Anti-CD19-ARTEMIS T Cells, Fludarabine Phosphate, and Cyclophosphamide in Treating Participants with CD19+ Relapsed or Refractory Non-Hodgkin's Lymphoma
This phase I trial studies the side effects and best dose of anti-CD19-ARTEMIS T cells when given together with fludarabine phosphate and cyclophosphamide in treating participants with non-Hodgkin's lymphoma that has come back or isn't responding to treatment. In engineered T-cell therapy, T cells (part of the immune system) are removed from the body and genetically modified in a laboratory before being transferred back into the participant. These modified cells (anti-CD19-ARTEMIS T cells) may be better able to recognize and kill cancer cells by targeting a protein on the cancer cell surface called CD19 (found on tumor cells and on normal antibody producing cells). Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving Anti-CD19-ARTEMIS T cells together with fludarabine phosphate and cyclophosphamide may work better in treating participants with non-Hodgkin's lymphoma.
- Subjects with relapsed/refractory CD19+ non-Hodgkin’s lymphoma of the following subtypes: * Diffuse large B-cell lymphoma (DLBCL) * Mantle cell lymphoma (MCL) * Follicular lymphoma (FL) * Chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) * Burkitt’s Lymphoma
- Ability to provide written informed consent for the protocol
- Willingness and ability to comply with scheduled visit, treatment plans, laboratory tests, and other procedures
- Eastern Cooperative Oncology Group performance status of =< 2
- Evidence of at least one measurable lesion on imaging with the following exceptions * Subjects treated with interim chemotherapy for disease control between enrollment verification and ET190L1-ARTEMIS T cell infusion who do not have measurable disease at re-screening are still eligible * CLL/SLL with documented B-cell absolute lymphocytosis > 5 x 10^9 cells/L peripheral blood or infiltration of lymph nodes and/or bone marrow infiltration by CLL phenotype cells defined as clonal B cells with majority population co-expressing CD5 and CD19, with surface immunoglobulin (sIg, kappa or lambda but not both) and CD20 (dim), CD23+ (if CD20 or sIg are bright or if CD23 is dim or negative [atypical CLL phenotype] then fluorescence in situ hybridization (FISH) for 11:14 translocation must be performed to differentiate from mantle cell lymphoma) * Lesions previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy ** Measurable lesions are nodes/nodal masses > 1.5 cm, extranodal masses > 1.0 cm or positron emission tomography (PET) avid lesions consistent with lymphoma
- Must have biopsy-proven primary refractory disease or relapsed disease and meet at least one of the following: * For subjects with DLBCL: relapsed or refractory disease after >= 2 prior line(s) of therapy; for both de novo and transformed disease, patients must have received at least 1 prior regimen with anti-CD20 monoclonal antibody (mAb) and anthracycline (anthracycline used for the prior low grade disease also would satisfy this requirement) * For subjects with FL or SLL: relapsed or refractory disease after >= 2 prior line(s) of therapy * For subjects with CLL: must be relapsed or refractory disease and ** With no unfavorable cytogenetics and have failed >= 3 prior line(s) of therapy ** With unfavorable cytogenetics including del17p/mutated p53 or unmutated immunoglobulin heavy chain variable region relapsed or refractory disease after >= 2 prior line(s) of therapy which must have included ibrutinib * For subjects with MCL: relapsed or refractory disease after at least 1 prior regimen with chemoimmunotherapy * For subjects with Burkitt’s: relapsed or refractory disease after at least 1 prior line of therapy * Any subject, with subtypes listed above, having either failed autologous hematopoietic stem cell transplantation (HSCT) after at least 1 prior regimen, or those subjects ineligible for, but not an appropriate candidate, or not consenting to autologous HSCT
- Creatinine clearance >= 45ml/min
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3x the institutional upper limit of normal (ULN), except for people with liver involvement by their lymphoma, who may be included if AST/ALT =< 5x the institutional ULN
- Total bilirubin =< 2x the institutional ULN with the exception of patients with Gilbert syndrome; patients with Gilbert syndrome may be included if their total bilirubin is =< 3.0x ULN and direct bilirubin is =< 2x ULN
- Must have a minimum level of pulmonary reserve defined as =< grade 1 dyspnea and pulse oximetry of >= 88% on room air
- Must be hemodynamically stable at the time of ET190L1-ARTEMIS T cell administration and have left ventricular ejection fraction (LVEF) >= 45% confirmed by echocardiogram or multigated acquisition scan (MUGA) scan
- Absolute neutrophil count (ANC) >= 1,000/mm^3
- Absolute lymphocyte count (ALC) >= 300/mm^3, and absolute number of CD3+ T cells > 150/mm^3
- Platelets >= 50,000/mm^3
- Hemoglobin >= 8 g/dL
- Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, and all male participants must use effective methods of contraception for at least 12 months following infusion of ET190L1-ARTEMIS T cells and ET190L1-ARTEMIS T cells are no longer present by PCR (with surveillance to cease at 5 years) * Highly effective contraception may change depending on current Institutional Review Board (IRB) standards but currently include ** Total abstinence, excluded are periodic abstinence utilizing the calendar, ovulation, symptothermal, or post-ovulation methods, or withdrawal technique ** Female sterilization including: 1) surgical bilateral oophorectomy with or without hysterectomy; in the case of oophorectomy alone when the reproductive status has been confirmed by follow up hormone level assessment and, 2) tubal ligation at least six weeks before taking study treatment ** Male sterilization at least 6 months prior to screening; in the case of female subjects with a male partner who has had a vasectomy, this partner should be the sole partner for that subject ** Contraception requiring consistent use of BOTH forms listed below must be utilized *** Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%) for example hormonal vaginal ring or transdermal hormonal contraception; women on oral contraception should be stable on the hormone pill for at least 3 months prior to infusion of study drug *** Barrier method of contraception to include: condom, occlusive cap (diaphragm or cervical/vault cap) with spermicidal foam/gel/film/cream/vaginal suppository *** Sexually active males must use a condom during intercourse for 12 months after treatment as they should not father a child in this period; a condom is required to be used by vasectomized men (as well as during intercourse with a male partner)
- Prior treatment * With any prior anti-CD19/anti-CD19 CAR-T or cellular therapy (prior blinatumomab therapy is allowed) * Treatment with any prior gene therapy * Prior allogeneic hematopoietic stem cell transplant * Received chemotherapy, radiation or surgical resection of malignancy within 2 weeks prior to the start of lymphodepleting chemotherapy (day -10 to -5)
- Active, uncontrolled serious infection or medical or psychiatric illness, that in the investigator’s opinion is likely to interfere with participation in this clinical trial
- Active central nervous system (CNS) involvement by malignancy
- History of seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement
- Active replication of hepatitis B or active hepatitis C (hepatitis C virus [HCV] ribonucleic acid [RNA] positive); those with prior disease who are PCR negative at enrollment and meet liver function eligibility criterion are eligible
- Known human immunodeficiency virus (HIV) positive patients
- Patients with unstable angina and/or myocardial infarction within 6 months prior to screening
- Cardiac arrhythmia not controlled with medical management, evidence of pericardial effusion on imaging that is compromising function
- Previous or concurrent malignancy with exception of adequately treated basal cell or squamous cell carcinoma, in-situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to study drug infusion, or prostate cancer that was treated with prostatectomy or radiotherapy over 2 years before day 1 of protocol therapy and patients whose prostate-specific antigen (PSA) is undetectable at study entry
- Autoimmune disease or history of primary immunodeficiency (excluding Hashimoto’s thyroiditis, vitiligo, or diabetes mellitus [DM] type I)
- Women who are pregnant or breast feeding
Locations & Contacts
Contact: David Alan Rizzieri
Trial Objectives and Outline
I. To estimate the maximum tolerated dose of ET190L1-ARTEMIS T cells in subjects with a relapsed and/or refractory CD19+ non-Hodgkin’s lymphoma and evaluate the overall safety of the ET190L1-ARTEMIS.
I. Evaluate the efficacy of ET190L1-ARTEMIS T cell therapy, defined as overall response rate (ORR), including complete response (CR) or partial response (PR), of subjects with relapsed/refractory CD19+ non-Hodgkin’s lymphoma who receive human ET190L1 ARTEMIS T cell therapy.
II. Evaluate the efficacy of ET190L1-ARTEMIS T cells in histologic subtypes of CD19+ non-Hodgkin’s lymphoma.
III. Evaluate duration of overall response (DOR).
IV. Evaluate progression free survival (PFS).
V. Evaluate overall survival (OS).
I. Evaluate the presence, expansion and persistence of ET190L1-ARTEMIS T cells in the peripheral blood at select time points after infusion, by quantitative polymerase chain reaction (qPCR) and/or flow cytometry.
II. Evaluate the phenotype and maturation profile of ET190L1-ARTEMIS T cells after in vitro expansion and at various time-points post-infusion by flow cytometric immunophenotyping. Markers include (but are not limited to): CD3, CD4, CD8, CD25, CD27, CD28, CD57, CD69, CD45RO, CCR7, PD1, TIM3, and Lag3.
III. Evaluate levels of serum cytokines/biomarkers before treatment and at various timepoints after ET190L1-ARTEMIS T cell infusion, including (but not limited to): IL-2, IFN-gamma, TNF-alpha, IL-6, GM-CSF, IL-10, IL-7, IL-15, C reactive protein (CRP), and ferritin.
IV. Determine the immunophenotype of malignant lymphoid cells pre- and post-treatment, at times of disease progression or therapy resistance by immunohistochemistry (IHC) (flow cytometry or sequencing, depending on tissue sampled peripheral blood versus tissue, bone marrow, lymph node) including (but not limited to): CD19, CD80, CD86, and standard immunophenotype profile dependent upon histology.
V. Investigate further correlates of ET190L1-ARTEMIS efficacy, product characteristics, and safety, with samples collected as a part of “research blood” which also includes cytokine, quantitative T cell and T cell phenotype assessment blood.
OUTLINE: This is a dose-escalation study of ET190L1-ARTEMIS T cells.
Participants receive fludarabine intravenously (IV) and cyclophosphamide IV on days -5 through -3. Participants then receive ET190L1-ARTEMIS T cells IV on day 0.
After completion of study treatment, participants are followed up on days 1-7, 11, 14, 17, 21 and 28, months 2, 3, 4, 6, 9, 12, 15, 18, 24, 36, 48, and 60. Then, they are followed up annually for up to 10 more years.
Trial Phase & Type
Duke University Medical Center
David Alan Rizzieri
Secondary IDs NCI-2018-00437
Clinicaltrials.gov ID NCT03379493