AZD0486 for Acute Lymphoblastic Leukemia

(SYRUS Trial)

Recruiting at 79 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: AstraZeneca

Disqualifiers: CNS involvement, Testicular leukemia, CNS pathology, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

142 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called AZD0486 for individuals with B-cell Acute Lymphoblastic Leukemia (B ALL) that hasn't responded to at least two other treatments. The study aims to determine the optimal dose of AZD0486 and assess its safety and effectiveness. Participants will receive AZD0486 through an intravenous (IV) infusion. The trial seeks participants aged 12 and up with B ALL who meet specific criteria, such as having a minimum of 5% cancer cells in their bone marrow and having tried at least two other treatments without success. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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.

Is there any evidence suggesting that AZD0486 is likely to be safe for humans?

Research has shown that AZD0486 is being tested for safety and effectiveness in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). Early results from past studies indicated that this treatment is generally well-tolerated. While some side effects have been noted, they are usually manageable. The researchers aim to find the optimal dose that maximizes effectiveness while minimizing side effects. For those considering joining a trial, it's important to know that AZD0486 remains under investigation, but initial findings suggest it could be a promising option with a strong focus on patient safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for acute lymphoblastic leukemia (ALL) involve chemotherapy or targeted therapies. However, AZD0486, a new investigational drug, is garnering attention because it works differently. Unlike traditional therapies, AZD0486 is designed to be more selective by directly targeting a specific pathway involved in the survival of leukemia cells, potentially reducing damage to healthy cells. Researchers are hopeful that this targeted approach will lead to fewer side effects and improve outcomes for patients.

What evidence suggests that AZD0486 might be an effective treatment for acute lymphoblastic leukemia?

Research has shown that AZD0486, which participants in this trial will receive, could be a promising treatment for people with B-cell acute lymphoblastic leukemia (B-ALL) that has returned or hasn't responded to other treatments. Studies have found that it helps the body's immune cells, called T cells, find and destroy leukemia cells by targeting a protein called CD19 on these cancer cells. This treatment uses the immune system to specifically attack the cancer, introducing a new method for this type of leukemia. Early results from patient studies suggest that AZD0486 is not only effective but also has manageable side effects. This makes it a hopeful option for those who haven't had success with other treatments. ^{1 2 4 6 7}

Are You a Good Fit for This Trial?

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.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• AZD0486

Trial Overview 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).

How Is the Trial Designed?

Group I: Part C: Dose Expansion Experimental Treatment 1 Intervention

Part C will consist of 1 cohort of participants aged 12 years and above, treated with the optimal dose selected in Part B and receive IV AZD0486 monotherapy.

Group II: Part B: Dose Optimization Experimental Treatment 1 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 years and above, will receive AZD0486 IV infusions and will be randomized in a 1:1 ratio.

Group III: Part A: AZD0486 Dose Escalation Experimental Treatment 1 Intervention

Ascending dose level cohorts of AZD0486 in B-ALL participants aged 12 years and above.

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Published Research Related to This Trial

The combination of the anti-CD3 × anti-CD19 diabody or ds-diabody with low-dose Ara-C significantly enhances T cell activation and cytotoxicity against B-acute lymphoblastic leukemia (B-ALL) cells, both in vitro and in vivo, indicating a promising therapeutic strategy.

Low-dose Ara-C treatment increased the expression of CD80 and CD86 on B-ALL patient-derived cells, which in turn activated CD4+ and CD8+ T cells, with CD8+ T cells primarily responsible for killing leukemia cells through a granzyme B and perforin-dependent mechanism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Fan, D., Li, W., Yang, Y., et al.[2018]

The addition of the anti-CD20 antibody rituximab to chemotherapy for newly diagnosed patients under 60 years with CD20+ pre-B acute lymphoblastic leukemia (ALL) improved 2-year event-free survival rates from 52% to 65%.

In adults with relapsed or refractory CD22+ ALL, the antibody-drug conjugate inotuzumab ozogamicin achieved an 81% complete response rate and a median overall survival of 7.7 months, demonstrating reduced toxicity compared to standard chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibody-based therapies in patients with acute lymphoblastic leukemia. Dinner, S., Liedtke, M.[2023]

TNB-486, a fully human bispecific antibody targeting CD19 and CD3, shows promise in treating B cell non-Hodgkin lymphoma (B-NHL) by inducing tumor cell lysis with minimal cytokine release, addressing safety concerns associated with existing therapies like blinatumomab and CAR-T.

In preclinical models, TNB-486 effectively cleared CD19+ tumor cells in immunocompromised mice and demonstrated pharmacokinetics similar to conventional antibodies, suggesting it could be a safer and more effective option for patients with B-NHL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TNB-486 induces potent tumor cell cytotoxicity coupled with low cytokine release in preclinical models of B-NHL. Malik-Chaudhry, HK., Prabhakar, K., Ugamraj, HS., et al.[2022]

Blinatumomab, a T-cell engager monoclonal antibody, shows promise as a treatment for patients with refractory B acute lymphoblastic leukemia, especially after they have not responded to CD19 chimeric antigen receptor T-cell therapy.

This study highlights blinatumomab's potential as an alternative therapeutic strategy for patients facing treatment-resistant forms of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complete remission in refractory acute lymphoblastic leukemia using blinatumomab after failure of response to CD-19 chimeric antigen receptor T-cell therapy. Tambaro, FP., Khazal, S., Nunez, C., et al.[2020]

Recombinant human CD19L-sTRAIL is significantly more effective than standard sTRAIL in inducing apoptosis in B cell precursor acute lymphoblastic leukemia (BPL) cells, demonstrating its potential as a targeted therapy for this type of leukemia.

In mouse models, CD19L-sTRAIL showed strong antileukemic activity at very low, nontoxic doses, suggesting it could be a safe and effective treatment option for patients with relapsed or chemotherapy-resistant BPL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant human CD19L-sTRAIL effectively targets B cell precursor acute lymphoblastic leukemia. Uckun, FM., Myers, DE., Qazi, S., et al.[2018]

In a phase I study involving 7 adults with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), the combination of the CDK4/6 inhibitor palbociclib and dexamethasone showed potential efficacy, with one patient achieving a complete response.

The treatment was well-tolerated with no dose-limiting toxicities reported, and biological markers indicated on-target effects, including reductions in specific cell populations and proteins associated with leukemic growth.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of the combination of palbociclib and dexamethasone for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia. Wilde, L., Porazzi, P., Trotta, R., et al.[2023]

CD200 is identified as a critical marker for leukemia-propagating cells in pediatric acute lymphoblastic leukemia (ALL), particularly in low-risk patients, indicating its potential as a therapeutic target.

Targeting CD200 with the monoclonal antibody TTI-CD200 in mouse models significantly reduced disease burden and improved survival, suggesting a promising new approach for treating refractory ALL with fewer off-target effects compared to current immunotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting pediatric leukemia-propagating cells with anti-CD200 antibody therapy. Diamanti, P., Cox, CV., Ede, BC., et al.[2022]

Transducing T lymphocytes with anti-CD19 chimeric receptors that include the 4-1BB signaling domain significantly enhances their ability to target and kill drug-resistant B-lineage acute lymphoblastic leukemia (ALL) cells, demonstrating superior cytotoxicity compared to receptors without this costimulatory molecule.

In experiments, as few as 1% of T cells expressing the anti-CD19-BB-zeta receptor were able to eliminate most ALL cells within 5 days, indicating a highly effective therapeutic potential for this approach in treating resistant forms of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Imai, C., Mihara, K., Andreansky, M., et al.[2023]

Panobinostat (LBH589) shows promising antineoplastic effects in treating acute lymphoblastic leukemia (ALL) with the t(4;11) mutation, leading to increased overall survival and reduced blast counts in xenotransplanted mice.

However, combining LBH589 with methotrexate or 6-mercaptopurine did not result in synergistic effects in the RS4;11 cell line, and there were no significant changes in the expression of key HOX genes after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Moreno, DA., Junior, HLR., Laranjeira, ABA., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8023237/

TNB-486 induces potent tumor cell cytotoxicity coupled with ... This new T cell engaging bispecific antibody targeting CD19 represents a novel therapeutic that induces potent T cell-mediated tumor-cell cytotoxicity ...

2. haematologica.org haematologica.org/article/view/12811

SAFETY AND EFFICACY OF AZD0486 IN ADOLESCENT ... Preliminary results of a dose-escalation study of intravenous AZD0486 in R/R B-cell acute lymphoblastic leukemia (B-ALL) (SYRUS; NCT06137118).

3. tandfonline.com tandfonline.com/doi/abs/10.1080/19420862.2021.1890411

TNB-486 induces potent tumor cell cytotoxicity coupled ... Outcome of patients with relapsed/refractory acute lymphoblastic leukemia after blinatumomab failure: No change in the level of CD19 expression. Source ...

4. astrazenecaclinicaltrials.com astrazenecaclinicaltrials.com/study/D7405C00001

AZD0486 as Monotherapy in B-cell Acute Lymphoblastic ... This dose escalation and optimization study is evaluating the safety, tolerability, PK, PD and clinical activity of AZD0486 monotherapy in r/r B-ALL.

5. researchgate.net researchgate.net/publication/337254748_TNB-486_a_Novel_Fully_Human_Bispecific_CD19_x_CD3_Antibody_That_Kills_CD19-Positive_Tumor_Cells_with_Minimal_Cytokine_Secretion

TNB-486, a Novel Fully Human Bispecific CD19 x CD3 ... Conclusions TNB-486 induced comparable lysis of CD19-positive tumor cells as the strongly activating control bispecific antibodies while inducing significantly ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06137118

NCT06137118 | AZD0486 as Monotherapy in B-cell Acute ... This dose escalation and optimization study is evaluating the safety, tolerability, PK, PD and clinical activity of AZD0486 monotherapy in r/r B-ALL.

7. researchgate.net researchgate.net/publication/395157202_ALL-774_Safety_and_Efficacy_of_AZD0486_in_Adolescent_and_Adult_Patients_With_Relapsed_or_Refractory_B-Cell_Acute_Lymphoblastic_Leukemia_Early_Results_From_the_Phase_12_SYRUS_Study

ALL-774: Safety and Efficacy of AZD0486 in Adolescent ... ... Safety and Efficacy of AZD0486 in Adolescent and Adult Patients With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia: Early Results ...