Venetoclax Combination Therapy for Blood Cancers

Recruiting at 4 trial locations

Overseen By Andrew Place, MD, PhD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Andrew E. Place

Must not be taking: CYP3A inhibitors/inducers

Disqualifiers: Active hepatitis, HIV, systemic infection, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 4 cycles of 35 days each for Cohorts A and B; 32 days for Cohort C

92 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not require stopping all current medications. Some medications like dexamethasone, prednisone, vincristine, and low-dose methotrexate can be continued without a break. However, you must stop using strong or moderate CYP3A inhibitors/inducers at least 3 days before starting the trial.

What data supports the effectiveness of the drug combination therapy for blood cancers?

Research shows that venetoclax combined with azacitidine improves remission rates and survival in older patients with acute myeloid leukemia (AML) compared to azacitidine alone. This suggests that the combination therapy could be effective for treating certain blood cancers. ^{1 2 3 4 5}

Is Venetoclax combination therapy safe for treating blood cancers?

Venetoclax combined with azacitidine has been shown to be generally safe for patients with acute myeloid leukemia who are not suitable for standard chemotherapy. Common side effects include low levels of white blood cells (neutropenia), low platelet counts (thrombocytopenia), and low red blood cell counts (anemia), but these were considered tolerable. ^{2 3 6 7 8}

What makes Venetoclax combination therapy unique for blood cancers?

Venetoclax combination therapy is unique because it targets the B-cell leukemia/lymphoma-2 protein, which helps cancer cells survive, and is used in combination with other drugs like azacitidine to treat acute myeloid leukemia (AML). This combination can be a bridge to a potentially curative transplant for some patients and offers a less aggressive treatment option for older patients who cannot undergo intensive therapies. ^{2 5 7 9 10}

What is the purpose of this trial?

This trial is evaluating the safety and tolerability of venetoclax with chemotherapy in pediatric and young adult patients with hematologic malignancies, including myelodysplastic syndrome (MDS), acute myeloid leukemia derived from myelodysplastic syndrome (MDS/AML), and acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL). The names of the study drugs involved in this study are below. Please note this is a list for the study as a whole, participants will receive drugs according to disease cohort. * Venetoclax * Azacitidine * Cytarabine * Methotrexate * Hydrocortisone * Leucovorin * Dexamethasone * Vincristine * Doxorubicin * Dexrazoxane * Calaspargase pegol * Hydrocortisone

Research Team

Andrew Place, MD, PhD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

This trial is for pediatric and young adult patients up to 40 years old with high-risk blood cancers like MDS, AML from MDS, or ALL/LBL. They should have recovered from previous treatments, not have severe organ damage or active infections, and can't be pregnant or breastfeeding. Participants must agree to use effective contraception.

Inclusion Criteria

I can do most activities but need help with some.

I am between 1 and 21 years old.

My leukemia has not responded to treatment or has come back.

Exclusion Criteria

Cohort B: Same exclusion criteria as Cohort A

Pregnant or nursing women

I do not have active GVHD, hepatitis, systemic infections, HIV, or other significant diseases.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive venetoclax in combination with chemotherapy. Treatment cycles vary by cohort: Cohorts A and B have cycles up to 35 days, and Cohort C has a single cycle of 32 days.

Up to 4 cycles of 35 days each for Cohorts A and B; 32 days for Cohort C

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of treatment-related toxicities and overall response.

Up to 30 days after last dose of study treatment

Long-term Follow-up

Participants are monitored for overall survival and event-free survival up to 2 years post-treatment.

Up to 2 years

Treatment Details

Interventions

• Azacitidine
• Calaspargase Pegol
• Cytarabine
• Dexamethasone
• Dexrazoxane
• Doxorubicin
• Leucovorin
• Methotrexate
• Venetoclax
• Vincristine

Trial Overview The trial tests the safety of venetoclax combined with chemotherapy drugs in treating various aggressive blood cancers. It aims to see how well patients tolerate this combination therapy and involves a range of medications tailored to specific disease cohorts.

Participant Groups

Group I: Cohort C Experimental Treatment 11 Interventions

Patients with relapsed/refractory acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LBL) or acute leuekmai of ambiguous lineage. It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 12 people will participate in Part 2 (Dose Expansion) of this cohort. Cohort C: Treatment cycle is approximately 32 days for one cycle and will be a single treatment cycle: Dosage, duration and timings as outlined in protocol. * Venetoclax * Dexamethasone * Vincristine * Doxorubicin * Dexrazoxane * Calaspargase pegol ---Short acting Erwinia preparations (recombinant or native Erwinia asparaginase) may be used for participants with known pegaspargase or calaspargase pegol allergy * Cytarabine * Methotrexate * Hydrocortisone * Leucovorin- \*Cytarabine, Methotrexate, Hydrocortisone and Leucovorin may be given more frequently if leukemia/lymphoma cells are detected in spinal fluid),

Group II: Cohort B Experimental Treatment 6 Interventions

Patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) with an underlying genetic condition that increases their risk for developing treatment-related toxicities. It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 6 people will participate in Part 2 (Dose Expansion) of this cohort. * Venetoclax-once daily on predetermined days per protocol * Azacitidine-once daily on predetermined days per protocol * Cytarabine, Methotrexate, Hydrocortisone and Leucovorin will be given only if MDS/leukemia cells are detected in spinal fluid per determination of treating physician

Group III: Cohort A Experimental Treatment 6 Interventions

For Part 1, participants will receive: * Patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 14-20 people will participate in Part 2 (Dose Expansion) of this cohort Treatment cycle is approximately 28 days for up to 4 cycles * Venetoclax-once daily on predetermined days per protocol * Azacitidine-once daily on predetermined days per protocol * Cytarabine, Methotrexate, Hydrocortisone and Leucovorin will be given only if MDS/leukemia cells are detected in spinal fluid per determination of treating physician

Azacitidine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

Andrew E. Place

Lead Sponsor

Trials

1

Recruited

90+

Andrew E. Place, MD

Lead Sponsor

Trials

1

Recruited

90+

Children's Cancer Research Fund

Collaborator

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

Servier

Industry Sponsor

Trials

55

Recruited

45,600+

Boston Children's Hospital

Collaborator

Trials

801

Recruited

5,584,000+

University of Colorado, Denver

Collaborator

Trials

1,842

Recruited

3,028,000+

Children's Cancer Research Fund

Collaborator

Trials

3

Recruited

150+

Gateway for Cancer Research

Collaborator

Trials

47

Recruited

2,500+

Findings from Research

In a phase II study involving 60 older or unfit patients with newly diagnosed acute myeloid leukemia (AML), the combination of venetoclax with cladribine and low-dose cytarabine alternating with venetoclax and 5-azacitidine resulted in a high composite complete response rate of 93%.

The treatment showed promising overall survival and disease-free survival rates, with only one death occurring within 4 weeks, indicating that this regimen is effective and has a favorable safety profile for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. Kadia, TM., Reville, PK., Wang, X., et al.[2023]

In a study of 13 patients with acute leukemia treated with venetoclax and azacitidine, 46% developed COVID-19, highlighting a significant risk associated with this treatment during the pandemic.

The study found that 33% of those who contracted COVID-19 died from the virus, indicating that COVID-19 can lead to severe outcomes in patients receiving AZA-VEN therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution. Drozd-Sokołowska, J., Mądry, K., Barankiewicz, J., et al.[2023]

In patients with newly diagnosed unfit acute myeloid leukemia (AML), the combination of azacitidine and venetoclax is a standard first-line treatment.

However, patients with TP53-mutated AML and poor-risk cytogenetics do not benefit from adding venetoclax to azacitidine, suggesting that alternative treatment regimens should be considered for these individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TP53 or Not TP53: That Is the Question. Green, SD., Zeidner, JF.[2023]

In a study of nine AML patients with acquired resistance to venetoclax, the typical BCL2 mutation associated with resistance was not found, suggesting that this mutation is not necessary for developing resistance in AML.

The study identified that existing mutations, particularly the expansion of FLT3-ITD, were primarily responsible for venetoclax resistance, indicating that monitoring these mutations could help in developing strategies to prevent or overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Not BCL2 mutation but dominant mutation conversation contributed to acquired venetoclax resistance in acute myeloid leukemia. Zhang, X., Qian, J., Wang, H., et al.[2022]

The combination of venetoclax with bendamustine-rituximab (BR) was found to be safe and tolerable in a study of 60 patients with relapsed/refractory non-Hodgkin's lymphoma, with the recommended phase II dose established at 800 mg daily.

The overall response rate to the treatment was 65%, with a median duration of response of 38.3 months, indicating preliminary efficacy for this combination therapy in managing B-cell NHL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study. de Vos, S., Swinnen, LJ., Wang, D., et al.[2021]

The VA regimen, combining venetoclax and azacitidine, demonstrated a high complete remission (cCR) rate of 78.8% after the first treatment cycle and 81.8% after prolonged treatment in 66 patients with newly diagnosed acute myeloid leukemia (AML) who were not suitable for conventional chemotherapy.

The treatment was generally safe, with manageable adverse effects, primarily neutropenia, thrombocytopenia, and anemia, and showed better outcomes in patients with specific gene mutations (IDH1/2 or NPM1) and those experiencing rebound thrombocytosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of venetoclax combined azacitidine in newly diagnosed acute myeloid leukemia unfit for standard chemotherapy: a single center experience]. Sun, L., Ye, SJ., Zhou, N., et al.[2023]

Coadministration of azithromycin with venetoclax resulted in a modest reduction in venetoclax levels (25% lower maximum concentration and 35% lower area under the curve), but did not require any dose adjustments, indicating that azithromycin is a safe option for patients taking venetoclax.

The study involved 12 healthy female subjects and found that venetoclax was well tolerated with no serious adverse events, suggesting that azithromycin can be used as an alternative antibiotic without significantly impacting venetoclax pharmacokinetics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Azithromycin on Venetoclax Pharmacokinetics in Healthy Volunteers: Implications for Dosing Venetoclax with P-gp Inhibitors. Agarwal, SK., Tong, B., Bueno, OF., et al.[2019]

In a study of 60 patients with acute myeloid leukemia (AML), the combination of venetoclax and azacitidine (Ven+AZA) demonstrated a high response rate, with 70.8% of previously untreated patients unfit for standard chemotherapy achieving complete remission (CR) or CR with incomplete hematological recovery (CRi) after one cycle.

Ven+AZA was found to be safe and tolerable, with some patients achieving minimal residual disease (MRD) negativity, particularly in those with favorable genetic mutations like NPM1, IDH1/IDH2, and TP53, indicating its potential effectiveness in specific patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience]. Yu, WJ., Jia, JS., Wang, J., et al.[2022]

Venetoclax is an oral medication with a favorable side-effect profile that shows promise in treating acute myeloid leukemia (AML), particularly for patients with refractory or relapsed cases.

This drug can serve as a bridge to hematopoietic cell transplant for curative treatment and may significantly extend survival for older patients who cannot tolerate more aggressive therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BCL2 Inhibition by Venetoclax: Targeting the Achilles' Heel of the Acute Myeloid Leukemia Stem Cell? Pullarkat, VA., Newman, EM.[2021]

In a study of 82 adult patients with acute myeloid leukemia (AML), 57% were able to start venetoclax treatment safely in an outpatient setting, demonstrating its feasibility outside of the hospital.

The risk of tumor lysis syndrome (TLS) was very low, with only 2.1% of patients experiencing TLS after starting venetoclax, and 98% of patients did not require hospitalization for TLS within the first week of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outpatient initiation of venetoclax in patients with acute myeloid leukemia. Palmer, S., Patel, A., Wang, C., et al.[2023]

References

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

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution. [2023]

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

TP53 or Not TP53: That Is the Question. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Not BCL2 mutation but dominant mutation conversation contributed to acquired venetoclax resistance in acute myeloid leukemia. [2022]

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

Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study. [2021]

6. China pubmed.ncbi.nlm.nih.gov

[Efficacy of venetoclax combined azacitidine in newly diagnosed acute myeloid leukemia unfit for standard chemotherapy: a single center experience]. [2023]

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

Effect of Azithromycin on Venetoclax Pharmacokinetics in Healthy Volunteers: Implications for Dosing Venetoclax with P-gp Inhibitors. [2019]

8. China pubmed.ncbi.nlm.nih.gov

[Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience]. [2022]

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

BCL2 Inhibition by Venetoclax: Targeting the Achilles' Heel of the Acute Myeloid Leukemia Stem Cell? [2021]

10. England pubmed.ncbi.nlm.nih.gov

Outpatient initiation of venetoclax in patients with acute myeloid leukemia. [2023]