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Treatment may be continued with a 50% reduction in the infusion rate if a grade 2 infusion-related reaction occurs. Symptoms may be treated as above and/or as clinically indicated. |
The infusion of T cells will be stopped if a grade 3 infusion-related reaction occurs. Symptomatic treatment, as outlined above, will be administered as necessary and the infusion can be resumed at a 50% rate reduction after resolution of symptoms. T cell infusion will be discontinued if a grade 3 reaction recurs after... |
In addition, T cell infusion will be discontinued if a grade 4 infusion-related toxicity occurs. Symptoms will be treated using the guidelines above and no further T cells will be infused. |
Study Population: B cell malignancies comprise a heterogeneous group of neoplasms including a vast majority of non-Hodgkin's lymphomas (NHL), acute lymphoblastic leukemias (ALL) and chronic lymphocytic leukemias (CLL). An estimated 80,500 new cases of Hodgkin's and non-Hodgkin's lymphomas are diagnosed in the US in 201... |
Follicular lymphoma (FL) is the second most frequent non-Hodgkin lymphoma accounting for about 10-20% of all lymphomas in western countries. In the United States, FL accounts for approximately 35 percent of NHLs and has an estimated incidence of 3.18 cases per 100,000 people. The incidence increases with age; FL most f... |
While FL is usually viewed as a disorder with an indolent clinical course, the recently published m7-FL International Prognostic Index (m7-FLIPI) allows for stratification of FL patients into risk groups according to progression of disease within 24 months, based on a clinicogenetic risk model assessment of the mutatio... |
CD19 is a 95kDa glycoprotein present on B cells from early development until differentiation into plasma cells. It is a member of the immunoglobulin (Ig) superfamily and a component of a cell surface signal transduction complex that regulates signal transduction through the B cell receptor. Mice lacking CD19 have a dec... |
Chimeric antigen receptor T (CAR-T) cell therapy is an emerging class of immunotherapy based on engineered autologous T-cells that has been proven to be an effective treatment in refractory/relapsing ALL and large B-cell lymphoma. However, these therapies are associated with significant risks to patients including cyto... |
To be eligible, the subjects must have an adequate number of T cells that can be successfully transduced and expanded with the anti-CD19 lentivirus vector, as determined from a sample of PBMC obtained by phlebotomy at the first screening visit (~week -8). The purpose of this screening procedure is to exclude subjects f... |
Female subjects of reproductive potential (women who have reached menarche or women who have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 months, or have not undergone a sterilization procedure [hysterectomy or bilateral oophorectomy]) must have a negati... |
Due to the high-risk level of this study, while enrolled, all subjects must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization). Additionally, if participating in sexual activity that could lead to pregnancy, the study subje... |
Acceptable birth control includes a combination of two of the following methods: • Condoms* (male or female) with or without a spermicidal agent. • Diaphragm or cervical cap with spermicide • Intrauterine device (IUD) • Hormonal-based contraception |
Subjects who are not of reproductive potential (women who have been post menopausal for at least 24 consecutive months or have undergone hysterectomy, salpingotomy, and/or bilateral oophorectomy or men who have documented azoospermia) are eligible without requiring the use of contraception. Acceptable documentation of ... |
Inclusion Criteria: Diagnosis and main criteria for inclusion: Patients must meet the following criteria to be enrolled in this study: |
Male and female subjects with CD19+ B cell malignancies, including subjects with no available curative treatment options (such as autologous or allogeneic SCT) who have limited prognosis (several months to <2 year survival) with currently available therapies will be enrolled: 1. Follicular Lymphoma (FLL) a) m7-FLIPI hi... |
2. Age > 18 years. 3. Expected survival > 12 weeks 4. Creatinine < 2.5 mg/dl. 5. ALT/AST < 3x normal 6. Bilirubin <2.0 mg/dl 7. Any relapse after prior autologous SCT will make patient eligible regardless of other prior therapy. 8. Adequate venous access for apheresis, and no other contraindications for leukapheresis. ... |
Exclusion Criteria: Any patient who meets any of the following criteria will not qualify for entry into the study: 1. Pregnant or lactating women. The safety of this therapy on unborn children is not known. Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed ... |
Study Endpoints: Primary Endpoints: Primary safety, feasibility and engraftment endpoints include: 1. Occurrence of study related adverse events, defined as NCI CTC > grade 3 signs/symptoms, laboratory toxicities and clinical events that are possible, likely or definitely related to study treatment. This will include i... |
Secondary Endpoints: 1. Duration of in vivo survival of CLBR001 cells is defined as "engraftment". The primary engraftment endpoint is the # DNA vector copies per ml blood of CLBR001 cells on week 4 after the first infusion. Q-PCR for CLBR001 vector sequences will also be performed after infusion at 24 hours, weekly x ... |
Exploratory Endpoints: |
Investigational Product, Dose and Mode of Administration: The investigational product is a combination of • CLBR001 cells, which are autologous T cells that have been engineered to express an extracellular single chain antibody (scFv) with specificity for SWI019, linked to an intracellular signaling molecule comprised ... |
Reference Therapy, Dose and Mode of Administration: None |
Study Duration The study is planned to start in Q2-3/2019, study recruitment is planned to be completed in Q3-4/2020. Patients will be offered the choice to continue dosing with SWI019 until disease progression is confirmed or an unacceptable toxicity occurs. |
Criteria for Evaluation: Pharmacokinetics of SWI019: Pharmacokinetic parameters will include: • Systemic clearance • Maximum observed serum concentration (Cmax) • Time to reach Cmax after drug administration • Minimum concentration at the end of a dosing interval • Terminal elimination half-life • Volume of distributio... |
Immunogenicity The status of the anti-SWI019 antibody (ADA response) will be determined for all patients. Assay results will be reported as positive or negative for the confirmatory and in neutralizing assays. The proportion of patients with positive results will be summarized. |
Pharmacodynamics: Pre- and post-treatment peripheral blood samples and bone marrow biopsies will be collected to assess the penetrance of CLBR001/ SWI019 in patients. The pharmacodynamic assessments of tumor biopsies may include, but are not limited to, SWI019 binding to CD19 and CLBR001, and presence of activated T-ce... |
Exploratory Biomarkers: Pre- and post-treatment peripheral blood samples will be collected to assess levels of serum cytokines and chemokines including but not limited to: IL-2, TNFa, IL-6, IFNg, MIP1a, MIP1b, sgp130, sIL6R, MCP-1. A panel of clinical laboratory tests for chemistries as well as C-reactive protein (CRP)... |
Efficacy Evaluations Efficacy of CLBR001/ SWI019 in FL patients will be evaluated as a secondary endpoint using endpoints of objective responses (OR). For this study, classification of response will be either Minimal Residual Disease (MRD), Overall Remission Rate (ORR), which includes Complete Remission (CR, with full,... |
Safety Evaluations Safety of CLBR001/ SWI019 in patients with FL will be evaluated based on criteria described by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Adverse events will be assessed continuously during the study and for 100 days after the last study d... |
Statistical Methods: For continuous variables, descriptive statistics (mean, SD, interquartiles and ranges) will be presented; for categorical variables, counts and percentages will be tabulated by cohort. Assessment of CR and OS will also be presented in tabular format. For safety-related parameters (ie, clinical sign... |
Statistical Analysis Plan: To be determined |
Study Hypothesis: The combination of CLBR001/ SWI019 is safe and well tolerated in adult patients with FL. |
Sample Size: Statistics were not used to calculate the proposed sample size of 36 patients. The anticipated drop-out rate is 30%. |
Pharmacokinetic Methods: CLBR001 cells will be monitored by a flow cytometry based assay to determine cells/uL of blood and separately be a qPCR based assay to vector copy number per ug of DNA. SWI001 will be quantified in serum by a sandwich based ELISA assay. |
Pharmacokinetic Population All patients treated with SWI019 who provide at least 1 valid concentration value will comprise the PK Population. The PK Population will be used for the analysis of PK data. The PK exposure-response analysis will include patients who have both available PK and PK/pharmacodynamics response da... |
Efficacy Analyses: Populations for Analysis There are three analysis populations for this study, as follows: the Full Analysis (FA) Population, the Safety Population, and the PK Population. Full Analysis Population The FA Population will include all enrolled patients that had at least one postbaseline observation. Full... |
Safety Analyses: All enrolled patients will be included in the Safety Population. Safety analyses will be based upon the treatment regimens actually received. |
Date of Protocol Synopsis: January 19th, 2018 |
APPENDIX |
'RESPONSE DEFINITIONS' |
Response Category Definition |
Complete remission (CR) All of the following criteria are met: Bone Marrow Peripheral Blood • Neutrophils > 1x 10e9/L, and • Platelets > 100 x 10e9/L, and • Circulating blasts < 1% Extramedullary disease • No evidence of extramedullary disease (by physical exam, spinal tap (D 28 or to ascertain CR/CR;), and symptom Tra... |
Complete remission with incomplete blood count recovery (CRi) All criteria for CR as defined above are met, except that the following exist: • Neutrophils ≤ 1x 10e9/L, and/or • Platelets ≤ 100 x 10e9/L and/or • Platelet and/or neutrophil transfusions ≤ 7 days before peripheral blood sample for disease assessment |
Relapsed Disease Only in patients who obtained a CR or CRi: • Reappearance of blasts in the blood (≥1%), or • Reappearance of blasts in the bone marrow (≥5%), or • (Re-)appearance of any extra-medullary disease after CR or CRi |
Source: National Comprehensive Cancer Network (NCCN) guidelines for response |
Table of Study Events Dosing Schedule CLBR001/ SWI019 IV QAD, Hospitalization 1st Cycle for 28 days |
Dosing Period Recovery Period Assessment Cycle 11 Screening/ Baseline Week -1 Week 1 Week 2 Week 3 Week 4 |
Study Day # Day -28 to Day-1 Day -4 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 |
Calendar Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 |
Informed Consent X |
Inclusion/Exclusion X |
Demographic Information X |
Medical History X |
Physical Examination X X X X X |
Height X |
Weight X X X X X |
12-Lead ECG X X X X X |
Eastern Cooperative Oncology Group Performance Status X X |
HBV, HCV, and HIV X |
Serology X |
PK X X X X X X X X X X X X X X X X X |
ADA X X X |
IP administration intravenously CLBR001 single dose X |
SWI019 X X X X X X X |
Adverse Events/Serious Adverse events X X X X X X X X X X X X X X X X X X X X X X X X X X X X X |
Chemistry, Hematology, and Urinalysis X X X X X X X X X X X X X X X X X |
Prior and Concomitant Medications/ Nonpharmacologic therapies X X X |
CTC X X X |
Bone Marrow Biopsy X X X |
Archival Bone Marrow Sample X |
Exploratory biomarkers X X X X X X X X X X |
1Assessment Cycle 1 - Patients will be admitted to the hospital for a period of approximately 28 days, i.e. from week -1 to week 3 (inclusive); single IV administration of CLBR001 CAR-T cells and subsequent IV administration of SWI019 Switch peptide every other day for week 1 and 2 followed by a recovery period from D1... |
Table of Study Events Dosing Schedule CLBR001/ SWI019 IV QAD, Second Cycle etc. |
Dosing Period Recovery Period Assessment Cycle 2 Week 1 Week 2 Week 3 Week 4 |
Study Day # 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 |
Calendar Day 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 |
Informed Consent |
Inclusion/Exclusion |
Demographic Information |
Medical History |
Physical Examination X X X X X X X |
Height |
Weight X X X X X X X |
12-Lead ECG X |
Eastern Cooperative Oncology Group Performance Status X X X |
HBV, HCV, and HIV |
Serology |
PK X X X X X X X |
ADA X X |
IV Administration CLBR0012 |
SWI0192 X X X X X X X |
Adverse Events/Serious Adverse events(6) X X X X X X X X X X X X X X X X X X X X X X X X X X X X |
Chemistry, Hematology, and Urinalysis X X X X X X |
Prior and Concomitant Medications/ Nonpharmacologic therapies |
CTC |
Bone Marrow Biopsy(3) X |
Archival Bone Marrow Sample X |
Exploratory biomarkers4 X X X X X X X X |
1Assessment Cycle 2 - Patients will be treated on an Outpatient basis 2Assessment Cycle 1 - Patients will be admitted on Day 28 for evaluation and scheduled procedures, i.e. bone marrow biopsy |
CD19 Program timeline: |
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