Genetically Engineered Cells (ATLCAR.CD30) for the Treatment of Patients with Refractory or Relapsed CD30+ Nonseminomatous Germ Cell Tumors

Inclusion Criteria

• Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information explained to, understood by, and signed by the subject or legally authorized representative.
• Age >= 18 years at the time of consent.
• Histological confirmed diagnosis of NSGCT of any primary site.
• Subjects must have received at least one prior lines of therapy for their NSGCT and meet one of the following criteria. There is not a maximum number of prior lines of treatment allowed. * Evidence of progressive or recurrent NSGCT after prior high dose chemotherapy (HDCT) treatment, defined as meeting at least one of the following criteria: ** Tumor biopsy of new or growing or unresectable lesions demonstrating viable NSGCT. In the event of an incomplete gross resection where viable NSGCT is found, subjects will be considered eligible for the study. ** Consecutive elevated serum tumor markers (beta human chorionic gonadotropin [beta-HCG] or alpha-fetoprotein [AFP]) that are increasing. Increase of an elevated lactate dehydrogenase (LDH) alone does not constitute progressive disease. ** Development of new or enlarging lesions in the setting of persistently elevated beta-HCG or AFP, even if the beta-HCG and AFP are not continuing to rise. * Subjects deemed not to be a candidate for or benefit from potentially curative HDCT or other curative treatment options defined as follows: ** Subjects with inadequate renal function for HDCT. ** Subjects who have had 3 or more lines of prior chemotherapy as this patient population has historically not benefited from HDCT. ** Subjects with late relapse (relapse > 2 years after last therapy) as this patient population has historically not benefited from HDCT. ** Subject with inadequate stem cell collection to move forward with HDCT. ** Subjects with significant medical or psychosocial comorbidities that are felt to be a contraindication to HDCT by the treating investigator. NOTE: Subjects with clinically growing “teratoma” (normal declining tumor markers and radiographic or clinical progression) should be considered for surgery. In subjects with rising tumor markers as their only evidence of disease progression where AFP is < 30 or beta-HCG is < 15, alternate causes of increased levels of these marks should be ruled out (e.g., hypogonadism by testosterone suppression of luteinizing hormone [LH], hepatitis, use of marijuana).
• Histologically confirmed diagnosis of NSGCT of any primary site expressing CD30. NOTE: CD30+ disease requires documented CD30 expression by immunohistochemistry based on the institutional hematopathology standard. This analysis will occur centrally at the University of North Carolina (UNC) site.
• Subject has available archival tissue for evaluation of CD30 expression OR is willing to undergo a mandatory biopsy to access expression. Subject must also be willing to undergo a pre-infusion (if one was not previously collected prior to procurement) and progression biopsy unless the tumor site is not easily accessible and there is more than minimal risk associated with obtaining the biopsy.
• Female subjects of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 6 months after study treatment discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method or an intrauterine device that meets < 1% failure rate for protection from pregnancy in the product label. Women of childbearing potential will also be instructed to tell their male partners to use a condom.
• Subject is willing and able to comply with study procedures based on the judgement of the investigator or protocol designee.
• PRIOR TO CELL PROCUREMENT: Informed consent to undergo cell procurement understood by and signed by the subject or legally authorized representative; subject and/or legally authorized representative given a copy of informed consent form for cell procurement.
• PRIOR TO CELL PROCUREMENT: Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• PRIOR TO CELL PROCUREMENT: Subject has life expectancy >= 6 weeks.
• PRIOR TO CELL PROCUREMENT: Serum bilirubin =< 1.5 x upper limit of normal (ULN) (=< 3 x ULN in subjects with Gilbert’s syndrome).
• PRIOR TO CELL PROCUREMENT: Aspartate aminotransferase (AST) =< 3 x ULN unless liver metastases are present, in which case it must be =< 5 x ULN.
• PRIOR TO CELL PROCUREMENT: Alanine aminotransferase (ALT) =< 3 x ULN unless liver metastases are present, in which case it must be =< 5 x ULN.
• PRIOR TO CELL PROCUREMENT: Creatinine clearance (CrCl) > 50 mL/min per Cockcroft and Gault for adult subjects. If creatinine clearance is > 50 mL/min and < 70mL/min, the subject must be dose reduced on fludarabine per institutional standards.
• PRIOR TO CELL PROCUREMENT: Pulse oximetry of > 90% on room air.
• PRIOR TO CELL PROCUREMENT: Subject has adequate cardiac function, as defined as: * No electrocardiogram (ECG) evidence of acute ischemia. * No ECG evidence of active, clinically significant conduction system abnormalities. * Prior to study entry, any ECG abnormality at screening is not felt to put the subject at risk has to be documented by the investigator as not medically significant. * No uncontrolled angina or severe ventricular arrhythmias. * No clinically significant pericardial disease. * No history of myocardial infarction within the last 6 months prior to infusion. * No class 3 or higher New York Heart Association congestive heart failure for adult subjects or a shortening fraction of >= 27% by echocardiogram (ECHO) for pediatric subjects.
• PRIOR TO CELL PROCUREMENT: Imaging results or serum tumor marker evaluation from within 8 weeks prior to procurement to assess presence of active disease (or AFP > 15 ng/mL or beta-HCG > 2.2 mIU/mL).
• PRIOR TO CELL PROCUREMENT: Current use of systemic corticosteroids at doses >= 10 mg prednisone daily or its equivalent; those receiving < 10 mg daily may be enrolled at discretion of investigator. Inhaled steroids are allowed. Physiologic replacement hydrocortisone at doses 6-12 mg/m^2/day is allowed. Equivalently dosed alternative steroids are allowed at discretion of investigator, though not to exceed 10 mg prednisone per day.
• PRIOR TO CELL PROCUREMENT: Negative serum pregnancy test within 72 hours prior to procurement or documentation that the subject is post-menopausal. Post-menopausal status must be confirmed with documentation of surgical menopause (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.
• PRIOR TO CELL PROCUREMENT: Subjects with brain metastases are allowed onto the study as long as patients have completed their treatment for brain metastasis, no longer require corticosteroids, and are asymptomatic. Subjects with neurological symptoms should undergo a head CT scan or brain MRI to exclude brain metastasis, at the discretion of the treating physician.
• PRIOR TO CELL PROCUREMENT: Subjects with prior malignancies of the same or different tumor type and subjects with concurrent malignancies of the same or different tumor type whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational product should generally be eligible for enrollment.
• PRIOR TO LYMPHODEPLETION #1: Written informed consent explained to, understood by and signed by the subject or legally authorized representative; subject and/or legally authorized representative given a copy of informed consent form.
• PRIOR TO LYMPHODEPLETION #1: Imaging results or serum tumor marker evaluation from within 14 days prior to lymphodepletion. Imaging must occur at least 3 weeks after most recent therapy (used as baseline measure for documentation of disease before the lymphodepletion) to document measurable or assessable disease (or AFP > 15 ng/mL or beta-HCG > 2.2 mIU/mL). Disease must be measurable either by imaging or serum tumor marker.
• PRIOR TO LYMPHODEPLETION #1: ECOG status 0-2.
• PRIOR TO LYMPHODEPLETION #1: Absolute neutrophil count >= 1.0 x 10^9 /L (obtained within 72 hours prior to lymphodepletion).
• PRIOR TO LYMPHODEPLETION #1: Platelet count >= 100 × 10^9 /L (obtained within 72 hours prior to lymphodepletion).
• PRIOR TO LYMPHODEPLETION #1: Serum bilirubin =< 1.5 x ULN (=< 3 x ULN in subjects with Gilbert’s syndrome) (obtained within 72 hours prior to lymphodepletion).
• PRIOR TO LYMPHODEPLETION #1: AST =< 3 x ULN unless liver metastases are present, in which case it must be =< 5 x ULN (obtained within 72 hours prior to lymphodepletion).
• PRIOR TO LYMPHODEPLETION #1: ALT =< 3 x ULN unless liver metastases are present, in which case it must be =< 5 x ULN (obtained within 72 hours prior to lymphodepletion).
• PRIOR TO LYMPHODEPLETION #1: Creatinine clearance (CrCl) > 50 mL/min per Cockcroft and Gault for adult subjects. If creatinine clearance is > 50 mL/min and < 70 mL/min, the subject must be dose reduced on fludarabine per institutional standards (obtained within 72 hours prior to lymphodepletion).
• PRIOR TO LYMPHODEPLETION #1: Pulse oximetry of > 90% on room air (obtained within 72 hours prior to lymphodepletion).
• PRIOR TO LYMPHODEPLETION #1: Subject must have available autologous transduced activated T cells product at a dose of 2 x 10^8 cells/m^2 and meets the Certificate of Analysis acceptance criteria.
• PRIOR TO LYMPHODEPLETION #1: No major surgery within 28 days prior to lymphodepletion. There is no minimum time requirement for minor procedures such as biopsy or vascular access placement.
• PRIOR TO LYMPHODEPLETION #1: Negative serum pregnancy test within 72 hours prior to lymphodepleting therapy or documentation that the subject is post-menopausal. Due to the fact that the tumor may produce HCG hormone, subjects will only be excluded from study once pregnancy is confirmed. Post-menopausal status must be confirmed with documentation of surgical menopause (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.
• PRIOR TO LYMPHODEPLETION #1: Subject has not received any investigational agents within the previous 21 days prior to lymphodepletion.
• PRIOR TO LYMPHODEPLETION #1: Subject has not received any tumor vaccines within the previous 30 days prior to lymphodepletion.
• PRIOR TO LYMPHODEPLETION #1: Subject has not received anti-CD30 antibody-based therapy within the previous 4 weeks prior to lymphodepletion.
• PRIOR TO LYMPHODEPLETION #1: Subject has not received anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) within the previous 21 days prior to lymphodepletion.
• PRIOR TO LYMPHODEPLETION #1: Subject has not received radiation within the previous 21 days prior to lymphodepletion.
• PRIOR TO LYMPHODEPLETION #1: Current use of systemic corticosteroids at doses >= 10 mg prednisone daily or its equivalent; those receiving < 10 mg daily may be enrolled at discretion of investigator. Inhaled steroids are allowed. Physiologic replacement hydrocortisone at doses 6-12 mg/m^2/day is allowed. Equivalently dosed alternative steroids are allowed at discretion of investigator, though not to exceed 10 mg prednisone per day.
• PRIOR TO LYMPHODEPLETION #1: Subject does not have rapidly progressive disease, per treating oncologist’s discretion.
• PRIOR TO LYMPHODEPLETION #1: Subjects with brain metastases are allowed onto the study as long as patients have completed their treatment for brain metastasis, no longer require corticosteroids, and are asymptomatic. Subjects with neurological symptoms should undergo a head CT scan or brain MRI to exclude brain metastasis, at the discretion of the treating physician. Subjects with a history of leptomeningeal carcinomatosis will be excluded.
• PRIOR TO LYMPHODEPLETION #1: Subjects with prior malignancies of the same or different tumor type and subjects with concurrent malignancies of the same or different tumor type whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational product should generally be eligible for enrollment.
• PRIOR TO LYMPHODEPLETION #1: Subject is a good candidate for CAR T cell therapy, per treating oncologist’s discretion.
• PRIOR TO LYMPHODEPLETION #1: Subject is not taking a prohibited or contraindicated medication prior to lymphodepletion.
• PRIOR TO CELL PRODUCT ADMINISTRATION #1: Subject has no evidence of uncontrolled infection or sepsis.
• PRIOR TO CELL PRODUCT ADMINISTRATION #1: Negative serum pregnancy within 7 days of cell product administration or documentation that the subject is post-menopausal (does not need to be repeated if pre-lymphodepletion pregnancy test is within window). Note: Post-menopausal status must be confirmed with documentation of surgical menopause (have undergone a hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.
• PRIOR TO CELL PRODUCT ADMINISTRATION #1: Serum bilirubin =< 2 x ULN (=< 3 x ULN in subjects with Gilbert’s syndrome).
• PRIOR TO CELL PRODUCT ADMINISTRATION #1: AST =< 5 x ULN unless liver metastases are present, in which case it must be =< 7 x ULN.
• PRIOR TO CELL PRODUCT ADMINISTRATION #1: ALT =< 5 x ULN unless liver metastases are present, in which case it must be =< 7 x ULN.
• PRIOR TO CELL PRODUCT ADMINISTRATION #1: Creatinine clearance (CrCl) > 30 mL/min per Cockcroft and Gault for adult subjects.
• PRIOR TO CELL PRODUCT ADMINISTRATION #1: Pulse oximetry of > 90% on room air.
• PRIOR TO CELL PRODUCT ADMINISTRATION #1: Subject has no clinical indication of rapidly progressing disease in the opinion of the clinical investigator.
• PRIOR TO CELL PRODUCT ADMINISTRATION #1: Subject is a good candidate for treatment with ATLCAR.CD30 cell product per the clinical investigator’s discretion.
• PRIOR TO LYMPHODEPLETION #2: Imaging results from within 21 days prior to lymphodepletion.
• PRIOR TO LYMPHODEPLETION #2: Subject had a complete response, partial response or stable disease as a result of the first infusion as defined by RECIST 1.1.
• PRIOR TO LYMPHODEPLETION #2: Subjects who experienced grade 4 cytokine release syndrome (CRS) or grade 4 immune effector cell associated neurotoxicity syndrome (ICANS) as a result of the initial ATLCAR.CD30 infusion are only eligible for a second round of lymphodepletion and infusion if they had a partial response per RECIST 1.1 to the initial ATLCAR.CD30 infusion.
• PRIOR TO LYMPHODEPLETION #2: Eastern Cooperative Oncology Group (ECOG) status 0-2.
• PRIOR TO LYMPHODEPLETION #2: Absolute neutrophil count >= 1.0 x 10^9 /L (obtained within 72 hours prior to lymphodepletion).
• PRIOR TO LYMPHODEPLETION #2: Platelet count >= 100 x 10^9 /L (obtained within 72 hours prior to lymphodepletion).
• PRIOR TO LYMPHODEPLETION #2: Serum bilirubin =< 1.5 x ULN (=< 3 x ULN in subjects with Gilbert’s syndrome) (obtained within 72 hours prior to lymphodepletion).
• PRIOR TO LYMPHODEPLETION #2: AST =< 3 x ULN unless liver metastases are present, in which case it must be =< 5 x ULN (obtained within 72 hours prior to lymphodepletion).
• PRIOR TO LYMPHODEPLETION #2: ALT =< 3 x ULN unless liver metastases are present, in which case it must be =< 5 x ULN (obtained within 72 hours prior to lymphodepletion).
• PRIOR TO LYMPHODEPLETION #2: Creatinine clearance (CrCl) > 50 mL/min per Cockcroft and Gault for adult subjects. If creatinine clearance is > 50 mL/min and < 70 mL/min, the subject must be dose reduced on fludarabine per institutional standards (obtained within 72 hours prior to lymphodepletion).
• PRIOR TO LYMPHODEPLETION #2: Pulse oximetry of > 90% on room air (obtained within 72 hours prior to lymphodepletion).
• PRIOR TO LYMPHODEPLETION #2: Subject must have available autologous transduced activated T cells product at a dose of 2 x 10^8 cells/m^2 and meets the Certificate of Analysis acceptance criteria.
• PRIOR TO LYMPHODEPLETION #2: Negative serum pregnancy test within 72 hours prior to lymphodepleting therapy for female participants of childbearing potential. Note: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.
• PRIOR TO LYMPHODEPLETION #2: Subject does not have evidence of uncontrolled infection or sepsis.
• PRIOR TO LYMPHODEPLETION #2: Subject has not received an off-protocol therapy for their cancer treatment since the initial infusion.
• PRIOR TO LYMPHODEPLETION #2: Current use of systemic corticosteroids at doses >= 10 mg prednisone daily or its equivalent; those receiving < 10 mg daily may be enrolled at discretion of investigator. Inhaled steroids are allowed. Physiologic replacement hydrocortisone at doses 6-12 mg/m^2/day is allowed. Equivalently dosed alternative steroids are allowed at discretion of investigator, though not to exceed 10 mg prednisone per day.
• PRIOR TO LYMPHODEPLETION #2: Subject is not receiving a prohibited medication at time of starting lymphodepletion up through 72 hours after the last dose of cyclophosphamide.
• PRIOR TO LYMPHODEPLETION #2: Subject is a good candidate for CAR T cell therapy, per treating oncologist’s discretion.
• PRIOR TO CELL PRODUCT ADMINISTRATION #2: Subject has no evidence of uncontrolled infection or sepsis.
• PRIOR TO CELL PRODUCT ADMINISTRATION #2: Negative serum pregnancy within 7 days of cell product administration for females of or documentation that the subject is post-menopausal (does not need to be repeated if pre-lymphodepletion pregnancy test is within window). Note: Post-menopausal status must be confirmed with documentation of surgical menopause (have undergone a hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.
• PRIOR TO CELL PRODUCT ADMINISTRATION #2: Serum bilirubin =< 2 x ULN (=< 3 x ULN in subjects with Gilbert’s syndrome).
• PRIOR TO CELL PRODUCT ADMINISTRATION #2: AST =< 5 x ULN unless liver metastases are present, in which case it must be =< 7 x ULN.
• PRIOR TO CELL PRODUCT ADMINISTRATION #2: ALT =< 5 x ULN unless liver metastases are present, in which case it must be =< 7 x ULN.
• PRIOR TO CELL PRODUCT ADMINISTRATION #2: Creatinine clearance (CrCl) > 30 mL/min per Cockcroft and Gault.
• PRIOR TO CELL PRODUCT ADMINISTRATION #2: Pulse oximetry of > 90% on room air.
• PRIOR TO CELL PRODUCT ADMINISTRATION #2: Subject is a good candidate for treatment with ATLCAR.CD30 cell product per the clinical investigator’s discretion.

Exclusion Criteria

• Subject is pregnant or lactating (Note: Breast milk cannot be stored for future use while the mother is being treated on study).
• Active infection with human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV), hepatitis B virus (HBV), hepatitis C virus (HCV) (tests can be pending at the time of cell procurement; only those samples confirming lack of active infection will be used to generate transduced cells). NOTE: To meet eligibility subjects are required to be negative for HIV antibody, negative for HTLV1 and 2 antibody or polymerase chain reaction (PCR) negative for HTLV1 and 2, negative for hepatitis B surface antigen, negative for HCV antibody or HCV viral load.