ADP-A2M4CD8 Monotherapy and in Combination With Nivolumab in HLA-A2+ Subjects With MAGE-A4 Positive Ovarian Cancer (SURPASS-3)

Exclusion Criteria

• •1. Positive for HLA-A\*02:05 in either allele as determined by Adaptimmune-designated central laboratory testing. HLA-A\*02 alleles having the same protein sequence as HLA-A\*02:05 in the peptide binding domains (P groups) will also be excluded. Other alleles may be exclusionary after adjudication with the Sponsor.
• •2. Subject has received or plans to receive the following therapy/treatment prior to to leukapheresis or lymphodepleting chemotherapy, unless stopped according to the washout requirements:
• •Cytotoxic chemotherapy Required Washout Prior to Leukapheresis 3 weeks Required Washout Prior to Lymphodepletion: 3 weeks
• •Small molecules/tyrosine kinase inhibitors (TKIs), such as dabrafenib, trametinib, vemurafenib, and cobimetinib Note: No washout period is required for compounds that do not cause bone marrow suppression/lymphopenia or for epidermal growth factor receptor and alkaline phosphatase/ ROS 1 inhibitors. Required Washout Prior to Leukapheresis 1 week Required Washout Prior to Lymphodepletion: 1 week
• •Immune therapy (including monoclonal antibody therapy, checkpoint inhibitors, and biologics) other than anti-PD(L)1 Required Washout Prior to Leukapheresis 2 weeks Required Washout Prior to Lymphodepletion: 2 weeks
• •Anti-PD(L)1 Required Washout Prior to Leukapheresis 2 weeks Required Washout Prior to Lymphodepletion: 6 weeks
• •Experimental anti-cancer vaccine Required Washout Prior to Leukapheresis: N/A Required Washout Prior to Lymphodepletion: Eight weeks 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 Subjects who have received a gene therapy using any DNA-integrating vector other than a lentivirus (retrovirus, Adeno-associated Virus (AAV), etc.) are excluded from this study. Use of previous gene therapy using a lentiviral vector is permitted. If transduced T-cells represent \< 1% of PBMCs (\< 1500 copies of vectors/μg of PBMC DNA) at the time of screening. Eligibility testing must be done by Adaptimmune's designated Contract Research Organization (CRO). Required Washout Prior to Lymphodepletion: N/A
• •Corticosteroids or any other immunosuppressive therapy Note: Use of topical or inhaled steroids is not an exclusion. See Section 6.5.1 for exceptions.
• •Required Washout Prior to Leukapheresis: 2 weeks Required Washout Prior to Lymphodepletion 2 weeks
• •Anti-MAGE-A4 therapy Note: Fresh screening biopsy post-anti-MAGE-A4 therapy must be obtained to confirm MAGE-A4 positivity by IHC. Required Washout Prior to Leukapheresis: 2 weeks Required Washout Prior to Lymphodepletion: 2 weeks
• •Investigational treatment Required Washout Prior to Leukapheresis 2 weeks or 5 half-lives, whichever is shorter Required Washout Prior to Lymphodepletion: 2 weeks or 5 half-lives, whichever is shorter.
• •Radiation to vital organs (e.g., liver, kidney) Required Washout Prior to Leukapheresis: N/A Required Washout Prior to Lymphodepletion: 4 weeks
• •Radiation to the pelvis Required Washout Prior to Leukapheresis: 4 weeks Required Washout Prior to Lymphodepletion: 4 weeks
• •Whole brain radiotherapy (WBRT) or brain stereotactic radiosurgery (SRS) Required Washout Prior to Leukapheresis N/A Required Washout Prior to Lymphodepletion: 2 weeks
• •Radiotherapy to the target lesions Required Washout Prior to Leukapheresis: N/A Required Washout Prior to Lymphodepletion: 3 months prior to lymphodepleting chemotherapy or a target lesion with progression post radiotherapy (Note: There is no washout period for palliative radiation to non-target organs.)
• •PARP inhibitor Required Washout Prior to Leukapheresis: 1 week Required Washout Prior to Lymphodepletion: 1 week
• •Antibody drug conjugates (such as mirvetuximab) Required Washout Prior to Leukapheresis: 3 weeks Required Washout Prior to Lymphodepletion: 3 weeks Note: Duration of any other anti-cancer therapies must be discussed and agreed upon with the Sponsor Study Physician
• •3. Toxicity from previous anti-cancer therapy that has not recovered to Grade ≤ 1 or baseline prior to enrollment (except for nonclinically significant toxicities, e.g., alopecia and vitiligo). Subjects with Grade 2 toxicities that are deemed stable or irreversible (e.g., peripheral neuropathy) can be enrolled.
• •4. Subject has a history of allergic reactions attributed to compounds of similar chemical or biological composition to fludarabine, cyclophosphamide, or other agents used in the study.
• •5. Subject has an active autoimmune or immune-mediated disease that has not yet been resolved. Subjects with immune-mediated AEs secondary to treatment with immunotherapy that resolve to Grade ≤ 1 off steroids are permitted. Subjects with hypothyroidism, type I diabetes, adrenal insufficiency, or pituitary insufficiency that are stable on replacement therapy are eligible. Subjects with disorders such as asthma, vitiligo, psoriasis, or atopic dermatitis that are well controlled without requiring systemic immunosuppression are also eligible. Other stable immune conditions that do not require prednisone \> 20 mg/day (or its equivalent for other corticosteroid agents) may be acceptable with the agreement of the Sponsor.
• •6. Subject had major surgery within 4 weeks prior to lymphodepletion; subjects should have been fully recovered from any surgical-related toxicities. Surgical-related toxicities that are not clinically significant per Investigator assessment may be acceptable after discussion and agreement with the Study Physician.
• •7. Leptomeningeal disease, carcinomatous meningitis, or symptomatic central nervous system (CNS) metastases. Subjects with prior history of symptomatic CNS metastases must have received treatment (i.e., SRS, WBRT, or surgery) and be neurologically stable for at least 1 month, not requiring anti-seizure medications, or off steroids for at least 14 days prior to leukapheresis and lymphodepletion. Subjects who have asymptomatic CNS metastases without associated edema, shift, or 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. Prophylactic anti-seizure medication is allowed.
• •8. Subject has any other prior malignancy that is not considered by the Investigator to be in complete remission. Resectable squamous or basal cell carcinoma of the skin is acceptable. Prior malignancies that have been surgically resected and show no evidence of disease are acceptable.
• •9. Clinically significant cardiovascular disease including, but not limited to, any of the following:
• •1. Electrocardiogram (ECG) showing clinically significant abnormality at Screening
• •2. Uncontrolled clinically significant arrhythmias
• •3. Known family history or congenital history of prolonged QT syndrome or history of torsade de pointes
• •4. Uncontrolled hypertension despite optimal medical therapy
• •5. Acute coronary syndrome (angina or myocardial infarction) in the last 6 months
• •6. Clinically significant cardiac disease defined by congestive heart failure New York Heart Association Class 3 and 4
• •7. History of stroke, CNS bleeding, transient ischemic attack, or reversible ischemic neurologic deficit within last 6 months
• •10. Uncontrolled intercurrent illness including, but not limited to, any of the following:
• •1. Ongoing or active systemic infection, or localized infection which may become systemic due to leukapheresis procedure, e.g., catheter insertion will be excluded. Subjects with urinary tract infections will be included only following treatment with antibiotics.(For SARS-CoV 2 \[COVID-19\] infection, see Section 10.4.4.1)
• •2. Clinically significant pulmonary disease with any 1 pulmonary function parameter \< 60% predicted (forced expiratory volume first forced breath \[FEV1\], total lung capacity \[TLC\], or diffusing capacity of lungs for carbon monoxide \[DLCO\]; note: for patients with anemia, corrected DLCO could be used) assessed prior to leukapheresis and within 2 months of the start of lymphodepleting chemotherapy
• •3. Requirement for oxygen support (due to cardiac or pulmonary disease)
• •4. Interstitial lung disease (pneumonitis) or history of pneumonectomy or chronic obstructive pulmonary disease with ≥ 1 exacerbation within 1 year prior to the Screening Visit that required treatment with systemic corticosteroids or resulted in hospitalization
• •5. Hospitalization for bowel obstruction in last 2 months
• •6. Hematosis or significant organ bleeding in last 2 months
• •7. Ascites or pleural effusion which requires repeated (2 within 4 weeks) paracentesis or thoracentesis within last 2 months
• •8. Cardiac or pericardial tumor involvement (prior to lymphodepletion)
• •11. Active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or human T cell leukemia virus (HTLV) as defined below. Re-screening for infectious disease markers is not required at baseline (prior to lymphodepletion) unless \> 6 months has elapsed.
• •1. Positive serology for HIV
• •2. Active hepatitis B infection as demonstrated by test for hepatitis B surface antigen. 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.
• •3. Active hepatitis C infection as demonstrated by hepatitis C ribonucleic acid (RNA) test. Subjects who are HCV antibody-positive will be screened for HCV RNA by any reverse transcription-polymerase chain reaction (RT PCR) or branched DNA (bDNA) assay. If HCV antibody is positive, eligibility will be determined based on a negative screening RNA value.
• •4. Positive serology for HTLV 1 or 2
• •12. Subject is pregnant or breastfeeding.
• •13. Subjects who have illicit drug or alcohol dependency within the past year.
• •14. In the opinion of the Investigator, subject will be unlikely to fully comply with protocol requirements.
• •15. Intolerance to nivolumab includes severe allergic reaction to nivolumab or any components (active or inactive) of nivolumab.