T-Cell Repertoire Sequencing: Assessing Pembrolizumab Efficacy in Advanced Non-small Lung Cancer

• ClinicalTrials.gov Identifier: NCT06045767
• Recruitment Status: Not yet recruiting
• First Posted: September 21, 2023
• Last Update Posted: September 21, 2023
• Sponsor: Ari Raphael
• Collaborators: Bar-Ilan University, Israel; Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Ari Raphael, Tel Aviv Medical Center

Study Description

Brief Summary:

This is a single site, non-randomized trial for the assessment of intravenous (IV) pembrolizumab (also known as MK-3475) combined with pemetrexed/platinum-based chemotherapy in subjects with advanced or metastatic non-squamous non-small lung cancer (NSCLC) who have not previously received systemic therapy for advanced disease and in whom directed therapy is not indicated. Approximately 30 subjects will be enrolled in this trial to examine the clonality and diversity dynamics matched with disease response evaluated by RECIST 1.1.

Condition or disease
Non-small Cell Lung Cancer Metastatic

Detailed Description:

Subjects will receive pembrolizumab 200 mg combined with pemetrexed and platinum (investigator's choice of cisplatin or carboplatin), as indicated below:

Pembrolizumab 200 mg + pemetrexed 500 mg/m2 (with vitamin supplementation) + cisplatin 75 mg/m2 OR carboplatin AUC 5, all on Day 1 every 3 weeks (Q3W) for 4 cycles followed by pembrolizumab 200 mg + pemetrexed 500 mg/m2 Q3W until progression.

Treatment with pembrolizumab and pemetrexed will continue until 35 trial treatments have been administered, documented disease progression or unacceptable adverse event(s).

Patients will be stratified according to clinical and histopathological parameters: 1. PD-L1 status (PD-L1 >/= 1 or <1) 2. Age < 65 vs => 65 3. Smoking history yes vs no 4. Platinum chemotherapy: cisplatin vs. carboplatin 5. Immune-related adverse events (irAEs).

TCR repertoire clonality and diversity will serve as an assessment measure for treatment response, along with PET/CT-scans, tumor exomal profile and ctDNA dynamics.

Study Design

• Study Type: Observational
• Estimated Enrollment: 30 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: T-Cell Repertoire Sequencing: Assessing Pembrolizumab Efficacy in Advanced Non-small Lung Cancer
• Estimated Study Start Date: January 2024
• Estimated Primary Completion Date: January 2029
• Estimated Study Completion Date: January 2029

Groups and Cohorts

Outcome Measures

Primary Outcome Measures :

1. Objective Response Rate (ORR) per RECIST 1.1 - correlated to TCR repertoire data, such as clonality/diversity. [ Time Frame: 5 years ]

   ORR defined as the percentage of participants who achieve a confirmed complete response (CR) or partial response (PR) per RECIST 1.1 as assessed by the investigator.

   By integrating serial TCR repertoire sequencing (Rep-seq) of NSCLC patients treated with pembrolizumab and platinum-based chemotherapy regimens we aim to capture the temporal clonality and diversity dynamics with the disease response.

Secondary Outcome Measures :

1. Objective Response Rate (ORR) correlated with circulating tumor DNA (ctDNA), by measurement of variant allele frequency (VAF). [ Time Frame: 5 years ]
   To capture the VAF in ctDNA, and correlate it with response to therapy evaluated by ORR per RECIST 1.1. We will capture its dynamics throughout blood samples collected longitudinally (pre-and during treatment).

Biospecimen Retention:   Samples With DNA

Peripheral Blood Mononuclear Cells (PBMC) Circulating Tumor DNA

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

Histologically confirmed diagnosis of NSCLC non-squamous stage IV or stage III, according to AJCC v8 that are not amenable for definitive therapy will be enrolled in this study.

Patients have not previously received systemic therapy for advanced disease and in whom directed therapy is not indicated.

Criteria

Inclusion Criteria:

• Participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
• Have measurable disease based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
• Archival tumor tissue sample or newly obtained [core, incisional or excisional] biopsy of a tumor lesion not previously irradiated has been provided.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Adequate organ function.

Exclusion Criteria:

• Pregnancy or breastfeeding
• Aberration in a known targetable molecular driver.
• Received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor.
• Received prior systemic anti-cancer therapy for metastatic disease.
• Received prior radiotherapy within 2 weeks of start of study intervention.
• Major surgery within 14 days.
• Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy.
• Known additional malignancy that is progressing or has required active treatment within the past 3 years.
• Known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated or asymptomatic brain metastases may participate provided they are radiologically stable.

Contacts and Locations

Contacts

Contact: Ari Raphael, M.D; +972-3-6973082; arir@tlvmc.gov.il

Sponsors and Collaborators

Ari Raphael

Bar-Ilan University, Israel

Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Ari Raphael, M.D; Tel-Aviv University school of medicine

More Information

• Responsible Party: Ari Raphael, Head Oncology Day-care unit, Tel Aviv Medical Center
• ClinicalTrials.gov Identifier: NCT06045767
• Other Study ID Numbers: 0435-23 TLV
• First Posted: September 21, 2023
• Last Update Posted: September 21, 2023
• Last Verified: September 2023

Keywords provided by Ari Raphael, Tel Aviv Medical Center:

T-cell repertoire; ctDNA

Additional relevant MeSH terms:

Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases