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出境医 / 临床实验 / A Study of Gene Edited Autologous Neoantigen Targeted TCR T Cells With or Without Anti-PD-1 in Patients With Solid Tumors

A Study of Gene Edited Autologous Neoantigen Targeted TCR T Cells With or Without Anti-PD-1 in Patients With Solid Tumors

Study Description
Brief Summary:
This is a first in human, single arm, open label, Phase 1a/1b study to determine the safety, feasibility, and efficacy of a single dose of NeoTCR-P1 T cells in participants with solid tumors.

Condition or disease Intervention/treatment Phase
Solid Tumor Biological: NeoTCR-P1 adoptive cell therapy Biological: nivolumab Biological: IL-2 Phase 1

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 148 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1a/1b, Open-label First-in-human Study of the Safety, Tolerability and Feasibility of Gene-edited Autologous NeoTCR-T Cells (NeoTCR-P1) Administered as a Single Agent or in Combination With Anti-PD-1 to Patients With Locally Advanced or Metastatic Solid Tumors
Actual Study Start Date : July 3, 2019
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2024
Arms and Interventions
Arm Intervention/treatment
Experimental: NeoTCR-P1
Single dose of NeoTCR-P1
 Biological: NeoTCR-P1 adoptive cell therapy
The investigational agent in this protocol is NeoTCR P1, an autologous adoptive T cell therapy (ACT) for patients with solid cancer. NeoTCR P1 is composed of apheresis derived CD8 and CD4 T cells that are precision genome engineered to express one autologous TCR of native sequence that targets a neoepitope (neoE) presented by human leukocyte antigen (HLA) receptors exclusively on the surface of that patient's tumor cells and not on other cells in the body.
Experimental: NeoTCR-P1 plus nivolumab
Single dose of NeoTCR-P1 plus nivolumab 480mg IV every four weeks for up to 6 doses.
 Biological: NeoTCR-P1 adoptive cell therapy
The investigational agent in this protocol is NeoTCR P1, an autologous adoptive T cell therapy (ACT) for patients with solid cancer. NeoTCR P1 is composed of apheresis derived CD8 and CD4 T cells that are precision genome engineered to express one autologous TCR of native sequence that targets a neoepitope (neoE) presented by human leukocyte antigen (HLA) receptors exclusively on the surface of that patient's tumor cells and not on other cells in the body.

Biological: nivolumab
Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody
Other Name: Opdivo
Experimental: NeoTCR-P1 plus IL-2
Single dose of NeoTCR-P1 plus IL-2 500,000 IU/m2 SC twice daily (BID) for 7 days.
 Biological: NeoTCR-P1 adoptive cell therapy
The investigational agent in this protocol is NeoTCR P1, an autologous adoptive T cell therapy (ACT) for patients with solid cancer. NeoTCR P1 is composed of apheresis derived CD8 and CD4 T cells that are precision genome engineered to express one autologous TCR of native sequence that targets a neoepitope (neoE) presented by human leukocyte antigen (HLA) receptors exclusively on the surface of that patient's tumor cells and not on other cells in the body.

Biological: IL-2
IL-2 is a biologic response modifier. It is a type of protein called a cytokine.
Other Names:
  • Proleukin
  • aldesleukin
  • interleukin-2
Outcome Measures
Primary Outcome Measures :
  1. Incidence of adverse events as defined as DLTs [ Time Frame: 28 days ]
    Dose limiting toxicity (DLT) is defined as protocol-defined adverse events that occur within 28 days following infusion of Neo-TCR-P1 administered as a single agent without or with IL-2, or in combination with nivolumab.

  2. Number of participants with adverse events as a measure of safety and tolerability of NeoTCR-P1 or NeoTCR-P1 in combination with nivolumab [ Time Frame: 2 years ]
    Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). Cytokine release syndrome (CRS) and neurotoxicity associated with NeoTCR-P1 will be graded according to ASBMT consensus grading.

  3. Maximum Tolerated Dose (MTD) of NeoTCR-P1 [ Time Frame: 2 years ]
    The MTD is defined as the highest dose with an observed incidence of DLT in no more than one out of six patients treated at a particular dose level.

  4. Feasibility of manufacturing NeoTCR-P1 [ Time Frame: 2 years ]
    Percent of screened patients that enroll on study and receive NeoTCR-P1


Secondary Outcome Measures :
  1. Maximum concentration of NeoTCR-P1 (Cmax) in the peripheral blood [ Time Frame: 2 years ]
  2. Area-under-the-concentration-vs-time-curve (AUC) in the peripheral blood [ Time Frame: 28 days ]
  3. Persistence of NeoTCR-P1 in samples of peripheral blood [ Time Frame: 2 years ]
  4. Objective Response Rate (ORR) in participants with solid tumors following infusion of NeoTCR-P1 as a single agent or in combination with nivolumab [ Time Frame: 2 years ]
    ORR will be defined as Complete Response (CR) or Partial Response (PR) per RECIST v1.1, as determined by the investigator

  5. Duration of Response mediated by neoTCR-P1 administered as a single agent or in combination with nivolumab to participants with solid tumors [ Time Frame: 2 years ]
    Duration of response, defined as time from the first occurrence of a documented objective response to the time of relapse or death from any cause

  6. Progression free survival (PFS) in participants with solid tumors following infusion of NeoTCR-P1 as a single agent or in combination with nivolumab [ Time Frame: 2 years ]
    PFS is defined from date of administration of NeoTCR-P1 cell infusion to the date of disease progression per the RECIST v1.1 or death as a result of any cause. Subjects who do not meet criteria for progression by the analysis data cut-off date will be censored at their last evaluable disease assessment date

  7. Overall survival (OS) in participants with solid tumors following infusion of NeoTCR-P1 as a single agent or in combination with nivolumab [ Time Frame: 2 years ]
    OS will be measured from the date of administration of NeoTCR-P1 to the date of death. Subjects who have not died by the analysis data cut-off date will be censored at their last date of contact.


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

Inclusion Criteria:

  • Histologically or cytologically documented incurable or metastatic solid tumors of the following types: melanoma, UC, ovarian cancer, colorectal cancer, breast cancer (HR+), or prostate cancer.
  • Disease has progressed after at least one available standard therapy or no additional curative therapies are available.
  • Measurable disease per RECIST v1.1
  • Eastern cooperative oncology group (ECOG) performance status of 0 or 1
  • Adequate hematologic and end organ function determined within 30 days prior to enrollment.
  • Disease-specific criteria related to the specific tumor type are required.

Note: There are additional inclusion criteria. The study center will determine if you meet all of the criteria.

Exclusion Criteria:

  • Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, and/or inherited liver disease
  • Known primary central nervous system (CNS) malignancy or symptomatic CNS metastases
  • Uncontrolled or symptomatic hypercalcemia
  • Pregnancy, lactation, or breastfeeding
  • Prior allogeneic stem cell transplant or solid organ transplant
  • Prior chimeric antigen receptor therapy or other genetically modified T cell therapy
  • Active HIV, Hepatitis B, or Hepatitis C infection
  • Active tuberculosis
  • Severe infection within 2 weeks prior to enrollment
  • Major surgical procedure within 4 weeks prior to enrollment or anticipation of need for a major surgical procedure during the study.

Note: There are additional exclusion criteria. The study center will determine if you meet all of the criteria.

Contacts and Locations

Locations
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United States, California
City of Hope Recruiting
Duarte, California, United States, 91010
Contact: Ripa Martirosyan, MPH    626-218-2835    hmartirosyan@coh.org   
Principal Investigator: Mihaela Cristea, MD         
University of California, Los Angeles Recruiting
Los Angeles, California, United States, 90024
Contact: Elizabeth Seja    310-794-6892    eseja@mednet.ucla.edu   
Contact: Alyssa Serna         
Principal Investigator: Bartosz Chmielowski, MD         
University of California, Irvine Medical Center Recruiting
Orange, California, United States, 92868
Contact: UCLA-UCI Alpha Stem Cell Clinic    949-824-3990    stemcell@uci.edu   
Principal Investigator: Daniela Bota, MD         
University of California, Davis Recruiting
Sacramento, California, United States, 95817
Contact: Christina Romo    916-734-1455    crromo@ucdavis.edu   
Principal Investigator: Mehrdad Abedi, MD         
University of California, San Francisco Recruiting
San Francisco, California, United States, 94158
Contact: Marissa Gin    415-476-3816    marissa.gin@ucsf.edu   
Principal Investigator: David Oh, MD         
United States, Illinois
Northwestern University Medical Center Recruiting
Chicago, Illinois, United States, 60611
Contact: Cancer Trials    312-695-1102    cancertrials@northwestern.edu   
Principal Investigator: Jeffrey Sosman, M.D.         
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Jeffrey Lau    646-608-2091    LauJ1@mskcc.org   
Principal Investigator: Adam Schoenfeld, MD         
United States, Washington
Fred Hutchinson Cancer Research Center Recruiting
Seattle, Washington, United States, 98109
Contact: Monica Dherin    206-667-3403    mdherin@fredhutch.org   
Principal Investigator: Sylvia Lee, MD         
Sponsors and Collaborators
PACT Pharma, Inc.
Tracking Information
First Submitted Date  ICMJE May 6, 2019
First Posted Date  ICMJE May 31, 2019
Last Update Posted Date May 3, 2021
Actual Study Start Date  ICMJE July 3, 2019
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 21, 2020)
  • Incidence of adverse events as defined as DLTs [ Time Frame: 28 days ]
    Dose limiting toxicity (DLT) is defined as protocol-defined adverse events that occur within 28 days following infusion of Neo-TCR-P1 administered as a single agent without or with IL-2, or in combination with nivolumab.
  • Number of participants with adverse events as a measure of safety and tolerability of NeoTCR-P1 or NeoTCR-P1 in combination with nivolumab [ Time Frame: 2 years ]
    Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). Cytokine release syndrome (CRS) and neurotoxicity associated with NeoTCR-P1 will be graded according to ASBMT consensus grading.
  • Maximum Tolerated Dose (MTD) of NeoTCR-P1 [ Time Frame: 2 years ]
    The MTD is defined as the highest dose with an observed incidence of DLT in no more than one out of six patients treated at a particular dose level.
  • Feasibility of manufacturing NeoTCR-P1 [ Time Frame: 2 years ]
    Percent of screened patients that enroll on study and receive NeoTCR-P1
Original Primary Outcome Measures  ICMJE
 (submitted: May 30, 2019)
  • Incidence of adverse events as defined as DLTs [ Time Frame: 28 days ]
    Dose limiting toxicity (DLT) is defined as protocol-defined adverse events that occur within 28 days following infusion of Neo-TCR-P1 administered as a single agent or in combination with nivolumab.
  • Number of participants with adverse events as a measure of safety and tolerability of NeoTCR-P1 or NeoTCR-P1 in combination with nivolumab [ Time Frame: 2 years ]
    Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). Cytokine release syndrome (CRS) and neurotoxicity associated with NeoTCR-P1 will be graded according to ASBMT consensus grading.
  • Maximum Tolerated Dose (MTD) of NeoTCR-P1 [ Time Frame: 2 years ]
    The MTD is defined as the highest dose with an observed incidence of DLT in no more than one out of six patients treated at a particular dose level.
  • Feasibility of manufacturing NeoTCR-P1 [ Time Frame: 2 years ]
    Percent of screened patients that enroll on study and receive NeoTCR-P1
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 30, 2019)
  • Maximum concentration of NeoTCR-P1 (Cmax) in the peripheral blood [ Time Frame: 2 years ]
  • Area-under-the-concentration-vs-time-curve (AUC) in the peripheral blood [ Time Frame: 28 days ]
  • Persistence of NeoTCR-P1 in samples of peripheral blood [ Time Frame: 2 years ]
  • Objective Response Rate (ORR) in participants with solid tumors following infusion of NeoTCR-P1 as a single agent or in combination with nivolumab [ Time Frame: 2 years ]
    ORR will be defined as Complete Response (CR) or Partial Response (PR) per RECIST v1.1, as determined by the investigator
  • Duration of Response mediated by neoTCR-P1 administered as a single agent or in combination with nivolumab to participants with solid tumors [ Time Frame: 2 years ]
    Duration of response, defined as time from the first occurrence of a documented objective response to the time of relapse or death from any cause
  • Progression free survival (PFS) in participants with solid tumors following infusion of NeoTCR-P1 as a single agent or in combination with nivolumab [ Time Frame: 2 years ]
    PFS is defined from date of administration of NeoTCR-P1 cell infusion to the date of disease progression per the RECIST v1.1 or death as a result of any cause. Subjects who do not meet criteria for progression by the analysis data cut-off date will be censored at their last evaluable disease assessment date
  • Overall survival (OS) in participants with solid tumors following infusion of NeoTCR-P1 as a single agent or in combination with nivolumab [ Time Frame: 2 years ]
    OS will be measured from the date of administration of NeoTCR-P1 to the date of death. Subjects who have not died by the analysis data cut-off date will be censored at their last date of contact.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Gene Edited Autologous Neoantigen Targeted TCR T Cells With or Without Anti-PD-1 in Patients With Solid Tumors
Official Title  ICMJE A Phase 1a/1b, Open-label First-in-human Study of the Safety, Tolerability and Feasibility of Gene-edited Autologous NeoTCR-T Cells (NeoTCR-P1) Administered as a Single Agent or in Combination With Anti-PD-1 to Patients With Locally Advanced or Metastatic Solid Tumors
Brief Summary This is a first in human, single arm, open label, Phase 1a/1b study to determine the safety, feasibility, and efficacy of a single dose of NeoTCR-P1 T cells in participants with solid tumors.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Solid Tumor
Intervention  ICMJE
  • Biological: NeoTCR-P1 adoptive cell therapy
    The investigational agent in this protocol is NeoTCR P1, an autologous adoptive T cell therapy (ACT) for patients with solid cancer. NeoTCR P1 is composed of apheresis derived CD8 and CD4 T cells that are precision genome engineered to express one autologous TCR of native sequence that targets a neoepitope (neoE) presented by human leukocyte antigen (HLA) receptors exclusively on the surface of that patient's tumor cells and not on other cells in the body.
  • Biological: nivolumab
    Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody
    Other Name: Opdivo
  • Biological: IL-2
    IL-2 is a biologic response modifier. It is a type of protein called a cytokine.
    Other Names:
    • Proleukin
    • aldesleukin
    • interleukin-2
Study Arms  ICMJE
  • Experimental: NeoTCR-P1
    Single dose of NeoTCR-P1
    Intervention: Biological: NeoTCR-P1 adoptive cell therapy
  • Experimental: NeoTCR-P1 plus nivolumab
    Single dose of NeoTCR-P1 plus nivolumab 480mg IV every four weeks for up to 6 doses.
    Interventions:
    • Biological: NeoTCR-P1 adoptive cell therapy
    • Biological: nivolumab
  • Experimental: NeoTCR-P1 plus IL-2
    Single dose of NeoTCR-P1 plus IL-2 500,000 IU/m2 SC twice daily (BID) for 7 days.
    Interventions:
    • Biological: NeoTCR-P1 adoptive cell therapy
    • Biological: IL-2
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 30, 2019) 		148
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2024
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically or cytologically documented incurable or metastatic solid tumors of the following types: melanoma, UC, ovarian cancer, colorectal cancer, breast cancer (HR+), or prostate cancer.
  • Disease has progressed after at least one available standard therapy or no additional curative therapies are available.
  • Measurable disease per RECIST v1.1
  • Eastern cooperative oncology group (ECOG) performance status of 0 or 1
  • Adequate hematologic and end organ function determined within 30 days prior to enrollment.
  • Disease-specific criteria related to the specific tumor type are required.

Note: There are additional inclusion criteria. The study center will determine if you meet all of the criteria.

Exclusion Criteria:

  • Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, and/or inherited liver disease
  • Known primary central nervous system (CNS) malignancy or symptomatic CNS metastases
  • Uncontrolled or symptomatic hypercalcemia
  • Pregnancy, lactation, or breastfeeding
  • Prior allogeneic stem cell transplant or solid organ transplant
  • Prior chimeric antigen receptor therapy or other genetically modified T cell therapy
  • Active HIV, Hepatitis B, or Hepatitis C infection
  • Active tuberculosis
  • Severe infection within 2 weeks prior to enrollment
  • Major surgical procedure within 4 weeks prior to enrollment or anticipation of need for a major surgical procedure during the study.

Note: There are additional exclusion criteria. The study center will determine if you meet all of the criteria.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03970382
Other Study ID Numbers  ICMJE PACT-0101
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party PACT Pharma, Inc.
Study Sponsor  ICMJE PACT Pharma, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account PACT Pharma, Inc.
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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