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MAGE-A10ᶜ⁷⁹⁶T for Urothelial Cancer, Melanoma or Head and Neck Cancers

This study is currently recruiting participants.
Verified October 2017 by Adaptimmune
Sponsor:
ClinicalTrials.gov Identifier:
NCT02989064
First Posted: December 12, 2016
Last Update Posted: November 1, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Adaptimmune
  Purpose
This study will investigate the safety and tolerability of MAGE A10ᶜ⁷⁹⁶T cell therapy in subjects who have the appropriate HLA-A2 tissue marker and whose melanoma or bladder or head and neck tumor has the MAGE-A10 protein expressed. This study will take a subject's T cells and give them a T cell receptor protein that recognizes and attacks the tumors.

Condition Intervention Phase
Urinary Bladder Cancer Head and Neck Cancer Melanoma Genetic: Autologous genetically modified MAGE A10ᶜ⁷⁹⁶T cells Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1 Cell Dose Escalation Study to Assess the Safety and Tolerability of Genetically Engineered MAGE-A10ᶜ⁷⁹⁶T in HLA-A2+ Subjects With MAGE-A10 Positive Urothelial, Melanoma or Head and Neck Tumors

Resource links provided by NLM:


Further study details as provided by Adaptimmune:

Primary Outcome Measures:
  • Number of subjects with adverse events (AE), including serious adverse events (SAE). [ Time Frame: 3 years ]
    Determine if treatment with autologous genetically modified T cells, (MAGE A10ᶜ⁷⁹⁶T ) is safe and tolerable through laboratory assessments including chemistry, hematology, coagulation and anti-MAGE-A10 antibodies; and cardiac assessments, including ECG/troponin.

  • Evaluation of the persistence of genetically modified T cells [ Time Frame: 3 years ]
    Evaluation of the persistence of the infused T cells in the periphery.

  • Measurement of RCL in genetically modified T cells. [ Time Frame: 3 years ]
    Evaluation of RCL in Subject PBMCs using PCR-based assay.

  • Proportion of subjects with a confirmed Complete Response (CR) and/or Partial Response (PR). [ Time Frame: 3 years ]
    Evaluation of the efficacy of the treatment by assessment of the Overall Response Rate according to RECIST v1.1

  • Interval between the date of first T cell infusion dose and first documented evidence of CR or PR. [ Time Frame: 3 years ]
    Evaluation of the efficacy of the treatment by assessment of time to first response.

  • 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: 3 years ]
    Evaluation of the efficacy of the treatment by assessment of duration of response.

  • Interval between the date of first documented evidence of SD until first documented disease progression or death due to any cause. [ Time Frame: 3 years ]
    Evaluation of the efficacy of the treatment by assessment of duration of stable disease.

  • Interval between the date of first T cell infusion and the earliest date of disease. progression or death due to any cause [ Time Frame: 3 years ]
    Evaluation of the efficacy of the treatment by assessment of progression-free survival.

  • Interval between the date of first T cell infusion and date of death due to any cause. [ Time Frame: 3 years ]
    Evaluation of the efficacy of the treatment by assessment of overall survival.


Other Outcome Measures:
  • Mean fluorescence intensity (expression) of specific surface markers on gene-modified T cells. [ Time Frame: 3 years ]
    Killing profile and cytokine profile of genetically modified T cells will be evaluated using flow cytometry.

  • Evaluation of MAGE A10 expression pre and post infusion using IHC. [ Time Frame: 3 years ]
    Determine MAGE A10 expression post therapy.

  • Measure polymorphisms in cytokine genes. [ Time Frame: 3 years ]
    Association of polymorphisms with cytokine production.


Estimated Enrollment: 22
Study Start Date: October 2016
Estimated Study Completion Date: May 2020
Estimated Primary Completion Date: November 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Autologous genetically modified MAGE A10ᶜ⁷⁹⁶T cells Genetic: Autologous genetically modified MAGE A10ᶜ⁷⁹⁶T cells

Detailed Description:

This Phase 1 study is designed as a cell dose escalation trial in HLA-A2*02:01 and -A*02:06 subjects with MAGE-A10 positive urothelial, melanoma or head and neck tumors. 16-22 subjects with inoperable or metastatic (advanced) urothelial cancer, head and neck cancer, or melanoma will be treated in this study. The study will enroll subjects using a modified 3+3 cell dose escalation design to evaluate dose limiting toxicities and determine the target cell dose range. Following the dose escalation phase additional subjects will be enrolled until 10 subjects are treated at the target cell dose range to further characterize safety, tolerability and anti-tumor activity.

Subjects may be screened in the Screening Protocol (ADP-0000-001) for the presence of HLA-A2*02:01 and/or HLA-A*02:06 and have MAGE-A10 expression in the tumor. The absence of HLA-A*02:05 in either allele, HLA-B*15:01 or HLA-B*46:01 will also be assessed. The presence of HLA A*02 null allele (designated with an "N", e.g. A*02:32N) as the sole HLA-A*02 allele will also be assessed as these are study exclusion criteria.

Leukapheresis is performed to obtain cells for the manufacture of autologous MAGE-A10ᶜ⁷⁹⁶T cell receptor (TCR) bearing T cells. Leukapheresis should be performed as soon as possible after the subject is determined to be eligible for study participation.

When the manufactured MAGE-A10ᶜ⁷⁹⁶T cells are available, subjects will undergo lymphodepleting chemotherapy with cyclophosphamide and fludarabine followed by infusion of MAGE-A10ᶜ⁷⁹⁶T on Day 1.

Safety and tolerability as well as anti-tumor activity and biomarker assessments to be conducted at each visit are outlined in the Schedule of Procedures. Anti-tumor activity will be assessed using RECIST v1.1 criteria.

All subjects, completing or withdrawing from the interventional portion of the study, will be rolled over to a long term follow-up (LTFU) protocol for observation of delayed adverse events for 15 years post-infusion in accordance with FDA and EMA requirements for gene therapy clinical trials as well as for overall survival. FDA and EMA follow-up requirements for gene therapy clinical trials, continues after the subject has been confirmed to have progression of disease.

  Eligibility

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.


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

Subjects will be assessed for and must meet eligibility for study participation prior to leukapheresis AND prior to lymphodepleting chemotherapy (unless otherwise noted).

A subject must meet the following inclusion criteria to be eligible for participation in this study:

Inclusion Criteria:

  1. Subject has voluntarily agreed to participate by giving written informed consent in accordance with ICH GCP guidelines and applicable local regulations.
  2. Subject has agreed to abide by all protocol required procedures including study related assessments, and management by the treating institution for the duration of the study and long term follow-up.
  3. Subject is ≥ 18 years of age at the time of signing the study informed consent.
  4. Subject has histologically confirmed diagnosis of any one of the following cancers: (A) urothelial cancer (transitional cell cancer of the bladder, ureter or renal pelvis), (B) melanoma, or (C) squamous cell carcinoma of the head and neck.
  5. Subject has measurable disease according to RECIST 1.1 criteria prior to lymphodepletion. Measurable disease is not required prior to leukapheresis.
  6. Subject has the following disease specific requirements for their tumor type:

    • Inoperable or metastatic (advanced) urothelial cancer

      • Has received a platinum containing regimen in the adjuvant or metastatic setting or is ineligible for, or has refused platinum as part of the prior chemotherapy regimen; may have received prior immunotherapy.
    • Inoperable or metastatic (advanced) melanoma

      • Has received a PD-1 inhibitor and/or a CTLA-4 inhibitor.
      • Has received BRAF inhibitor or the combination of BRAF and MEK inhibitors for BRAFv600 mutant melanoma.
    • Inoperable or metastatic (advanced) squamous cell head and neck cancer

      • May have received a platinum containing chemotherapy for treatment of primary tumor in adjuvant or metastatic setting or refused such treatment. May have received prior immunotherapy.
  7. Subject is HLA-A*02:01 and/or HLA-A*02:06 positive. (This determination will be made under screening protocol ADP-0000-001).
  8. Subject's tumor (either an archival specimen or a fresh biopsy) shows positive MAGE-A10 expression. The threshold requirement for MAGE-A10 expression by IHC is defined in the Study Procedures Manual. All samples must have been pathologically reviewed by an Adaptimmune designated central laboratory confirming expression. (This determination will be made under screening protocol ADP-0000-001).
  9. Subject has anticipated life expectancy >3 months
  10. Subject has an ECOG Performance Status 0-1.
  11. Subject has a left ventricular ejection fraction ≥50%.
  12. Subject is fit for leukapheresis and has adequate venous access for the cell collection.
  13. Female subject of childbearing potential (FCBP) must have a negative urine or serum pregnancy test. NOTE: FCBP is defined as premenopausal and not surgically sterilized. FCBP must agree to use maximally effective birth control or to abstain from heterosexual activity throughout the study, starting at the first dose of chemotherapy for 12 months after receiving the investigational product, or 4 months after there is no evidence of persistence/gene modified cells in the subject's blood, whichever is longer.

Adequate contraceptive methods for females include: intra-uterine device, injectable hormonal contraception, oral 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 subject 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.

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

  • Absolute Neutrophil count (ANC) ≥ 1.0 x10⁹/L (without G-CSF support)
  • Platelets ≥ 75 x10⁹/L
  • Hemoglobin> 80 g/L (without transfusion support within 7 days prior to leukapheresis)
  • 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

Exclusion Criteria:

A subject meeting any of the following criteria is not eligible for participation in the study:

  1. Subject is HLA-A*02:05 in either allele, HLA-B*15:01 and/or HLA-B*46:01 positive. Subject has any A*02 null allele (designated with an "N", e.g. A*02:32N) as the sole HLA-A*02 allele.
  2. Subject has received or plans to receive the excluded therapy/treatment prior to leukapheresis or lymphodepleting chemotherapy (see protocol)
  3. Subject that has toxicity from previous anti-cancer therapy must have recovered to ≤ Grade 1 prior to enrollment (except for non-clinically significant toxicities, e.g., alopecia, vitiligo). Subjects with Grade 2 toxicities that are deemed stable or irreversible e.g. peripheral neuropathy) can be enrolled.
  4. Subject has history of allergic reactions attributed to compounds of similar chemical or biologic composition to fludarabine, cyclophosphamide or other agents used in the study.
  5. Subject has history of chronic or recurrent (within the last year prior to screening) severe autoimmune or immune mediated disease requiring steroids or other immunosuppressive treatments.
  6. Subject had major surgery within 4 weeks prior to lymphodepletion; subjects should have been fully recovered from any surgical related toxicities.
  7. Subject has symptomatic CNS metastases. Subject with a prior history of symptomatic CNS metastases must have received treatment (i.e., stereotactic radiosurgery (SRS), whole brain radiation (WBRT) or surgery) and be neurologically stable for at least 1 month, not requiring anti-seizure medications and off of 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.
  8. Subject has any other active malignancy besides the tumor under study within 3 years prior to Screening (prior to leukapheresis and prior to lymphodepletion). 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.
  9. Subject has an electrocardiogram (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. Either Fridericia's or Bazett's formula may be used to correct the QT interval.
  10. Subject has uncontrolled intercurrent illness including, but not limited to:

    • Ongoing or active infection
    • Clinically significant cardiac disease defined by CHF New York Heart Association (NYHA) > Class1; uncontrolled clinically significant arrhythmia in last 6 months; Acute Coronary Syndrome (ACS) (angina or MI) in last 6 months
    • 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. Subject has active infection with HIV, HBV, HCV or HTLV as defined below:

    • Positive serology for HIV
    • Positive HBV surface antigen test. Positive HBV DNA test. Subjects who are hepatitis B surface antigen negative but are hepatitis B core antibody positive must have undetectable hepatitis B DNA and receive prophylaxis against viral reactivation. Prophylaxis should be initiated prior to lymphodepleting therapy and continued for 6 months.
    • Positive hepatitis C RNA test. Subjects who are HCV antibody positive will be screened for HCV RNA by any RT PCR or bDNA assay. If HCV antibody is positive, eligibility will be determined based on a negative screening RNA value
    • Positive serology for HTLV 1 or 2
  13. Subject is pregnant or breastfeeding.
  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): NCT02989064


Contacts
Contact: David Hong, MD 713-563-1930

Locations
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Ryan Sullivan, MD    617-724-4000    rsullivan7@partners.org   
Principal Investigator: Ryan Sullivan, MD         
United States, Tennessee
Tennessee Oncology - Sarah Cannon Research Institute Recruiting
Nashville, Tennessee, United States, 37203
Contact: Amanda Mundy    615-329-7400    amanda.mundy@scresearch.net   
Contact: Allie Cooper         
Principal Investigator: Melissa Johnson, MD         
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Danxia Ke    713-792-4384    dke@mdanderson.org   
Contact: Ly M Nguyen         
Principal Investigator: David S Hong, MD         
Canada, Ontario
Princess Margaret Cancer Centre Recruiting
Toronto, Ontario, Canada, M5G1X6
Contact: Marcus Butler, MD    416-946-4501    TIP@uhn.ca   
Contact: Anna Spreafico         
Principal Investigator: Marcus Butler, MD         
Sponsors and Collaborators
Adaptimmune
Investigators
Principal Investigator: David Hong, MD M.D. Anderson Cancer Center
  More Information

Responsible Party: Adaptimmune
ClinicalTrials.gov Identifier: NCT02989064     History of Changes
Other Study ID Numbers: ADP-0022-004
First Submitted: November 7, 2016
First Posted: December 12, 2016
Last Update Posted: November 1, 2017
Last Verified: October 2017

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

Additional relevant MeSH terms:
Melanoma
Head and Neck Neoplasms
Urinary Bladder Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Neoplasms by Site
Urologic Neoplasms
Urogenital Neoplasms
Urinary Bladder Diseases
Urologic Diseases