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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of drugs to determine their safety and effectiveness in treating acute lymphoblastic leukemia (ALL), a type of blood cancer. Participants will receive venetoclax (a targeted therapy) and inotuzumab ozogamicin (an antibody-drug conjugate), along with dexamethasone, to evaluate the combined treatment's efficacy. It targets individuals whose ALL has returned or did not respond to previous treatments. Those with a specific type of ALL with certain cell markers (CD22+ B-ALL) who have not succeeded with other treatments might be suitable for this trial. 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 therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Earlier studies found that using venetoclax and inotuzumab ozogamicin with dexamethasone is safe for treating relapsed B-cell Acute Lymphoblastic Leukemia (B-ALL) in both children and adults. Research shows that these drugs work well together, enhancing their cancer-fighting effectiveness.

Evidence indicates that venetoclax and inotuzumab ozogamicin can be combined without causing serious side effects. Studies have shown that most people tolerate this combination well. However, like any treatment, some side effects might occur. The safety data from these studies suggest that this drug combination is a promising option for people with ALL. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Venetoclax and Inotuzumab Ozogamicin for treating Acute Lymphoblastic Leukemia because they offer a fresh approach compared to the usual chemotherapy treatments. Venetoclax works by targeting and blocking a protein called BCL-2, which cancer cells use to stay alive, essentially forcing them to self-destruct. Inotuzumab Ozogamicin combines an antibody that homes in on leukemia cells with a toxin that directly attacks them, delivering a one-two punch to the cancer. This combination has the potential to enhance treatment effectiveness and possibly shorten the time needed to see improvements, offering new hope for patients with this challenging condition.

What evidence suggests that this trial's treatments could be effective for acute lymphoblastic leukemia?

Research has shown that venetoclax, when combined with chemotherapy, can enhance the treatment of acute lymphoblastic leukemia (ALL). Venetoclax blocks a protein called Bcl-2, which helps cancer cells survive, thereby aiding in their destruction. In this trial, participants will receive a combination of venetoclax and inotuzumab ozogamicin, along with dexamethasone. Inotuzumab ozogamicin, approved for certain types of leukemia, delivers medicine directly to cancer cells. Early studies suggest that combining venetoclax with inotuzumab ozogamicin may improve outcomes for patients with ALL. ^{6 7 8 9}

Who Is on the Research Team?

Marlise R Luskin, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

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 have had HSCT or CAR-T therapy and meet specific criteria.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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 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]

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]

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 (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]

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, 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]

Citations

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Venetoclax plus low-intensity chemotherapy for adults with ... In acute lymphoblastic leukemia (ALL), the B-cell lymphoma 2 inhibitor venetoclax may enhance the efficacy of chemotherapy, allowing dose reductions. This phase ...

2. 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 ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S2473952924000454

A phase 1/2 study of mini-hyper-CVD plus venetoclax in ... Preclinical studies suggest that Bcl-2 inhibition with venetoclax has antileukemic activity in acute lymphoblastic leukemia (ALL) and may ...

4. dana-farber.org dana-farber.org/for-physicians/clinical-resources/hematologic-malignancies/advances-newsletter/2023-issue-17/venetoclax-plus-mini-hyper-cvd

Clinical Trial Spotlight: Venetoclax plus Mini-hyper-CVD for ... Novel agents are improving outcomes for older patients with PH- ALL. Blinatumomab (2014) and inotuzumab ozogamicin (2017) have been approved for ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03236857

NCT03236857 | A Study of the Safety and ... An open-label, global, multi-center study to evaluate the safety and pharmacokinetics of venetoclax monotherapy, to determine the dose limiting toxicity (DLT)

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33512436/

Venetoclax and dexamethasone synergize with ... To improve pharmacotherapy we analyzed apoptosis induction by venetoclax and inotuzumab-ozogamicin in terms of cytotoxicity and mode of action.

7. ashpublications.org ashpublications.org/bloodadvances/article/9/3/617/525999/Venetoclax-plus-low-intensity-chemotherapy-for

Venetoclax plus low-intensity chemotherapy for adults with ... In acute lymphoblastic leukemia (ALL), the B-cell lymphoma 2 inhibitor venetoclax may enhance the efficacy of chemotherapy, allowing dose ...

8. cincinnatichildrens.org cincinnatichildrens.org/service/c/clinical-trials/studies/IoVeX-JR-2024-052925

Study of Inotuzumab Ozogamicin, Venetoclax, and ... ... Ozogamicin, Venetoclax, and Dexamethasone (IoVeX) are safe to treat relapsed B-cell Acute Lymphoblastic Leukemia (B-ALL) in pediatric and adult patients.

9. ctsearchsupport.org ctsearchsupport.org/clinical-trials/study-of-inotuzumab-ozogamicin-venetoclax-and-dexamethasone-for-relapsed-b-cell-all

Three drugs, dexamethasone , inotuzumab ozogamicin ... If the combination of dexamethasone , inotuzumab ozogamicin and venetoclax is safe and works well to treat B-ALL that has relapsed or is ...