CT Antigen TCR-redirected T Cells for Ovarian Cancer.

• ClinicalTrials.gov Identifier: NCT01567891
• Recruitment Status: Completed
• First Posted: March 30, 2012
• Results First Posted: January 3, 2019
• Last Update Posted: June 27, 2019
• Sponsor: Adaptimmune
• Information provided by (Responsible Party): Adaptimmune

Study Description

Brief Summary:

This study, will take a subject's "T cells" and "teach" them to be able to recognize and attack the ovarian cancer cells. This is done by putting in a gene or genetic material that will change how a subject's T cells work and hopefully get them to attack and kill ovarian cancer cells. These new T cells are called "engineered T cells" because the new gene is causing them to become directed toward the ovarian cancer cells rather than their usual targets. These are also called "gene-modified T cells". For subjects who have the HLA A2 tissue-type marker, the T cells would be engineered to recognize a substance called "NY-ESO-1". After putting this new gene in T cells (a procedure called "gene therapy") the investigators will grow the cells in the laboratory and give these cells back to subjects.

Condition or disease	Intervention/treatment	Phase
Ovarian Cancer	Biological: NYESO-1c259 T cells	Phase 1; Phase 2

Detailed Description:

This is an open label clinical trial. Patients with the HLA-A201, HLA-A205, and/or HLA-A206 allele and whose tumor expresses the NY-ESO-1 tumor antigen will be eligible to receive NY-ESO-1ᶜ²⁵⁹T. The trial is conducted entirely with outpatient procedures; however, patients may be hospitalized for the cytoreductive chemotherapy at the discretion of the investigator. Upon enrollment, patients will undergo leukapheresis for T cell collection, and their cells will be genetically engineered and expanded ex vivo. Seven days prior to receiving T-cells patients will undergo a cyclophosphamide conditioning regimen to potentiate the immunotherapy. The cell product will be infused as a single infusion (Day 0, typically Monday) to mitigate risks associated with unanticipated infusion reactions. Patients will be followed daily for the first week, weekly until 4 weeks, 8 weeks, and 12 weeks and then at 6 months and every 3 months until disease progression. Patients will undergo disease monitoring by MRI/CT scan (as appropriate for disease) at baseline, day 28, 8 weeks and 12 weeks, and months 6, and every 3 months until progression. Tumor biopsies will be taken at baseline, Week 8, and upon progression. In patients who have progressive disease following initial infusion but whose tumors continue to express NY-ESO-1, these patients may be eligible for a second infusion with redirected T cells. At disease progression, the interventional portion of the protocol ends and long term follow-up (LTFU) begins, in accordance with FDA regulations. LTFU occurs semiannually for up to 5 years post infusion and then annually thereafter for up to 15 years.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/IIa, Open Label Clinical Trial Evaluating the Safety and Efficacy of Autologous T Cells Expressing Enhanced TCRs Specific for NY-ESO-1 in Patients With Recurrent or Treatment Refractory Ovarian Cancer.
• Actual Study Start Date: July 9, 2013
• Actual Primary Completion Date: June 6, 2017
• Actual Study Completion Date: June 6, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1; This is an open label clinical trial. Patients with the HLA-A201, HLA-A205, and/or HLA-A206 allele and whose tumor expresses the NY-ESO-1 tumor antigen will be eligible to receive NYESO-1c259 T cells.	Biological: NYESO-1c259 T cells; Cytoreductive chemotherapy followed by infusion with NYESO-1(C259) transduced autologous T cells. Patients will receive at least 1x10⁹ transduced cells, however the target dose for this protocol is for patients to receive 5x10⁹ transduced cells with a maximum possible dose of 6x10⁹ administered as a single intravenous (IV) infusion.

Outcome Measures

Primary Outcome Measures :

1. Adverse Events Related to Study Treatment [ Time Frame: Up to 12 months ]
   Number of Participants with Adverse Events related to study treatment

Secondary Outcome Measures :

1. Tumor Response [ Time Frame: Change from baseline, every 4 weeks until month 3 and then every 3 month until disease progression ]
   Number of participants with response as assessed by Immune-related Response Criteria (irRC)
2. Peak Persistence of Modified T-cells in the Peripheral Blood [ Time Frame: Days: 1, 2-4, weeks 1 to 4, Week 8, 12 and Month 6, then every 3 months thereafter until progression then during LTFU ]
   Measurement of NY-ESO-1ᶜ²⁵⁹T cells in blood
3. Determine Functional Properties and Phenotype of Modified T-cells From Peripheral Blood. [ Time Frame: Weeks 4 and 8 post T-cell infusion ]
   Percentage of CD4+pentamer+ or CD8+pentamer+ cells expressing LAG-3, PD-1, TIM-3 in the functionality of NY-ESO-1ᶜ²⁵⁹T cells in the manufactured product and post-treatment blood.
4. Correlate NY-ESO-1 Expression in Tumor Tissue Before Treatment With Archival Tumor Tissue to Assess Impact of Therapy on Expression of NY-ESO-1 Protein [ Time Frame: Screening and at Baseline ]

   NY-ESO-1 expression as determined by Histoscore (H score). Histoscore (0-300) represents the amount of NY-ESO-1 protein present in the tissue sample.

   H-Score formula:

   [1 × (% cells 1+) + 2 × (% cells 2+) + 3 × (% cells 3+)]

   (It is not clearly established if NY-ESO-1 H score has an association with prognosis.)

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Must have a diagnosis of recurrent epithelial ovarian, primary peritoneal or fallopian tube carcinoma with refractory or platinum resistant disease and/or have received ≥ 2 lines of chemotherapy
• Age ≥ 18 years of age
• No significant immunodeficiency
• Have been informed of other treatment options
• Must be HLA A*0201, HLA-A*0205, and/or HLA-A*0206 positive by high resolution testing.
• Patient's tumor must be positive by histological assay for NY-ESO-1ᶜ²⁵⁹T, according to the screening algorithm as described in Section 3.3.1. Positive expression is defined as ≥ 50% of cells that are 2+ and/or 3+ by immunohistochemistry
• ECOG performance status of 0 or 1
• Life expectancy of > 4 months

• Prior therapies:

  1. prior immunotherapy, or prior investigational agents should be washed out 4 weeks before apheresis and must be completed 4 weeks prior to pre-infusion lymphodepletive chemotherapy.
  2. monoclonal antibody therapy must be completed at least 6 weeks prior to pre-infusion lymphodepletive chemotherapy
  3. All previous cytotoxic chemotherapy, monoclonal antibody therapy, immune therapy should be washed out 3 weeks before apheresis and must be completed at least 3 weeks prior to pre-infusion lymphodepletive chemotherapy.
  4. Systemic corticosteroid or other immunosuppressive therapy should be washed out 2 weeks before apheresis and must be completed at least 2 weeks prior to pre-infusion lymphodepletive chemotherapy
  5. Biologic or other approved molecular targeted small molecule inhibitors should be washed out 1 week before apheresis and must be completed at least 1 week prior to pre-infusion lymphodepletive chemotherapy.
  6. Any grade 3 or 4 -hematologic toxicity of previous therapy must have resolved to grade 2 or less prior to apheresis and any grade 3 or 4 toxicity must have resolved to grade 2 or less prior to pre-infusion lymphodepletive chemotherapy.
• Must have measurable disease as defined by RECIST 1.1.
• Must have adequate venous access for apheresis.
• Women of childbearing potential are requested to use acceptable methods of birth control for the duration of the study and until persistence of the study drug is no longer detected in the patient. This may be a period of several years. Methods for acceptable birth control include: condoms, diaphragm or cervical cap with spermicide, intrauterine device, and hormonal contraception. It is recommended that a combination of two methods be used.

Patients must have normal organ and marrow function as defined below:

• Leukocytes ≥ 3,000/mcL
• Absolute Neutrophil Count ≥ 1,500/mcL
• Platelets ≥ 100,000/mcL
• Total bilirubin ≤ 1.5 ULN
• AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional upper limit of normal
• creatinine ≤ 2.0 mg/dL OR
• creatinine clearance > 60 mL/min for patients with creatinine levels above institutional normal
• Patient must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure.

Exclusion Criteria:

• Currently receiving any other investigational agents
• Patients with active brain metastases. Patients with prior history of brain metastasis who have undergone local therapy (i.e. metastatectomy and/or radiation) and show no evidence of local recurrence or progression over the past 6 months are eligible
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to cyclophosphamide or other agents used in the study
• Prior malignancy (except non-melanoma skin cancer) within 18 months of study entry NOTE: Patients must be in complete remission from prior malignancy in order to be eligible to enter the study.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Use of chronic corticosteroids, hydroxyurea, or immunomodulating agents (e.g. interleukin-2, interferon-alpha or gamma, granulocyte colony stimulating factors, etc.) within 30 days prior to study entry. NOTE: Recent or current use of inhaled steroids is not exclusionary. If subjects are prescribed a brief course of oral corticosteroids, the use should be limited to less than 7 days. Use of steroids before apheresis and immune assessment blood draws should be discouraged as it will affect white blood cell function.
• Active infection with HIV, HBV or HCV
• Receipt of an experimental vaccine within 2 months or in the opinion of the Investigator is responding to an experimental vaccine given within 6 months, or has received any previous gene therapy using an integrating vector
• History of severe autoimmune disease requiring steroids or other immunosuppressive treatments
• Lack of availability of a patient for immunological and clinical follow-up assessment
• Evidence or history of significant cardiac disease

Contacts and Locations

Locations

United States, California

City of Hope National Medical Center

Duarte, California, United States, 91010

Stanford Cancer Institute

Stanford, California, United States, 94305

United States, Florida

University of Miami, Sylvester Comprehensive Cancer Center

Miami, Florida, United States, 33136

United States, New York

Roswell Park Cancer Institute

Buffalo, New York, United States, 14263

United States, Texas

MD Anderson Cancer Center

Houston, Texas, United States, 77030

Sponsors and Collaborators

Adaptimmune

Investigators

• Study Chair: Kunle Odunsi, MD, PhD; Roswell Park Cancer Institute

  Study Documents (Full-Text)

Documents provided by Adaptimmune:

Statistical Analysis Plan  [PDF] February 7, 2017

Study Protocol  [PDF] February 7, 2017

More Information

• Responsible Party: Adaptimmune
• ClinicalTrials.gov Identifier: NCT01567891
• Other Study ID Numbers: ADP-0011-001; 230612 ( Other Identifier: Adaptimmune )
• First Posted: March 30, 2012
• Results First Posted: January 3, 2019
• Last Update Posted: June 27, 2019
• Last Verified: December 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Adaptimmune:

Ovarian Cancer; Cell Therapy; T Cell Therapy; NY-ESO-1; Immuno-oncology; Metastatic; Previously treated; T Cell Receptor

Additional relevant MeSH terms:

Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Endocrine System Diseases; Gonadal Disorders; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type