A Phase 1/2 Multi-Center Study Evaluating the Safety and Efficacy of KTE-C19 in Adult Subjects with Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (r/r ALL)
William G. Wierda
The goal of this research study is to learn if KTE-C19 can help to control ALL after you receive 3 days of fludarabine and cyclophosphamide. The safety of KTE-C19 will also be studied.
Disease Group: Leukemia,Malignant neoplasms stated as primary lymphoid haematopoietic
Treatment Agent: Cyclophosphamide,Fludarabine,KTE-C19,MESNA
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Kite Pharma, Inc.
The primary objective of phase 1 is to evaluate the safety of KTE-C19. The primary objective of phase 2 is to evaluate the efficacy of KTE-C19, as measured by the overall complete remission rate defined as complete remission (CR) and complete remission with incomplete hematologic recovery (CRi) in adult subjects with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL). Secondary objectives will include assessing the safety and tolerability of KTE-C19, and additional efficacy endpoints, and change in EQ-5D scores.
IRB Review and Approval Date: 07/21/2016
Recruitment Status: Open
Projected Accrual: Up to 100
1) Relapsed or refractory B-precursor ALL as defined as one of the
following: Primary refractory disease; First relapse if first remission
</=12 months; Relapsed or refractory disease after 2 or more lines of
systemic therapy; Relapsed or refractory disease after allogeneic
transplant provided subject is at least 100 days from stem cell
transplant at the time of enrollment and off of immunosuppressive
medications for at least 4 weeks prior to enrollment
2) Morphological disease in the bone marrow (>/= 5% blasts)
3) Subjects with Ph+ disease are eligible if they are intolerant to tyrosine kinase inhibitor (TKI) therapy, or if they have relapsed/refractory disease despite treatment with at least 2 different TKIs
4) Age 18 or older
5) Eastern cooperative oncology group (ECOG) performance status of 0 or 1
6) ANC >/= 500/muL unless in the opinion of the PI cytopenia is due to underlying leukemia and is potentially reversible with leukemia therapy
7) Platelet count >/= 50,000/muL unless in the opinion of the PI cytopenia is due to underlying leukemia and is potentially reversible with leukemia therapy
8) Absolute lymphocyte count >/= 100/muL
9) Adequate renal, hepatic, pulmonary, and cardiac function defined as: Creatinine clearance (as estimated by Cockcroft Gault) >/= 60 cc/min; Serum ALT/AST </= 2.5 x ULN (upper limit of normal); Total bilirubin </= 1.5 mg/dl, except in subjects with Gilbert’s syndrome. Left ventricular ejection fraction >/= 50% and no evidence of pericardial effusion as determined by an ECHO, no NYHA class III or class IV functional classification, and no clinically significant arrhythmias; No clinically significant pleural effusion; Baseline oxygen saturation > 92% on room air.
10) Females of childbearing potential must have a negative serum or urine pregnancy test
11) In subjects previously treated with blinatumomab, CD19 tumor expressions on blasts obtained from bone marrow or peripheral blood must be documented after completion of the most recent prior line of therapy. If CD19 expression is quantified, then blasts must be >/= 90% CD19 positive.
1) Diagnosis of Burkitt’s leukemia/lymphoma according to WHO
classification or chronic myelogenous leukemia lymphoid blast crisis
2) History of malignancy other than non-melanoma skin cancer or carcinoma in situ (eg, cervix, bladder, breast) unless disease free for at least 3 years
3) History of severe hypersensitivity reaction to aminoglycosides or any of the agents used in this study
4) CNS Abnormalities: Presence of CNS-3 disease, defined as detectable cerebrospinal blast cells in a sample of CSF with >/= 5 WBCs per mm^3 with or without neurological changes, and presence of CNS-2 disease defined as detectable cerebrospinal blast cells in a sample of CSF with <5 WBCs per mm^3 with neurological changes. Note: Subjects with CNS-1 (no detectable leukemian in the CSF) and those with CNS-2 without clinically evident neurological changes are eligible to partipate in the study. History or presence of any CNS disorder such as a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, any autoimmune disease with CNS involvement, poterior reversible encephalopathy syndrome (PRES), or cerebral edema.
5) History of concomitant genetic syndrome associated with bone marrow failure such as Fanconi anemia, Kostmann syndrome, Shwachman-Diamond syndrome
6) History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment
7) History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of enrollment.
8) Primary immunodeficiency
9) Known infection with HIV, hepatitis B or hepatitis C virus. A history of hepatitis B or hepatitis C is permitted if the viral load is undetectable per quantitative PCR and/or nucleic acid testing.
10) Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring antimicrobials for management. Simple UTI and uncomplicated bacterial pharyngitis are permitted if responding to active treatment and after consultation with the Kite medical monitor.
11) Prior medication: Salvage systemic therapy (including chemotherapy, TKIs for Ph+ ALL and blinatumomab) within 1 week or 5 half-lives (whichever is shorter) prior to enrollment; Prior CD19 directed therapy other than blinatumomab; History of CTCAE grade 4 neurologic event or grade 4 CRS with prior CD19-directed therapy. Treatment with alemtuzumab within 6 months prior to enrollment, clofarabine or cladribine within 3 months prior to enrollment, or PEG-asparaginase witin 3 weeks prior to enrollment; Donor lymphocyte infusion (DLI) within 28 days prior to enrollment; Any drug used for GVHD within 4 weeks prior to enrollment (eg, calcineurin inhibitors, methotrexate, mycophenolyate, rapamycin, thalidomide), or immunosuppressive antibody used within 4 weeks pror to enrollment (eg, anti-CD20, anti-tumor necrosis factor, anti-interleukin 6 or anti-interleukin 6 receptor);
12) Continued from #11 above: At least 3 half-lives must have elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule therapy prior to enrollment (eg, ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists etc); Corticosteroid therapy at a pharmacologic dose (>5 mg/day of prednisone or equivalent doses of other corticosteroids) and other immunosuppressive drugs must be avoided for 7 days prior to enrollment.
13) Presence of any indwelling line or drain (eg, percutaneous nephrostomy tube, indwelling Foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter). Ommaya reservoirs and dedicated central venous access catheters such as a Port-a-Cath or Hickman catheter are permitted
14) Acute GVHD grade II-IV by Glucksberg criteria or severity B-D by IBMTR index; acute or chronic GVHD requiring systemic treatment within 4 weeks prior to enrollment
15) Live vaccine </=4 weeks prior to enrollment
16) Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant. Females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential
17) Subjects of both genders of child-bearing potential who are not willing to practice birth control from the time of consent through 6 months after the completion of KTE-C19
18) In the investigators judgment, the subject is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation.
19) History of autoimmune disease (eg, Crohns, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years
Information and next steps
Leukemia,Malignant neoplasms stated as primary lymphoid haematopoietic
Phase I/Phase II
William G. Wierda
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