None listed
Conditions
Brief summary
EphA2 Chimeric Antigen Receptor (CAR) T cell Therapy for Children with Bone Tumours: A Phase I Clinical Trial Brief description of the study purpose: This study aims to assess the safety and feasibility of EphA2 CAR-T cell treatment for osteosarcoma and Ewing sarcoma in children where the sarcomas have either not responded to (refractory) or returned after (recurrent) standard treatment and no longer responding to standard treatment and no alternative treatment option exists, or the location of osteosarcoma prevents first time standard treatment. CAR T-cell therapy (Chimeric Antigen Receptor T-cell therapy) is a type of immunotherapy that uses a patient’s own genetically modified immune cells (T-cells) to fight certain cancers. Who is it for: Stage 1: You may be eligible for Stage 1 of this study if you are male or female age less than or equal to 21 years, with documented refractory or recurrent Ewing sarcoma or osteosarcoma no longer responding to standard treatment and no alternative treatment option exists, or osteosarcoma where disease location precludes standard first line treatment and you have enough previously collected tumour previously to testing for the EphA2 protein on your tumour cells. Stages 2 & 3: You may be eligible for Stages 2 & 3 if you have EphA2 protein on your tumour cells, measurable MRI, CT or PET scans, a life expectancy of at least 12 weeks (at least 8 weeks at Stage 3), sufficient heart, kidney, lung, liver and blood function, you have recovered from acute toxicities caused by any previous treatments, and your immune (T) cells have been successfully collected and made into EphA2 CAR-T cells. Study Details: Eligible participant's own immune (T) cells will be collected by filtering the participant's blood (leukapheresis) then genetically modified in a laboratory to a Chimeric Antigen Receptor (CAR) targeting the tumour associated antigen, EphA2. Approximately 14-21 days following leukapheresis, participants will receive lymphodepletion chemotherapy, then 7 days later, a single intravenous infusion of autologous EphA2 CAR T cells according to dose escalation trial design and subject to a maximum 50kg body weight. Cohorts of 3 to 6 participants will be treated at a dose level to determine the maximum tolerated or maximum administered dose. CAR T cell manufacturing feasibility will be determined by whether the manufactured CAR T cells meet quality acceptance criteria. CAR T cell safety will be determined by adverse events occurring after CAR T cell infusion. After CAR T cell infusion, follow-up assessments will include participant clinical assessment, including blood assays to determine anti-tumour efficacy, and to determine the rates of disease response, disease progression, and survival. It is hoped this study will improve treatment outcomes for these patients with otherwise limited treatment options, and increase knowledge of CAR T cell treatment of solid tumours.
Interventions
The E2CAR trial is a single arm intervention trial. Eligible participants' autologous T-cells will be collected via leukapheresis then the T cells will be genetically modified in an on-site clean room laboratory to express a Chimeric Antigen Receptor (CAR) targeting the tumour associated antigen, EphA2. These modified T cells (the intervention) are called EphA2CAR T cells (GENERIC), Approximately 14-21 days following leukapheresis, participants will receive lymphodepletion chemotherapy, then 7 d
The E2CAR trial is a single arm intervention trial. Eligible participants' autologous T-cells will be collected via leukapheresis then the T cells will be genetically modified in an on-site clean room laboratory to express a Chimeric Antigen Receptor (CAR) targeting the tumour associated antigen, EphA2. These modified T cells (the intervention) are called EphA2CAR T cells (GENERIC), Approximately 14-21 days following leukapheresis, participants will receive lymphodepletion chemotherapy, then 7 days later, a single intravenous infusion of autologous EphA2CAR T cells between 1 x 10e5 EphA2CAR T cells/kg and 1 x 10e7 EphA2CAR T cells/kg according to dose escalation trial design and subject to a maximum 50kg body weight. Target cell dose and dose escalations/de-escalations will be determined by a Clinical Committee using the ‘3+3’ trial design. Cohorts of 3 to 6 participants will be treated at each dose level to determine the maximum tolerated or maximum administered dose. Dose escalation for a new cohort will proceed if fewer than 33% of 3 or 6 subjects in the previous cohort experienced a dose limiting toxicity at their dose level. Data from both osteosarcoma and Ewing sarcoma patients will be combined when determining primary and secondary outcomes.
Sponsors
Sydney Children's Hospitals Network
Study design
Allocation
Non-randomised trial
Intervention model
Single group
Primary purpose
Treatment
Eligibility
Sex/Gender
All
Age
0 to 21 Years
Healthy volunteers
No
Inclusion criteria
Eligibility will be evaluated first by screening the tumour to determine EphA2-positivity (Stage 1). Participants with EphA2-positive tumours will then be assessed again to confirm eligibility for T-cell collection (apheresis) and manufacture of EphA2 CAR-T cell product (Stage 2), lymphodepletion and administration of CAR-T cells (Stage 3). STAGE 1 (SCREENING) * Age less than or equal to 21 years * Documentation of high-risk osteosarcoma or Ewing sarcoma either through review of medical record, or in correspondence from a referring oncologist. * Available tissue for tumour analysis of EphA2 expression, either archival, or planned biopsy * Written informed consent for screening STAGE 2 (APHERESIS AND CAR-T CELL MANUFACTURE) * Confirmed EphA2-positive Ewing sarcoma or osteosarcoma (from STAGE 1, above) * Relapsed or refractory disease after standard of care treatment or osteosarcoma undergoing first-line therapy where disease location precludes surgical resection of the primary tumour o for which standard curative measures do not exist or are no longer effective o evaluable for anatomic and/or metabolic response using cross sectional and/or PET scan imaging * Lansky or Karnofsky score greater than or equal to 50 percent * Estimated life expectancy of greater than or equal to 12 weeks * Recovered from acute toxicities of prior therapy * Adequate cardiac, renal, respiratory, liver and haematological function * Using an acceptable form of contraception (female or male) * Written informed consent for apheresis, CAR-T cell manufacture, lymphodepletion, and CAR-T cell infusion STAGE 3 (LYMPHODEPLETION/CAR-T CELL INFUSION) ELIGIBILITY * EphA2-positive Ewing sarcoma or osteosarcoma evaluable for anatomic and/or metabolic response using cross sectional or PET scan imaging * Previously enrolled on the apheresis and manufacture STAGE of this trial with availability of an EphA2 CAR-T cell product meeting release criteria * Estimated life expectancy of greater than or equal to 8 weeks * Lansky or Karnofsky score greater than or equal to 50 percent * Recovered from acute toxicities of prior therapy * Adequate cardiac, renal, respiratory, liver and haematological function * Using an acceptable form of contraception (female or male)
Exclusion criteria
STAGE 1 (SCREENING) *Pregnancy or currently breast feeding *Any major co-morbidity which would preclude subsequent participation in STAGEs 2 and 3 STAGE 2 (APHERESIS AND CAR-T CELL MANUFACTURE) * Active hepatitis B or hepatitis C, * HIV infection * Uncontrolled active infection * Primary or acquired immunodeficiency disorder * Concurrent use of systemic steroids or immunosuppression at the time of apheresis, or a condition, in the treating physician's opinion, that is likely to require steroid therapy or immunosuppression during apheresis (steroids for disease treatment at times other than apheresis, and/or use of physiologic replacement hydrocortisone or inhaled steroids, are permitted) * CNS metastases, including parenchymal or leptomeningeal involvement * Active medical disorder that, in the opinion of the investigator, would substantially increase the risk of uncontrollable CRS and/or neurotoxicity * Received any live vaccines within 30 days prior to apheresis STAGE 3 (LYMPHODEPLETION/CAR-T CELL INFUSION) ELIGIBILITY * Uncontrolled active infection. * CNS metastases, including parenchymal or leptomeningeal involvement. * Active medical disorder that, in the opinion of the investigator, would substantially increase the risk of uncontrollable CRS and/or neurotoxicity. * Concurrent use of systemic steroids or immunosuppression at the time of cell infusion (steroids for disease treatment at times other than apheresis or cell infusion, and/or use of physiologic replacement hydrocortisone or inhaled steroids, are permitted).
Outcome results
None listed