Venetoclax + Inotuzumab for Acute Lymphoblastic Leukemia

Recruiting at 1 trial location

Overseen By Marlise R Luskin, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Dana-Farber Cancer Institute

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: CNS disease, Severe liver disease, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 22

26 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a combination of drugs including venetoclax, inotuzumab ozogamicin, and dexamethasone in patients with a specific type of leukemia that hasn't responded to standard treatments. Venetoclax helps kill cancer cells by blocking proteins they need to survive, while inotuzumab ozogamicin targets and kills cancer cells by delivering chemotherapy directly inside them.

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

The trial protocol does not specify if you must stop all current medications, but you cannot take strong CYP3A4 inhibitors or inducers within 7 days of starting the study drugs. Some medications like steroids, hydroxyurea, and vincristine are allowed to reduce blast count. Check with your doctor to review your medication list for any potential interactions.

What data supports the idea that Venetoclax + Inotuzumab for Acute Lymphoblastic Leukemia is an effective drug?

The available research shows that the combination of Venetoclax and Inotuzumab, along with Dexamethasone, was highly effective in preclinical models of Acute Lymphoblastic Leukemia (ALL). In these studies, the combination led to long-term leukemia-free survival and treatment-free survival in all tested models. This suggests that the drug combination works well together to fight the disease, making it a promising option for further clinical trials. ^{1 2 3 4 5}

What safety data is available for the treatment of Venetoclax and Inotuzumab for Acute Lymphoblastic Leukemia?

The safety data for Venetoclax and Inotuzumab, when used in combination for Acute Lymphoblastic Leukemia (ALL), is derived from various studies. Venetoclax, primarily used for Chronic Lymphocytic Leukemia (CLL), has an acceptable tolerability profile with manageable adverse events like neutropenia. Inotuzumab ozogamicin has been studied in both pediatric and adult patients with relapsed or refractory ALL. It is generally well-tolerated but has notable risks such as hepatic veno-occlusive disease (VOD) and hematologic adverse events. In combination with dexamethasone, Venetoclax and Inotuzumab ozogamicin have shown synergistic effects in preclinical models, leading to long-term leukemia-free survival. However, the risk of VOD and other adverse events requires careful monitoring. Overall, the combination therapy shows promise but necessitates further clinical evaluation to fully understand its safety profile. ^{1 2 6 7 8}

Is the drug Inotuzumab Ozogamicin a promising treatment for Acute Lymphoblastic Leukemia?

Yes, Inotuzumab Ozogamicin is a promising drug for treating Acute Lymphoblastic Leukemia. It has shown better response rates and survival outcomes compared to standard chemotherapy, especially in patients whose disease has returned or is resistant to other treatments. It also helps more patients become eligible for stem cell transplants, which can be a crucial step in treatment. ^{7 9 10 11 12}

Research Team

Marlise R Luskin, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

Adults with confirmed CD22+ B-ALL or B-LBL, including those with chronic myeloid leukemia in lymphoid blast crisis refractory to treatments. Must have adequate organ function, no severe liver disease, and agree to contraception. Excludes pregnant women, those on certain drugs affecting venetoclax metabolism, and individuals with uncontrolled illnesses.

Inclusion Criteria

I can care for myself but may not be able to do active work.

I have had hepatitis C but my current viral load is undetectable.

I am 18 years old or older.

Exclusion Criteria

I haven't taken strong CYP3A4 inhibitors or inducers in the last week.

Absolute blast count of ≥25 K/µL prior to initiation of study treatment

I cannot take venetoclax by mouth due to absorption issues.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lead In Cycle

Dose escalated venetoclax 1x daily for days 1-3 with Dexamethasone daily for days 1-3, 7 days total

1 week

1 visit (in-person)

Induction Cycle 1

Dose escalated venetoclax 1x daily for days 1-21, Dexamethasone daily for days 1-4, Inotuzumab ozogamicin on days 1, 8, and 15

4 weeks

3 visits (in-person)

Induction Cycle 2

Dose escalated venetoclax 1x daily and Inotuzumab ozogamicin on days 1, 8, and 15

4 weeks

3 visits (in-person)

Consolidation Cycles

Up to 5 cycles of dose escalated Venetoclax 1x daily and Inotuzumab ozogamicin on days 1, 8, and 15

5 months

15 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Treatment Details

Interventions

• Dexamethasone
• Inotuzumab Ozogamicin
• Venetoclax

Trial Overview The trial is testing the safety and effectiveness of combining venetoclax with inotuzumab ozogamicin for treating acute lymphoblastic leukemia (ALL). Dexamethasone is also part of the treatment regimen. The goal is to see how well these drugs work together against ALL.

Participant Groups

Group I: Venetoclax + Inotuzumab Ozogamicin with Dexamethasone Experimental Treatment 3 Interventions

Phased 28 day treatment cycles with lead in: Lead In Cycle: Dose escalated venetoclax 1x daily for days 1-3 with and Dexamethasone daily for days 1-3 lead in, 7 days total. Induction Cycle 1: Dose escalated venetoclax 1x daily for days 1-21, Dexamethasone daily for days 1-4, Inotuzumab ozogamicin on days 1, 8, and 15 Induction Cycle 2: Dose escalated venetoclax 1x daily for days and Inotuzumab ozogamicin on days 1, 8, and 15 Consolidation Cycles: Up to 5 cycles of dose escalated Venetoclax 1x daily for days and Inotuzumab ozogamicin on days 1, 8, and 15

Inotuzumab Ozogamicin is already approved in European Union, United States for the following indications:

Approved in European Union as Besponsa for:

• Relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL)

Approved in United States as Besponsa for:

• Relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients 1 year and older

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

AbbVie

Industry Sponsor

Trials

1,079

Recruited

535,000+

Founded

2013

Headquarters

North Chicago, USA

Known For

Immunology treatments

Top Products

Humira (adalimumab), Skyrizi (risankizumab), Rinvoq (upadacitinib)

Dr. Roopal Thakkar

AbbVie

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Robert A. Michael

AbbVie

Chief Executive Officer

Bachelor's degree in Finance from the University of Illinois

Findings from Research

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 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 venetoclax and obinutuzumab was found to be safe and well-tolerated in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia, with no dose-limiting toxicities observed during the study.

The treatment resulted in a high overall response rate of 95% in relapsed/refractory patients and 100% in previously untreated patients, with significant rates of undetectable minimal residual disease, indicating effective disease control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. Flinn, IW., Gribben, JG., Dyer, MJS., et al.[2021]

In a retrospective study of 14 patients with chronic lymphocytic leukemia (CLL) treated with the venetoclax and obinutuzumab (VenG) regimen, 73% developed grade 3 or 4 neutropenia, indicating a high incidence of this side effect.

The study suggests that the high rate of neutropenia may be linked to patients having more comorbidities and high-risk disease features, highlighting the need for further research on supportive treatments to manage this side effect and allow for optimal dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation and associated risk factors for neutropenia with venetoclax and obinutuzumab in the treatment of chronic lymphocytic leukemia. Samuels, C., Abbott, D., Niemiec, S., et al.[2022]

The combination of 225 Ac-lintuzumab and venetoclax showed a synergistic effect in killing tumor cells in venetoclax-resistant acute myeloid leukemia (AML) models, indicating a potential new treatment strategy.

This combination therapy not only induced DNA damage but also reduced MCL-1 protein levels, which is linked to resistance against venetoclax, leading to better tumor control and prolonged survival in preclinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models. Garg, R., Allen, KJH., Dawicki, W., et al.[2021]

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 subgroup analysis of 55 Asian patients with relapsed or refractory B-cell acute lymphoblastic leukemia, those treated with Inotuzumab ozogamicin (InO) achieved a higher complete remission rate (71%) compared to standard of care (21%).

Patients receiving InO also had a better median overall survival of 5.8 months versus 3.9 months for those on standard treatment, indicating improved efficacy while maintaining a safety profile similar to the overall study population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inotuzumab ozogamicin versus standard of care in Asian patients with relapsed/refractory acute lymphoblastic leukemia. Fujishima, N., Uchida, T., Onishi, Y., et al.[2022]

Inotuzumab ozogamicin (InO) was well tolerated in a small group of six pediatric patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia, with no dose-limiting toxicities observed during the study.

The treatment led to significant antileukemic efficacy, with five out of six patients achieving complete remission or complete remission with incomplete blood cell recovery, similar to outcomes seen in adults, although there is a noted risk for hepatic veno-occlusive disease (VOD).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of inotuzumab ozogamicin as a single agent in pediatric patients in Japan with relapsed/refractory CD22-positive acute lymphoblastic leukemia (INO-Ped-ALL-1). Nakayama, H., Ogawa, C., Sekimizu, M., et al.[2023]

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 demonstrated a high overall response rate of 84% in 31 patients with relapsed/refractory B-ALL with extramedullary disease, with 55% achieving complete remission and 29% partial remission after two treatment cycles.

While inotuzumab ozogamicin was effective as a short-term treatment, it did not improve long-term disease control when followed by allogeneic hematopoietic stem cell transplantation, as indicated by the median overall survival of 12.8 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcome of relapsed or refractory acute B-lymphoblastic leukemia patients and BCR-ABL-positive blast cell crisis of B-lymphoid lineage with extramedullary disease receiving inotuzumab ozogamicin. Kayser, S., Sartor, C., Luskin, MR., et al.[2022]

In a phase 2 study involving 59 adults with relapsed or refractory acute lymphoblastic leukemia (ALL), the combination of inotuzumab ozogamicin and low-intensity mini-hyper-CVD chemotherapy resulted in a high overall response rate of 78%, with 59% achieving complete response and an 82% minimal residual disease negativity rate among responders.

While the treatment showed promising efficacy, it was associated with significant safety concerns, including high rates of prolonged thrombocytopenia (81%) and infections (73%), as well as a notable risk of veno-occlusive disease (15%), particularly in patients with prior liver damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Salvage Chemoimmunotherapy With Inotuzumab Ozogamicin Combined With Mini-Hyper-CVD for Patients With Relapsed or Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: A Phase 2 Clinical Trial. Jabbour, E., Ravandi, F., Kebriaei, P., et al.[2022]

Inotuzumab ozogamicin, a targeted immunotherapy using a CD22 monoclonal antibody, has shown improved complete remission rates and overall survival in adults with relapsed or refractory acute lymphoblastic leukemia (ALL) compared to standard chemotherapy, based on results from Phase 1/2 and Phase 3 clinical trials.

This drug targets CD22, which is present on over 90% of leukemic blasts in ALL patients, highlighting its potential effectiveness and the shift towards using targeted therapies in treating this challenging disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inotuzumab ozogamicin: a CD22 mAb-drug conjugate for adult relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Yurkiewicz, IR., Muffly, L., Liedtke, M.[2019]

References

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

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

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

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

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

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. [2021]

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

Evaluation and associated risk factors for neutropenia with venetoclax and obinutuzumab in the treatment of chronic lymphocytic leukemia. [2022]

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

225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models. [2021]

6. 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]

7. Japan pubmed.ncbi.nlm.nih.gov

Inotuzumab ozogamicin versus standard of care in Asian patients with relapsed/refractory acute lymphoblastic leukemia. [2022]

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

A phase I study of inotuzumab ozogamicin as a single agent in pediatric patients in Japan with relapsed/refractory CD22-positive acute lymphoblastic leukemia (INO-Ped-ALL-1). [2023]

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

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

10. Italy pubmed.ncbi.nlm.nih.gov

Outcome of relapsed or refractory acute B-lymphoblastic leukemia patients and BCR-ABL-positive blast cell crisis of B-lymphoid lineage with extramedullary disease receiving inotuzumab ozogamicin. [2022]

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

Salvage Chemoimmunotherapy With Inotuzumab Ozogamicin Combined With Mini-Hyper-CVD for Patients With Relapsed or Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: A Phase 2 Clinical Trial. [2022]

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

Inotuzumab ozogamicin: a CD22 mAb-drug conjugate for adult relapsed or refractory B-cell precursor acute lymphoblastic leukemia. [2019]