Clinical Trials /

Autologous T Cells Expressing MET scFv CAR (RNA CART-cMET)

NCT03060356

Description:

This is a pilot study to evaluate feasibility, safety, and preliminary evidence of efficacy for intravenously administered, RNA electroporated autologous T cells expressing MET chimeric antigen receptors with tandem TCRζ and 4-1BB (TCRζ /4-1BB) co-stimulatory domains (referred to as "RNA CART-cMET") in patients with advanced melanoma or breast carcinoma.

Related Conditions:
  • Breast Carcinoma
  • Melanoma
Recruiting Status:

Terminated

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Autologous T Cells Expressing MET scFv CAR (RNA CART-cMET)
  • Official Title: Clinical Trial of Autologous cMET Redirected T Cells Administered Intravenously in Patients With Melanoma & Breast Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: UPCC 11916, 825376
  • NCT ID: NCT03060356

Conditions

  • Malignant Melanoma
  • Breast Cancer

Interventions

DrugSynonymsArms
T cells modified with RNA anti -cMET CARBreast

Purpose

This is a pilot study to evaluate feasibility, safety, and preliminary evidence of efficacy for intravenously administered, RNA electroporated autologous T cells expressing MET chimeric antigen receptors with tandem TCRζ and 4-1BB (TCRζ /4-1BB) co-stimulatory domains (referred to as "RNA CART-cMET") in patients with advanced melanoma or breast carcinoma.

Detailed Description

      This is a pilot study to evaluate feasibility, safety, and preliminary evidence of efficacy
      for intravenously administered, RNA electroporated autologous T cells expressing MET chimeric
      antigen receptors with tandem TCRζ and 4-1BB (TCRζ /4-1BB) co-stimulatory domains (referred
      to as "RNA CART-cMET") in patients with advanced melanoma or breast carcinoma. Subjects will
      be treated with IV administration of the RNA transduced anti-cMET CAR T cells for a total of
      up to six doses over a 2 week period.

      Each dose is 1x108 total T cells modified with RNA anti-cMET CAR. All subjects in both the
      melanoma and breast carcinoma arms will receive up to 6 doses of RNA CART-cMET cells, with no
      lymphodepleting chemotherapy administered prior to cell infusion Cell numbers are based on
      total cells with a portion of them having CAR expression depending on transduction efficiency
      and determined by flow cytometry Based on the product release criteria, at least 20% of the
      total cells will express the anti-cMET CAR. Treatment limiting toxicity (TLT). Adverse event
      reporting will begin at the start of the first dose of RNA CART-cMET and will continue until
      4 months after the first infusion, or until another alternative therapy is initiated,
      whichever occurs earlier. Subjects will be continually reassessed for evidence of acute and
      cumulative toxicity.
    

Trial Arms

NameTypeDescriptionInterventions
MelanomaActive ComparatorIntravenous infusion 1x10^8 total T cells modified with RNA anti-cMET CAR
  • T cells modified with RNA anti -cMET CAR
BreastActive ComparatorIntravenous infusion 1x10^8 total T cells modified with RNA anti-cMET CAR
  • T cells modified with RNA anti -cMET CAR

Eligibility Criteria

        Inclusion Criteria:

          -  Unresectable histologically confirmed stage III/IV melanoma or metastatic or locally
             advanced unresectable ER and PR negative, HER2 neu nonamplified by IHC and/or FISH
             breast carcinoma

          -  cMET expression in ≥ 30% tumor cells as demonstrated on immunohistochemistry analysis
             at the University of Pennsylvania. MET IHC may be performed on tissue from screening
             biopsy, or archival slides of a metastatic deposit or primary tumor. Punch biopsy or
             percutaneous core biopsy will be offered to obtain tissue as required for this
             purpose.

          -  Patients must have measureable disease as defined by RECIST 1.1 criteria; must have CT
             scan of chest, abdomen, pelvis within 1 month of enrollment that demonstrates
             measurable disease by RECIST 1.1 criteria in a tumor other than the one being
             potentially biopsied and resected for correlative studies

          -  Failure of at least one prior standard of care therapy for advanced stage disease

          -  If previously treated with any form of immunotherapy (including agents targeting PD1
             or CTLA4, oncolytic viruses) the last administered treatment must be at least 2 weeks
             prior to enrollment

          -  Males or female patients age > 18 years old

          -  Eastern Cooperative Oncology Group (ECOG) Clinical Performance Status 0 or 1

          -  Adequate hematologic and organ function as defined by:

          -  WBC > 3.0 and ANC >1500

          -  Plt > 75,000 (no transfusion permitted within 2 weeks to achieve this goal)

          -  Hgb > 9 g/dl (transfusions are permitted to achieve this goal)

          -  serum creatinine ≤ 1.5 times upper limit of normal

          -  Total bilirubin ≤ 2times upper limit of normal

          -  ALT and AST ≤ 2 times upper limit of normal

          -  Cardiac ejection fraction of >40% as measured by resting echocardiogram

          -  Women of child bearing potential must have a negative serum or urine pregnancy test
             and agree to use appropriate contraception from enrollment through the duration of the
             trial. Men must agree to use appropriate contraception from enrollment through the
             duration of the trial.

          -  Patients must provide written informed consent.

        Exclusion Criteria:

          -  Known metastatic tumor encasing a great vessel or at risk for imminently causing
             spinal cord compression

          -  Known HIV-1/HIV-2 infection

          -  Known active infection with Hepatitis B virus or Hepatitis C virus

          -  Received an experimental therapy within 30 days of enrollment

          -  Pregnant women or lactating women

          -  History of alcohol abuse or illicit drug use within 12 months of enrollment

          -  Clinically significant comorbid disease or other underlying condition, including
             significant active infection, in the opinion of the PI or sub-investigators, would
             contraindicate study therapy or interfere with interpretation of study results

          -  Significant psychiatric disorder and/or any other reason in the Investigator's opinion
             that would jeopardize protocol compliance or compromise the patient's ability to give
             informed consent.

          -  Patients with known allergy or hypersensitivity to study product excipients (human
             serum albumin, DMSO, and Dextran 40).

          -  Patients with clinically apparent arrhythmia, or arrhythmias that are not stable on
             medical management within 2 weeks of the Screening/Enrollment visit.

          -  Having received prior genetically manipulated T-cells in prior clinical trial

          -  History of autoimmune disease (including but not limited to: systemic lupus
             erythematosis, Sjogren syndrome, rheumatoid arthritis, psoriasis multiple sclerosis,
             inflammatory bowel disease etc).

          -  History of immune related adverse event with previous immunotherapy.

          -  Chronic use of therapeutic anti-coagulants such as coumadin, heparin, or lovenox

          -  Symptomatic or untreated CNS metastases. Pts with previously treated CNS metastases
             are eligible if lesions are radiographically/clinically stable without requirement of
             steroids within 4 weeks prior to treatment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants with treatment-related adverse events as assessed by CTCAE v4.03 in melanoma and breast cancer subjects
Time Frame:from day 0 - month 4
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Objective overall response rate by clinical exam for visible cutaneous tumors
Time Frame:day 25 and month 4
Safety Issue:
Description:
Measure:Objective overall response rate by radiologic imaging using RECIST 1.1
Time Frame:day 25 and month 4
Safety Issue:
Description:
Measure:Estimate the activity of RNA CART-cMET in subjects who receive at least 1 dose of cells by objective response rate using RECIST 1.1 criteria
Time Frame:day -7 and day 11
Safety Issue:
Description:
Measure:Estimate the activity of RNA CART-cMET in subjects who receive at least 1 dose of cells by objective response rate using pathological evaluation of resected or biopsied tissue
Time Frame:day -7 and day 11
Safety Issue:
Description:

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:University of Pennsylvania

Last Updated

April 1, 2020