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

Trial Summary

What is the purpose of this trial?

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 CD33-expressing refractory/relapsed myeloid malignancies in adults ≥ 18 years of age who are not a candidate for potentially curative therapy, including hematopoietic stem cell transplantation, and are refractory to, intolerant of, or ineligible for therapy options that are known to provide clinical benefit. The hypothesis is GTB-3650 TriKE will induce natural killer (NK) cell function by targeting malignant cells, as well as, CD33+ myeloid derived suppressor cells (MDSC) which contribute to a tumor induced immunosuppression. Because CD16 is the most potent activating receptor on NK cells, this single agent may induce a targeted antiCD33+ tumor response

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.

What data supports the effectiveness of the treatment GTB-3650 for Myelodysplastic Syndrome and Acute Myeloid Leukemia?

Research shows that similar trispecific killer engager (TriKE) molecules, which include components like IL-15 and target antigens such as CD33, have been effective in enhancing the activity of natural killer (NK) cells to attack leukemia cells. These TriKEs have demonstrated the ability to target and kill leukemia cells in laboratory settings, suggesting potential effectiveness for GTB-3650 in treating these conditions. ^{1 2 3 4 5}

What safety data exists for GTB-3650 or similar treatments in humans?

The research does not provide specific safety data for GTB-3650 in humans, but similar treatments like JNJ-67571244 were well tolerated in animal studies, suggesting potential safety in humans. ^{1 3 6 7 8}

What makes the drug GTB-3650 unique for treating Myelodysplastic Syndrome and Acute Myeloid Leukemia?

GTB-3650 is unique because it is a trispecific killer engager (TriKE) that targets CD33 on leukemia cells and uses IL-15 to enhance the activity and survival of natural killer (NK) cells, making them more effective in attacking cancer cells. This approach is different from traditional treatments that may not specifically engage NK cells or promote their expansion and persistence. ^{1 2 3 4 6}

Eligibility Criteria

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.

I am not pregnant or breastfeeding and have a negative pregnancy test.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

A trispecific killer engager molecule against CLEC12A effectively induces NK-cell mediated killing of AML cells. [2021]

2. England 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. [2022]

3. United States 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. [2022]

4. United States 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. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Bifunctional PD-1 × αCD3 × αCD33 fusion protein reverses adaptive immune escape in acute myeloid leukemia. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

A novel C2 domain binding CD33xCD3 bispecific antibody with potent T-cell redirection activity against acute myeloid leukemia. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets. [2022]

8. United States 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. [2021]