Patient case: 71-year-old female with lung cancer; genetic feature: ROS1

Clinical trial: MAGE A10ᶜ⁷⁹⁶T for Advanced NSCLC

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.

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 with measurable disease 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 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 treating subjects in Group 1 and a 7-day stagger between treating subjects in Groups 2 and 3.
  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.
  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.

Eligibility: 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 Subjects with known EGFR mutations or ALK or ROS1 gene rearrangements have failed (progressive disease or unacceptable toxicity) prior EGFR or ALK or ROS1 tyrosine kinase inhibitor (TKI), respectively. There is no limit on lines of prior anti-cancer therapy.
  4. Measurable disease according to RECIST v1.1 criteria.
  5. Subject is HLA-A*02:01 and/or HLA-A*02:06 positive.
  6. 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.
  7. ECOG Performance Status 0-1 and anticipated life expectancy >3 months.
  8. Subject has left ventricular ejection fraction ≥50%.
  9. Subject is fit for leukapheresis and has adequate venous access for the cell collection.
  10. 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 maximally 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).
  11. 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 platinum-containing regimen and has PD. Subject may have received PD-1 or PDL-1 inhibitors; there is no limit to lines of prior anti-cancer therapy.
  Or
  2. Subject has persistent, measurable disease following 4-6 cycles of chemotherapy.
  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 4 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.
  -  Tyrosine kinase inhibitors (TKI) (e.g. erlotinib, gefitinib) or any other anti-cancer treatment within 1 week prior to leukapheresis;
  -  Investigational treatment within 4 weeks prior to leukapheresis;
  -  Experimental anti-cancer vaccine within 2 months prior to leukapheresis in the absence of response or in the opinion of the Investigator is responding to an experimental vaccine given within 6 months 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 active brain or leptomeningeal metastases. Subjects with prior history of brain metastasis who have undergone local therapy (i.e., metastasectomy and/or radiation) and show no evidence of local recurrence or PD over the past 3 months prior to screening are 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

Relevance to patient case: not relevant