CLN-049 for Leukemia and Myelodysplastic Syndrome

Recruiting at 6 trial locations

Overseen By Meagan Sardinha

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Cullinan Therapeutics Inc.

Must not be taking: Immunotherapy, CAR-T, Glucocorticoids, others

Disqualifiers: APL, CNS leukemia, Organ allograft, 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: 9

60 Participants Needed

Trial Summary

What is the purpose of this trial?

CLN-049-001 is a Phase 1, open-label, multicenter, first-in-human trial of CLN-049 in patients with Relapsed/Refractory Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, certain treatments like radiation therapy, immunotherapy, and some growth factors must be stopped before starting the trial. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug CLN-049 for treating leukemia and myelodysplastic syndrome?

Research shows that bispecific antibodies, like CLN-049, can effectively engage T-cells to target and destroy leukemia cells. Similar FLT3 x CD3 bispecific antibodies have demonstrated strong anti-leukemia activity by activating T-cells to attack cancer cells, suggesting potential effectiveness for CLN-049. ^{1 2 3 4 5}

What safety data exists for the treatment CLN-049 (FLT3 x CD3 bispecific antibody) in humans?

The FLT3 x CD3 bispecific antibody, similar to CLN-049, has shown reversible blood-related side effects in animal studies, and bispecific antibodies in general have an acceptable safety profile in humans, though they can cause neurotoxicity (nerve damage) and cytokine-release syndrome (a severe immune reaction). ^{1 5 6 7 8}

What makes the drug CLN-049 unique for treating leukemia and myelodysplastic syndrome?

CLN-049 is a bispecific antibody that targets both FLT3, a protein on leukemia cells, and CD3, a protein on T-cells, to help the immune system attack cancer cells more effectively. This dual-targeting approach is different from traditional treatments and aims to improve outcomes by engaging the body's own immune response. ^{1 2 3 5 7}

Eligibility Criteria

Adults diagnosed with recurrent or resistant AML or MDS, who have an ECOG performance status of 0-2 and adequate organ function. They must not have had certain treatments recently, like CAR-T therapy or allogeneic hematopoietic transplantation within six months. Participants need to be able to consent and follow the trial procedures.

Inclusion Criteria

Willing and able to give written informed consent and adhere to protocol requirements

The patient's laboratory values meet specific criteria for Creatinine clearance, Total bilirubin, AST, and ALT

Side effects from my previous cancer treatment have mostly gone away.

Exclusion Criteria

QT interval corrected for heart rate using Fridericia's formula (QTcF) of ≥ 480 milliseconds

I don't have any health issues that could make the treatment unsafe for me.

Specific restrictions related to pregnancy and contraception

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Single Ascending Dose (SAD)

Patients receive a single dose of CLN-049 via IV administration and are followed for safety

4 weeks

1 visit (in-person)

Multiple Ascending Dose (MAD) - IV

Patients receive CLN-049 every 7 days via IV administration after an initial Lead-In Dose and are followed for safety

4 weeks

4 visits (in-person)

Multiple Ascending Dose (MAD) - SC

Patients receive CLN-049 every 7 days via SC injection and are followed for safety

4 weeks

4 visits (in-person)

Long-term Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Treatment Details

Interventions

• CLN-049

Trial Overview The study is testing CLN-049 in a Phase 1 trial for patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) that has come back or hasn't responded to treatment. It's an open-label, multicenter trial where everyone knows what treatment they're getting.

Participant Groups

Group I: Part C - Multiple ascending dose (MAD) design of SC administered CLN-049 Experimental Treatment 1 Intervention

Patients with relapsed/refractory AML or MDS will receive CLN-049 via SC injection

Group II: Part B - Multiple ascending dose (MAD) design of IV administered CLN-049 Experimental Treatment 1 Intervention

Patients with relapsed/refractory AML or MDS will receive CLN-049 via IV administration

Group III: Part A - Single ascending dose (SAD) design of IV administered CLN-049 Experimental Treatment 1 Intervention

Patients with relapsed/refractory AML or MDS will receive CLN-049 via IV administration

CLN-049 is already approved in United States for the following indications:

Approved in United States as CLN-049 for:

• Relapsed/Refractory Acute Myeloid Leukemia (AML)
• Myelodysplastic Syndrome (MDS)

Who Is Running the Clinical Trial?

Cullinan Therapeutics Inc.

Lead Sponsor

Trials

9

Recruited

1,000+

Cullinan Oncology Inc.

Lead Sponsor

Trials

6

Recruited

710+

Cullinan Oncology, LLC

Lead Sponsor

Trials

7

Recruited

990+

Findings from Research

Bispecific antibodies, like blinatumomab, are innovative immunotherapy treatments that engage immune cells to target and destroy tumor cells, specifically approved for Ph-negative B-cell acute lymphoblastic leukemia.

While bispecific antibodies have an acceptable safety profile, they can cause side effects such as neurotoxicity and cytokine-release syndrome, which are important considerations in their use for treating hematological malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Bispecific antibodies in onco-hematology: Applications and perspectives]. Barrière, S., El-Ghazzi, N., Garcia, M., et al.[2021]

A new bispecific antibody targeting CLL-1 has been developed for treating acute myeloid leukemia (AML), showing potential for effective treatment while sparing hematopoietic stem cells, which is crucial for patient recovery.

In preclinical studies, a low-affinity CD3/CLL-1 TDB was well tolerated in monkeys and effectively depleted target cells, suggesting that careful engineering of the antibody can enhance safety and efficacy in AML treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An anti-CD3/anti-CLL-1 bispecific antibody for the treatment of acute myeloid leukemia. Leong, SR., Sukumaran, S., Hristopoulos, M., et al.[2021]

The newly developed bispecific FLT3 X CD3 antibody, 4G8 X UCHT1 Fabsc, shows superior affinity and production yield compared to traditional bispecific formats, making it a promising candidate for targeting leukemic cells.

In patient-derived primary blood samples, the 4G8 X UCHT1 Fabsc antibody effectively activated T cells and killed acute myeloid leukemia (AML) cells, outperforming a previously optimized monospecific FLT3 antibody, highlighting its potential for enhanced therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of a bispecific FLT3 X CD3 antibody in an improved, recombinant format for the treatment of leukemia. Durben, M., Schmiedel, D., Hofmann, M., et al.[2018]

Bispecific antibodies (BiAB) that target the CD123 antigen can redirect T-cell activity against malignant cells in high-risk myelodysplastic syndrome (MDS) patients, potentially delaying disease progression.

These BiABs may also reduce the risk of leukemic transformation to secondary acute myeloid leukemia (AML), highlighting their promise as a new treatment strategy for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD123-Directed Bispecific Antibodies for Targeting MDS Clones and Immunosuppressive Myeloid-Derived Suppressor Cells (MDSC) in High-Risk Adult MDS Patients. Uckun, FM., Watts, J.[2022]

The bispecific antibody 7370 targets FLT3 on acute myeloid leukemia (AML) cells and shows high potency in killing these cells in both laboratory and animal models, making it a promising treatment option for a broader range of AML patients.

7370 effectively activates T cells from AML patients, enhancing their ability to attack leukemia cells, and has been well tolerated in animal studies, indicating potential for safe use in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Optimized Full-Length FLT3/CD3 Bispecific Antibody Demonstrates Potent Anti-leukemia Activity and Reversible Hematological Toxicity. Yeung, YA., Krishnamoorthy, V., Dettling, D., et al.[2021]

The study identified three fully human antibodies (EB10, A2IN, and D4-3) that specifically target the FLT3 receptor, which is crucial for the survival of leukemia cells, indicating their potential as effective therapies for FLT3-expressing leukemia.

EB10 and D4-3 were particularly effective, blocking ligand binding and inhibiting cell proliferation in leukemia cells, suggesting they could be developed into treatments either alone or combined with cytotoxic agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cell-based selection of internalizing fully human antagonistic antibodies directed against FLT3 for suppression of leukemia cell growth. Williams, B., Atkins, A., Zhang, H., et al.[2013]

Mesothelin (MSLN) is highly expressed on leukemic cells in a subset of pediatric AML patients, making it a promising target for immunotherapy, particularly with bispecific antibodies (BsAbs) that engage T-cells.

Two engineered MSLN/CD3-targeting BsAbs demonstrated significant efficacy in reducing leukemic burden and inducing complete remission in patient-derived xenograft models, suggesting they could be safe and effective treatment options for MSLN-positive pediatric AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapeutic Targeting of Mesothelin Positive Pediatric AML Using Bispecific T Cell Engaging Antibodies. Gopalakrishnapillai, A., Correnti, CE., Pilat, K., et al.[2022]

Bispecific antibodies, like blinatumomab, are showing promise in treating relapsed and refractory hematological malignancies by creating artificial connections between tumor cells and T cells, enhancing the immune response against cancer.

Future treatments may involve combining bispecific antibodies with traditional chemotherapy or stem-cell transplants, aiming to improve efficacy while managing potential side effects like cytokine release syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Recent progress of bispecific antibody-based therapy for hematological malignancies]. Ochi, T.[2022]

References

1. France pubmed.ncbi.nlm.nih.gov

[Bispecific antibodies in onco-hematology: Applications and perspectives]. [2021]

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

An anti-CD3/anti-CLL-1 bispecific antibody for the treatment of acute myeloid leukemia. [2021]

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

Characterization of a bispecific FLT3 X CD3 antibody in an improved, recombinant format for the treatment of leukemia. [2018]

4. Switzerland pubmed.ncbi.nlm.nih.gov

CD123-Directed Bispecific Antibodies for Targeting MDS Clones and Immunosuppressive Myeloid-Derived Suppressor Cells (MDSC) in High-Risk Adult MDS Patients. [2022]

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

An Optimized Full-Length FLT3/CD3 Bispecific Antibody Demonstrates Potent Anti-leukemia Activity and Reversible Hematological Toxicity. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Cell-based selection of internalizing fully human antagonistic antibodies directed against FLT3 for suppression of leukemia cell growth. [2013]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Immunotherapeutic Targeting of Mesothelin Positive Pediatric AML Using Bispecific T Cell Engaging Antibodies. [2022]

8. Japan pubmed.ncbi.nlm.nih.gov

[Recent progress of bispecific antibody-based therapy for hematological malignancies]. [2022]