Flotetuzumab for CD123-Positive Hematological Malignancies

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: CNS involvement, Autoimmune disorders, others

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

Compensation: Varies

Number of Visits: 3

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and understand the side effects of flotetuzumab, a monoclonal antibody treatment, for individuals with certain advanced blood cancers. These cancers have either returned after treatment or did not respond to previous therapies. Flotetuzumab may help stop cancer cells from growing and spreading. This trial suits those with blood cancers like acute lymphoblastic leukemia or other CD123-positive blood cancers that have not responded to standard treatments. Participants should have measurable disease and a life expectancy of at least four weeks. 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 protocol does not specify if you must stop taking your current medications. However, certain treatments like chemotherapy, radiation, and some immunotherapies must be stopped 14 days before starting the trial, and high-dose steroids must be stopped 3 days before. It's best to discuss your specific medications with the study team.

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

Research has shown that flotetuzumab is generally safe for individuals with advanced blood cancers. Studies have found that most patients tolerate this treatment well, though some side effects can occur. Common side effects include fever, chills, and tiredness, which are usually mild and manageable. While some patients might experience more serious side effects, these are less common. Overall, flotetuzumab appears to be a promising treatment for these cancers, with safety remaining a key focus of ongoing research. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Flotetuzumab is unique because it targets CD123, a specific protein often overexpressed in certain blood cancers, like acute myeloid leukemia (AML). This targeted approach is different from the standard chemotherapy treatments, which generally attack both healthy and cancerous cells, leading to significant side effects. Researchers are excited about flotetuzumab because it offers a more precise mechanism of action, potentially reducing collateral damage to healthy cells and improving patient outcomes with fewer side effects. Additionally, its continuous IV infusion method allows for sustained delivery, which might enhance its effectiveness against rapidly growing cancer cells.

What evidence suggests that flotetuzumab might be an effective treatment for blood cancers?

Research has shown that flotetuzumab, the treatment under study in this trial, may help treat certain blood cancers. In studies, 26.7% of patients whose cancer did not respond to other treatments achieved complete remission with flotetuzumab. This drug targets a protein called CD123 on cancer cells, aiding the immune system in identifying and attacking these cells. Early results suggest that targeting CD123 is effective for various blood cancers. Although this treatment remains under investigation, the initial findings are promising for those with hard-to-treat cancer. ^{1 2 4 6 7}

Who Is on the Research Team?

Ibrahim Aldoss, MD

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for adults with advanced blood cancers expressing CD123 who have not responded to standard treatments or whose disease has returned. Eligible participants must meet specific health criteria, including organ function and blood counts, and agree to use effective birth control. Those with recent transplants, untreated autoimmune disorders, active infections, or certain other medical conditions are excluded.

Inclusion Criteria

Platelets >= 75,000/ul (without bone marrow involvement, performed within 14 days prior to day 1 of protocol therapy)

My Hodgkin lymphoma did not respond to PD-1/PD-L1 inhibitors or brentuximab vedotin.

My hairy cell leukemia didn't respond to or got worse after purine analog treatment.

Exclusion Criteria

I have had or been checked for brain involvement but am currently free of it.

I haven't had most cancer treatments in the last 2 weeks but some medications are exceptions.

I have not had major surgery or serious injury in the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Patients receive flotetuzumab via continuous IV infusion on days 1-28. Additional cycles may be given based on response.

4-24 weeks

Continuous IV infusion

Consolidation Therapy

Patients who achieve certain responses receive flotetuzumab via continuous IV infusion on days 1-28 for up to 5 or 6 cycles.

4-24 weeks

Continuous IV infusion

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Flotetuzumab

Trial Overview The trial is testing the optimal dose and side effects of flotetuzumab in patients with various hematological malignancies that express CD123. Flotetuzumab is a monoclonal antibody designed to inhibit cancer cell growth. The study includes supportive medications like acetaminophen and dexamethasone to manage potential reactions.

How Is the Trial Designed?

Group I: Treatment (flotetuzumab) Experimental Treatment 6 Interventions

INDUCTION THERAPY: Patients receive flotetuzumab via continuous IV infusion on days 1-28. Patients who achieve SD/PR (Cohort A) or PR/CI (Cohort B), receive an additional induction cycle. Patients who achieve PR (Cohort A) or PR/CI/MMR (Cohort B) after cycle 2 re-induction, may continue induction therapy for up to 4 more cycles. CONSOLIDATION THERAPY: Patients who achieve CR/CRi/CRh/MLFS (Cohort A) or CR/MR (Cohort B) after cycle 1 or cycle 2 of induction therapy, receive flotetuzumab via continuous IV infusion on days 1-28 for up to 5 and 6 cycles, respectively, in the absence of disease progression or unacceptable toxicity. Patients with PR (Cohort A) or PR/CI/MMR (Cohort B) who have received up to 6 cycles of induction therapy may receive up to 2 cycles of consolidation therapy in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

CD123 is highly expressed in B acute lymphoblastic leukemia/lymphoma, with 89.6% of patients showing expression, making it a potential target for therapies like IMGN632.

IMGN632, a CD123-targeted antibody-drug conjugate, showed strong cytotoxic effects in vitro, eliminating over 90% of B acute lymphoblastic leukemia/lymphoma blasts at low concentrations while sparing normal lymphocytes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD123 expression patterns and selective targeting with a CD123-targeted antibody-drug conjugate (IMGN632) in acute lymphoblastic leukemia. Angelova, E., Audette, C., Kovtun, Y., et al.[2020]

Targeting the interleukin 3 receptor α chain (CD123) on leukemia stem cells has been explored as a treatment for various myeloid malignancies, but the success of these therapies has been limited, indicating a need for better patient selection criteria.

Understanding the patterns of CD123 expression and its biological significance is essential for improving the effectiveness of CD123-targeting therapies in hematologic malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting CD123 in hematologic malignancies: identifying suitable patients for targeted therapy. Patnaik, MM., Mughal, TI., Brooks, C., et al.[2021]

In a comprehensive analysis of 65,099 patient-years of tocilizumab (TCZ) exposure, the rates of serious adverse events (SAEs) reported in postmarketing data were found to be similar to those observed in clinical trials and external comparator populations, indicating consistent safety profiles across different settings.

The study highlights that the rates of specific SAEs, such as serious hepatic events and myocardial infarctions, were comparable to those seen in anti-tumor necrosis factor (aTNF) treated rheumatoid arthritis patients, suggesting that TCZ's safety profile is in line with existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tocilizumab in rheumatoid arthritis: a case study of safety evaluations of a large postmarketing data set from multiple data sources. Curtis, JR., Perez-Gutthann, S., Suissa, S., et al.[2019]

CD123, a receptor highly expressed in leukemic stem cells (LSCs) but not in normal stem cells, is a promising target for therapies aimed at treating refractory or relapsed leukemia, as it is linked to treatment response and prognosis.

Recent advancements in anti-CD123 therapies, including neutralizing antibodies and CAR-T cell therapies, show potential in effectively targeting LSCs, which could improve outcomes for patients with leukemia who do not respond to traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD123: A Novel Biomarker for Diagnosis and Treatment of Leukemia. Shi, M., Su, RJ., Parmar, KP., et al.[2020]

Pertuzumab is an effective treatment for metastatic HER2-positive breast cancer, especially when combined with trastuzumab and docetaxel, showing significant improvements in progression-free and overall survival in treatment-naive patients.

As a HER dimerization inhibitor, pertuzumab works differently than trastuzumab, allowing for a more complete blockade of HER2 signaling, and has a tolerable safety profile, making it a recommended first-line therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab for the treatment of human epidermal growth factor receptor type 2-positive metastatic breast cancer. Chung, C., Lam, MS.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04681105

Flotetuzumab for the Treatment of Relapsed or Refractory ... This phase I trial studies the best dose and side effects of flotetuzumab for the treatment of patients with blood cancers (hematological malignancies) that ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7885824/

Flotetuzumab as salvage immunotherapy for refractory ... Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response ...

3. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT03739606/

Clinical Trial: NCT03739606 This phase II trial studies how well flotetuzumab works in treating patients with CD123 positive blood cancer that has come back or does not ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6769702/

CD123 as a Therapeutic Target in the Treatment of ... The studies carried out in the last two decades support CD123 as a biomarker and therapeutic target for various hematological malignancies, and particularly ...

5. researchgate.net researchgate.net/publication/350660801_Preliminary_Results_of_a_Phase_1_Study_of_Flotetuzumab_a_CD123_x_CD3_Bispecific_DartR_Protein_in_Patients_with_RelapsedRefractory_Acute_Myeloid_Leukemia_and_Myelodysplastic_Syndrome

Preliminary Results of a Phase 1 Study of Flotetuzumab ... Flotetuzumab (MGD006/S80880) is a novel T-cell redirecting (CD123 x CD3) bispecific DART® protein being tested in a phase 1 study in patients ...

6. tandfonline.com tandfonline.com/doi/abs/10.1080/10428194.2024.2343029

Flotetuzumab as a salvage immunotherapy in advanced ... In conclusion, flotetuzumab had a manageable safety profile in advanced CD123-positive hematological malignancies. Keywords: Flotetuzumab · immunotherapy ...

7. ashpublications.org ashpublications.org/blood/article/140/Supplement%201/11753/488234/A-Phase-1-First-in-Human-Dose-Escalation-Study-of

A Phase 1, First-in-Human, Dose-Escalation Study of MGD024 ... The interleukin-3 receptor alpha chain CD123 is overexpressed in a number of hematologic malignancies and is particularly upregulated in ...