any adjuvant chemotherapy given for resected disease must have been at least 100 days prior to enrollment	Other: Circulating tumour DNA (ctDNA); Circulating tumour DNA (ctDNA) will be isolated from blood samples
Cohort 2; Stage IV NSCLC or stage III NSCLC, as per the AJCC 8th ed.; Planning to start systemic cytotoxic chemotherapy, without concurrent radiation; Previous treatment with tyrosine kinase inhibitors or immunotherapy (PD-1, PD-L1, CTLA4 directed antibodies) is allowed as long as no cytotoxic chemotherapy was given concurrently; Previous palliative radiation is permitted, but must have been completed at least at least 21 days prior to the initiation of treatment; Chemotherapy regimen must include a platinum agent plus one of the following doublet agents: etoposide, pemetrexed, paclitaxel, vinorelbine, docetaxel, gemcitabine or vincristine; Day 1 platinum dose must be ≥ carboplatin 1.6 AUC or cisplatin 30 mg/m2; If cytotoxic chemotherapy was previously given for adjuvant or stage III NSCLC it must have been at least 100 days prior to enrollment	Other: Circulating tumour DNA (ctDNA); Circulating tumour DNA (ctDNA) will be isolated from blood samples
Cohort 3; Patients with advanced NSCLC set to undergo palliative radiation to the primary or regional or distant metastatic lesion(s), including intracranial lesions; Radiation dose scheduling must be 2.5 to 4.0 Gy on days 1 through 3 for extracranial treatment, ideally 40 Gy in 15 fractions, 20 Gy in 5 fractions, or 30 Gy in 10 fractions.; Radiation dose for brain lesions must be 6 to 9 Gy per dose, ideally 30 to 35 Gy in 5 daily fractions or 27 Gy in 3 fractions on alternating days; No plans for concurrent chemotherapy to be given; Five patients in cohort 3 will receive radiation to the primary tumor and five patients will receive radiation to brain lesions	Other: Circulating tumour DNA (ctDNA); Circulating tumour DNA (ctDNA) will be isolated from blood samples

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To measure the change in quantitative ctDNA levels following the initiation of cytotoxic chemotherapy or radiation	Post-treatment ctDNA levels will be reported as the mean percent increase with standard deviation at maximum compared to baseline (pre-treatment) ctDNA levels.	Cohort 1 and 2: Baseline (pre-treatment) to end of cycle 1 (each cycle is 21 days) of chemotherapy. Cohort 3: Baseline (pre-treatment) to end of radiotherapy (up to 3 weeks)
To identify the timepoint after the initiation of treatment at which the quantified level of ctDNA peaks	This will be reported as the mean time to maximal ctDNA level with standard deviation from the initiation of treatment	Cohort 1 and 2: Baseline (pre-treatment) to end of cycle 1 (each cycle is 21 days) of chemotherapy. Cohort 3: Baseline (pre-treatment) to end of radiotherapy (up to 3 weeks)
To detect genetic alterations at the time point of maximal ctDNA that were not present in baseline testing	Will be reported as gene names, with allelic frequencies, found in post-treatment samples that were not present in samples collected at baseline.	Cohort 1 and 2: Baseline (pre-treatment) to end of cycle 1 (each cycle is 21 days) of chemotherapy. Cohort 3: Baseline (pre-treatment) to end of radiotherapy (up to 3 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To identify the proportion of patients that do not have genetic alterations present in baseline samples but have genetic alterations detected at the timepoint of maximal quantified ctDNA	This will be reported as frequency counts and proportions.	Cohort 1 and 2: Baseline (pre-treatment) to end of cycle 1 (each cycle is 21 days) of chemotherapy. Cohort 3: Baseline (pre-treatment) to end of radiotherapy (up to 3 weeks)
To determine the percentage of stage III patients with clinically relevant (targetable or prognostic), at any stage of lung cancer, ctDNA genetic alterations.	Will be reported as frequency counts and proportions.	Cohort 1 and 2: Baseline (pre-treatment) to end of cycle 1 (each cycle is 21 days) of chemotherapy. Cohort 3: Baseline (pre-treatment) to end of radiotherapy (up to 3 weeks)

Collaborators and Investigators

• Sponsor: Lawson Health Research Institute

Publications and helpful links

General Publications

• Breadner DA, Vincent MD, Correa R, Black M, Warner A, Sanatani M, Bhat V, Morris C, Jones G, Allan A, Palma DA, Raphael J. Exploitation of treatment induced tumor lysis to enhance the sensitivity of ctDNA analysis: A first-in-human pilot study. Lung Cancer. 2022 Jan 29;165:145-151. doi: 10.1016/j.lungcan.2022.01.013. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2019
• Primary Completion (Actual): December 31, 2020
• Study Completion (Actual): December 31, 2020

Study Registration Dates

• First Submitted: April 30, 2019
• First Submitted That Met QC Criteria: June 13, 2019
• First Posted (Actual): June 14, 2019

Study Record Updates

• Last Update Posted (Actual): February 18, 2021
• Last Update Submitted That Met QC Criteria: February 17, 2021
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms; Lung Neoplasms
• Other Study ID Numbers: CITaDeL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No