Inclusion
1. Patient (and/or their legal guardian) has provided written informed consent using the PLATYPS Patient Information and Consent Form (PICF)
2. Patient must be at least 16 years of age on the day of signing informed consent
3. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 to 2
4. Have a confirmed diagnosis of a CD19 expressing B-cell malignancy, with confirmed CD19 expression by flow cytometry and/or immunohistochemistry prior to registration. Note: Patients who have had prior treatment with anti CD19 directed cellular or antibody-based therapies will be accepted, so long as detectable CD19 expression on malignant cells can be demonstrated and there is no CD19 meaningful negative population
5. Have measurable disease, being either:
• Radiographically assessable nodal and or extra-nodal disease on PET-CT and or MRI brain ± spine, with acceptable recent histological confirmation of
CD19+ B-cell malignancy, as assessed by the Principal Investigator (PI)
OR
• Measurable CD19+ B-cell malignancy in peripheral blood and/or bone marrow, which can be quantified in absolute terms (i.e., malignant cells per 109/L) or by percentage of total cells by flow cytometry and/or immunohistochemistry
6. Meet at least one of the following disease criteria:
• Have relapsed, or progressed following at least 2 prior lines of systemic therapy, noting that corticosteroids or rituximab monotherapy are not
considered a line of therapy
• Be refractory to at least one prior line of systemic therapy, noting that corticosteroids or rituximab monotherapy are not considered a line of therapy
• Have relapsed or have had progression of disease within 24 months of initial systemic therapy (POD24), and have no other suitable treatment options in the
opinion of the Investigator
• Have high grade B-cell lymphoma transformed from a known low-grade lymphoma, with at least 2 prior lines of systemic therapy (including an anthracycline) delivered for the low-grade and high-grade lymphoma combined, noting that corticosteroids or rituximab monotherapy are not considered a line of therapy
• Have relapsed disease after allogeneic or autologous haematopoietic stem cell transplant meeting one of the following:
o After prior allogeneic transplant, patient has no active graft versus host disease (GVHD [>Grade II]), does not require systemic immunosuppression, is more than 3 months from transplant, and at least 3 months off GVHD prophylaxis
OR
o After prior autologous or syngeneic transplant, patient has been more than 3 months from transplant
7. Have a life expectancy of greater than or equal to 3 months, as judged by the Investigator
8. Adequate haematological function documented within 7 days prior to registration, defined as:
• Haemoglobin greater than or equal to 80 g/L (peripheral red blood cell transfusion support is allowed)
• Absolute neutrophil count (ANC) greater than or equal to 1.0 x 109/L (G-CSF support is allowed, and ANC > 0.5 x 109/L is allowed if neutropenia is due to disease infiltration of bone marrow)
• Absolute lymphocyte count (ALC) greater than or equal to 0.1 x 109/L
• Platelets greater than or equal to 50 x 109/L (platelet transfusion support is allowed for platelets greater than or equal to 30 if due to disease infiltration of bone marrow, or splenomegaly due to disease involvement)
9. Adequate cardiac function, defined as:
• Left ventricular ejection fraction (LVEF) greater than or equal to 40% on echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 90 days prior to registration
• No suspicion for intercurrent deterioration in left ventricular function as assessed by the Investigator
10. Adequate pulmonary function, defined as:
• Oxygen saturation measured by pulse oximetry greater than or equal to 90% on room air
11. Adequate renal function documented within 7 days prior to registration, defined as any one of:
• A serum creatinine less than or equal to 1.5 x upper limit of normal (ULN)
• Creatinine clearance (CrCl) of greater than or equal to 40 mL/min calculated by Cockcroft-Gault formula
• CrCl greater than or equal to 40 mL/min calculated by 24-hour urine collection
• Glomerular filtration rate (GFR) greater than or equal to 40 mL/min by renal scintigraphy
12. Adequate hepatic function documented within 7 days prior to registration, defined as all of:
• Total bilirubin less than or equal to 1.5 x ULN (or less than or equal to 3.0 x ULN in patients with Gilbert’s syndrome or documented liver involvement)
• Alanine aminotransferase (ALT) less than or equal to 3.0 x ULN (or less than or equal to 5.0 x ULN in patients with documented liver involvement)
• Aspartate aminotransferase (AST) less than or equal to 3.0 x ULN (or less than or equal to 5.0 x ULN in patients with documented liver involvement)
13. Taking a maximum corticosteroid dose of 20 mg of oral prednisolone or equivalent
14. Females of childbearing potential (FCBP) and non-sterile male patients (with partners of childbearing potential) must agree to use highly effective methods of contraception from registration on the study to 2 months after the PMCC-COE19 infusion or until PMCC-COE19 is no longer present by quantitative polymerase chain reaction on two consecutive tests whichever is later. Effective methods of contraception are:
• Total abstinence from sexual intercourse when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
• Female sterilisation (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least 6 weeks prior to registration. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment
• Male sterilisation (at least 6 months prior to Screening), noting that for female patients on the study, the vasectomised male partner should be the sole partner for that patient
• Use of oral, (oestrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device or intrauterine system, or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months prior to registration
• Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age-appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks prior to registration. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of childbearing potential
15. Females of childbearing potential must have a negative serum beta-human chorionic gonadotropin (ß-hCG) pregnancy test within 3 days prior to registration
16. Sexually active male patients must use a condom during intercourse and must agree to refrain from sperm donation, from registration on the study until 52 weeks (12 months) after PMCC-COE19 infusion
Exclusion
1. A significant CD19-negative malignant cell population, as assessed by multi-parameter flow cytometry and/or immunohistochemistry
2. Uncontrolled central nervous system (CNS) disease, or CNS disease anticipated to be uncontrolled at the time of PMCC-COE19 infusion, defined as:
• Rising levels of disease in cerebral spinal fluid (CSF), as measured by cytology and/or flow cytometry
• Rapidly expanding CNS parenchymal lesions
• Bulky leptomeningeal disease and/or CSF protein greater than or equal to 100 mg/dL
• Uncontrolled seizures likely due to CNS disease
Note: Patients with uncontrolled CNS disease detectable in CSF must have this treated such that no exclusion criteria are satisfied in order to be eligible for enrolment. Patients with stable parenchymal disease may proceed without CNS directed therapy, as long as all eligibility criteria are satisfied
3. Primary vitreoretinal lymphoma and intraocular primary CNS lymphoma without evidence of brain disease, including patients with prior history of intraocular involvement treated only with intraocular methotrexate and no prior systemic therapy
4. Patients with CNS disease who cannot undergo MRI assessment
5. Patients with brain stem lesions
6. Major surgery within 4 weeks prior to registration
7. Receipt of a live, attenuated vaccine within 4 weeks prior the planned commencement of lymphodepleting conditioning
8. Receipt of any investigational medical product within the last 30 days, or after 5 half-lives (whichever is the shortest) prior to planned leukapheresis
9. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure or myocardial infarction within 6 months of screening or class III to IV cardiac disease as defined by the New York Heart Association Functional Classification
10. Clinically significant neurological disorders (e.g., epilepsy, severe brain injury, dementia, Parkinson’s disease, or autoimmune/inflammatory disorders [e.g., Guillain-Barre syndrome, motor neuron disease, chronic inflammatory demyelinating polyneuropathy])
11. History of other active malignancy, with the exception of:
• Adequately treated in situ carcinoma of the cervix or breast
• Adequately treated basal cell carcinoma of skin or localised squamous cell carcinoma of the skin
• Low grade malignancies that are being observed and do not require treatment (e.g., low risk prostate cancer)
• Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent and without evidence of recurrence for at least 2 years prior to registration
12. Active HIV or hepatitis A, B, or C infection
• Patients who are positive for HIV by enzyme-linked immunosorbent assay or Western Blot, are ineligible
• Patients who are seropositive for hepatitis C virus (HCV) are eligible if their most recent HCV DNA assay is undetectable (including those that have received curative therapy)
• Patients who are seropositive for hepatitis B virus (HBV) because of vaccination (surface antibody positivity only) are eligible
13. Other clinically significant active infection confirmed by clinical evidence, imaging, or positive laboratory tests (e.g., blood cultures, viral DNA/RNA by PCR)
14. A known history or current autoimmune disease or other diseases resulting in permanent immunosuppression or requiring permanent immunosuppressive therapy (with the exception of corticosteroids up to 20 mg/day of oral prednisolone or equivalent)
15. Current active GVHD requiring immunosuppression (with the exception of corticosteroids up to 20 mg/day of oral prednisolone or equivalent)
16. Other significant life-threatening illness, medical condition, or laboratory abnormality that, in the opinion of the Investigator, could compromise the patient’s safety, impair their ability to receive PMCC-COE19, or put the study outcomes at undue risk
17. Known hypersensitivity to the excipients of PMCC-COE19 or to any product to be given to the patient as per the study protocol (e.g., tocilizumab and lymphodepleting agents)
18. Women who are lactating
19. Presence of any psychological, social, geographical, or other condition for which, in the opinion of the site Investigator, participation would not be in the best interest of the patient (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments