Autologous Redirected RNA Meso-CIR T Cells

NCT01355965 | Completed Phase 1 DMC

• 1 other identifier: UPCC 17510
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

To determine the safety and manufacturing feasibility of IV autologous chimeric immune receptor (CIR) T cells transfected with anti-mesothelin messenger RNA (mRNA) expressing a single chain antibody variable fragment linked to the intracellular CD 3 zeta T cell receptor domain and the 4-1BB costimulatory domain.

Conditions

Malignant Pleural Mesothelioma

Keywords

completed standard first line therapy; platinum based double regimen; Progressive Disease; chosen not to pursue primary standard of care therapy

Outcome Measures

Primary Outcomes (1)

• Adverse Events

  Occurence of study related adverse events greater than to equal to Grade 3 events that are possibly, likely or definitely related to study treatment.

  Until week 4

Secondary Outcomes (1)

• Clinical response Rate

  through 6 months post dosing

Study Arms (2)

Cohort 1 - One dose of cells

EXPERIMENTAL

Subjects receive one dose of 1x108 cells on day 0 followed by one dose of 1x109 autologous transfected anti-mesothelin CAR T cells on day 7.

Biological: Autologous T cells

Cohort 2 - three doses of cells

EXPERIMENTAL

receive three doses of 1x108 cells on day 0, 2, 4 (Monday-Wednesday-Friday (MWF) of Cycle 1) followed by three doses of 1x109 T cells on day 7, 9, 11 (MWF of Cycle 2). Total target dose for Cohort 2 is 3.3x109 cells.

Biological: Autologous T cells

Interventions

Autologous T cells BIOLOGICAL

Cohort 1 - One dose of cells; Cohort 2 - three doses of cells

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects must have histologically confirmed MPM (epithelial or biphasic).
• Subjects must have completed standard first line therapy with a platinum-based double regimen and had PD or they must have chosen not to pursue primary standard of care therapy.
• ECOG performance status 0 to 1.
• Age greater than 18 years
• Life expectancy \> 4 months
• At least 2 weeks since prior and no other concurrent chemotherapy, radiotherapy, or immunotherapy (e.g., interferons, tumor necrosis factor, interleukins, or monoclonal antibodies). In addition, the patient must have fully recovered from any adverse events related to these agents.
• More than 4 weeks since prior and no other concurrent investigational agents.
• Subjects must have measurable disease as defined by accepted MPM measurement techniques (modified RECIST criteria).
• Blood coagulation parameters: PT such that international normalized ratio (INR) is \< 1.5 (or an in-range INR, usually between 2 and 3, if a subject is on a stable dose of therapeutic warfarin for management of venous thrombosis including pulmonary thromboembolus) and a PTT \< 1.2 times the upper limit of normal.
• Subjects must have adequate venous peripheral access for apheresis. Patients must also have adequate venous access for subsequent modified CIR T-cell administration which can be done through a central venous access (e.g. port of systemic chemotherapy).
• Short-term therapy for acute conditions not specifically related to MPM is allowed if such therapy does not include any immune modulating agents.
• Male and Female subjects agree to use approved contraceptive methods (e.g. birth control pills, barrier device, intrauterine device , abstinence) during the study and for 3 months following the last dose of the study cell infusion.
• Subject must understand and sign the study-specific informed consent .
• Satisfactory organ and bone marrow function as defined by :
• Absolute neutrophil count \> 1,000/µl Platelets \> 100,000/µl Hematocrit \> 30 % AST(SGOT)/ALT(SGPT) \< 3x the institutional normal upper limit Bilirubin \< 2.0 mg/dL unless secondary to malignant bile duct obstruction Creatinine \< 1.5x the institutional normal upper limit

You may not qualify if:

• Previously treated with any investigation therapy within 1 month prior to screening.
• Sacromatoid MPM histology which does not express mesothelin
• Prior invasive malignancies unless surgically and medically cured without evidence of recurrent disease for 5 years with the exception of non-melanoma skin cancer, prostate cancer with PSA level \< 1.0.
• Prior hematologic malignancy with bone marrow transplantation or immune modifying therapy within the past 4 weeks with the exception of thyroid replacement.
• Use of immunosuppressive drugs with 4 weeks prior to study entry, or anticipated use of immunosuppressive agents.
• Any clinically -significant pericardial effusion, CHF (NY Heart Association Grade II-IV ), or cardiovascular condition.
• Any clinically -significant pleural effusion or ascites that cannot be drained with standard approaches or with pre-enrollment in dwelling drainage device placement.
• Forced vital capacity \< 50% predicted, DLCO \< 40% predicted.
• Underlying lung disease requiring supplemental oxygen therapy.
• Have a recognized immunodeficiency disease including cellular immunodeficiency, hypogammaglobulinemia, or dysgammaglobulinemia; patients who have acquired hereditary, congenital immunodeficiency.
• Viral infections: HIV, HCV, HBV.
• Pregnant women are excluded from this study because autologous transduced T cells, breastfeeding should be discontinued if the mother is treated.
• Feasibility assessment during screening demonstrates \< 30% transfection of target lymphocytes, or \< 5-fold expansion in modified CIR T-cells in response to CD3/CD28 costimulation.

Sponsors & Collaborators

• University of Pennsylvania: lead

Study Sites (1)

Abramson Cancer Center of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (1)

• Maus MV, Haas AR, Beatty GL, Albelda SM, Levine BL, Liu X, Zhao Y, Kalos M, June CH. T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol Res. 2013 Jul;1(1):26-31. doi: 10.1158/2326-6066.CIR-13-0006. Epub 2013 Apr 7.

  PMID: 24777247 DERIVED

MeSH Terms

Conditions

Mesothelioma, Malignant; Disease Progression

Condition Hierarchy (Ancestors)

Mesothelioma; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Mesothelial; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Pleural Neoplasms; Lung Diseases; Respiratory Tract Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Andrew Haas, MD, PhD

  Abramson Cancer Center at Penn Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 17, 2011
• First Posted: May 19, 2011
• Study Start: May 1, 2011
• Primary Completion: July 1, 2015
• Study Completion: October 1, 2015
• Last Updated: September 19, 2017

Record last verified: 2017-09

Locations

US (1)