Patient case: 38-year-old male with melanoma; genetic feature: BRAF (K601E)

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

Summary: 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.

Detailed description: This Phase 1 study is designed as a cell dose escalation trial evaluating the safety of MAGE A10ᶜ⁷⁹⁶T cell therapy in subjects with inoperable or metastatic urothelial cancer, melanoma or head and neck cancers. Anti-tumor activity and other exploratory objectives will be assessed. Subjects enter from a Screening Protocol (ADP-0000-001) and are positive for HLA-A2*02:01 and/or HLA-A*02:06, negative for HLA-A*02:05, HLA-B*15:01 or HLA-B*46:0 and have tumors that express MAGE-A10. 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.
  Leukapheresis is performed to obtain cells for the manufacture of autologous MAGE A10ᶜ⁷⁹⁶T 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 multiple visits outlined in the Schedule of Procedures. Anti-tumor activity will be assessed using RECIST v1.1 criteria at week 6, 12, 18 and 24 months and every 3 months up to year 2 and every 6 months from year 2-5.
  In accordance with FDA requirements for gene therapy clinical trials, long term monitoring of subjects for gene therapy related delayed adverse events (Long term follow-up, LTFU) continues for 15 years after the T cell infusion. Subjects in this study will enroll in a long term follow up study for these safety assessments. All subjects will continue to be followed for overall survival during the LTFU phase.

Eligibility: A subject must meet the following inclusion criteria to be eligible for participation in this study:
  Inclusion Criteria:
  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 on study entry.
  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, HLA-B*15:01 and/or HLA-B*46:01 positive.
  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 known active brain or leptomeningeal metastases. Subjects with prior history of brain metastasis who have undergone local therapy (i.e., metastatectomy and/or radiation) and show no evidence of local recurrence or progression over the past 3 months prior to Screening are eligible.
  8. 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.
  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.

Relevance to patient case: not relevant