GTB-3650 for Myelodysplastic Syndrome and Acute Myeloid Leukemia

Overseen By Mark Juckett, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Masonic Cancer Center, University of Minnesota

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Pregnancy, HIV, Hepatitis B/C, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 72

Duration: 16 weeks

45 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called GTB-3650 (a Tri-Specific Killer Engager) for certain blood cancers, specifically myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) that have not responded to other treatments. The goal is to determine if GTB-3650 can help the body's natural killer cells target and destroy cancer cells. Candidates for this trial include those with high-risk MDS or relapsed/refractory AML who are not eligible for other effective treatments like stem cell transplants. The trial will test different doses of GTB-3650 to find the safest and most effective amount. As a Phase 1 trial, this research focuses on understanding how GTB-3650 works in people, offering participants the chance to be among the first to receive this innovative 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, if you are on steroids or other immunosuppressive medications, you may need to stop them 14 days before starting the trial, unless they are low-dose or topical.

Is there any evidence suggesting that GTB-3650 is likely to be safe for humans?

Research shows that GTB-3650 remains in the early stages of testing for safety in humans, so there is limited information on how well people tolerate it. This treatment is being tested for adults with certain blood cancers that don't respond to other treatments.

In these early studies, the main goal is to determine the right dose and monitor side effects. Since the trial is in its first phase, researchers are still learning about its safety. Some side effects might emerge as the trial progresses, but currently, information is limited.

Because this is an early-phase trial, the focus is on understanding safety and dosage, not efficacy. If considering joining a trial, discussing concerns with a healthcare provider is crucial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for myeloid malignancies?

GTB-3650 is unique because it's administered through a continuous infusion over a 72-hour period, which is different from the typical oral or intermittent IV treatments used for Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). This delivery method might allow for more consistent drug exposure, potentially improving effectiveness. Researchers are excited about GTB-3650 because it targets cancer cells in a novel way, offering a fresh approach to treating these conditions compared to conventional chemotherapy or targeted therapies like Azacitidine and Decitabine.

What evidence suggests that GTB-3650 might be an effective treatment for myelodysplastic syndrome and acute myeloid leukemia?

Research has shown that GTB-3650, a new treatment under study in this trial, could be effective against certain blood cancers like myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). GTB-3650 activates natural killer (NK) cells, part of the immune system, to attack cancer cells. It specifically targets cancer cells with the CD33 protein on their surface. Early results suggest that this treatment could slow tumor growth by boosting the body's natural defenses. This targeted approach may break down the cancer cells' protective barriers and strengthen the immune response. Although research is still in its early stages, this method offers hope for treating these challenging conditions. ^{1 2 5 6 7}

Are You a Good Fit for This Trial?

This trial is for adults over 18 with certain types of myeloid leukemia or myelodysplastic syndrome who can't have curative therapy like a stem cell transplant. They must have an adequate number of lymphocytes or natural killer cells, not too many leukemia cells in the blood, and good organ function. Participants need to stay close to the Study Center for a month and use effective contraception if they can have children.

Inclusion Criteria

My organs are functioning well as of the last 14 to 30 days.

I will use effective birth control during and for 4 months after the study.

Provides voluntary written consent prior to the performance of any research related activity

Exclusion Criteria

I am currently on IV antibiotics for an infection or have recovered from a recent infection with treatment.

I am not on high-dose steroids or immunosuppressants for an autoimmune disease.

New or progressive pulmonary infiltrates on screening chest x-ray or chest CT scan unless cleared for study by Pulmonary. Infiltrates attributed to infection must be stable/improving with associated clinical improvement after 1 week of appropriate therapy (4 weeks for presumed or documented fungal infections)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

GTB-3650 is administered during an inpatient stay by continuous infusion over a 72-hour period, repeated in two blocks per 28-day cycle, for up to four cycles

16 weeks

Inpatient stays for each 72-hour infusion block

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• GTB-3650

Trial Overview The study tests GTB-3650 TriKE®, which aims to boost natural killer (NK) cell activity against CD33-expressing cancer cells and immune-suppressing cells in patients with refractory/relapsed myeloid malignancies. It's a Phase I trial focused on finding the right dose for this new treatment.

How Is the Trial Designed?

Group I: Arm 7: Dose Level 7: 100 ug/kg/day Experimental Treatment 1 Intervention

GTB-3650 is administered during an inpatient stay by continuous infusion (CI) consisting of three consecutive 24 hour infusion "bags" over a 72 hour period. Each 72-hour infusion period is designated a "block". A 28-day treatment cycle consists of two blocks followed by approximately 18 days of no treatment. Prior to each block start, the patient must meet the safety criteria.GTB-3650 may continue for up to four treatment cycles total provided disease based response criteria is met and the patient is otherwise eligible to continue.

Group II: Arm 6: Dose Level 6: 50 ug/kg/day Experimental Treatment 1 Intervention

GTB-3650 is administered during an inpatient stay by continuous infusion (CI) consisting of three consecutive 24 hour infusion "bags" over a 72 hour period. Each 72-hour infusion period is designated a "block". A 28-day treatment cycle consists of two blocks followed by approximately 18 days of no treatment. Prior to each block start, the patient must meet the safety criteria.GTB-3650 may continue for up to four treatment cycles total provided disease based response criteria is met and the patient is otherwise eligible to continue.

Group III: Arm 5: Dose Level 5: 25 ug/kg/day Experimental Treatment 1 Intervention

GTB-3650 is administered during an inpatient stay by continuous infusion (CI) consisting of three consecutive 24 hour infusion "bags" over a 72 hour period. Each 72-hour infusion period is designated a "block". A 28-day treatment cycle consists of two blocks followed by approximately 18 days of no treatment. Prior to each block start, the patient must meet the safety criteria.GTB-3650 may continue for up to four treatment cycles total provided disease based response criteria is met and the patient is otherwise eligible to continue.

Group IV: Arm 4: Dose Level 4: 10 ug/kg/day Experimental Treatment 1 Intervention

GTB-3650 is administered during an inpatient stay by continuous infusion (CI) consisting of three consecutive 24 hour infusion "bags" over a 72 hour period. Each 72-hour infusion period is designated a "block". A 28-day treatment cycle consists of two blocks followed by approximately 18 days of no treatment. Prior to each block start, the patient must meet the safety criteria.GTB-3650 may continue for up to four treatment cycles total provided disease based response criteria is met and the patient is otherwise eligible to continue.

Group V: Arm 3: Dose Level 3: 5 ug/kg/day Experimental Treatment 1 Intervention

GTB-3650 is administered during an inpatient stay by continuous infusion (CI) consisting of three consecutive 24 hour infusion "bags" over a 72 hour period. Each 72-hour infusion period is designated a "block". A 28-day treatment cycle consists of two blocks followed by approximately 18 days of no treatment. Prior to each block start, the patient must meet the safety criteria.GTB-3650 may continue for up to four treatment cycles total provided disease based response criteria is met and the patient is otherwise eligible to continue.

Group VI: Arm 2: Dose Level 2: 2.5 ug/kg/day Experimental Treatment 1 Intervention

GTB-3650 is administered during an inpatient stay by continuous infusion (CI) consisting of three consecutive 24 hour infusion "bags" over a 72 hour period. Each 72-hour infusion period is designated a "block". A 28-day treatment cycle consists of two blocks followed by approximately 18 days of no treatment. Prior to each block start, the patient must meet the safety criteria.GTB-3650 may continue for up to four treatment cycles total provided disease based response criteria is met and the patient is otherwise eligible to continue.

Group VII: Arm 1: Dose Level 1: 1.25 ug/kg/day Experimental Treatment 1 Intervention

GTB-3650 is administered during an inpatient stay by continuous infusion (CI) consisting of three consecutive 24 hour infusion "bags" over a 72 hour period. Each 72-hour infusion period is designated a "block". A 28-day treatment cycle consists of two blocks followed by approximately 18 days of no treatment. Prior to each block start, the patient must meet the safety criteria.GTB-3650 may continue for up to four treatment cycles total provided disease based response criteria is met and the patient is otherwise eligible to continue.

GTB-3650 is already approved in United States for the following indications:

Approved in United States as GTB-3650 for:

• None; currently in Phase I clinical trials for refractory/relapsed myeloid malignancies

Who Is Running the Clinical Trial?

Masonic Cancer Center, University of Minnesota

Lead Sponsor

Trials

285

Recruited

15,700+

Published Research Related to This Trial

The CLEC12A TriKE molecule effectively activates natural killer (NK) cells to target and kill acute myeloid leukemia (AML) cells and leukemic stem cells (LSCs) while sparing healthy hematopoietic stem cells, minimizing off-target effects.

In preclinical mouse models, the CLEC12A TriKE significantly reduced tumor burden, demonstrating its potential as a promising therapeutic strategy for improving outcomes in AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A trispecific killer engager molecule against CLEC12A effectively induces NK-cell mediated killing of AML cells. Arvindam, US., van Hauten, PMM., Schirm, D., et al.[2021]

The tri-specific agent SPM-2 targets both CD33 and CD123 on AML cells while engaging NK cells, showing effective cytolytic activity against primary leukemic cells from 29 patients, regardless of their AML subtype.

SPM-2 demonstrated the ability to lyse leukemia stem cells (LSCs) at lower concentrations, suggesting it could potentially eliminate these hard-to-treat cells and improve survival outcomes for a wide range of AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual-targeting triplebody 33-16-123 (SPM-2) mediates effective redirected lysis of primary blasts from patients with a broad range of AML subtypes in combination with natural killer cells. Braciak, TA., Roskopf, CC., Wildenhain, S., et al.[2021]

The novel bifunctional checkpoint inhibitory T cell-engaging (CiTE) antibody effectively targets acute myeloid leukemia (AML) cells while minimizing immune-related adverse events (irAEs), showing complete AML eradication in mouse models without initial signs of toxicity.

This CiTE antibody enhances T-cell activation significantly (3.3-fold increase in interferon-γ) and demonstrates high selectivity against CD33+PD-L1+ AML cells, indicating its potential as a safer and more effective treatment for patients with relapsed or refractory AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bifunctional PD-1 × αCD3 × αCD33 fusion protein reverses adaptive immune escape in acute myeloid leukemia. Herrmann, M., Krupka, C., Deiser, K., et al.[2021]

The CD33/CD3 BiTE antibody construct AMG 330 effectively recruits T cells to kill acute myeloid leukemia (AML) cells, with the effectiveness influenced by the ratio of effector to target cells and the level of CD33 expression, based on tests with 38 primary AML samples.

AMG 330 induces a proinflammatory environment that upregulates PD-L1 on AML cells, which can hinder its effectiveness; however, blocking the PD-1/PD-L1 interaction significantly enhances T-cell activity and lysis of AML cells, suggesting that combining AMG 330 with checkpoint inhibitors could improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism. Krupka, C., Kufer, P., Kischel, R., et al.[2022]

The 161533 trispecific killer engager (TriKE) significantly enhances NK cell cytotoxicity, survival, and proliferation against CD33(+) leukemia targets compared to the previous bispecific killer engager (BiKE), indicating improved efficacy for treating acute myeloid leukemia (AML).

In preclinical models, the TriKE not only restored NK cell function in patients with defective NK cells post-stem cell transplantation but also demonstrated superior antitumor activity and prolonged survival of NK cells in vivo, suggesting its potential for effective NK cell therapy in myeloid malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL15 Trispecific Killer Engagers (TriKE) Make Natural Killer Cells Specific to CD33+ Targets While Also Inducing Persistence, In Vivo Expansion, and Enhanced Function. Vallera, DA., Felices, M., McElmurry, R., et al.[2022]

JNJ-67571244 is a novel bispecific antibody that effectively targets CD33 in acute myeloid leukemia (AML) patients, inducing T-cell activation and cytotoxicity against CD33+ tumor cells, regardless of the patient's SNP genotype status.

In preclinical studies, JNJ-67571244 demonstrated significant antitumor activity in mouse models of AML and was well tolerated in cynomolgus monkeys, showing promise for further clinical evaluation in phase 1 trials for patients with relapsed/refractory AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel C2 domain binding CD33xCD3 bispecific antibody with potent T-cell redirection activity against acute myeloid leukemia. Nair-Gupta, P., Diem, M., Reeves, D., et al.[2021]

In a study involving 67 patients with myelodysplastic syndromes (MDS), the CD16xCD33 bispecific killer cell engager (BiKE) was shown to significantly enhance the function of natural killer (NK) cells, promoting their ability to attack MDS cells and overcome immunosuppression.

The BiKE effectively reversed the negative impact of immunosuppressive myeloid-derived suppressor cells (MDSCs) on NK cells, indicating its potential as a therapeutic option for MDS patients, regardless of the disease stage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets. Gleason, MK., Ross, JA., Warlick, ED., et al.[2022]

AMG 330, a bispecific T-cell engager antibody targeting CD33, shows strong cytotoxic activity against acute myeloid leukemia (AML) cells, with effectiveness dependent on CD33 expression levels and the ratio of T cells to target cells.

Unlike previous CD33-targeted therapies, AMG 330 does not reduce CD33 expression on the surface of cells and is not influenced by common genetic variations or drug resistance mechanisms, making it a promising candidate for clinical use in AML treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cellular determinants for preclinical activity of a novel CD33/CD3 bispecific T-cell engager (BiTE) antibody, AMG 330, against human AML. Laszlo, GS., Gudgeon, CJ., Harrington, KH., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06594445

HM2023-05: GTB-3650 Trike for High Risk MDS and R ... This is a Phase I dose finding study of GTB-3650 (anti-CD16/IL-15/anti-CD33) Tri-Specific Killer Engager (TriKE®) for the treatment of select ...

2. cancer.gov cancer.gov/clinicaltrials/NCI-2024-10399

GTB-3650 TriKE® for the Treatment of Patients with High ... GTB-3650 is designed to target CD33 on patient's AML/MDS cancer cells. CD16 is a marker found on natural killer (NK) cells. NK cells are part of a person's ...

3. studyfinder.umn.edu studyfinder.umn.edu/studies/31745

GTB-3650 (anti-CD16/IL-15/anti-CD33) Tri-Specific Killer ... The primary purpose of this study is to identify a safe dose of GTB-3650. The study also provides preliminary disease response information for larger future ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03214666

GTB-3550 Tri-Specific Killer Engager (TriKE®) for High ... The hypothesis is that GTB-3550 TriKE® will induce natural killer cell function by targeting malignant cells as well as CD33+ myeloid derived suppressor cells ( ...

5. withpower.com withpower.com/trial/phase-1-myeloid-malignancy-9-2024-d406d

GTB-3650 for Myelodysplastic Syndrome and Acute ... This trial is for adults over 18 with certain types of myeloid leukemia or myelodysplastic syndrome who can't have curative therapy like a stem cell transplant.

6. gtbiopharma.com gtbiopharma.com/product-pipeline/overview

Overview :: GT Biopharma, Inc. (GTBP) GTB-3650 is the companies first 2nd generation camelid nanobody TriKE® being tested clinically for the treatment of CD33 positive leukemias, ...

7. targetedonc.com targetedonc.com/view/fda-receives-ind-for-gtb-3650-in-cd33-aml-and-mds

FDA Receives IND for GTB-3650 in CD33+ AML and MDS An investigational new drug (IND) application has been submitted to the FDA for the development of GTB-3650 for patients with CD33-positive leukemia.