PHASE 1 CELL DOSE ESCALATION STUDY TO ASSESS THE SAFETY AND TOLERABILITY OF GENETICALLY ENGINEERED MAGE-A10 C796T IN HLA-A2+ SUBJECTS WITH MAGE-A10 POSITIVE UROTHELIAL, MELANOMA OR HEAD AND NECK TUMORS

T cells are a type of white blood cell that work as a part of your immune system. In this study, your own T cells will be collected and genetically changed to make the MAGE-A10 study drug. The study drug is designed to use your genetically changed T cells to specifically target and attack cancer cells. The goal of this clinical research study is to find the highest tolerable dose of the study drug that can be safely given to cancer patients. Researchers also want to learn about possible side effects of the study drug and if the study drug can help to control the disease. This is the first study using the MAGE-A10 study drug in humans.

Disease Group: Malignant neoplasms of ill-defined secondary and unspecified sites,Malignant neoplasms of urinary tract,Melanoma and other malignant neoplasms of skin

Treatment Agent: Cyclophosphamide,Fludarabine,MAGE-A10c796T,MESNA,Neupogen

Treatment Location: Both at MDACC & and Other Sites

Sponsor: STRATEGIC ALLIANCE: Adaptimmune, LLC

Key Objectives To evaluate the safety and tolerability of autologous genetically modified T cells (MAGE-A10c796T) in subjects with HLA-A*02:01 and/or HLA-A*02:06 and MAGE-A10 positive inoperable or metastatic tumors. To evaluate the anti-tumor activity of autologous genetically modified T cells (MAGE-A10c796T) in HLA-A*02:01 and/or HLA-A*02:06 subjects with MAGE-A10 positive inoperable or metastatic tumors. Exploratory Objectives To evaluate the persistence, phenotype and functionality of MAGE-A10c796T To understand mechanisms of resistance to MAGE-A10c796T To evaluate antigen spreading as a mechanism of response

IRB Review and Approval Date: 12/09/2016

Recruitment Status: Open

Projected Accrual: 22

1) Subject (or legally authorized representative) has voluntarily agreed to participate by giving written informed consent (and assent as applicable) 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.
6) Subject has the following disease specific requirements for their tumor type: (A) 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. (B) 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. (C) 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/ MDACC PA15-0890).
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/ MDACC PA15-0890).
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).
14) (continued from 13) 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.
15) Subject must have adequate organ function as indicated by the following laboratory values- Hematological: Absolute neutrophil count (ANC) >/= 1.0 x10^9/L (without G-CSF support), Platelets >/= 75 x10^9/L, Hemoglobin > 80 g/L (without transfusion support within 7 days prior to leukapheresis); Coagulation: 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; Renal: Calculated or measured creatinine clearance >/= 40 mL/min;
16) (continued from 15) Hepatic: Serum total bilirubin </= 1.5 x ULN (unless subject has documented Gilbert’s Syndrome), Alanine aminotransferase (ALT)/Serum Glutamic Pyruvic Transaminase (SGPT) </= 2.5x ULN. Creatinine Clearance will be calculated using the Cockcroft-Gault Method for subjects <65 years of age: Creatinine clearance=((140-age)×weight kg)/(2 ×serum creatinine mg/dl)(×0.85 in females) Subjects’ >/=65 years of age must have renal function measured either by 24-hour urine creatinine collection or by nuclear medicine EDTA GFR measurement, according to standard practice at the treating institution.

1) Subject is HLA-A*02:05, HLA-B*15:01 and/or HLA-B*46:01 positive.
2) Subject has received or plans to receive the following excluded therapy/treatment prior to leukapheresis: Cytotoxic chemotherapy within 3 weeks; Small Molecule/Tyrosine kinase inhibitor (TKI) (Note: no washout period is required for EGFR and ALK/ROS-1 inhibitors unless the multi-kinase inhibitor targets VEGFR (e.g. afatinib), -PDGFR, or -c-Kit receptors) within 1 week; Immune therapy (including monoclonal antibody therapy, checkpoint inhibitors) within 2 weeks; Experimental anti-cancer Vaccine within 2 months in the absence of tumor response (the subject should be excluded if their disease is responding to an experimental vaccine given within 6 months); Gene therapy using an integrating vector (any use of previous gene therapy using an integrating vector is not permitted); Corticosteroids or any other immunosuppressive therapy. NOTE: Use of inhaled or topical steroids is not an exclusion within 2 weeks; Investigational treatment within 4 weeks; radiation to the pelvis within 4 weeks;
3) (continued from 2) NOTE: Duration of any other anti-cancer therapies must be discussed with the Sponsor Study Physician. Subject has received or plans to receive the following excluded therapy/treatment prior to lymphodepletion: Cytotoxic chemotherapy within 3 weeks; Small Molecule/Tyrosine kinase inhibitor (TKI) (Note: no washout period is required for EGFR and ALK/ROS-1 inhibitors unless the multi-kinase inhibitor targets VEGFR (e.g. afatinib), -PDGFR, or -c-Kit receptors) within 1 week; Immune therapy (including monoclonal antibody therapy, checkpoint inhibitors) within 2 weeks; Experimental anti-cancer Vaccine within 2 months in the absence of tumor response (the subject should be excluded if their disease is responding to an experimental vaccine given within 6 months); Gene therapy using an integrating vector (any use of previous gene therapy using an integrating vector is not permitted); Corticosteroids or any other immunosuppressive therapy.
4) (Continued from #2) [NOTE: Duration of any other anti-cancer therapies must be discussed with the Sponsor Study Physician]
5) 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.
6) 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.
7) 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.
8) Subject had major surgery within 4 weeks prior to lymphodepletion; subjects should have been fully recovered from any surgical related toxicities.
9) Subject has known symptomatic CNS metastases. Subjects with prior history of symptomatic CNS metastases must have received treamtent (i.e. stereotactic radiosurgery (SRS), whole brain radiation (WBRT) or surgery and be neurological stable for at least 1 month, not requiring anti-seizure medication and off of steroid for at least 14 days prior to leukapharesis and lymphodepletion. Subject who has asymptomic 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.
10) Subject has any other active malignancy besides the tumor under study 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.
11) 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.
12) 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).
13) Subjects who in the opinion of the Investigator will be unlikely to fully comply with protocol requirements.
14) 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 month. - 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. Re-screening for infectious disease markers is not required at baseline (prior to lymphodepletion).
15) Subject is pregnant or breastfeeding.

713-563-1930

Phone Number: 1-877-MDA-6789

clinicaltrials.gov NCT No: NCT02989064