JCAR017 for Chronic Leukemia or Lymphoma
Recruiting in Palo Alto (17 mi)
+94 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Juno Therapeutics, a Subsidiary of Celgene
Must be taking: Ibrutinib, Venetoclax
Must not be taking: Alemtuzumab, Cladribine
Disqualifiers: Active CNS malignancy, Richter's transformation, others
No Placebo Group
Breakthrough Therapy
Approved in 1 jurisdiction
Trial Summary
What is the purpose of this trial?This trial tests JCAR017, a therapy using modified immune cells, in adults with hard-to-treat CLL or SLL. It aims to see if these enhanced immune cells can better fight the cancer.
Do I need to stop my current medications for the trial?
The trial protocol does not specify if you need to stop all current medications, but certain medications must be stopped before joining. For example, venetoclax must be stopped 4 days before, and some other medications like corticosteroids and anti-CD20 antibodies have specific stop times before starting the trial.
What data supports the effectiveness of the drug JCAR017 for Chronic Leukemia or Lymphoma?
Research indicates that venetoclax, a component of the treatment, is improving outcomes for patients with chronic lymphocytic leukemia, a type of leukemia, when used with other targeted therapies. Additionally, Bruton tyrosine kinase inhibitors, like ibrutinib, are showing potential in making chronic lymphocytic leukemia potentially curable.
12345Is lisocabtagene maraleucel (JCAR017) safe for humans?
Lisocabtagene maraleucel (JCAR017) has been shown to have a manageable safety profile in treating large B-cell lymphoma, but it can cause serious side effects like cytokine release syndrome (a severe immune reaction) and neurological issues. Patients need to be closely monitored for at least seven days after receiving the treatment.
678910How is the drug JCAR017 (lisocabtagene maraleucel) unique for treating chronic leukemia or lymphoma?
JCAR017 (lisocabtagene maraleucel) is a type of CAR T-cell therapy, which is unique because it involves modifying a patient's own immune cells to better recognize and attack cancer cells, offering a personalized approach compared to traditional chemotherapy.
1112131415Eligibility Criteria
Adults with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) who have failed multiple prior therapies can join. Participants must have adequate organ and bone marrow function, not be pregnant, and cannot have active infections like hepatitis B/C or HIV.Inclusion Criteria
I am eligible for a therapy combining ibrutinib and JCAR017.
My cancer is CD19 positive, even after CD19-targeted treatment.
I have been diagnosed with CLL and need treatment according to my doctor.
+8 more
Exclusion Criteria
My condition has progressed to Richter's transformation.
I am experiencing severe symptoms from a transplant rejection.
I have a significant brain or nervous system condition.
+12 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Phase 1 Treatment
Phase 1 to determine the recommended dose of JCAR017 monotherapy and assess combinations with ibrutinib and venetoclax
Up to 48 months
Phase 2 Treatment
Phase 2 to further assess the efficacy and safety of JCAR017 monotherapy at the recommended dose
Up to 24 months
Follow-up
Participants are monitored for safety and effectiveness after treatment
Up to 48 months
Participant Groups
The trial is testing JCAR017 alone or in combination with either ibrutinib or venetoclax to treat CLL/SLL. It's a multi-phase study starting with finding the right dose of JCAR017 before moving on to test its effectiveness and safety at that dose.
5Treatment groups
Experimental Treatment
Group I: Phase 2 JCAR017 monotherapyExperimental Treatment1 Intervention
Subjects will receive JCAR017 (lisocabtagene maraleucel) at the recommended dose from the Phase 1 monotherapy arm
Group II: Phase 2 JCAR017 Double-Exposed Monotherapy Expansion (DEME)Experimental Treatment1 Intervention
Subjects will receive JCAR017 monotherapy
Group III: Phase 1 JCAR017 monotherapyExperimental Treatment1 Intervention
Subjects will be assigned to receive JCAR017 (lisocabtagene maraleucel)
Group IV: Phase 1 JCAR017 + venetoclaxExperimental Treatment2 Interventions
Subjects will receive venetoclax as bridging anticancer therapy until lymphodepletion chemotherapy/ JCAR017 (lisocabtagene maraleucel) at the recommended dose from the Phase 1 monotherapy arm. After JCAR017 infusion subjects will receive venetoclax until Day 90.
Group V: Phase 1 JCAR017 + ibrutinibExperimental Treatment1 Intervention
Subjects receiving ibrutinib at baseline will be assigned to receive JCAR017 (lisocabtagene maraleucel) at the recommended dose from the Phase 1 monotherapy arm + ibrutinib
JCAR017 (lisocabtagene maraleucel) is already approved in United States for the following indications:
🇺🇸 Approved in United States as Breyanzi for:
- Large B-cell lymphoma
- Relapsed or refractory CLL or SLL
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
City of HopeDuarte, CA
City Of HopeDuarte, CA
University Of California San Diego Moores Cancer CenterLa Jolla, CA
Northwestern Memorial HospitalChicago, IL
More Trial Locations
Loading ...
Who Is Running the Clinical Trial?
Juno Therapeutics, a Subsidiary of CelgeneLead Sponsor
References
The cure of leukemia through the optimist's prism. [2023]Progress is occurring at a dizzying rate across all leukemias. Since the authors' review of the topic in Cancer in 2018, numerous discoveries have been made that have improved the therapy and outcomes of several leukemia subsets. Hairy cell leukemia is potentially curable with a single course of cladribine followed by rituximab (10-year survival, ≥90%). Acute promyelocytic leukemia is curable at a rate of 80% to 90% with a nonchemotherapy regimen of all-trans retinoic acid and arsenic trioxide. The cure rate for core-binding factor acute myeloid leukemia (AML) is ≥75% with fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin. Survival for patients with chronic myeloid leukemia is close to that for an age-matched normal population with BCR-ABL1 tyrosine kinase inhibitors (TKIs). Chronic lymphocytic leukemia, a previously incurable disease, may now be potentially curable with a finite duration of therapy with Bruton tyrosine kinase inhibitors and venetoclax. The estimated 5-year survival rate for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) exceeds 70% with intensive chemotherapy and ponatinib, a third-generation BCR-ABL1 TKI, and more recent nonchemotherapy regimens using dasatinib or ponatinib with blinatumomab are producing outstanding results. Survival in both younger and older patients with ALL has improved with the addition of antibodies targeting CD20, CD19 (blinatumomab), and CD22 (inotuzumab) to chemotherapy. Several recent drug discoveries (venetoclax, FLT3 and IDH inhibitors, and oral hypomethylating agents) are also improving outcomes for younger and older patients with AML and for those with higher risk myelodysplastic syndrome.
Targeting BCR-ABL and JAK2 in Ph+ ALL. [2021]In this issue of Blood, Appelmann et al provide evidence for prolonged survival and prevention of resistance in a mouse model of Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) by combined targeting of the BCR-ABL kinase and Janus kinase 2 (JAK2) with dasatinib and ruxolitinib, respectively.
Dasatinib Approved for Pediatric CML. [2019]The FDA approved dasatinib to treat pediatric chronic myeloid leukemia. This drug is the second tyrosine kinase inhibitor, alongside imatinib, approved for this indication and represents an important new option for first- and second-line treatment.
Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia. [2023]Dasatinib is effective therapy for chronic myeloid leukemia (CML) after imatinib failure. In this study, we investigate the efficacy of dasatinib as initial therapy for patients with CML in early chronic phase.
[Molecular targeted therapy in lymphoid leukemias]. [2014]Recent advances in the treatment of lymphoid leukemias have incorporated molecular targeted drugs (CD20-targeting rituximab and BCR-ABL tyrosine kinase inhibitors) into the traditional chemotherapeutic agents. This article reviews novel molecular targeted therapies for patients with lymphoid leukemias including acute lymphoblastic leukemia, chronic lymphocytic leukemia, hairly cell leukemia and HTLV-I-related adult T-cell leukemia. Investigational agents that will be discussed in this review include inotuzumab, blinatumomab, alemtuzumab, ofatumumab, ibrutinib, idelalisib, bafetinib, lenalidomide, ABT-199 and mogamulizumab. Novel approaches warrant continued research to improve outcomes for patients with lymphoid leukemias.
Lisocabtagene Maraleucel for the treatment of B-cell lymphoma. [2022]Introduction: Lisocabtagene Maraleucel (Liso-cel) is a second-generation Chimeric Antigen Receptor T-cell (CAR-T) therapy product targeting CD19. It is currently being evaluated for B-cell lymphomas with pivotal trials conducted in Aggressive B-cell LymphomasAreas covered: To prepare this article reviewing preclinical and clinical data studying Liso-cel, we performed a Pubmed search using the terms 'JCAR017' and 'Lisocabtagene maraleucel'. Pre-clinical work done with Liso-cel demonstrate the synergistic activity of CD4 + T-cells and CD8+ central memory T-cells (TCM) at a predefined ratio of 1:1. The trial, TRANSCEND NHL001 in aggressive B-cell lymphoma, confirms robust antitumor activity while demonstrating manageable toxicity profile.Expert Opinion: There are inherent differences amongst the three CD19 directed CAR-T products. This could explain the differences in efficacy and safety profiles of the products. In the absence of randomized data, it would be scientifically unsound to prioritize one product over another. Nevertheless, when aiming to balance efficacy and safety, current prospective data indicate that Liso-cel is well positioned with impressive response rates.
New Approval for Drug Treating Large B-Cell Lymphoma. [2023]The Food and Drug Administration has approved lisocabtagene maraleucel (Breyanzi) to treat large B-cell lymphoma in adults who relapsed or were refractory after first-line treatment.Lisocabtagene maraleucel continues to be prescribed under the Risk Evaluation and Mitigation Strategy due to the risk of fatal or potentially fatal cytokine release syndrome and neurologic toxicities.Nurses need to closely monitor patients for these and for other serious adverse effects for at least seven days after infusion of the drug.
Lisocabtagene maraleucel in the treatment of relapsed/refractory large B-cell lymphoma. [2023]Lisocabtagene maraleucel (liso-cel) is one of the three US FDA-approved chimeric antigen receptor T-cell therapies for the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). TRANSCEND is the landmark trial that led to the approval of liso-cel in the third-line setting for R/R diffuse LBCL, primary mediastinal B-cell lymphoma, follicular lymphoma grade 3B and transformed lymphoma. The TRANSFORM and PILOT studies evaluated the use of liso-cel in the second-line treatment of R/R LBCL. This review details the structure and manufacturing process of liso-cel that make it distinct from other approved chimeric antigen receptor constructs, outlines results from landmark trials of liso-cel in LBCL and discusses liso-cel toxicity.
Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. [2021]Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product. We aimed to assess the activity and safety of liso-cel in patients with relapsed or refractory large B-cell lymphomas.
Phase 2 results of lisocabtagene maraleucel in Japanese patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. [2023]The autologous anti-CD19 chimeric antigen receptor (CAR) T-cell product, lisocabtagene maraleucel (liso-cel), is administered at equal target doses of CD8+ and CD4+ CAR+ T cells. This analysis assessed safety and efficacy of liso-cel in Japanese patients with relapsed or refractory (R/R) aggressive large B-cell lymphoma (LBCL) in Cohort 3 of TRANSCEND WORLD (NCT03484702). Liso-cel (100 × 106 total CAR+ T cells) was administered 2-7 days after lymphodepletion. The primary efficacy endpoint was objective response rate (ORR; Lugano 2014 criteria) assessed by an independent review committee. Fourteen patients were enrolled; 10 received liso-cel infusion (median time to liso-cel availability, 23 days) and were evaluable at data cutoff (median follow-up, 12.5 months). Grade ≥ 3 treatment-emergent adverse events were neutropenia (90%), leukopenia (80%), anemia (70%), and thrombocytopenia (70%). All-grade cytokine release syndrome (CRS) was observed in 50% of patients, though no grade ≥3 CRS events were reported. Grade 1 neurological events occurred in 1 patient but were resolved without any intervention. Prolonged cytopenia (grade ≥ 3 at day 29) was reported for 60% of patients. The ORR was 70%, and complete response rate was 50%. The median duration of response was 9.1 months (95% confidence interval [CI], 2.1-not reached), and overall survival was 14.7 months (95% CI, 1.7-not reached). One patient diagnosed with central nervous system involvement after screening but before liso-cel infusion, responded to liso-cel. Liso-cel demonstrated meaningful efficacy and a manageable safety profile in Japanese patients with R/R LBCL.
Elacytarabine--lipid vector technology overcoming drug resistance in acute myeloid leukemia. [2013]Ara-C (cytarabine arabinoside) is a deoxycytidine analog that has an established role in the treatment of hematologic malignancies, especially acute myeloid leukemia. Resistance to ara-C occurs and impacts negatively on survival. To combat this, an elaidic acid ester of ara-C, called elacytarabine, has been developed. This novel agent is highly efficacious in cells with demonstrable resistance to the parent agent, including in solid tumor xenografts.
New agents for the treatment of acute myelogenous leukemia: focus on topotecan and retinoids. [2013]Topotecan and retinoids are among the most promising agents being evaluated for the treatment of acute myelogenous leukemia (AML), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transformation (RAEB-t). Single-agent topotecan is similar to single-agent ara-C, but may be superior in patients with poor-prognosis chromosome abnormalities (ie, -5,-7). Topotecan plus ara-C is equivalent to topotecan alone in chronic myelomonocytic leukemia (CMML), but significantly more effective in RAEB and RAEB-t. Compared with single-agent ara-C, the complete remission (CR) rate with topotecan plus ara-C is comparable, although it offers special advantages in patients with the -5,-7 karyotype. In patients with poor-prognosis cytogenetics, the combination of cyclophosphamide, ara-C, and topotecan, plus all-trans retinoic acid (ATRA) and granulocyte colony-stimulating factor (G-CSF) appears favorable. In a recent study of triple-agent chemotherapy using fludarabine, ara-C, and idarubicin, with or without ATRA and G-CSF, median survival among poor-prognosis patients was 6-7 months, but those who received ATRA did better than those who did not, primarily because it improved survival in those who did not achieve CR. G-CSF produced higher CR rates but had no effect on survival or disease-free survival.
High-dose cytosine arabinoside as the initial treatment of poor-risk patients with acute nonlymphocytic leukemia: a Leukemia Intergroup Study. [2017]Sixty-seven patients with newly diagnosed acute nonlymphocytic leukemia (ANLL) who were considered to be poor candidates for treatment with cytosine arabinoside (ara-C)/anthracycline antibiotic therapy were treated with high-dose ara-C (HDara-C) remission induction therapy. Thirty-four of the 67 patients had a hematologic disorder before developing acute leukemia or had a history of exposure to marrow toxins, 23 patients were greater than 70 years old, and 10 patients had medical problems that were felt to be a contraindication to therapy with an anthracycline antibiotic. Forty-two percent of patients entered complete remission (CR), whereas 22% failed to enter remission because of persistent leukemia. Treatment was associated with substantial toxicity varying from nausea and vomiting to irreversible cerebellar toxicity. Thirty-four percent of patients died during therapy. Poor performance status, a low serum albumin, and a low platelet count were associated with death during remission induction therapy, whereas a high pretherapy leukemic cell mass and a large number of residual leukemic cells in the marrow after six days of therapy were associated with treatment failure due to persistent leukemia.
Cytosine arabinoside and mitoxantrone followed by second allogeneic transplant for the treatment of children with refractory juvenile myelomonocytic leukemia. [2021]Hematopoietic stem cell transplantation (HSCT) remains the only curative option for most patients with juvenile myelomonocytic leukemia (JMML). However, persistent disease and relapse rates after transplant range from 26% to 58%. We report the successful use of second HSCT after preparation with mitoxantrone and cytosine arabinoside (Ara-C) for patients with refractory or recurrent disease. Between 1993 and 2006, 5 children who underwent HSCT at our institution as initial therapy for JMML had persistent disease or relapsed. Pre-HSCT conditioning varied and donors were either HLA-matched siblings (n=2) or matched unrelated donors (n=3). After initial HSCT, they subsequently received high-dose Ara-C (3 g/m IV) every 12 hours on days -8 through -3 and mitoxantrone (10 mg/m/d IV) on days -8, -7, -6 followed by second HSCT from their original donors. All 5 patients are alive at 88, 179, 199, 234, and 246 months with no evidence of JMML, no significant toxicity, and 100% donor chimera as determined by PCR short-tandem repeat analysis. Our experience supports second transplant utilizing high-dose Ara-C and mitoxantrone in children with JMML who do not respond or relapse after first transplant.
Cytosine arabinoside (ara-C) resistance confers cross-resistance or collateral sensitivity to other classes of anti-leukemic drugs. [2018]The major limitation of treatment with antimetabolite drugs is that they produce resistant clones both in vitro and in patients who either do not respond to treatment or relapse soon after response has been documented. To better understand the phenomenon of cross-resistance, we developed seven CEM/ara-C-resistant leukemic clones from the CEM/0 (wt) cell line. These clones ranged from 4- to 3.5 x 10(8)-fold more resistant to ara-C than the wt CEM/0 cell line. Using this model, we determined IC50 concentrations to several chemotherapeutic agents and gamma radiation, and we also studied pro- (p53) and anti-apoptotic (bcl-2) proteins, as well as P-glycoprotein (P-gp) and multidrug resistance related protein (MRP). The cell viability assays showed that these clones were cross-resistant to 6-thioguanine (6-TG) or 6-mercaptoguanosine (6-TGuo) from 1.1- to 8.8-fold with ara-C; cross-resistance to vincristine (VCR) was from 200- to 1 x 10(4)-fold with ara-C. Taxotere (TXR) showed cross-resistance with ara-C from 1.39- to 3.03 x 10(3)-fold; dexamethasone (DEX) also showed a significant degree of cross-resistance from 27.4- to 3.87 x 10(7)-fold. Gamma radiation treatments from 0.77 Gy to 12.3 Gy showed a radiation dose-dependent cross-resistance with ara-C from 1.43- to 2.93-fold. Idarubicin was collaterally sensitive with ara-C from 4.6- to 1 x 10(9)-fold in these cell lines. The CEM/ara-C/G resistant cell line was 3-fold more sensitive to 6-TG or VCR than CEM/0 (wt), and 5-fold more sensitive to 6-TGuo. This cell clone expressed p53 and did not overexpress bcl-2 protein. All of the cell lines studied, CEM/0 (wt) and the ara-C resistant clones, showed functional p53 protein. The cell treatment with 0.1, 1 and 10 microM ara-C for 48 hours showed increased p53 protein expression in most of these lines. No increase in bcl-2 protein expression was seen in the wt cell line after ara-C treatment for 48 hours. Three cell lines resistant to ara-C (CEM/ara-C/B, CEM/ara-C/D and CEM/ara-C/I) showed an important increased expression of bcl-2 protein after treatment with 1 microM ara-C, but not after 10 microM. This alteration may lead to resistance to apoptosis and enhanced cell survival. The ratio of bcl-2 to p53 was increased significantly in these three clones, thus favoring an anti-apoptotic drive. All of the cell lines examined were negative for MRP expression and only two, CEM/ara-C/B and CEM/ara-C/J, were positive for MRP functional activity. However, three ara-C resistant cell clones, CEM/ara-C/7A, CEM/ara-C/B and CEM/ara-C/G, were positive for P-gp expression and functional activity. It is apparent that selection for ara-C resistance confers cross-resistance to many other classes of drugs and gamma radiation, probably due to bcl-2 protein overexpression or P-gp and MRP expression, as independent mechanisms.