Inotuzumab + Venetoclax + Dexamethasone for Acute Lymphoblastic Leukemia

Overseen By Site Primary Contact Cancer line

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Children's Hospital Medical Center, Cincinnati

Must not be taking: Investigational drugs, Anti-cancer agents, Anti-GVHD agents

Disqualifiers: Prior SOS, Isolated CNS relapse, CNS3 disease, Active infection, Genetic syndromes, Pregnancy, Breastfeeding, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 4-8 weeks

28 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety of a drug combination called IoVeX for patients with relapsed B-cell Acute Lymphoblastic Leukemia (B-ALL), a type of blood cancer. The trial aims to determine if the combination of Inotuzumab Ozogamicin (a targeted therapy), Venetoclax (a BCL-2 inhibitor), and Dexamethasone (a corticosteroid) is safe and well-tolerated. Ideal candidates for this trial are those whose B-ALL has returned after treatment, particularly if they have experienced multiple relapses or did not respond to initial treatments. Participants will receive the drug combination over a 28-day cycle and undergo regular checkups to monitor their health. 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 requires that certain medications be stopped before starting the study drugs. For example, corticosteroids, vincristine, 6MP, and oral methotrexate must be stopped at least 24 hours before starting the trial. If you are on other anti-cancer agents or investigational drugs, you will need to stop those as well, except for hydroxyurea, which can be continued until 24 hours before the trial starts.

Is there any evidence suggesting that the combination of Inotuzumab Ozogamicin, Venetoclax, and Dexamethasone is likely to be safe for humans?

Research shows that the combination of Inotuzumab Ozogamicin, Venetoclax, and Dexamethasone (IoVeX) is under study for safety in treating relapsed B-cell Acute Lymphoblastic Leukemia (B-ALL) in both children and adults. Previous studies with Venetoclax and Inotuzumab Ozogamicin have shown that patients with acute leukemia can tolerate these drugs. However, side effects remain a risk.

Inotuzumab Ozogamicin has been used in other treatments and is generally well-tolerated, but it can cause side effects like low blood cell counts and liver problems. Venetoclax is also used in different leukemia treatments and may lead to low blood counts and infections.

Since this trial is in an early phase, it primarily focuses on assessing the safety of this new combination. While some evidence of safety exists from using these drugs separately or in pairs, the combination is still under evaluation. Participants will receive close monitoring for any medical issues during the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Inotuzumab Ozogamicin, Venetoclax, and Dexamethasone for treating Acute Lymphoblastic Leukemia because it targets cancer cells in unique ways. Unlike traditional chemotherapy, Inotuzumab Ozogamicin is an antibody-drug conjugate that specifically targets CD22, a protein found on the surface of leukemia cells, delivering a toxic agent directly to the cancer. Venetoclax adds another layer of innovation by inhibiting BCL-2, a protein that helps cancer cells survive, leading to their death. Finally, Dexamethasone is a steroid that can reduce inflammation and leukemia cell growth, offering a comprehensive approach when combined with the other two agents. This triple-threat strategy has the potential to be more effective and less harmful than existing treatments.

What evidence suggests that this treatment might be an effective treatment for Acute Lymphoblastic Leukemia?

Studies have shown that the combination of Inotuzumab Ozogamicin, Venetoclax, and Dexamethasone (IoVeX), which participants in this trial will receive, holds promise for treating relapsed B-cell Acute Lymphoblastic Leukemia (B-ALL). Research indicates that Venetoclax, when combined with Inotuzumab Ozogamicin, enhances the targeting and destruction of leukemia cells. This combination has been tested in patients with acute leukemia, yielding positive results in reducing cancer cells. Inotuzumab Ozogamicin specifically targets CD22+ cancer cells, common in B-ALL, potentially making it a strong option for this type of leukemia. Overall, early findings suggest this drug combination could effectively treat relapsed B-ALL. ^{1 2 3 6 7}

Who Is on the Research Team?

Jeremy Rubinstein, MD, PhD

Principal Investigator

Children's Hospital Medical Center, Cincinnati

Are You a Good Fit for This Trial?

This trial is for pediatric and adult patients with relapsed B-cell Acute Lymphoblastic Leukemia (B-ALL). Participants should have experienced a return of leukemia after initial treatment. Specific eligibility criteria are not provided, but typically include factors like age, health status, and previous treatments.

Inclusion Criteria

I took Venetoclax but stopped it at least 30 days ago.

I am between 1 and 39 years old.

My B-ALL has returned with more than 5% cancer cells in my bone marrow.

Exclusion Criteria

I have had SOS before, regardless of how severe it was.

I have recovered from side effects of previous cancer treatments, except for hair loss.

I have CNS3 disease at the time of joining the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive the combination of drugs Inotuzumab Ozogamicin, Venetoclax, and Dexamethasone for 1 cycle of 28 days. If tolerated, they continue to cycle 2, also 28 days.

4-8 weeks

Checkups and tests at the beginning and throughout each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Dexamethasone
• Inotuzumab Ozogamicin
• Venetoclax

Trial Overview The study tests the safety and tolerance of a drug combo called IoVeX (Inotuzumab Ozogamicin, Venetoclax, Dexamethasone) in treating relapsed B-ALL. Patients receive IoVeX over one 28-day cycle with an option to continue if well-tolerated. They'll undergo regular checkups and tests.

How Is the Trial Designed?

Group I: IoVeX Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Children's Hospital Medical Center, Cincinnati

Lead Sponsor

Trials

844

Recruited

6,566,000+

Published Research Related to This Trial

A 26-year-old man with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) that was negative for common immunotherapy targets (CD19, CD20, and CD22) was successfully treated using a combination of venetoclax and daratumumab with chemotherapy.

This case highlights a potential new treatment strategy for patients with R/R B-ALL lacking traditional immunotherapeutic targets, suggesting that targeting Bcl-2 and CD38 may provide effective options in otherwise limited scenarios.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab and venetoclax in combination with chemotherapy provide sustained molecular remission in relapsed/refractory CD19, CD20, and CD22 negative acute B lymphoblastic leukemia with KMT2A-AFF1 transcript. Voruz, S., Blum, S., de Leval, L., et al.[2021]

Inotuzumab ozogamicin (InO) demonstrated significant antitumor activity in patients with CD22-positive relapsed/refractory acute lymphoblastic leukemia, with 68% of patients achieving complete remission or complete remission with incomplete marrow recovery, and 84% achieving minimal residual disease negativity.

The recommended phase 2 dose of InO was confirmed at 1.8 mg/m2 per cycle, and while treatment-related toxicities were primarily cytopenias, the drug was generally well tolerated, indicating a favorable safety profile alongside its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inotuzumab ozogamicin in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia: a phase 1/2 study. DeAngelo, DJ., Stock, W., Stein, AS., et al.[2019]

Inotuzumab ozogamicin, a CD22-targeting antibody-drug conjugate, has been approved for treating adults with relapsed or refractory acute lymphoblastic leukemia (ALL) and shows improved response rates and survival compared to standard chemotherapy.

This treatment not only enhances the chances of achieving minimal residual disease negativity but also increases the likelihood of patients being eligible for allogeneic stem cell transplants, which can be crucial for their long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inotuzumab Ozogamicin in Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia. Williams, S., Kim, M.[2020]

Inotuzumab ozogamicin (InO) is effective and well-tolerated in both younger (<55 years) and older (≥55 years) patients with relapsed/refractory acute lymphoblastic leukemia (ALL), showing similar remission rates and duration of remission across age groups.

Younger patients had a longer overall survival (OS) compared to older patients (8.6 months vs 5.6 months), and older patients experienced a higher incidence of veno-occlusive disease after hematopoietic stem cell transplantation, indicating a need for careful monitoring in this age group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety analysis by age cohort of inotuzumab ozogamicin in patients with relapsed or refractory acute lymphoblastic leukemia enrolled in INO-VATE. Jabbour, EJ., DeAngelo, DJ., Stelljes, M., et al.[2019]

In a study of 15 patients with relapsed or refractory early T-cell precursor acute lymphoblastic leukemia (R/R ETP-ALL), Venetoclax combined with multidrug chemotherapy resulted in a 67.7% overall response rate and a 60% complete response rate, indicating significant efficacy.

The treatment was found to be safe, with manageable hematological toxicities and no severe adverse reactions, suggesting that Venetoclax combined with chemotherapy could be a promising option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical efficacy and safety of venetoclax combined with multidrug chemotherapy in the treatment of 15 patients with relapsed or refractory early T-cell precursor acute lymphoblastic leukemia]. Kong, JY., Zong, LH., Pu, Y., et al.[2023]

In a study of 6 children with refractory or relapsed acute myeloid leukemia (AML), the combination of venetoclax, azacitidine, and cladribine (VAC regimen) resulted in significant treatment responses, with 4 achieving complete remission and 1 showing partial remission.

Despite severe side effects like grade IV neutropenia and thrombocytopenia, there were no treatment-related deaths or infections, indicating that the VAC regimen is both effective and safe for this vulnerable patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety and the Short-Term Efficacy of Venetoclax Combined with Azacitidine Followed by Cladribine in Children with Refractory/Relapsed Acute Myeloid Leukemia]. DU, WW., Liu, SX., Wang, Y., et al.[2023]

A patient with relapsed T-cell acute lymphoblastic leukemia (T-ALL) showed a clinical response to venetoclax, an oral BCL-2 inhibitor, combined with a hypomethylating agent, highlighting a potential new treatment strategy for this challenging condition.

Given that less than 7% of patients with relapsed T-ALL achieve long-term survival, targeting antiapoptotic proteins like BCL-2 could offer a promising approach to improve outcomes in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax and decitabine for treatment of relapsed T-cell acute lymphoblastic leukemia: A case report and review of literature. Farhadfar, N., Li, Y., May, WS., et al.[2021]

In the phase III CLL14 trial, a 12-month treatment with venetoclax combined with obinutuzumab significantly improved progression-free survival and rates of undetectable minimal residual disease compared to traditional chemoimmunotherapy with chlorambucil and obinutuzumab in patients with untreated chronic lymphocytic leukaemia.

Venetoclax + obinutuzumab is a well-tolerated, chemotherapy-free treatment option for CLL, with manageable side effects like neutropenia, making it suitable for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. Blair, HA.[2021]

The study evaluates the safety and efficacy of venetoclax combined with oral azacitidine as maintenance therapy for patients with acute myeloid leukemia (AML) who are in complete remission but have incomplete blood count recovery after intensive treatment.

The primary goal of the trial is to assess relapse-free survival, with secondary outcomes including overall survival and quality of life, highlighting the potential of this combination therapy to prevent relapse in AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design of the VIALE-M phase III trial of venetoclax and oral azacitidine maintenance therapy in acute myeloid leukemia. Ivanov, V., Yeh, SP., Mayer, J., et al.[2022]

In preclinical models of relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL), the combination of venetoclax, inotuzumab ozogamicin, and dexamethasone showed significant synergy, leading to long-term leukemia-free survival, which is promising for future clinical trials.

While inotuzumab ozogamicin alone induced complete remission in murine models, it did not prevent relapse, highlighting the importance of combination therapy for achieving sustained treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax and dexamethasone synergize with inotuzumab ozogamicin-induced DNA damage signaling in B-lineage ALL. Kirchhoff, H., Karsli, U., Schoenherr, C., et al.[2022]

The combination of ruxolitinib and venetoclax shows a dose-dependent effect on T cell acute lymphoblastic leukemia (T-ALL) but does not improve survival in a xenograft model, leading to increased leukemic infiltration in the central nervous system (CNS).

Adding the CXCR4 inhibitor plerixafor to the treatment regimen enhances survival and reduces clinical symptoms, suggesting that targeting the CXCR4-CXCL12 axis may be necessary for achieving better outcomes in T-ALL therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CXCR4 allows T cell acute lymphoblastic leukemia to escape from JAK1/2 and BCL2 inhibition through CNS infiltration. Walker, KL., Rinella, SP., Hess, NJ., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06863259

Study of Inotuzumab Ozogamicin, Venetoclax, and ... The goal of this clinical trial is to learn if the combination of drugs Inotuzumab Ozogamicin, Venetoclax, and Dexamethasone (IoVeX) are safe to treat ...

2. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/1509/502864/A-Phase-I-Study-of-Venetoclax-in-Combination-with

A Phase I Study of Venetoclax in Combination with ... A Phase I study of Venetoclax in combination with Inotuzumab Ozogamicin for relapsed or refractory ALL in adults.

3. dana-farber.org dana-farber.org/clinical-trials/21-196

A Phase 1 Study of Venetoclax in combination with ... This research study is evaluating the safety and efficacy of administering venetoclax and inotuzumab ozogamicin in combination in patients with acute ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0006497123081120

A Phase I Study of Venetoclax in Combination ... The primary objective is to determine the maximum tolerated dose (MTD) of VEN plus INO at the FDA-approved doses in adults with R/R CD22+ ALL.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05016947

NCT05016947 | Venetoclax Plus Inotuzumab for B-ALL This research study is evaluating the safety and efficacy of administering venetoclax and inotuzumab ozogamicin in combination in patients with acute ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12533514/

Inotuzumab ozogamicin in adult acute lymphoblastic leukemia Outcomes have been historically poor in adults with relapsed/refractory (R/R) B-cell ALL, with a 5-year overall survival (OS) rate of <10% with ...

7. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT05016947/

Clinical Trial: NCT05016947 This research study is evaluating the safety and efficacy of administering venetoclax and inotuzumab ozogamicin in combination in patients with acute ...