TC-210 Eligibility Criteria

Inclusion Criteria

A patient must meet the following inclusion criteria to be eligible to receive therapy on this study:

1. Patient (or legally authorized representative) has voluntarily agreed to participate by giving written informed consent in accordance with International Conference on Harmonisation Good Clinical Practice guidelines and applicable local regulations.

2. Patient 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 LTFU.

3. Patient is ≥ 18 years of age at the time the Informed Consent is signed.

4. Patient has a pathologically confirmed diagnosis of either MPM, serous ovarian adenocarcinoma (patients with serous ovarian, fallopian tube or primary peritoneal cancers will be permitted), cholangiocarcinoma, or NSCLC at screening. (Note: cytology is insufficient).

5. Patient’s tumor has been pathologically reviewed by a TCR2 Therapeutics designated central laboratory with confirmed positive MSLN expression on ≥ 50% of tumor cells that are 2+ and/or 3+ by immunohistochemistry. If the patient had a fresh biopsy during prescreening, that biopsy sample may be used. If archival tissue was used during pre-screening, the patient must undergo a fresh biopsy, unless deemed unsafe by the PI and/or the lesion is inaccessible and upon discussion with the medical monitor.

6. Patient has advanced (ie, metastatic or unresectable) cancer. Unresectable refers to a tumor lesion in which clear surgical excision margins cannot be obtained without leading to significant functional compromise.

7. Patient has at least 1 lesion that meets evaluable and measurable criteria defined by RECIST v 1.1 after the pre-TC-210 T cell infusion fresh-tissue biopsy has been performed. Patients who have received prior local therapy (including but not limited to embolization, chemoembolization, radiofrequency ablation, or radiation therapy) are eligible provided measurable disease falls outside of the treatment field or within the field and has shown ≥ 20% growth in size since post-treatment assessment.

8. Prior to TC-210 T cell infusion, patients must have received at least 1 systemic standard of care therapy for metastatic or unresectable disease (unless otherwise specified), as follows:

A. MPM

• Patients must have received standard frontline therapy with a platinum-based regimen or they must have elected not to pursue frontline standard of care therapy.
• The patient must not have required a paracentesis or thoracentesis within the preceding 4 weeks nor be projected to require a paracentesis or thoracentesis within the next 8 weeks.

B. NSCLC

• Patients must have a pathologically confirmed (by histology or cytology) diagnosis of NSCLC, which is currently stage 3B or stage 4 disease.
• A patient with non-squamous NSCLC must have been tested for relevant epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase translocation or other genomic aberrations (eg, ROS rearrangement, BRAF V600E mutation) for which FDA-approved targeted therapy is available and, if positive, the patient should have received at least one such therapy prior to study enrollment.
• Patients with the EGFR T790M mutation must have received the FDA-approved tyrosine kinase inhibitor osimertinib.
• For patients without an actionable mutation, the patient must have received a currently approved frontline regimen (eg, immune checkpoint inhibitor-based therapy).

C. Serous Ovarian Adenocarcinoma

•  The patient must have a histologically confirmed diagnosis of recurrent serous ovarian adenocarcinoma, fallopian tube or primary peritoneal cancer which is currently stage 3 or stage 4 disease. A histologic diagnosis of borderline, low malignant potential epithelial carcinoma is not permitted.
• Patients with a BReast CAncer genes 1 and 2 (BRCA1/2) mutation must have received an FDA-approved poly (ADP-ribose) polymerase (PARP) inhibitor.
• The patient must not have required a paracentesis or thoracentesis within the preceding 4 weeks nor be projected to require a paracentesis or thoracentesis within the next 8 weeks.
• The patient has no evidence of a bowel obstruction within the last 8 weeks.

9. Cholangiocarcinoma 

• Patients must have received at least 1 standard systemic regimen for unresectable or metastatic disease (eg, gemcitabine- or 5-FU-containing regimens) or they must have elected not to pursue frontline standard of care therapy.
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm (≥ 2 cm) with conventional techniques or as ≥ 10 mm (≥ 1 cm) with computed tomography scan or magnetic resonance imaging.
• Prior to TC-210 T cell infusion, patients must have received at least 1 systemic standard of care therapy for metastatic or unresectable disease (unless otherwise specified).
• Patients who have received systemic adjuvant chemotherapy will be permitted.

10. Patient has an Eastern Cooperative Oncology Group performance status 0 or 1.

11. All patients must have undergone a rapid influenza diagnostic test and/or a respiratory viral panel (as per Institutional guidelines) within 14 days prior to the planned TC-210 T cell infusion. If the patient is positive for influenza, oseltamivir phosphate or zanamivir should be administered for 10 days (see Tamiflu® or Relenza® package insert for dosing). The patient must complete their 10-day treatment course prior to receiving TC-210 T cells. For patients residing in the United States, Canada, Europe and Japan, influenza testing is required during the months of October through May (inclusive). For patients residing in the southern hemisphere such as Australia, influenza testing is required during the months of April through November (inclusive). For patients with significant international travel, both calendar intervals above may need to be considered. Respiratory viral panel should be performed according to institutional guidelines and include coronavirus disease 2019 (Covid-19; SARS-CoV-2), when available. If patient is symptomatic or tests positive, TC-210 T cell infusion should be delayed until the patient is asymptomatic and deemed fit for infusion by the treating physician.

12. Patient has a left ventricular ejection fraction ≥ 45% as measured by resting echocardiogram, with no clinically significant pericardial effusion.

13. Female patient of childbearing potential (FPCP) must have a negative urine or serum pregnancy test (FPCP is defined as premenopausal and not surgically sterilized). FPCP must agree to use effective birth control or to abstain from heterosexual activity throughout the study, starting on the day of first dose of lymphodepleting chemotherapy through 12 months post TC-210 T cell infusion or for 4 months after there is no evidence of persistence of 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 (eg, diaphragm with spermicide, cervical cap with spermicide, or female condom with spermicide). Spermicides alone are not an adequate method of contraception.

Or

Male patients 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 protocol-defined treatment and for 4 months thereafter or longer (if indicated in the country specific monograph/label for cyclophosphamide).

14. Patient must have adequate organ function as indicated by the laboratory values in the table below:

Exclusion Criteria 

A patient meeting any of the following exclusion criteria is not eligible for participation in the treatment portion of this study:

1. Inability to follow the procedures of the study (eg, due to language problems, psychological disorders, dementia, confusional state).

2. Known or suspected non-compliance, drug, or alcohol abuse.

3. Participation in another study with investigational drug within the 28 days or 5 half-lives of the drug, whichever is shorter, preceding and during the present study.

4. Patient is pregnant (or intends to become pregnant during the course of the study) or breastfeeding.

5. Patient has received or plans to receive the following therapy/treatment prior to the first protocol-defined therapy: − Cytotoxic chemotherapy within 3 weeks of TC-210 T cell infusion.

• Corticosteroids: therapeutic doses of steroids must be stopped at least 2 weeks prior to TC-210 T cell infusion. Use of inhaled steroids or topical cutaneous steroids is not exclusionary. Corticosteroid therapy at a pharmacologic dose (> 5 mg/day of prednisone or equivalent doses of other corticosteroids) and other immunosuppressive drugs should be avoided until 3 months after TC-210 T cell administration, unless medically indicated to treat new toxicity. Physiological replacement doses of steroids (up to 5 mg/day of prednisone equivalent, or higher if warranted by the patient’s BMI) may be allowed.
• Immunosuppression: any other immunosuppressive medication must be stopped ≥ 4 weeks prior to first protocol defined treatment, including calcineurin inhibitors, methotrexate or other chemotherapy drugs, mycophenolate, steroids (see above), rapamycin, thalidomide, or immunosuppressive antibodies such as rituximab, anti-tumor necrosis factor, anti-interleukin (IL) 6 or anti-IL6R.
• Use of an anti-cancer vaccine within 2 months in the absence of tumor response. The patient should be excluded if their disease is responding to an experimental vaccine given within 6 months;
• Any previous gene therapy using an integrating vector;
• Tyrosine kinase inhibitor (eg, EGFR inhibitors) within 72 hours;
• Any previous allogeneic hematopoietic stem cell transplant;
• Investigational treatment or clinical trial within 4 weeks or 5 half-lives of investigational product, whichever is shorter;
• Radiotherapy to the target lesions within 3 months prior to lymphodepleting chemotherapy. A lesion with unequivocal progression may be considered a target lesion regardless of time from last radiotherapy dose. NOTE: There is no washout period for palliative radiation to non-target lesions;
• Hepatic radiation, chemoembolization, and/or radiofrequency ablation within 4 weeks.
• Current anticoagulative therapy (excluding deep vein thrombosis prophylaxis).
• Immune therapy (monoclonal antibody therapy, checkpoint inhibitors) within 4 weeks.

6. Toxicity from previous anti-cancer therapy that has not recovered to ≤ grade 1 (except for nonclinically significant toxicities, eg, alopecia, vitiligo). Patients with grade 2 toxicities that are deemed stable or irreversible (eg, peripheral neuropathy) can be enrolled.

7. History of allergic reactions attributed to compounds of similar chemical or biologic composition to fludarabine, cyclophosphamide, or other agents used in the study.

8. History of autoimmune or immune mediated disease such as multiple sclerosis, lupus, rheumatoid arthritis, inflammatory bowel disease, or small vessel vasculitis.

9. Major surgery (other than diagnostic surgery) within 4 weeks prior to first protocol defined therapy, minor surgery including diagnostic surgery within 2 weeks (14 days) excluding central intravenous port placements and needle aspirate/core biopsies. Radio frequency ablation or transcatheter arterial chemoembolization within 6 weeks prior to enrollment.

10. Central nervous system (CNS) disease/brain metastases:

Patients with leptomeningeal disease, carcinomatous meningitis, or symptomatic CNS metastases: patients are eligible if they have completed their treatment, have recovered from the acute effects of radiation therapy or surgery prior to study entry, and a) have no evidence of brain metastases post treatment or b) are asymptomatic, have discontinued corticosteroid treatment or anti-seizure medications for these metastases for at least 4 weeks and have radiographically stable CNS metastases without associated edema or shift for at least 3 months prior to study entry (note: prophylactic anti-seizure medications are acceptable; up to 5 mg/day of prednisone or equivalent will be allowed; higher doses may be allowed if warranted due to patient BMI).

11. Patient has any other prior or concurrent malignancy with the following exceptions:

• Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry)
• In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 12 months prior to the study
• Treated non-melanoma skin cancer
• Stage 0 or 1 melanoma completely resected at least 12 months prior to enrollment
• Successfully treated organ-confined prostate cancer with no evidence of progressive disease based on prostate specific antigen (PSA) levels and are not on active therapy
• A primary malignancy which has been completely resected and in complete remission for ≥ 5 years
• Malignancies deemed unlikely to be of clinical significance during TC-210 T cell therapy by principal investigator and as approved by sponsor

12. Patient has an electrocardiogram showing a clinically significant abnormality at screening or showing an average QTc interval > 450 msec in males and > 470 msec in females (> 480 msec for patients with bundle branch block). Either Fridericia’s or Bazett’s formula may be used to correct the QT interval.

13. Patient has uncontrolled intercurrent illness including, but not limited to:

• Ongoing or active infection; eg, sepsis, prolonged unresolved bacterial cholangitis with destruction of bile duct branches (eg, after endoprosthesis insertion) or 2 or more cholangitis in the last 6 months.
• Clinically significant cardiac disease defined by congestive heart failure New York Heart Association class 3 or class 4;
• Uncontrolled clinically significant arrhythmia;
• Acute coronary syndrome (angina or myocardial infarction), stroke, or peripheral vascular event in the last 6 months;
• Interstitial lung disease (patients with existing pneumonitis as a result of radiation are not excluded; however, patients must not be oxygen dependent as demonstrated by oxygen saturation < 92% on room air);
• Liver cirrhosis or primary sclerosing cholangitis.

14. Patient has active infection with human immunodeficiency virus (HIV), hepatitis B virus, hepatitis C virus (HCV), or human T-lymphotropic virus (HTLV) as defined below:

• Positive serology for HIV, HTLV-1, or HTLV-2;
• Active hepatitis B infection as demonstrated by test for hepatitis B surface antigen. Patients who are hepatitis B surface antigen negative but are hepatitis B core antibody positive must have undetectable hepatitis B deoxyribonucleic acid (DNA) and receive prophylaxis against viral reactivation;
• Active hepatitis C infection as demonstrated by hepatitis C ribonucleic acid (RNA) test. Patients who are HCV antibody positive will be screened for HCV RNA by any reverse transcription polymerase chain reaction (PCR) or branched DNA assay. If HCV antibody is positive, eligibility will be determined based on a negative screening RNA value.