A Phase 1/2 Trial (CheckCell-2) in Patients With Metastatic Non-small Cell Lung Cancer (NSCLC) Administering Tumor-Infiltrating Lymphocytes (TILs) in Which the Gene Encoding CISH Was Inactivated Using the CRISPR/Cas9 System

Plain English Summary

CISH Inactivated TILs in the Treatment of NSCLC is a Phase 2 clinical trial sponsored by Intima Bioscience, Inc. studying Carcinoma, Non-Small-Cell Lung, Metastatic Non Small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer, Squamous Cell Lung Cancer, Adenocarcinoma of Lung, Large Cell Lung Cancer. This trial tested a new type of immunotherapy called CISH inactivated TILs for advanced lung cancer. It was designed for patients with metastatic non-small cell lung cancer (NSCLC) who were candidates for first-line immunotherapy. Participation involved a surgical procedure to obtain tumor tissue for cell therapy manufacturing, followed by chemotherapy, immune-boosting drugs, and the engineered TILs. This trial is no longer available as it has been withdrawn.

Official Summary

A clinical trial to assess the safety and efficacy of genetically-engineered Tumor Infiltrating Lymphocytes (TIL) in which the intracellular immune checkpoint CISH has been inhibited using CRISPR gene editing for the treatment of Metastatic Non-small Cell Lung Cancer (NSCLC).

Who Can Participate

Here is what you need to know about eligibility for this trial. Patients with a confirmed diagnosis of metastatic non-small cell lung cancer (NSCLC) were eligible. Patients needed to be candidates for first-line immunotherapy with chemotherapy or have started it recently. Specific health requirements included good organ function, certain blood counts, and the ability to undergo surgery to obtain tumor tissue. Patients with treated or stable brain metastases could be eligible, but required discussion with the study doctor. This trial is studying Carcinoma, Non-Small-Cell Lung, Metastatic Non Small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer, Squamous Cell Lung Cancer, Adenocarcinoma of Lung, Large Cell Lung Cancer, so participants generally need a confirmed diagnosis.

What They're Measuring

The primary outcome measured how safe the treatment was and how well it worked in shrinking tumors, which indicates the potential benefit for patients. The specific primary outcome measures are: Phase I: Safety and Initial Efficacy (11 months); Phase II: Objective Response Rate (ORR) (3.5 years). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 2, which tests whether the treatment actually works against the target condition. Phase 2 trials involve 100-300 patients and continue to monitor safety while evaluating effectiveness. This phase often tests different dosages to find the optimal amount. About 33% of Phase 2 drugs advance to Phase 3. If successful, the treatment will move to large-scale Phase 3 trials needed for FDA approval.

Why This Trial Matters

This trial aimed to address a gap in treating advanced lung cancer by using a patient's own immune cells, genetically modified to better fight the cancer. Phase 2 success would typically lead to larger Phase 3 trials needed for regulatory approval. This research targets Carcinoma, Non-Small-Cell Lung, Metastatic Non Small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer, Squamous Cell Lung Cancer, Adenocarcinoma of Lung, Large Cell Lung Cancer, where improved treatment options are needed.

Investor Insight

This trial, though withdrawn, explored a novel approach to cancer treatment using gene editing and immunotherapy, signaling potential future directions in a competitive oncology market. Phase 2 trials have approximately a 15-20% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor if this trial was suitable for your specific type and stage of lung cancer. Participation would have involved a surgery to get tumor tissue, followed by a series of treatments including chemotherapy, immune-boosting drugs, and the engineered cells. You would need to stay near the treatment center for monitoring and treatment. The trial is being conducted at 2 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NON_RANDOMIZED
• Model: SEQUENTIAL
• Masking: NONE

Interventions

• DRUG: Fludarabine — Day -7 to Day -3 : Fludarabine 25 mg/m\^2/dose as a 1 hour intravenous infusion per institutional guidelines once a day for 5 doses beginning on Day -7. Fludarabine will be started approximately 1 to 2 hours after the cyclophosphamide on Day -6 and Day -5.
• DRUG: Cyclophosphamide — Day -6 and Day -5: Cyclophosphamide 60 mg/kg/dose as a 2 hour intravenous infusion with Mesna 15 mg/kg/dose, 1st dose prior to Cyclophosphamide infusion then at 3,6,9 and 12 hours later.
• BIOLOGICAL: CISH Inactivated TIL — Day 0 : Each bag of autologous CISH inactivated TIL for infusion will be administered intravenously (IV) on the Patient Care Unit over 10-20 minutes at assigned dose level.
• DRUG: Aldesleukin — Days 1-4 : Aldesleukin at 720,000 U/kg as an intravenous infusion, every 8 -12 hours but, no more than 24 hours apart as tolerated for up to 6 doses.
• DRUG: Pembrolizumab — Administered as maintenance therapy in some patients starting at first follow-up (400 mg/dose starting Day 28 /Week 4 then every 6 weeks thereafter until disease progression, unacceptable toxicity, or up to 24 months)

Primary Outcomes

• Phase I: Safety and Initial Efficacy (11 months)
• Phase II: Objective Response Rate (ORR) (3.5 years)

Secondary Outcomes

• Progression Free Survival (PFS) (2-5 years)
• Overall Survival (OS) (2-5 years)
• Duration of Response (DoR) (2-5 years)
• Clinical Benefit Rate (2-5 years)
• Tumor Growth Change (2-5 years)

Full Eligibility Criteria

Inclusion Criteria (1st Screening prior to Tumor Resection - See below for evaluation of continuing eligibility prior to start of investigational treatment):

* Confirmed histologic diagnosis of either PD-L1 negative or positive metastatic non-small cell lung cancer (NSCLC)
* Candidate to receive 1st line treatment with anti-PD-1/anti-PD-L1 immunotherapy in combination with chemotherapy or be within 6 months (Phase 1) or 3 months (Phase 2) of initiation of this type of systemic treatment (regardless of where such treatment was started) when the tumor resection is performed. Patients who have received adjuvant or neoadjuvant anti-PD-1/anti-PD-L1 immunotherapy and/or chemotherapy can be screened for the trial if they experienced a relapse more than 6 months from the end of their last systemic treatment. The tumor resection for investigational product manufacturing should be undertaken before the initiation of this 1st line therapy; however, patients who have already started their 1st line treatment should have these procedures performed and completed as soon as deemed clinically appropriate, but no later than 6 months (Phase 1) or 3 months (Phase 2) from the start of 1st line treatment. After documented radiographic disease progression on or following this 1st line of treatment, patients will receive investigational product as 2nd line therapy.
* Measurable disease per RECIST v1.1 with at least one lesion identified as resectable for cell therapy manufacturing (minimum volume of tumor tissue required is 1 cm\^2 as single mass or fragments) and at least one other lesion meeting the RECIST criteria for measurable disease to serve as an indicator of disease response. The location of the tumor resection and method used to obtain tumor (i.e., laparoscopy, endoscopic ultrasound, etc.) will be determined based on an individual patient's disease. Note: previously irradiated lesions with radiographic progression are not eligible for tumor resection.
* Patients who have asymptomatic and or treated brain metastases are eligible, but must be discussed with and approved by the Coordinating Investigator. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible. Patients with brain metastases must not be receiving systemic steroids (oral progestin/estrogen combinations used for contraception are an exception). Brain metastases are assessed using the RANO-BM criteria.
* Clinical performance status of Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 and an estimated life expectancy of ≥ 6 months.
* Age ≥ 18 years and ≤ 70 years.
* Hematology within 14 days of study enrollment:

  * Absolute neutrophil count \> 1000/mm\^3 without the support of filgrastim
  * White Blood Cells (WBC) ≥ 3000/mm\^3
  * Platelet count ≥ 75,000/mm\^3
  * Hemoglobin \> 8.0 g/dL. Subjects may be transfused to reach this cutoff.
* Adequate organ function within 14 days of study enrollment defined as:

  * Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5.0 x upper limit of normal (ULN)
  * Serum creatinine ≤ 1.6 mg/dL or creatinine clearance by Cockroft-Gault ≥ 50 mL/min.
  * Total bilirubin ≤ to 2.0 mg/dL, except in patients with Gilbert's Syndrome, who must have a total bilirubin ≤ 3.0 mg/dL.
* Serology testing within 3 months of study enrollment (tumor resection):

  * Seronegative for HIV antibody. (The investigational treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immunocompetence and thus may be less responsive to the study treatment and more susceptible to its toxicities.)
  * Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.
* Sexually active females of childbearing potential and males with female partners of childbearing potential must agree to use effective contraception for the duration of study treatment starting with Screening and for 12 months (females) and 4 months (males) after the last dose of cyclophosphamide; if receiving pembrolizumab, for 4 months (females and males) after the last dose of pembrolizumab. Examples of effective contraception include oral progestin/estrogen combinations (an exception to the strict prohibition of systemic steroid use), an IUD or implant plus a condom. Women of non-childbearing potential are defined as those who have no uterus, ligation of the fallopian tubes, or permanent cessation of ovarian function due to ovarian failure or surgical removal of the ovaries. A woman also is presumed to be infertile due to natural causes if she has been amenorrheic for \> 12 months and/or has a follicle-stimulating hormone (FSH) \> 40 IU/L.
* Agrees to remain near the treatme

Trial Locations

• City of Hope Comprehensive Cancer Center, Duarte, California, United States
• Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States

Frequently Asked Questions

Related Conditions

• Carcinoma, Non-Small-Cell Lung
• Metastatic Non Small Cell Lung Cancer
• Stage IV Non-small Cell Lung Cancer
• Squamous Cell Lung Cancer
• Adenocarcinoma of Lung
• Large Cell Lung Cancer
• Lung Cancer
• Metastatic Cancer
• Oncology
• Immunotherapy

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