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MAGE A10ᶜ⁷⁹⁶T for Advanced NSCLC

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ClinicalTrials.gov Identifier: NCT02592577
Recruitment Status : Recruiting
First Posted : October 30, 2015
Last Update Posted : January 11, 2018
Sponsor:
Information provided by (Responsible Party):

Study Description
Brief Summary:

This first time in human study is intended for men and women at least 18 years of age who have advanced lung cancer which has grown or returned after being treated. In particular, it is a study for subjects who have a blood test positive for HLA-A*02:01 and/or HLA-A*02:06 and a tumor test positive for MAGE A10 protein expression (protein or gene). The study will take the subject's T cells, which are a natural type of immune cell in the blood, and send them to a laboratory to be modified. The changed T cells used in this study will be the subject's own T cells that have been genetically changed with the aim of attacking and destroying cancer cells.

The manufacturing of T cells takes about 1 month to complete. The T cells will be given back to the subject through an intravenous infusion. The purpose of this study is to test the safety of genetically changed T cells and find out what effects, if any, they have in subjects with lung cancer. The study will evaluate three different cell dose levels in order to find out the target cell dose. Once the target cell dose is determined, additional subjects will be enrolled to further test the safety and effects at this cell dose.

Subjects will be seen frequently by the Study Physician right after receiving their T cells back and up to first 6 months. After that, subjects will be seen every three months. If subjects have disease progression or withdraw from the study, they will then be entered into a long-term follow up for safety monitoring. Subjects will be seen every 6 months by their Study Physician for the first 5 years after the T cell infusion. If the T cells are found in the blood at five years, then the subjects will continue to be seen once a year until the T cells are no longer found in the blood for a maximum of 15 years. If the T cells are no longer found in the blood at 5 years, then the subject will be contacted by the Study Physician for the next 10 years.


Condition or disease Intervention/treatment Phase
Non-Small Cell Lung Cancer Carcinoma Biological: Autologous Genetically modified T cells, MAGEA10ᶜ⁷⁹⁶T Phase 1

Detailed Description:

This first time in human study is a single-arm study of genetically engineered MAGE A10ᶜ⁷⁹⁶T cells in HLA-A*02:01 and/or HLA-A*02:06 positive subjects with advanced (Stage IIIb or IV) NSCLC. Subjects will be screened for general health, performance status and disease stage. Following screening, subjects meeting all eligibility will undergo a large-volume leukapheresis to obtain cells for the manufacture of autologous MAGE A10ᶜ⁷⁹⁶TCR bearing T cells. When the MAGE A10ᶜ⁷⁹⁶T cells are available, subjects will receive lymphodepleting chemotherapy with cyclophosphamide on Days -7 and -6 or cyclophosphamide and fludarabine on Days -7, Day -6, and Day -5 followed by the T cell infusion on Day 1.

This trial is a dose escalation trial that will evaluate 3 doses of transduced cells administered after a lymphodepleting chemotherapy regimen using a 3+3 dose escalation design. The doses for each cell dose group are as follows.

Group 1a and 1b: 0.1 x 10⁹ (range: 0.08 x 10⁹-0.12 x 10⁹) transduced cells. Group 2: 1 x 10⁹ (range: 0.8 x 10⁹- 1.2 x 10⁹) transduced cells. Group 3: 5 x 10⁹ (range: 1 x 10⁹- 6 x 10⁹) transduced cells.

There will be a 21-day staggering of treatment in between the first 3 subjects treated in the study. For subsequent subjects a 7-day stagger between treatments will be followed.

NOTE: If a DLT occurs in Group 1 or Group 2 which requires expansion of the group (n=6), then a 14-day stagger would be implemented in Group 2 or 3, respectively. The study will enroll 12-24 subjects to evaluate DLTs and determine target dose. The sample size of the target cell dose may be expanded up to 10 subjects to characterize safety and any preliminary evidence of antitumor activity. The Safety Review Committee (SRC) may recommend adding additional patients to a given group (not to exceed 9 subjects in total in any group apart from target dose expansion group) resulting in a potential maximum number of 37 subjects treated.

Subjects will visit the clinic for safety assessments daily from T cell infusion (Day 1) through Day 5, Days 8, 10, 12, and then weekly until week 6 and then at 8, 10, 12, 16, 20 and 24 weeks, and every 3 months until 2 years and then every 6 months until progression of their disease (or withdrawal of consent for the interventional portion of the study).

Subjects who have a confirmed response (or have stable disease for >4 months) but subsequent disease progression following the initial infusion and whose tumor continues to express the appropriate antigen target may be eligible for a second infusion.

All subjects, completing or withdrawing from the Interventional Phase of the study, will enter a 15-year long-term follow-up phase for observation of delayed adverse events. All subjects will continue to be followed for overall survival during the long-term follow-up phase.


Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 28 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Dose Escalation Open Label Clinical Trial Evaluating the Safety and Efficacy of MAGE A10ᶜ⁷⁹⁶T in Subjects With Stage IIIb or Stage IV Non-Small Cell Lung Cancer (NSCLC)
Study Start Date : November 2015
Estimated Primary Completion Date : April 2019
Estimated Study Completion Date : April 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer
U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: Autologous Genetically modified T cells, MAGEA10ᶜ⁷⁹⁶T Biological: Autologous Genetically modified T cells, MAGEA10ᶜ⁷⁹⁶T


Outcome Measures

Primary Outcome Measures :
  1. Number of subjects with dose-limiting toxicity (DLT) and adverse events (AE), including serious adverse events (SAE) [ Time Frame: 24 months ]
    Determine if treatment with autologous genetically modified T cells, (MAGE A10ᶜ⁷⁹⁶T ) is safe and tolerable through assessment of DLTs, AEs, including SAEs; laboratory assessments, including chemistry, hematology, and coagulation and anti-MAGE A10ᶜ⁷⁹⁶T antibodies; cardiac and pulmonary assessments, including ECG and pulmonary function (pulse oximetry), persistence of MAGE A10ᶜ⁷⁹⁶T, and circulating cytokines.


Secondary Outcome Measures :
  1. Proportion of subjects with a confirmed Complete Response (CR) or Partial Response (PR) [ Time Frame: 24 months ]
    Evaluation of the efficacy of the treatment by assessment of the Overall Response Rate according to RECIST v1.1

  2. Interval between the date of first T cell infusion dose and first documented evidence of CR or PR [ Time Frame: 24 months ]
    Evaluation of the efficacy of the treatment by assessment of time to first response

  3. Interval between the date of first documented evidence of CR or PR until first documented disease progression or death due to any cause [ Time Frame: 24 months ]
    Evaluation of the efficacy of the treatment by assessment of duration of response

  4. Interval between the date of first documented evidence of SD until first documented disease progression or death due to any cause [ Time Frame: 24 months ]
    Evaluation of the efficacy of the treatment by assessment of duration of stable disease

  5. Interval between the date of first T cell infusion and the earliest date of disease progression or death due to any cause [ Time Frame: 24 months ]
    Evaluation of the efficacy of the treatment by assessment of progression-free survival

  6. Interval between the date of first T cell infusion and date of disease progression or death due to any cause [ Time Frame: 24 months ]
    Evaluation of the efficacy of the treatment by assessment of overall survival


Other Outcome Measures:
  1. Correlation of MAGE A10ᶜ⁷⁹⁶T persistence, phenotype and functionality with response to treatment [ Time Frame: 24 months ]
    Flow cytometry will be used to assess the phenotype of transduced T cells in the manufactured product and in post-infusion samples.

  2. Investigation of antigen loss (MAGE A10) as an escape mechanism [ Time Frame: 24 months ]
    Assessment of expression of MAGE A10 in tumor samples after T cell infusion

  3. Correlation of clonal outgrowth of T cell populations with response following T cell infusion [ Time Frame: 24 months ]
    Assessment of the polyclonality status of the T cell population in peripheral blood (and tumor samples, if available) by TCR sequencing


Eligibility Criteria

Information from the National Library of Medicine

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

Inclusion Criteria:

  1. Subject has voluntarily agreed to participate by giving written informed consent
  2. Subject is ≥18 years of age
  3. Histologically or cytologically confirmed diagnosis of advanced non-small cell lung cancer (stage IIIB or IV) or recurrent disease
  4. Subjects with known EGFR mutations or ALK or ROS1 gene rearrangements have failed (progressive disease or unacceptable toxicity) at least one prior EGFR or ALK or ROS1 tyrosine kinase inhibitor (TKI), respectively. There is no limit on lines of prior anti-cancer therapy.
  5. Subject has received or is receiving at least one line of prior therapy
  6. Subject is HLA-A*02:01 and/or HLA-A*02:06 positive.
  7. Subject's tumor (either an archival specimen or a fresh biopsy if archival tissue is unavailable) has been pathologically reviewed by an Adaptimmune designated central laboratory confirming MAGE A10 expression.
  8. ECOG Performance Status 0-1 and anticipated life expectancy >3 months.
  9. Subject has left ventricular ejection fraction ≥50%.
  10. Subject is fit for leukapheresis and has adequate venous access for the cell collection.
  11. Female patients of childbearing potential (FPCP) must have a negative urine or serum pregnancy test. NOTE: FPCP is defined as premenopausal and not surgically sterilized. FPCP must agree to use effective birth control or to abstain from heterosexual activity throughout the study, starting at the first dose of lymphodepleting chemotherapy through 12 months after the infusion of cells or for 4 months after there is no evidence of persistence/ gene modified cells in the blood, whichever is longer. Effective contraceptive methods include intra-uterine device, oral or injectable hormonal contraception, or 2 adequate barrier methods (e.g. diaphragm with spermicide, cervical cap with spermicide, or female condom with spermicide). Spermicides alone are not an adequate method of contraception.

    Or Male subjects must be surgically sterile or agree to use a double barrier contraception method or abstain from heterosexual activity with a female of childbearing potential starting at the first dose of chemotherapy and for 4 months thereafter or longer (if indicated in the country specific monograph/label for cyclophosphamide).

  12. Subject must have adequate organ function as indicated by the following laboratory values in the table below:

    • Absolute Neutrophil count (ANC) ≥ 1.0 x 10⁹/L (without GCSF support)
    • Platelets ≥ 75 x 10⁹/L
    • Hemoglobin > 80 g/dL (without transfusion support within 7 days from start of chemotherapy)
    • Prothrombin Time or INR ≤ 1.5x upper limit of normal (ULN) unless receiving therapeutic anticoagulation.
    • Partial Thromboplastin Time (PTT) ≤ 1.5x upper limit of normal (ULN) unless receiving therapeutic anticoagulation.
    • Calculated or measured creatinine clearance ≥ 40 mL/min
    • Serum total bilirubin ≤ 1.5 x ULN (unless subject had documented Gilbert's Syndrome)
    • Alanine aminotransferase (ALT)/Serum Glutamic Pyruvic Transaminase (SGPT) ≤ 2.5x ULN

Prior to lymphodepleting chemotherapy, all subjects must meet the following inclusion criteria:

1. Subject has failed at least one prior line of therapy and has measurable disease according to RECIST 1.1. Subject may have received chemotherapy or PD-1 or PDL-1 inhibitors. Subjects with known EGFR mutations or ALK or ROS1 gene rearrangements have failed (PD or unacceptable toxicity) at least one prior EGFR or ALK or ROS1 tyrosine kinase inhibitor (TKI), respectively. There is no limit on lines of prior anti-cancer therapy.

Exclusion Criteria:

  1. Subject has received

    • cytotoxic chemotherapy within 3 weeks prior to leukapheresis;
    • Immune therapy (including monoclonal antibody therapy, checkpoint inhibitors) or biological therapy within 2 weeks prior to leukapheresis;
    • Corticosteroids or any other immunosuppressive therapy within 2 weeks prior to leukapheresis NOTE: recent or current use of inhaled or topical steroids is not exclusionary.
    • Small molecules/Tyrosine kinase inhibitors (TKI) or any other anti-cancer treatment associated with myelosuppression within 1 week prior to leukapheresis;
    • Investigational treatment within 4 weeks prior to leukapheresis;
    • Any prior gene therapy using an integrating vector
  2. Subject is HLA-A*02:05, HLA-B*15:01 and/or HLA-B*46:01 positive.
  3. Subject has toxicity from previous anti-cancer therapy that has not recovered to ≤ Grade 1 prior to enrollment (except for non-clinically significant toxicities, e.g., alopecia, vitiligo). Subjects with existing pneumonitis as a result of radiation are not excluded; however, subjects cannot be oxygen dependent.
  4. History of allergic reactions attributed to compounds of similar chemical or biologic composition to cyclophosphamide, fludarabine or other agents used in the study.
  5. History of chronic or recurrent (within the last year prior to enrollment) severe autoimmune or active immune-mediated disease requiring steroids or other immunosuppressive treatments.
  6. Subject has symptomatic CNS metastases. Subjects with prior history of symptomatic CNS metastasis must have received treatment (i.e., stereotactic radiosurgery (SRS), whole brain radiotherapy (WBRT) or surgery) and be neurologically stable for at least 1 month, not requiring anti-seizure medications and off steroids for at least 14 days prior to leukapheresis and lymphodepletion. Subject who has asymptomatic CNS metastatic disease without associated edema, shift, requirement for steroids or anti-seizure medications are eligible. If such a subject receives SRS or WBRT, a minimum period of 2 weeks needs to lapse between the therapy and lymphodepletion. Patients with leptomeningeal disease or carcinomatous meningitis are NOT eligible.
  7. Active malignancy besides NSCLC within 3 years prior to screening. Exceptions: adequately treated malignancies not likely to require therapy (e.g. completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma). Subjects must be in complete remission from prior malignancy in order to be eligible to enter the study.
  8. Unintended weight loss >10% in 6 months preceding study entry.
  9. ECG showing clinically significant abnormality at Screening or showing an average QTc interval ≥450 msec in males and ≥470 msec in females (≥480 msec for subjects with Bundle Branch Block (BBB) over 3 consecutive ECGs).
  10. Uncontrolled intercurrent illness including, but not limited to:

    • Ongoing or active infection;
    • Clinically significant cardiac disease defined by CHF New York Heart Association (NYHA) > Class 1; uncontrolled clinically significant arrhythmia in last 6 months; acute coronary syndrome (ACS) (angina or MI) in last 6 months;
    • Inadequate pulmonary function with mechanical parameters < 40% predicted (FEV1, FVC, TLC, DLCO);
    • Interstitial lung disease (subjects with existing pneumonitis as a result of radiation are not excluded; however, subjects cannot be oxygen dependent).
  11. Subjects who in the opinion of the Investigator will be unlikely to fully comply with protocol requirements.
  12. Active infection with HIV, HBV, HCV, or HTLV as minimally defined below:

    • Positive serology for HIV;
    • Active hepatitis B infection as determined by test for hepatitis B surface antigen;
    • Active hepatitis C infection as determined by hepatitis C RNA;
    • Positive serology for HTLV 1 or 2.
  13. Are pregnant or breastfeeding
  14. Additional exclusion criteria prior to lymphodepleting chemotherapy:

    • Cytotoxic chemotherapy within 3 weeks prior to lymphodepleting chemotherapy;
    • Immune therapy (including monoclonal antibody therapy, checkpoint inhibitors) or biological therapy within 2 weeks prior to lymphodepleting chemotherapy;
    • Corticosteroids or any other immunosuppressive therapy within 2 weeks prior to lymphodepleting chemotherapy; NOTE: A brief course of oral corticosteroids limited to less than 7 days is not exclusionary if completed 2 weeks prior to lymphodepleting chemotherapy; a recent or current use of inhaled or topical steroids is not exclusionary.
    • Experimental anti-cancer vaccine within 2 months prior to lymphodepletion in the absence of response or in the opinion of the Investigator is responding to an experimental vaccine given within 6 months prior to lymphodepletion;
    • Major surgery within 4 weeks prior to lymphodepleting chemotherapy; subjects must have recovered from any surgical-related toxicities in the opinion of the Investigator;
    • Radiotherapy that involves the lung (V20 exceeding 30% lung volume) or mean heart dose of >20Gy within 3 months prior to lymphodepleting chemotherapy; for a lesser dose of radiation exposure to lung/mediastinum than stated, administered within 4 weeks prior to lymphodepletion. Electron beam radiotherapy to superficial structures in the chest is permitted. Radiation to other vital organs (e.g., liver, spleen, GI tract) within 2 weeks prior to lymphodepletion. Radiotherapy to the pelvis within 4 weeks, NOTE: there is no washout period for palliative radiation to non-target organs other than the lung and mediastinum. If radiation was to an intended target lesion within 3 months of baseline imaging studies, and the lesion is progressing within this time frame it may be considered as a target lesion after review and discussion with the Sponsor.
Contacts and Locations

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): NCT02592577


Contacts
Contact: Ben Creelan, MD, MS 813-745-3050
Contact: Ani Suwarno

Locations
United States, California
City of Hope Recruiting
Duarte, California, United States, 91010
Principal Investigator: Karen Reckamp, MD         
Stanford Cancer Center Recruiting
Palo Alto, California, United States, 94304
Contact: Jordan S Preiss, BA    650-723-1002    jpreiss2@stanford.edu   
Contact: Melanie G San Pedro-Salcedo         
Principal Investigator: Joel W Neal, MD PhD         
United States, Florida
University of Miami Sylvester Comprehensive Cancer Center Recruiting
Miami, Florida, United States, 33136
Contact: Claudia M Grandas, RN, BSN    305-243-7530    cgrandas@med.miami.edu   
Contact: Michelle Mikhail         
Principal Investigator: Raja Mudad, M.D.         
H. Lee Moffitt Cancer Center Recruiting
Tampa, Florida, United States, 33612
Contact: Jeff L Edelman, MS    813-745-1040    Jeffrey.Edelman@moffitt.org   
Contact: Ani Suwarno    813-745-6779    Ani.Suwarno@moffitt.org   
Principal Investigator: Ben Creelan, MD, MS         
United States, Georgia
Winship Cancer Institute of Emory University Recruiting
Atlanta, Georgia, United States, 30322
Contact: Shantina N Walls, BS    404-778-4995    shantina.n.walls@emory.edu   
Contact: Ellie C Butler         
Principal Investigator: Taofeek K Owonikoko, MD, PhD         
United States, Maryland
University of Maryland, Greenebaum Cancer Center Recruiting
Baltimore, Maryland, United States, 21157
Contact: Brett Goldberger, MS    410-328-1160    brett.goldberger@umm.edu   
Contact: Maha Khalil         
Principal Investigator: Nancy Hardy, MD         
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Justin F Gainor, M.D.    617-724-4000    jgainor@partners.org   
Principal Investigator: Justin F Gainor, M.D.         
United States, Missouri
Washington University, School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Melissa Meredith    314-362-4140    mmeredit@dom.wustl.edu   
Contact: Molly Karl         
Principal Investigator: Ramaswamy Govindan, MD         
United States, Ohio
Ohio State University Wexner Medical Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Catherine Schweitzer    614-685-5414    catherine.schweitzer@osumc.edu   
Principal Investigator: Kai He, MD         
United States, Tennessee
Tennessee Oncology- Sarah Cannon Research Institute Recruiting
Nashville, Tennessee, United States, 37203
Contact    615-329-7400    asksarah@sarahcannon.com   
Principal Investigator: Melissa Johnson, MD         
United States, Texas
The University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Matthew Parker, RN    713-745-6767    mrparker@mdanderson.org   
Contact: Sylvia Y Contreras         
Principal Investigator: Vincent K Lam, MD         
Canada, Ontario
Princess Margaret Cancer Centre Recruiting
Toronto, Ontario, Canada, M5G1X6
Contact: Penelope Bradbury, MD    416-946-4501 ext 3544    TIP@uhn.ca   
Principal Investigator: Penelope Bradbury, MD         
United Kingdom
University College Hospital Macmillan Cancer Centre Recruiting
London, United Kingdom, WC1E 6AG
Contact: Gemma Hector    07852219920    Gemma.Hector@uclh.nhs.uk   
Contact: Krishna Patel       krishna.patel@uclh.nhs.uk   
Principal Investigator: Martin D Forster, MBBS, FRCP, PhD         
Sponsors and Collaborators
Adaptimmune
Investigators
Study Chair: Ben Creelan, MD, MS H. Lee Moffitt Cancer Center
More Information

Responsible Party: Adaptimmune
ClinicalTrials.gov Identifier: NCT02592577     History of Changes
Other Study ID Numbers: ADP 0022-003
First Posted: October 30, 2015    Key Record Dates
Last Update Posted: January 11, 2018
Last Verified: January 2018

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

Keywords provided by Adaptimmune:
Previously Treated
Cell Therapy
T Cell Therapy
MAGE-A10
Immuno-oncology
T Cell Receptor
Metastatic

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms