Tagraxofusp + Gemtuzumab for Acute Myeloid Leukemia

(GO-TAG Trial)

Overseen By Joan McFadden-Cain, RN

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must not be taking: Immunosuppressants, others

Disqualifiers: CNS involvement, Cardiovascular disease, others

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

Compensation: Varies

Number of Visits: 32

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments: tagraxofusp-erzs (Elzonris) and gemtuzumab ozogamicin (Mylotarg) for individuals with acute myeloid leukemia (AML) that has returned or is unresponsive to treatment. The main goal is to determine the optimal dose for the next phase and assess the safety and tolerability of the combination. This trial may suit those with AML whose cancer has returned or not responded after one treatment cycle, particularly if the condition affects their daily lives. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you have received chemotherapy, wide-field radiation, or biologic therapy within 14 days of the study entry, or if you are on immunosuppressive therapy, except for low-dose prednisone.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research explores the safety of using two drugs, tagraxofusp-erzs and gemtuzumab ozogamicin, to treat relapsed or refractory acute myeloid leukemia (AML). Tagraxofusp-erzs targets cancer cells, while gemtuzumab ozogamicin has previously been used in AML treatment. Studies have shown that gemtuzumab ozogamicin can cause side effects like fever, chills, and low blood counts, but these are usually manageable.

Although research on the combination of tagraxofusp-erzs and gemtuzumab continues, early results suggest it might be safe and tolerable. The research aims to find the optimal dose that minimizes side effects, ensuring the treatment remains as safe as possible for patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Tagraxofusp-erzs and Gemtuzumab Ozogamicin for treating acute myeloid leukemia (AML) because it targets the disease in a novel way. Unlike standard chemotherapy drugs, which often attack both cancerous and healthy cells, Tagraxofusp-erzs is a targeted therapy that specifically aims at a protein called CD123, prevalent on AML cells, potentially reducing harm to normal cells. Gemtuzumab Ozogamicin works by binding to CD33, another protein on AML cells, delivering a powerful cytotoxic agent directly to the cancer cells. This dual targeting approach may increase the effectiveness of the treatment while minimizing side effects, offering hope for those with relapsed or refractory AML.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

This trial will evaluate the combination of two drugs, tagraxofusp-erzs and gemtuzumab ozogamicin, for treating relapsed or hard-to-treat acute myeloid leukemia (AML). Research has shown that in a study of patients with CD33-positive AML, 30% went into remission after using gemtuzumab ozogamicin alone. Tagraxofusp-erzs is a drug that links an immune protein, interleukin-3, with a toxin to target cancer cells. Early studies suggest that combining tagraxofusp-erzs with gemtuzumab may enhance treatment effectiveness, potentially improving outcomes for patients with challenging AML. Participants in this trial will receive these drugs in different dosing regimens to determine the most effective combination. ^{1 2 3 4 5}

Who Is on the Research Team?

Alexander Ambinder, MD

Principal Investigator

SKCCC Johns Hopkins Medical Institution

Are You a Good Fit for This Trial?

This trial is for patients aged 12 or older with relapsed/refractory AML, confirmed by WHO criteria. Participants must have a good heart function (LVEF ≥ 50%), no significant ECG abnormalities, adequate kidney function (CrCl ≥ 60mL/min), and acceptable liver function tests. They should not have received certain treatments recently and must be able to consent and follow the study schedule. Women of childbearing potential need a negative pregnancy test.

Inclusion Criteria

My condition worsened or didn't improve after one treatment cycle, excluding certain drugs.

Adequate baseline organ function including cardiac, renal, and hepatic function as defined by: Left ventricular ejection fraction (LVEF) ≥ 50% by multi-gated acquisition scan (MUGA) or 2-dimensional (2-D) echocardiogram (ECHO) within 28 days prior to the start of therapy, No clinically significant abnormalities on a 12-lead electrocardiogram (ECG), Creatinine Clearance (CrCl) ≥ 60mL/min, Serum albumin ≥ 3.2 g/dL, Total bilirubin ≤ 1.5 mg/dL, Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 times the upper limit of normal (ULN), Absolute neutrophil count (ANC) ≥ 0.5 x 109/L, white blood cell (WBC) < 20,000/uL on day of first therapy, Ability to understand and willingness to sign a written informed consent document, Able to adhere to study visit schedule and other protocol requirements including follow up for survival assessment, If the patient is a woman of child-bearing potential (WOCBP), they should have a negative serum or urine pregnancy test within 1 week prior to tagraxofusp-erzs treatment, Patients agree to use acceptable contraceptive methods for the duration of time in the study, and to continue to use acceptable contraceptive methods for 1 week after the last tagraxofusp-erzs infusion, The patient has signed informed consent prior to initiation of any study-specific procedures or treatment, The patient is able to adhere to the study visit schedule and other protocol requirements

My leukemia cells show CD33 and CD123 markers.

Exclusion Criteria

The patient is pregnant or breastfeeding

I do not have serious heart problems or uncontrolled high blood pressure.

I have not had a blood or bone marrow transplant in the last 60 days and do not have active graft versus host disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1A Treatment

Dose escalation of tagraxofusp-erzs in combination with gemtuzumab ozogamicin to determine the optimal dose

16 weeks

4 cycles of 28 days each

Phase 1B Treatment

Dose expansion at the recommended Phase 2 dose (RP2D) of tagraxofusp-erzs in combination with gemtuzumab ozogamicin

Variable, based on patient response

Cycles of 28 days each

Follow-up

Participants are monitored for safety and effectiveness after treatment

2.5 years

What Are the Treatments Tested in This Trial?

Interventions

• Gemtuzumab Ozogamicin
• Tagraxofusp-erzs

Trial Overview The trial is testing tagraxofusp-erzs combined with gemtuzumab ozogamicin in patients with AML that has come back or didn't respond to treatment. It's an open-label Phase Ia/Ib study aiming to find the safest dose for phase 2 trials while checking how well patients tolerate this drug combination.

How Is the Trial Designed?

Group I: Phase 1b recommended Phase 2 dose (RP2D) of tagraxofusp- erzs in r/r AML Experimental Treatment 1 Intervention

This is dose expansion at the RP2D of tagraxofusp. Participants with relapsed or refractory acute myeloid leukemia (r/r AML) will receive the RP2D of tagraxofusp-erzs, as determined in Phase 1a, and gemtuzumab at a dose of 3mg/m2 (max absolute dose of 4.5mg) on days 1,4, and 7 of cycle 1 and day 1 of subsequent cycles.

Group II: Phase 1a Dose Escalation of tagraxofusp-erzs in r/r AML Experimental Treatment 1 Intervention

Tagraxofusp-erzs and gemtuzumab ozogamicin (GO) will be administered every 4 weeks with 28 days defined as a treatment cycle. Tagraxofusp-erzs dose escalation for cycles 1-4 in combination with fixed dose GO. This is a dose escalation design . The dose-limiting toxicity (DLT) period will be the 28 days following the first dose of GO. The initial dose level 1 (DL1) cohort will receive GO 3mg/m2 (capped at a maximum dose of 4.5mg) intravenously (IV) on cycle 1 days 1, 4, and 7 and tagraxofusp-erzs at an initial dose of 7μg/kg/day on days 10, 11, 12. For subsequent cycles of DL1, GO will continue to be administered at a dose of 3mg/m2 IV on day 1 and tagraxofusp-erzs will be administered IV at a dose of 7μg/kg/day on days 4,5,and 6. Subsequent escalation dose levels will receive tagraxofusp-erzs doses of 7mcg/kg/day, 9mcg/kg/day or 12mcg/kg/day. Initial cycle doses of tagraxofusp at these levels will be given on Days 5,6 and 7, then in subsequent cycles on days 1,2 and 3.

Gemtuzumab Ozogamicin is already approved in United States, European Union for the following indications:

Approved in United States as Mylotarg for:

• Acute myeloid leukemia (AML)

Approved in European Union as Mylotarg for:

• Acute myeloid leukemia (AML)

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

StemlineTherapeutics, Inc.

Collaborator

Trials

1

Recruited

40+

Published Research Related to This Trial

Gemtuzumab ozogamicin (GO) has shown moderate effectiveness as a single agent in treating acute myeloid leukemia (AML), but it demonstrates promising results when combined with intensive chemotherapy, particularly in patients with relapsed AML defined by specific genetic mutations.

Recent Phase III trials did not show overall survival benefits for GO in newly diagnosed AML, but there is potential for improved outcomes in genetically defined subgroups, highlighting the importance of personalized therapy in AML treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemtuzumab ozogamicin in non-acute promyelocytic acute myeloid leukemia. Hütter, ML., Schlenk, RF.[2019]

Gemtuzumab ozogamicin (Mylotarg) is an effective treatment for relapsed acute myeloid leukemia (AML), targeting CD33 on leukemic cells and using a potent cytotoxic agent to induce cell death, with promising results from early phase I/II studies.

While it shows significant efficacy, there are concerns about potential adverse effects, including veno-occlusive disease and increased liver toxicity, which are important considerations as it is being tested in new patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early phase I/II trials with gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia. Nabhan, C., Tallman, MS.[2019]

Gemtuzumab ozogamicin is an effective treatment for patients with CD33 positive acute myeloid leukemia (AML) in first relapse, showing an overall response rate of 30% in Phase 2 trials involving 142 patients, with a complete response rate of 16%.

While it offers a potentially better tolerability profile compared to conventional chemotherapy, it carries risks of significant side effects, including myelosuppression, hepatotoxicity, and severe allergic reactions, necessitating careful patient monitoring and management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Bross, PF., Beitz, J., Chen, G., et al.[2022]

In a study of 142 patients with CD33-positive acute myeloid leukemia (AML) in first relapse, 30% achieved remission after treatment with Mylotarg (gemtuzumab ozogamicin), indicating its efficacy as a targeted chemotherapy agent.

While Mylotarg was associated with some adverse effects, such as myelosuppression and elevated liver enzymes, it had a favorable safety profile overall, with low incidences of severe nausea, vomiting, and no significant cardiotoxicity or hair loss.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. Sievers, EL., Larson, RA., Stadtmauer, EA., et al.[2022]

Gemtuzumab ozogamicin (Mylotarg) is being studied in ongoing trials for its safety and efficacy in treating acute myeloid leukemia (AML) patients, both newly diagnosed and those with relapsed or refractory disease.

While gemtuzumab ozogamicin shows an acceptable toxicity profile as a standalone treatment, there is a notable risk of veno-occlusive disease when used in combination with chemotherapy, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trials with gemtuzumab ozogamicin (Mylotarg) combined with chemotherapy regimens in acute myeloid leukemia. Stadtmauer, EA.[2019]

Gemtuzumab ozogamicin is an effective treatment option for relapsed acute myeloid leukemia (AML), as demonstrated in Phase II trials, showing promising results in patients with poor prognosis.

While gemtuzumab ozogamicin has an acceptable safety profile as a standalone treatment, there is a significant risk of veno-occlusive disease of the liver when used in combination with chemotherapy or during hematopoietic stem cell transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemtuzumab ozogamicin in the treatment of acute myeloid leukemia. Stadtmauer, EA.[2019]

In a study of 19 patients with relapsed acute myeloid leukemia (AML), gemtuzumab ozogamicin (GO) showed a response rate of 31.6%, with 15.8% achieving complete remission, particularly in patients with fewer prior treatments.

The most common adverse event was febrile neutropenia (84%), but no cases of veno-occlusive disease were reported, indicating that while GO is effective, it carries significant risks that need to be managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcomes of gemtuzumab ozogamicin for relapsed acute myeloid leukemia: single-institution experience. Hosono, N., Ookura, M., Araie, H., et al.[2021]

Gemtuzumab ozogamicin (Mylotarg) is an FDA-approved treatment for older patients (60+) with CD33+ acute myeloid leukemia (AML) who cannot undergo chemotherapy, targeting the CD33 antigen found on over 80% of AML cases.

The treatment has shown clinical remissions in patients, although it can cause side effects like fever, chills, and low blood cell counts, indicating the need for careful monitoring during administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mylotarg approved for patients with CD33+ acute myeloid leukemia. Sorokin, P.[2012]

The combination treatment of gemtuzumab ozogamicin, intermediate-dose cytarabine, and mitoxantrone (MIDAM) resulted in a 63% overall response rate in 62 patients with refractory or relapsed CD33(+) acute myeloid leukemia, with 50% achieving complete remission.

While the MIDAM regimen showed promising efficacy, it also had safety concerns, including a 16% rate of severe hyperbilirubinemia and four early toxic deaths, highlighting the need for further randomized trials to establish its safety and effectiveness as a standard treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term disease-free survival after gemtuzumab, intermediate-dose cytarabine, and mitoxantrone in patients with CD33(+) primary resistant or relapsed acute myeloid leukemia. Chevallier, P., Delaunay, J., Turlure, P., et al.[2019]

Gemtuzumab ozogamicin, the first antibody-drug conjugate approved for CD33-positive acute myeloid leukemia (AML), was initially withdrawn from the market due to lack of clinical benefit, but later studies with new dosing regimens demonstrated its efficacy.

Pharmacokinetic modeling revealed significant relationships between drug exposure and clinical outcomes, leading to its full FDA approval in 2017 for both newly diagnosed and relapsed AML in adults and children aged 2-17 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic/Pharmacodynamic Modeling to Support the Re-approval of Gemtuzumab Ozogamicin. Fostvedt, LK., Hibma, JE., Masters, JC., et al.[2020]

In a study of 237 older patients with acute myeloid leukemia, treatment with gemtuzumab ozogamicin (GO) significantly improved overall survival (OS) compared to best supportive care, with a median OS of 4.9 months for GO versus 3.6 months for BSC.

The treatment was well-tolerated, showing similar rates of serious adverse events between the GO and BSC groups, indicating that GO can be a safe and effective first-line therapy for patients unsuitable for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemtuzumab Ozogamicin Versus Best Supportive Care in Older Patients With Newly Diagnosed Acute Myeloid Leukemia Unsuitable for Intensive Chemotherapy: Results of the Randomized Phase III EORTC-GIMEMA AML-19 Trial. Amadori, S., Suciu, S., Selleslag, D., et al.[2022]

Citations

1. healthtree.org healthtree.org/aml/community/articles/asco-25-tagraxofusp-and-chemo-for-rr-aml

Tagraxofusp and Chemo for Relapsed AML Study explores tagraxofusp with low-intensity chemotherapy for relapsed AML after Ven/HMA.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05716009

Study Details | NCT05716009 | Tagraxofusp-erzs, an IL-3 ... The goal of this study is to study the safety and tolerability of a novel combination of medications in relapsed or refractory AML: tagraxofusp and gemtuzumab ...

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-10533

Tagraxofusp-Erzs in Combination with Gemtuzumab ... Giving tagraxofusp-erzs in combination with gemtuzumab ozogamicin may be safe, tolerable, and/or effective in treating patients with relapsed or refractory AML.

4. withpower.com withpower.com/trial/phase-1-diphtheria-1-2023-25270

Tagraxofusp + Gemtuzumab for Acute Myeloid Leukemia In a study of 142 patients with CD33-positive acute myeloid leukemia (AML) in first relapse, 30% achieved remission after treatment with Mylotarg (gemtuzumab ...

5. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05716009/tagraxofusp-erzs-an-il-3-diphtheria-fusion-protein-in-combination-with-gemtuzumab-ozogamicin-in-patients-with-relapsed-refractory-aml

Tagraxofusp-erzs, an IL-3 Diphtheria Fusion Protein, in ... The goal of this study is to study the safety and tolerability of a novel combination of medications in relapsed or refractory AML: tagraxofusp ...