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

Trial Summary

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.

What data supports the effectiveness of the drug combination Inotuzumab, Venetoclax, and Dexamethasone for treating Acute Lymphoblastic Leukemia?

Research shows that the combination of Venetoclax, Inotuzumab, and Dexamethasone works well together to fight leukemia in preclinical models, leading to long-term leukemia-free survival in tested models. This suggests that the combination could be effective in clinical trials for treating Acute Lymphoblastic Leukemia. ^{1 2 3 4 5}

Is the combination of Inotuzumab, Venetoclax, and Dexamethasone safe for treating acute lymphoblastic leukemia?

Inotuzumab ozogamicin has been shown to be generally safe in patients with relapsed or refractory acute lymphoblastic leukemia, with some risks of side effects like low blood cell counts and liver issues. The safety of Venetoclax and Dexamethasone in combination with Inotuzumab for this condition specifically isn't detailed here, but these drugs have been used safely in other treatments. ^{6 7 8 9 10}

What makes the drug combination of Inotuzumab, Venetoclax, and Dexamethasone unique for treating acute lymphoblastic leukemia?

This drug combination is unique because it combines the DNA damage signaling effects of Inotuzumab with the apoptosis-inducing (cell death) properties of Venetoclax, enhanced by Dexamethasone, to achieve long-term leukemia-free survival in preclinical models, which is not typically achieved with other treatments. ^{1 2 11 12 13}

What is the purpose of this trial?

The goal of this clinical trial is to learn if the combination of drugs Inotuzumab Ozogamicin, Venetoclax, and Dexamethasone (IoVeX) are safe to treat relapsed B-cell Acute Lymphoblastic Leukemia (B-ALL) in pediatric and adult patients. It will also learn if these drugs are well tolerated. The main questions it aims to answer are: Is the drug combination of Inotuzumab Ozogamicin, Venetoclax, and Dexamethasone (IoVeX) safe when given to patients? What medical problems do patients taking IoVeX experience? Participants will: Receive this combination of drugs for 1 cycle which is 28 days at various timepoints. If participants tolerate cycle 1 they will be eligible to continue to cycle 2 which is also 28 days. Have checkups and tests at the beginning of the study and throughout the course of each cycle.

Research Team

Jeremy Rubinstein, MD, PhD

Principal Investigator

Children's Hospital Medical Center, Cincinnati

Eligibility Criteria

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 am between 1 and 39 years old.

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

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

Venetoclax and dexamethasone synergize with inotuzumab ozogamicin-induced DNA damage signaling in B-lineage ALL. [2022]

2. England 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. [2021]

3. China 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]. [2023]

4. Saudi Arabia pubmed.ncbi.nlm.nih.gov

Venetoclax and decitabine for treatment of relapsed T-cell acute lymphoblastic leukemia: A case report and review of literature. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Design of the VIALE-M phase III trial of venetoclax and oral azacitidine maintenance therapy in acute myeloid leukemia. [2022]

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

Phase II Trial of Inotuzumab Ozogamicin in Children and Adolescents With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia: Children's Oncology Group Protocol AALL1621. [2023]

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

Inotuzumab Ozogamicin in Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia. [2020]

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

ADC Approval Likely to Spur More Research. [2019]

9. United States 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. [2019]

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

Inotuzumab ozogamicin in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia: a phase 1/2 study. [2019]

11. New Zealand pubmed.ncbi.nlm.nih.gov

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

12. China 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]. [2023]

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

CXCR4 allows T cell acute lymphoblastic leukemia to escape from JAK1/2 and BCL2 inhibition through CNS infiltration. [2022]