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CART-EGFRvIII + Pembrolizumab in GBM

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ClinicalTrials.gov Identifier: NCT03726515
Recruitment Status : Recruiting
First Posted : October 31, 2018
Last Update Posted : April 18, 2019
Sponsor:
Information provided by (Responsible Party):
University of Pennsylvania

Brief Summary:
This is an open-label, phase 1 study to assess the safety and tolerability of EGFRvIII T cells in combination with pembrolizumab (PD-1 Inhibitor) in patients with newly diagnosed, EGFRvIII+, MGMT-unmethylated glioblastoma.

Condition or disease Intervention/treatment Phase
Glioblastoma Biological: CART-EGFRvIII T cells Biological: Pembrolizumab Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 7 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1 Study of EGFRvIII-Directed CAR T Cells Combined With PD-1 Inhibition in Patients With Newly Diagnosed, MGMT-Unmethylated Glioblastoma
Actual Study Start Date : March 11, 2019
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2034

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: CART-EGFRvIII + Pembrolizumab Biological: CART-EGFRvIII T cells
autologous T cells that have been engineered to express an extracellular Humanized single chain antibody (scFv) with specificity for EGFRvIII linked to an intracellular signaling molecule comprised of a tandem signaling domain of the 4-1BB and TCRζ signaling modules.

Biological: Pembrolizumab
humanized monoclonal immunoglobulin (Ig) G4 antibody directed against human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1) with potential immune checkpoint inhibitory and antineoplastic activities.
Other Name: Keytruda




Primary Outcome Measures :
  1. Number of subjects with treatment-related adverse events, using NCI CTCAE v5.0. [ Time Frame: 5 Months ]

Secondary Outcome Measures :
  1. Overall survival Rate [ Time Frame: 15 Years ]
    Number of days from the date of the first CART-EGFRvIII infusion to the date of death of any cause. The survival function of OS will be calculated by the Kaplan-Meier method.

  2. Progression-free survival (PFS) [ Time Frame: 15 Years ]
    The number of days from the date of the first CART-EGFRvIII infusion to the first documented disease progression (based on standard MRI evaluation using the modified RANO criteria) or date of death, whichever occurs first. PFS will be calculated by the Kaplan-Meier method.

  3. Objective response rate (ORR) [ Time Frame: 15 Years ]
    The proportion of patients with complete response (CR) or partial response (PR) out of the total number of efficacy evaluable subjects. Exact 90%confidence interval for ORR will be computed.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Newly diagnosed glioblastoma (GBM) that is histologically confirmed by pathology review of surgically resected tissue.
  2. Undergone tumor resection.
  3. No prior systemic therapies, radiation, tumor-treating fields, or intratumoral therapeutic agents including Gliadel wafers are allowed. Tumor resection must be the only tumor-directed treatment that the patient has received for glioboblastoma.
  4. Tumor tissue is positive for EGFRvIII expression, as performed by either the University of Pennsylvania's in-house fusion transcript panel (RNA-based assay using Illumina HiSeq platform) or NeoGenomics Laboratories (quantitative RT-PCR assay).
  5. Tumor tissue is negative for MGMT promoter methylation (i.e. the tumor is MGMT-unmethylated), as performed by either the University of Pennsylvania's in-house pyrosequencing protocol or NeoGenomics Laboratories.
  6. Patients ≥ 18 years of age
  7. ECOG performance status 0-1
  8. Provides written informed consent
  9. Must have adequate organ function as measured by:

    1. White blood count ≥ 2500/mm3; platelets ≥ 100,000/mm3, hemoglobin ≥ 9.0 g/dL; without transfusion or growth factor support
    2. AST, ALT, LDH, alkaline phosphatase within 2.5 x upper normal limit, and total bilirubin ≤ 2.0 mg/dL
    3. Serum creatinine < 1.5 x upper limit of normal
    4. Adequate cardiac function (LVEF ≥ 45%)
  10. Subjects of reproductive potential must agree to use acceptable birth control methods.

Exclusion Criteria:

  1. Pregnant or lactating women
  2. Inadequate venous access for or contraindications to leukapheresis.
  3. Active Hepatitis B, hepatitis C, or HIV infection, or other active, uncontrolled infection
  4. History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40)
  5. History of severe hypersensitivity reactions to other monoclonal antibodies which in the opinion of the investigator may post an increased risk of serious infusion reactions.
  6. Requirement for immunosuppressive agents including but not limited to cyclosporine, MMF, tacrolimus, rapamycin, or anti-TNF agents within 4 weeks of eligibility confirmation by the physician-investigator.
  7. Subjects with a history of known or suspected, severe or uncontrolled autoimmune or connective tissue disease. Patients with vitiligo, controlled type 1 diabetes mellitus (on stable insulin dose), residual autoimmune-related hypothyroidism (due to autoimmune condition only requiring hormone replacement), or psoriasis (not requiring systemic treatment), or conditions not expected to recur in the absence of an external trigger, are permitted to enroll.
  8. Known history or current interstitial lung disease or non-infectious pneumonitis
  9. Prior allogenic bone marrow or solid organ transplant
  10. Any concurrent malignancy other than non-melanoma skin cancer that has been curatively treated, or carcinoma in situ of the cervix or bladder that has been curatively treated. For any prior invasive malignancy, at least 5 years must have elapsed since curative therapy and patients must not have received any radiation to the brain. Monoclonal gammopathy of undetermined significance (MGUS) is permitted.
  11. Any uncontrolled active medical or psychiatric disorder that would preclude participation as outlined.
  12. Severe, active co-morbidity in the opinion of the physician-investigator would preclude participation in this study, including but not limited to the following:

    1. Unstable angina within 6 months prior to eligibility confirmation by the physician-investigator
    2. Transmural myocardial infarction within the last 6 months prior to eligibility confirmation by the physician-investigator
    3. New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to eligibility confirmation by the physician-investigator.
    4. Serious and inadequately controlled cardiac arrhythmia
    5. Serious or non-healing wound, ulcer, or history of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to eligibility confirmation by the physician-investigator, with the exception of the craniotomy for tumor resection.

12. Patients with tumors primarily localized to the brain stem or spinal cord.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03726515


Contacts
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Contact: Eileen Maloney, MSN, ACNP-BC 215-662-6264 Eileen.Maloney@uphs.upenn.edu

Locations
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United States, Pennsylvania
Abramson Cancer Center of the University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Emerging Med    855-216-0098    PennCancerTrials@emergingmed.com   
Sponsors and Collaborators
University of Pennsylvania
Investigators
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Principal Investigator: Donald O'Rourke, MD Abramson Cancer Center of the University of Pennsylvania

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Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT03726515     History of Changes
Other Study ID Numbers: 831706, UPCC 13318
First Posted: October 31, 2018    Key Record Dates
Last Update Posted: April 18, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents