AZD0486 for Acute Lymphoblastic Leukemia
(SYRUS Trial)
Recruiting in Palo Alto (17 mi)
+54 other locations
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: AstraZeneca
Disqualifiers: CNS involvement, Testicular leukemia, CNS pathology, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This is a Phase 1/2, global multicentre, open-label, single-arm, dose escalation and dose optimisation study of AZD0486 to evaluate the safety, tolerability, and efficacy of AZD0486 monotherapy in participants with R/R B ALL who have received ≥ 2 prior lines of therapies. The study will consist of 3 parts. Part A monotherapy dose escalation. Part B dose optimisation. Part C Dose expansion at the recommended phase 2 dose (RP2D)
Will I have to stop taking my current medications?
The trial information does not specify if you need to stop taking your current medications. However, it mentions that certain prior therapies must be completed a specific number of weeks before starting the trial, which might imply a need to stop some treatments. It's best to discuss your current medications with the trial team.
What data supports the effectiveness of the treatment AZD0486 for Acute Lymphoblastic Leukemia?
Research shows that treatments targeting CD19, like blinatumomab, have been effective in achieving remission in patients with acute lymphoblastic leukemia (ALL), especially after other therapies have failed. This suggests that AZD0486, which also targets CD19, may have potential in treating ALL.
12345What makes the drug AZD0486 unique for treating acute lymphoblastic leukemia?
AZD0486 is a bispecific antibody that targets both CD19 on leukemia cells and CD3 on T cells, which helps the immune system attack cancer cells more effectively. It is designed to minimize cytokine release, a common side effect in similar treatments, making it potentially safer and more effective than existing options like blinatumomab and CAR-T therapies.
16789Eligibility Criteria
This trial is for people aged 16+ (Part A) or 12+ (Parts B and C) with a type of blood cancer called CD19+ B-cell Acute Lymphoblastic Leukemia. They must have had at least two prior treatments, or one if no other options exist. Participants should be relatively active and not have severe brain conditions, unresolved serious side effects from past treatments, recent cell therapies or transplants, or active cancer in the brain.Inclusion Criteria
I am at least 16 years old for Part A or 12 years old for Parts B and C.
My leukemia involves more than 5% of bone marrow cells.
My leukemia has not improved after at least 2 treatments, or after 1 if no other treatments are available.
+2 more
Exclusion Criteria
I have been on immunosuppressive therapy for GVHD within the last 3 weeks.
I do not have serious brain-related health issues like severe epilepsy, stroke, or dementia.
I have had cancer before, but it might not affect my eligibility.
+5 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Dose Escalation
Part A involves ascending dose level cohorts of AZD0486 in B-ALL participants
28 days
Multiple visits for dose escalation monitoring
Dose Optimization
Part B involves evaluating up to 2 cohorts to determine the recommended phase 2 dose (RP2D)
8 months
Regular visits for dose optimization and safety evaluation
Dose Expansion
Part C involves treating participants with the optimal dose selected in Part B
8 months
Regular visits for treatment and monitoring
Follow-up
Participants are monitored for safety and effectiveness after treatment
Up to 36 months
Participant Groups
The study tests AZD0486 as a single treatment for relapsed/refractory B-cell Acute Lymphoblastic Leukemia. It has three parts: dose escalation to find safe levels (Part A), dose optimization to refine the amount given (Part B), and expansion at the recommended phase 2 dose to see how well it works on more patients (Part C).
3Treatment groups
Experimental Treatment
Group I: Part C: Dose ExpansionExperimental Treatment1 Intervention
Part C will consist of 1 cohort of participants aged 12-80 years, treated with the optimal dose selected in Part B and receive IV AZD0486 monotherapy.
Group II: Part B: Dose OptimizationExperimental Treatment1 Intervention
Up to 2 cohorts will be evaluated prior declared safe-doses and schedules in order to determine the recommended phase 2 dose (RP2D). Participants, aged 12-80 years, will receive AZD0486 IV infusions and will be randomized in a 1:1 ratio.
Group III: Part A: AZD0486 Dose EscalationExperimental Treatment1 Intervention
Ascending dose level cohorts of AZD0486 in B-ALL participants aged 16-80 years.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Research SiteAtlanta, GA
Research SiteChicago, IL
Research SiteDuarte, CA
Research SiteNew York, NY
More Trial Locations
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Who Is Running the Clinical Trial?
AstraZenecaLead Sponsor
References
Recombinant human CD19L-sTRAIL effectively targets B cell precursor acute lymphoblastic leukemia. [2018]Patients with B cell precursor acute lymphoblastic leukemia (BPL) respond well to chemotherapy at initial diagnosis; however, therapeutic options are limited for individuals with BPL who relapse. Almost all BPL cells express CD19, and we recently cloned the gene encoding a natural ligand of the human CD19 receptor (CD19L). We hypothesized that fusion of CD19L to the soluble extracellular domain of proapoptotic TNF-related apoptosis-inducing ligand (sTRAIL) would markedly enhance the potency of sTRAIL and specifically induce BPL cell apoptosis due to membrane anchoring of sTRAIL and simultaneous activation of the CD19 and TRAIL receptor (TRAIL-R) apoptosis signaling pathways. Here, we demonstrate that recombinant human CD19L-sTRAIL was substantially more potent than sTRAIL and induced apoptosis in primary leukemia cells taken directly from BPL patients. CD19L-sTRAIL effectively targeted and eliminated in vivo clonogenic BPL xenograft cells, even at femtomolar-picomolar concentrations. In mice, CD19L-sTRAIL exhibited a more favorable pharmacokinetic (PK) profile than sTRAIL and was nontoxic at doses ranging from 32 fmol/kg to 3.2 pmol/kg. CD19L-sTRAIL showed potent in vivo antileukemic activity in NOD/SCID mouse xenograft models of relapsed and chemotherapy-resistant BPL at nontoxic fmol/kg dose levels. Together, these results suggest that recombinant human CD19L-sTRAIL has clinical potential as a biotherapeutic agent against BPL.
Complete remission in refractory acute lymphoblastic leukemia using blinatumomab after failure of response to CD-19 chimeric antigen receptor T-cell therapy. [2020]The T-cell engager monoclonal antibody, blinatumomab, is a potential therapeutic strategy for refractory B acute lymphoblastic leukemia after failure of CD 19 chimeric antigen receptor T-cell therapy.
Antibody-based therapies in patients with acute lymphoblastic leukemia. [2023]The use of multiagent combination chemotherapy regimens results in cure rates of >90% for children and ∼40% for adults with acute lymphoblastic leukemia (ALL) but is associated with extensive toxicity and disappointingly low efficacy in relapsed patients. ALL blast cells express several surface antigens, including CD20, CD22, and CD19, which represent valuable targets for immunotherapy. Monoclonal antibodies, antibody-drug conjugates, and bispecific T-cell-engaging antibodies targeting these antigens offer novel mechanisms of action. Within the last several years, the anti-CD20 antibody rituximab has been added to chemotherapy for newly diagnosed patients <60 years with CD20+ pre-B ALL and significantly improved the 2-year event-free survival from 52% to 65%. In adults with relapsed or refractory CD22+ ALL, the antibody-drug conjugate inotuzumab ozogamicin resulted in a complete response rate of 81% and median overall survival of 7.7 months with reduced toxicity compared with standard chemotherapy. Similarly, the bispecific T-cell-engaging antibody blinatumomab yielded a complete response rate of 44% and a median overall survival of 7.7 months in an extensively treated ALL population. Moreover, ∼80% of ALL patients in complete remission with evidence of minimal residual disease (MRD) achieved a complete MRD response following treatment with blinatumomab. These results highlight the tremendous promise of antibody-based treatment approaches for ALL. Ongoing and future research is critical to further define the role of the various immunotherapies in the frontline treatment of ALL. Additional challenges include the optimal sequencing of the available antibodies in the relapsed setting as well as their integration with stem cell transplant and chimeric antigen receptor T-cell therapy.
Targeting pediatric leukemia-propagating cells with anti-CD200 antibody therapy. [2022]Treating refractory pediatric acute lymphoblastic leukemia (ALL) remains a challenge despite impressive remission rates (>90%) achieved in the last decade. The use of innovative immunotherapeutic approaches such as anti-CD19 chimeric antigen receptor T cells does not ensure durable remissions, because leukemia-propagating cells (LPCs) that lack expression of CD19 can cause relapse, which signifies the need to identify new markers of ALL. Here we investigated expression of CD58, CD97, and CD200, which were previously shown to be overexpressed in B-cell precursor ALL (BCP-ALL) in CD34+/CD19+, CD34+/CD19-, CD34-/CD19+, and CD34-/CD19- LPCs, to assess their potential as therapeutic targets. Whole-genome microarray and flow cytometric analyses showed significant overexpression of these molecules compared with normal controls. CD58 and CD97 were mainly co-expressed with CD19 and were not a prerequisite for leukemia engraftment in immune deficient mice. In contrast, expression of CD200 was essential for engraftment and serial transplantation of cells in measurable residual disease (MRD) low-risk patients. Moreover, these CD200+ LPCs could be targeted by using the monoclonal antibody TTI-CD200 in vitro and in vivo. Treating mice with established disease significantly reduced disease burden and extended survival. These findings demonstrate that CD200 could be an attractive target for treating low-risk ALL, with minimal off-tumor effects that beset current immunotherapeutic approaches.
Panobinostat (LBH589) increase survival in adult xenografic model of acute lymphoblastic leukemia with t(4;11) but promotes antagonistic effects in combination with MTX and 6MP. [2022]Patients diagnosed with acute lymphoblastic leukemia (ALL) bearing t(4;11)/MLL-AF4 have aggressive clinical features, poor prognosis and there is an urgent need for new therapies to improve outcomes. Panobinostat (LBH589) has been identified as a potential therapeutic agent for ALL with t(4;11) and studies suggest that the antineoplastic effects are associated with reduced MLL-AF4 fusion protein and reduced expression of HOX genes. Here, we evaluated the in vitro effects of the combination of LBH589 with methotrexate (MTX) or 6-mercaptopurine (6MP) by cell proliferation assays and Calcusyn software in ALL cell line (RS4;11); the in vivo effects of LBH589 in xenotransplanted NOD-scid IL2Rgammanull mice measuring human lymphoblasts by flow cytometry; and the expression of HOX genes by qPCR after treatment in an adult model of ALL with t(4;11). LBH589 combination with MTX or 6MP did not promote synergistic effects in RS4;11 cell line. LBH589 treatment leads to increased overall survival and reduction of blasts in xenotransplanted mice but caused no significant changes in HOXA7, HOXA9, HOXA10, and MEIS1 expression. The LBH589, alone, showed promising antineoplastic effects in vivo and may represent a potential agent for chemotherapy in ALL patients with t(4;11).
Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. [2023]To develop a therapy for drug-resistant B-lineage acute lymphoblastic leukemia (ALL), we transduced T lymphocytes with anti-CD19 chimeric receptors, consisting of an anti-CD19 single-chain variable domain (reactive with most ALL cases), the hinge and transmembrane domains of CD8alpha, and the signaling domain of CD3zeta. We compared the antileukemic activity mediated by a novel receptor ('anti-CD19-BB-zeta') containing the signaling domain of 4-1BB (CD137; a crucial molecule for T-cell antitumor activity) to that of a receptor lacking costimulatory molecules. Retroviral transduction produced efficient and durable receptor expression in human T cells. Lymphocytes expressing anti-CD19-BB-zeta receptors exerted powerful and specific cytotoxicity against ALL cells, which was superior to that of lymphocytes with receptors lacking 4-1BB. Anti-CD19-BB-zeta lymphocytes were remarkably effective in cocultures with bone marrow mesenchymal cells, and against leukemic cells from patients with drug-resistant ALL: as few as 1% anti-CD19-BB-zeta-transduced T cells eliminated most ALL cells within 5 days. These cells also expanded and produced interleukin-2 in response to ALL cells at much higher rates than those of lymphocytes expressing equivalent receptors lacking 4-1BB. We conclude that anti-CD19 chimeric receptors containing 4-1BB are a powerful new tool for T-cell therapy of B-lineage ALL and other CD19+ B-lymphoid malignancies.
Redirection of CD4+ and CD8+ T lymphocytes via an anti-CD3 × anti-CD19 bi-specific antibody combined with cytosine arabinoside and the efficient lysis of patient-derived B-ALL cells. [2018]B-acute lymphoblastic leukemia (B-ALL) is derived from B cell progenitors. Recently, the development of appropriate combinations of chemotherapy and immunotherapy represents a promising approach for eliminating cancer. We previously constructed an anti-CD3 × anti-CD19 bi-specific antibody in a diabody configuration and its disulfide-stabilized format (ds-diabody). The combination of the diabody or ds-diabody and Ara-C was highly effective in enhancing the cytotoxicity of T cells against the CD19+ human leukemia cell-line, Nalm-6, both in vitro and in vivo. This study verified whether B-ALL patient-derived cells were sensitive to the diabody or ds-diabody and low-dosage Ara-C combination.
A phase I study of the combination of palbociclib and dexamethasone for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia. [2023]Despite advances in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), outcomes for relapsed/refractory (R/R) disease remain poor. Preclinical studies suggest that the combination of the CDK4/6 inhibitor palbociclib and dexamethasone may be effective in targeting leukemic cell growth. We conducted a phase I study of escalating doses of palbociclib in combination with dexamethasone in adults with R/R B-ALL.
TNB-486 induces potent tumor cell cytotoxicity coupled with low cytokine release in preclinical models of B-NHL. [2022]The therapeutic potential of targeting CD19 in B cell malignancies has garnered attention in the past decade, resulting in the introduction of novel immunotherapy agents. Encouraging clinical data have been reported for T cell-based targeting agents, such as anti-CD19/CD3 bispecific T-cell engager blinatumomab and chimeric antigen receptor (CAR)-T therapies, for acute lymphoblastic leukemia and B cell non-Hodgkin lymphoma (B-NHL). However, clinical use of both blinatumomab and CAR-T therapies has been limited due to unfavorable pharmacokinetics (PK), significant toxicity associated with cytokine release syndrome and neurotoxicity, and manufacturing challenges. We present here a fully human CD19xCD3 bispecific antibody (TNB-486) for the treatment of B-NHL that could address the limitations of the current approved treatments. In the presence of CD19+ target cells and T cells, TNB-486 induces tumor cell lysis with minimal cytokine release, when compared to a positive control. In vivo, TNB-486 clears CD19+ tumor cells in immunocompromised mice in the presence of human peripheral blood mononuclear cells in multiple models. Additionally, the PK of TNB-486 in mice or cynomolgus monkeys is similar to conventional antibodies. This new T cell engaging bispecific antibody targeting CD19 represents a novel therapeutic that induces potent T cell-mediated tumor-cell cytotoxicity uncoupled from high levels of cytokine release, making it an attractive candidate for B-NHL therapy.