Inclusion Criteria:
1. Be 18 years or older of age on the day of signing informed consent.
2. Have had historical or current histologically confirmed isocitrate dehydrogenase
1(IDH1) wild-type glioblastoma and variants as defined by the World Health
Organization. 3. Patient must have a T1 weighted 3D MRI with Gadolinium enhancement within 14 days
prior to lymphodepletion at Day -5. 4. Patient must understand and voluntarily sign an ICF prior to any study-related
assessments/procedures being conducted.
5. Radiologically confirmed recurrent glioblastoma at first or second recurrence have
contrast enhancing measurable disease with a bidimensional diameter greater than or
equal to 10 mm x 10 mm according to RANO and be eligible to undergo tumor resection.
6. Patients must be a candidate to undergo non-emergent surgical resection of the
primary target lesion.
7. Multifocal GBM is permissible in the study if there is contiguous T2FLAIR
hyperintensity between enhancing lesions on T1 post gadolinium sequences and if in
the opinion of the PI surgical resection of the multifocal disease is achievable.
• NOTE: Multicentric disease with no demonstrated ventricle communication at the
time of screening is excluded.
8. The patient must either be on no steroids or on a stable dose of dexamethasone or
equivalent no greater than > 2 mg a day for at least 5 days prior to
lymphodepletion.
9. Karnofsky performance status (KPS) ≥ 60. 10. Have washout periods for prior therapies defined as at five half-lives or (4 weeks)
prior to the administration of lymphodepletion whichever is shorter. 11. Demonstrate at screening adequate organ function by laboratory values as follows:
- - Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L.
- - Platelet count ≥ 100 x 10^9/L (patient needs to have a minimum of 70 x10^9/L to
undergo resection)
- Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L.
- - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2 .
5 the
upper limit of normal (ULN)
- - Calculated creatinine clearance ≥ 45.0 mL/minute as estimated by
Cockcroft-Gault formula.
- - Total bilirubin ≤ 1.5 x ULN, unless due to Gilbert's syndrome.
- - Total albumin ≥ 3.0 g/dL (30 g/L)
- Prothrombin Time (PT) ≤1.5 x ULN unless patient is receiving anticoagulant
therapy if PT or PTT is within therapeutic range of intended use of
anticoagulants.
- - activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN unless patient is
receiving anticoagulant therapy if PT or PTT is within therapeutic range of
intended use of anticoagulants.
- - Adequate coagulation function defined as INR ≤ 1.5 x ULN, unless the patient is
receiving anticoagulant therapy with PT or a PTT/PTT is within therapeutic
range.
12. Patients must agree to use a highly effective method of contraception if procreative
potential exists from the start of the study until one year after the completion of
lymphodepletion for females and 4 months after completion of lymphodepletion for
males.
- - A Female of Childbearing Potential (FCBP) is defined as: 1) has achieved
menarche at some point, 2) has not undergone a hysterectomy or bilateral
oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following
cancer therapy does not rule out childbearing potential) for at least 24
consecutive months (ie, has had menses at any time in the preceding 24
consecutive months).
Exclusion Criteria:
Exclusion Criteria:
1. Midline shift greater than 0.5 cm or pending herniation.
2. Patients who were previously treated with Bevacizumab. The use of Bevacizumab for
edema or radiation necrosis treatments may be allowed with prior approval from the
medical monitor. 3. Anticipated Extent of Resection by volumetric analysis is less than 70%
4. Patients with greater than two recurrences of GBM are excluded. 5. Patients with any contraindications to MRIs. 6. Treatment with other investigational agents, check point inhibitors and prior
immunotherapy such as Vaccine therapy, dendritic cells vaccine within 4 weeks prior
to lymphodepletion.
7. Prior radiation therapy within 12 weeks of screening MRI unless there is unequivocal
histological confirmation of tumor progression.
8. Patients with known disease in the posterior fossa, gliomatous meningitis,
extracranial disease or multicentric enhancing disease. Multicentric disease is
defined as discrete sites of contrast enhancing disease without contiguous T2/FLAIR
abnormality.
• NOTE: Satellite lesions that are associated with a contiguous area of T2/FLAIR
abnormality as the main lesion(s) may be included.
9. Patients with concurrent use of tumor treating fields (TTF) or laser interstitial
thermal therapy (LITT) is excluded. Prior use of TTF or LITT is allowed prior to
signing the ICF. 10. Patients with current Carmustine wafers. (Patients that agree to remove the
Carmustine wafers at the time of tumor resection during the study are allowed in the
study)
11. Patents who are receiving systemic steroid therapy > 2 mg of dexamethasone or
equivalent total dose per day or any other form of immunosuppressive therapy within
5 days of lymphodepletion.
• Patients that require intermittent use of bronchodilators or local steroid
injections would not be excluded from the study. Patients requiring physiological
doses of steroids (i.e., adrenal insufficiency or hypopituitarism) not to exceed
equivalent of dexamethasone 2 mg will not be excluded from the study.
12. Patients with history of anaphylaxis, angioedema, interstitial pneumonitis, or acute
respiratory distress syndrome. 13. Active autoimmune disease other than controlled connective tissue disorder or those
who are not on active therapy.
14. Any other organ dysfunction (CTCAE Version 5.0 Grade 3 or greater) that will
interfere with the administration of the lymphodepletion regimen, rhIL-2, CYNK-001
or the surgical resection as outlined.
15. Known hypersensitivity to cyclophosphamide, fludarabine, Mesna or rhIL-2.
16. Have active or clinically significant cardiac disease including:
- - History or presence of serious uncontrolled cardiac arrhythmias.
- - Clinically significant resting bradycardia.
- - Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) <50% or
multiple gated acquisition scan (MUGA) <45%.
- - Any of the following within 6 months prior to the start of the study
treatments: myocardial infarction (MI), severe/unstable angina, congestive
heart failure (CHF), transient ischemic attack (TIA).
17. Patients with an SaO2 ≤ 92% on room air.
• Pulmonary Function Tests may be performed during screening for patients with SaO2
≤ 92% on room air and based on the clinical judgment of the treating physician,
patients with an FEV1 ≥ 50% of predicted and DLCO (corrected) of ≥ 40% of predicted
may be enrolled.
18. Has any form of primary immunodeficiency, such as severe combined immunodeficiency
disease or acquired immune deficiency syndrome (AIDS).
• Patients with history of human immunodeficiency virus (HIV) infection must have
undetectable HIV ribonucleic acid (RNA).
19. Known active infection with hepatitis B, hepatitis C or other viral infections
requiring systemic therapy.
20. Has a QTc prolongation to > 450 millisecond (ms) in males and > 470 ms in females.
21. Is Pregnant or breastfeeding.
22. Received a live vaccine within 30 days prior to lymphodepletion (Day -5).
23. Any other clinically significant medical disease or condition that, in the Principal
Investigator's opinion, may interfere with protocol adherence or the patient's
ability to provide informed consent.
