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NY-ESO-1 TCR Engineered T Cell and HSC After Melphalan Conditioning Regimen in Treating Participants With Recurrent or Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

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ClinicalTrials.gov Identifier: NCT03691376
Recruitment Status : Recruiting
First Posted : October 1, 2018
Last Update Posted : April 18, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Roswell Park Cancer Institute

Brief Summary:
This phase I trial studies the best dose and side effects of NY-ESO-1 T cell receptor (TCR) engineered T cells and how well they work with NY-ESO-1 TCR engineered hematopoietic stem cells (HSCs) after melphalan conditioning regimen in treating participants with ovarian, fallopian tube, or primary peritoneal cancer that has come back or does not respond to treatment. The melphalan conditioning chemotherapy makes room in the patient's bone marrow for new blood cells and blood-forming cells (stem cells) to grow. Giving NY-ESO-1 TCR T cells and stem cells after the conditioning chemotherapy is intended to replace the immune system with new immune cells that have been redirected to attack and kill the cancer cells and thereby improve immune system function against cancer. Giving NY-ESO-1 TCR engineered T cells and HSCs after melphalan may work better in treating participants with ovarian, fallopian tube, or primary peritoneal cancer.

Condition or disease Intervention/treatment Phase
HLA-A*0201 Positive Cells Present HLA-DP4 Positive Cells Present Platinum-Resistant Ovarian Carcinoma Recurrent Fallopian Tube Carcinoma Recurrent Ovarian Carcinoma Recurrent Primary Peritoneal Carcinoma Refractory Fallopian Tube Carcinoma Refractory Ovarian Carcinoma Refractory Primary Peritoneal Carcinoma Biological: Aldesleukin Biological: Autologous NY-ESO-1-specific CD8-positive T Lymphocytes Other: Cellular Therapy Drug: Melphalan Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To assess the safety and feasibility of intravenous infusion of autologous peripheral blood mononuclear cells (PBMC) and CD34+ peripheral blood stem cells (PBSC) that have been genetically modified ex vivo to express NY-ESO-1 TCR, following a myeloablative conditioning regimen. Safety and feasibility will include: Assessment of toxicities using Common Terminology Criteria for Adverse Events (CTCAE version 5) and estimation of a maximum tolerated dose (MTD). Feasibility: ability to manufacture the intended cell therapies in >80% of cases.

SECONDARY OBJECTIVES:

I. TCR engineered hematopoietic stem cell (HSC) engraftment. II. Functional assays for TCR transgenic cells. III. Progression-free survival (PFS) (compare with the duration of the PFS in the last treatment regimen).

IV. Durable tumor response in at least 30% of the patients defined as immune-related complete response (irCR) or immune-related partial response (irPR) by immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) criteria at 6 months.

V. Long-term persistence of TCR transgenic cells (regardless of cell origin) as evidenced by > 5% of CD3 lymphocytes being NY-ESO-1 specific by major histocompatibility complex (MHC) tetramer assay at 3 and 6 months.

VI. Discrimination of TCR transgenic cells resulting from retrovirally-transduced mature lymphocytes and lentivirally-transduced HSCs and their phenotyping.

VII. Long term monitoring for replication competent retrovirus and lentivirus. VIII. Analysis of viral insertion sites in long term persisting NY-ESO-1 TCR clones: absence of a clonal expansion of TCR transgenic cells with a particular transgene insertion site (defined as a clone comprising > 20% of all PBSC-derived gene-marked cells).

IX. Gut microbiota pre and post treatment to evaluate the role of microbiota on the therapeutic efficacy of the proposed therapy.

OUTLINE: This is a dose-escalation study of autologous NY-ESO-1-specific CD8-positive T lymphocytes.

Following conditioning therapy participants then receive autologous NY-ESO-1 CD4-TCR CD34+ HSC IV on day 0 and autologous NY-ESO-1-specific CD8-positive T lymphocytes IV on days 3 and 90. Participants also receive aldesleukin subcutaneously (SC) twice daily (BID) on days 4-17 After completion of study treatment, participants are followed up every 6 months for 5 years, then annually for up to 15 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I, Open Label Study Evaluating the Safety and Efficacy of Adoptive Transfer of Autologous NY-ESO-1 CD8-TCR Engineered T Cells and NY-ESO-1 CD4-TCR Engineered Hematopoietic Stem Cells (HSC) After a Myeloablative Conditioning Regimen, With Administration of IL-2 in Patients With Recurrent or Treatment Refractory Ovarian, Fallopian Tube or Primary Peritoneal Cancer
Actual Study Start Date : January 24, 2019
Estimated Primary Completion Date : October 1, 2019
Estimated Study Completion Date : October 1, 2020


Arm Intervention/treatment
Experimental: Treatment (autologous NY-ESO-1 engineered T and HSC)
Participants receive melphalan IV over 30 minutes on day -1. Participants then receive autologous NY-ESO-1 CD4-TCR CD34+ HSC IV on day 0 and autologous NY-ESO-1-specific CD8-positive T lymphocytes IV on days 3 and 90. Participants also receive aldesleukin SC BID on days 3-16 and 91-104.
Biological: Aldesleukin
Given SC
Other Names:
  • 125-L-Serine-2-133-interleukin 2
  • Proleukin
  • r-serHuIL-2
  • Recombinant Human IL-2
  • Recombinant Human Interleukin-2

Biological: Autologous NY-ESO-1-specific CD8-positive T Lymphocytes
Given IV

Other: Cellular Therapy
Given autologous NY-ESO-1 CD4-TCR CD34+ HSC IV
Other Name: Cell Therapy

Drug: Melphalan
Given IV
Other Names:
  • Alanine Nitrogen Mustard
  • CB-3025
  • L-PAM
  • L-Phenylalanine Mustard
  • L-sarcolysin
  • L-Sarcolysin Phenylalanine mustard
  • L-Sarcolysine
  • Melphalanum
  • Phenylalanine Mustard
  • Phenylalanine nitrogen mustard
  • Sarcoclorin
  • Sarkolysin
  • WR-19813




Primary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 9 months post infusion ]
    The frequency of toxicities will be tabulated by grade across all dose levels and cycles.

  2. Maximum tolerated dose (MTD) [ Time Frame: Up to 9 months post-infusion ]
    Dose limiting toxicities will be used in the estimation of the MTD and the accompanying of the dose escalation decisions. The frequency of toxicities will also be tabulated for the dose estimated to be the MTD.


Secondary Outcome Measures :
  1. Immunological parameters associated with T cell persistence, bioactivity and functionality [ Time Frame: Baseline up to 15 years ]
    Measure the pre and post treatment percentage of T cell persistence, bioactivity and functionality

  2. Tumor response rates to treatment [ Time Frame: Up to 15 years ]
    Tumor response defined as immune-related complete response (irCR), for at least 4 weeks and is based on the immune-related Response Evaluation Criteria in Solid Tumors criteria. Will also calculate the percentage of irCR+ irPR and the corresponding 95% confidence interval.

  3. Progression-free survival [ Time Frame: From start of the treatment until the first occurrence of confirmed progression, assessed up to 15 years ]
    Will calculate the median progression free survival (PFS) and the corresponding 95% confidence interval.

  4. Overall survival [ Time Frame: From start of the treatment until death, assessed up to 15 years ]
  5. Duration of response [ Time Frame: Up to 15 years ]
  6. Appearance of target antigen/major histocompatibility complex (MHC) loss variants upon disease recurrence [ Time Frame: Up to 15 years ]
    NY-ESO-1 expression will be evaluated by quantitative reverse transcriptase polymerase chain reaction (Q-RT-PCR) and/or immunohistochemistry. HLA-A*0201 and -DP*04 expression on samples will be evaluated by immunohistochemistry.

  7. Tumor response rates to treatment [ Time Frame: Up to 15 years ]
    Tumor response defined as immune-related partial response (irPR) for at least 4 weeks and is based on the immune-related Response Evaluation Criteria in Solid Tumors criteria

  8. Tumor response rates to treatment [ Time Frame: Up to 15 years ]
    Tumor response defined as immune related stable disease (irSD) for at least 4 weeks and is based on the immune-related Response Evaluation Criteria in Solid Tumors criteria



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  • Must have a diagnosis of platinum-sensitive or platinum-resistant recurrent or refractory epithelial ovarian, primary peritoneal or fallopian tube carcinoma and have progressed, relapsed, or recurred through at least one or more prior lines of standard of care therapies. For platinum sensitive patients, the standard of care therapies include additional platinum containing regimens and bevacizumab.
  • Have been informed of other treatment options
  • Must be HLA- A*02.1 and HLA-DP*04 positive. Retesting is not required for patients who have previous documented positivity
  • Patient's tumor must be positive by histological or molecular assay for NY-ESO-1
  • Have an Eastern Cooperative Oncology group (ECOG) performance status of 0 or 1
  • Life expectancy of > 4 months
  • At least 4 weeks from prior chemotherapy, radiotherapy or immunotherapy, or prior investigational agents
  • Must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Must have adequate venous access for apheresis (pheresis catheter placement for cell collection is allowed)
  • Since the study drug may affect pregnancy since it targets proteins present during development, 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 by polymerase chain reaction (PCR). 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
  • Leukocytes >= 3 x 10^9/L
  • Absolute neutrophil count >= 1.5 x 10^9/L
  • Platelets >= 100 x 10^9/L
  • Total bilirubin within normal institutional limits
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
  • Creatinine =< 2 X upper limit of normal (ULN); if creatinine level > 2 X ULN, then creatinine clearance must be > 60 mL/min
  • 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
  • Participant must agree to and arrange for a caregiver (age ≥ 18 years old) available 24 hours a day/ 7 days a week and arrange for lodging within 45 minutes drive to Roswell Park and transportation for a period of time after discharge from the hospital. The exact amount of time will depend on the individual status as determined by the treating physician

Exclusion Criteria:

  • Patients may not be receiving any other investigational agents
  • Known cases of clinically active brain metastases (brain MRI as clinically indicated). Prior evidence of brain metastasis successfully treated with surgery or radiation therapy will not be exclusion for participation as long as they are deemed under control at the time of study enrollment
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to agents used in the study
  • Prior malignancy (except non melanoma skin cancer) within 3 years
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 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 and topical steroids are 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 human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or cytomegalovirus (CMV) as defined below, due to the immunosuppressive effects of chemo-conditioning used and the unknown risks associated with viral replication

    • Positive serology for HIV
    • Active hepatitis B infection as determined by test for hepatitis B surface antigen (Ag)
    • Active hepatitis C. Patients will be screened for HCV antibody. If the HCV antibody is positive, a screening HCV ribonucleic acid (RNA) by any reverse transcriptase (RT) PCR or branched deoxyribonucleic acid (bDNA) assay must be performed at screening by a local laboratory with a Clinical Laboratory Improvement Act (CLIA) certification or its equivalent. Eligibility will be determined based on a negative screening value. The test is not required if documentation of a negative result of a HCV RNA test performed within 60 days prior to screening is provided.
    • Serology (CMV IgG) positive for active CMV
  • Received any previous gene therapy using an integrating vector within 6 months
  • Pregnancy or breast-feeding
  • Lack of availability of a patient for immunological and clinical follow up assessment
  • Evidence or history of significant cardiac disease (including MI in the past 6 months, significant cardiac arrhythmia, stage III or IV congestive heart failure [CHF]). Cardiac stress test will be done if clinically indicated. (The specific test to be chosen at the discretion of the principal investigator [PI])
  • Patients with pulmonary function test abnormalities as evidenced by a forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) < 70% of predicted for normality will be excluded

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): NCT03691376


Locations
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United States, New York
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
Contact: Kunle Odunsi    716-845-8376    kunle.odunsi@roswellpark.org   
Principal Investigator: Kunle Odunsi         
Sponsors and Collaborators
Roswell Park Cancer Institute
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Kunle Odunsi Roswell Park Cancer Institute

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Responsible Party: Roswell Park Cancer Institute
ClinicalTrials.gov Identifier: NCT03691376     History of Changes
Other Study ID Numbers: i 287616
NCI-2018-01758 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
i 287616 ( Other Identifier: Roswell Park Cancer Institute )
P30CA016056 ( U.S. NIH Grant/Contract )
First Posted: October 1, 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
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Carcinoma
Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Fallopian Tube Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Fallopian Tube Diseases
Aldesleukin
Melphalan
Mechlorethamine
Nitrogen Mustard Compounds
Interleukin-2
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs