Venetoclax Combination Therapy for Leukemia

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: CYP3A4 inducers, Live vaccines

Disqualifiers: T cell ALL, Active infection, Others

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

Compensation: Varies

Number of Visits: 3

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the safety and optimal dose of a new combination treatment for individuals with B-cell acute lymphoblastic leukemia (ALL). The treatment combines venetoclax, a targeted therapy that may prevent cancer cells from surviving, with several chemotherapy drugs that work together to kill cancer cells or inhibit their growth. This study targets those recently diagnosed with B-cell ALL who have a specific level of leukemia cells in their bone marrow. Participants should not have received prior leukemia treatment, except for specific medications to lower white blood cell counts. The goal is to determine if this combination is tolerable and effective for older patients. 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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take strong or moderate CYP3A4 inducers within 14 days before starting the trial. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

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

Research shows that venetoclax, combined with the C10403 chemotherapy plan, is under evaluation for safety and effectiveness in treating B cell acute lymphoblastic leukemia. Venetoclax has been studied in other diseases like chronic lymphocytic leukemia. In those studies, it helped 84% of patients with relapsed or hard-to-treat leukemia, suggesting its potential effectiveness. However, since this trial is in its early stages, the focus is on determining the safest dose and monitoring side effects.

Earlier studies found venetoclax generally well-tolerated, though some patients experienced side effects like low blood cell counts, infections, and nausea. It's important to note that the C10403 plan includes several chemotherapy drugs, each with its own possible side effects, such as tiredness, hair loss, and a higher chance of infection.

As a Phase 1 trial, researchers primarily assess the treatment's safety and patient tolerance. This trial is a crucial step toward understanding if this combination can be safely used to treat leukemia. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Venetoclax combination therapy is unique because it targets a specific protein called BCL-2, which helps cancer cells survive, making it different from the standard chemotherapy options for leukemia. Researchers are excited about this treatment because it can work in synergy with other drugs, potentially leading to more effective results. Additionally, venetoclax may offer a targeted approach, which could mean fewer side effects compared to traditional chemotherapy.

What evidence suggests that this venetoclax combination therapy could be effective for leukemia?

Research has shown that venetoclax, one of the treatments in this trial, may help treat leukemia by targeting a protein called Bcl-2, which aids cancer cell survival. In patients with chronic lymphocytic leukemia (CLL), venetoclax has improved survival rates. The C10403 chemotherapy treatment, also part of this trial, is used for young adults with acute lymphoblastic leukemia (ALL) and has demonstrated good results in past studies. This trial will explore the combination of venetoclax with the C10403 treatment, potentially enhancing therapy effectiveness by employing different methods to inhibit cancer cell growth. Although data on this combination for ALL is limited, the success of each treatment in similar contexts is promising. ^{1 2 4 6 7}

Who Is on the Research Team?

Ibrahim Aldoss, MD

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

Adults aged 18-54 with newly diagnosed B-cell acute lymphoblastic leukemia (ALL) can join this trial. They must be in good physical condition, not pregnant or breastfeeding, and willing to use non-hormonal birth control. People with certain heart conditions, other cancers, uncontrolled infections or those who have taken strong medications that affect liver enzymes recently cannot participate.

Inclusion Criteria

My leukemia involves the bone marrow.

Alanine aminotransferase (ALT) =< 2.5 x ULN (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)

Note: Echocardiogram to be performed within 42 days prior to day 1 of protocol therapy

Exclusion Criteria

I do not have any other active cancer.

I have not received any live vaccines recently.

You have eaten grapefruit, grapefruit products, Seville oranges, or star fruit within three days before starting the study drug.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive venetoclax and a combination of chemotherapy drugs including cytarabine, prednisone, vincristine, daunorubicin, pegaspargase, and methotrexate

4 weeks

Weekly visits for drug administration

Extended Induction

Patients continue to receive venetoclax and chemotherapy drugs if they have stable disease or partial response after initial induction

2 weeks

Consolidation

Patients receive venetoclax and a combination of chemotherapy drugs including cyclophosphamide, cytarabine, mercaptopurine, vincristine, pegaspargase, and methotrexate

12 weeks

Bi-weekly visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 1 year

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• C10403
• Venetoclax

Trial Overview The trial is testing the safety and optimal dose of a drug called Venetoclax when added to a pediatric-inspired chemotherapy regimen (C10403). This combination targets cancer cell growth by blocking essential proteins and using various chemo drugs to kill or stop cancer cells from dividing.

How Is the Trial Designed?

Group I: Treatment (venetoclax, C10403 regimen) Experimental Treatment 9 Interventions

See Detailed Description

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase II trial involving 48 patients with untreated advanced colorectal cancer, the combination of irinotecan and raltitrexed showed an overall response rate of 27%, with a median duration of response of 10 months.

Despite its activity, the treatment was associated with significant side effects, including grade III-IV diarrhea and neutropenia, leading to a dose reduction and highlighting the need for careful patient selection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of irinotecan and raltitrexed in chemotherapy-naive advanced colorectal cancer. Chiara, S., Nobile, MT., Tomasello, L., et al.[2018]

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]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

A new regimen combining doxorubicin and paclitaxel has been developed that is both well-tolerated and highly effective, utilizing bolus administration of doxorubicin and a 3-hour infusion of paclitaxel, overcoming previous schedule-dependent toxicity issues.

Paclitaxel has shown promising results when combined with fluorouracil and folinic acid in patients with extensive prior chemotherapy, and adding mitoxantrone to this combination appears to enhance its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel-based combination chemotherapy for breast cancer. Hortobagyi, GN.[2015]

Venetoclax is an effective oral treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), showing durable responses and a manageable safety profile in clinical trials, including patients with poor prognostic factors.

In combination with rituximab, venetoclax significantly improved progression-free survival and achieved undetectable minimal residual disease compared to bendamustine plus rituximab, with benefits lasting for at least 36 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. Scott, LJ.[2020]

In a study of children with acute lymphoblastic leukemia, the L-10 protocol, which includes both methotrexate (MTX) and cytosine arabinoside (Ara-C), showed significantly better prevention of central nervous system (CNS) leukemia compared to the L-2 protocol, with only one case of CNS disease among 31 children.

For treating established CNS leukemia, a combination of intralumbar MTX and Ara-C, along with CNS irradiation, resulted in three out of five children remaining in remission for extended periods (up to 39 months), indicating the potential effectiveness of this treatment strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antimetaboliths in the prophylaxis and treatment of central nervous system leukemia. Haghbin, M.[2013]

In a study of 18 pediatric and young adult patients with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL), venetoclax demonstrated a complete remission rate of 61%, indicating its potential efficacy in this population.

No new safety concerns were identified with venetoclax, with myelosuppression being the most common side effect, and no deaths occurred within 30 days of starting treatment, suggesting it is a safe option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax for Children and Adolescents with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma. Gibson, A., Trabal, A., McCall, D., et al.[2022]

Combination therapies using paclitaxel with other antineoplastic agents show promise for treating metastatic breast cancer, but optimal dosing and scheduling remain unclear, which complicates their development.

Unexpected toxic interactions between paclitaxel and other drugs have been observed, highlighting the need for careful evaluation of combination therapies in clinical trials before they are used outside of research settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel combination therapy in the treatment of metastatic breast cancer: a review. Holmes, FA.[2015]

Venetoclax is an oral medication that selectively inhibits the BCL-2 protein, which helps cancer cells survive, thereby restoring the ability of these malignant cells to undergo programmed cell death (apoptosis).

It has been approved in the USA for treating chronic lymphocytic leukaemia (CLL) in patients with a specific genetic marker (17p deletion) who have already undergone at least one prior therapy, and it is being studied for various other blood cancers and conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: First Global Approval. Deeks, ED.[2018]

In a retrospective study of 34 adult patients with various types of non-Hodgkin lymphoma treated off-label with venetoclax, the overall response rate was 26%, indicating modest efficacy in heavily pretreated patients.

Adverse events occurred in 76% of patients, with higher incidence than reported in clinical trials, highlighting the need for further investigation into the safety and dosing strategies of venetoclax in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma With Venetoclax: A Single-Center Evaluation of Off-Label Use. Hughes, ME., Landsburg, DJ., Rubin, DJ., et al.[2020]

In a study involving 29 patients with acute lymphocytic leukemia, the combination of cytosine arabinoside (Ara-C) and methotrexate (MTX) was tested for safety, revealing that gastrointestinal toxicity, particularly recurrent vomiting, limited the feasibility of this treatment regimen.

The study found that while Ara-C and MTX could be administered at higher doses sequentially (90 mg/m2 and 150 mg/m2) compared to simultaneous dosing (60 mg/m2 and 90 mg/m2), the gastrointestinal side effects made the treatment unsuitable for long-term maintenance therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity study of cytosine arabinoside and methotrexate in the maintenance therapy of childhood leukemia. A Southwest Oncology Group study. Nitschke, R., Komp, DM., Morgan, SK., et al.[2019]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5026291/

The potential of venetoclax (ABT-199) in chronic lymphocytic ... The post-progression survival for patients with progressive CLL was 69% at 1 year, and about 50% for those with RT.

2. venclextahcp.com venclextahcp.com/cll/efficacy/ven-g/data.html

VENCLEXTA efficacy results: 6-year overall survival 1 In patients with CLL, Grade 3 or 4 neutropenia developed in 63% to 64% of patients and Grade 4 neutropenia developed in 31% to 33% of patients when treated with ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6245970/

Genetics and prognosis of ALL in children vs adults - PMC Favorable outcomes for older adolescents and young adults with acute lymphoblastic leukemia: early results of U.S. Intergroup trial C10403. Blood. 2014;124 ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02141282

Study Details | NCT02141282 | A Phase 2 Open-Label ... This was an open-label, non-randomized, multicenter, Phase 2 study evaluating the efficacy and safety of ABT-199 in 127 participants with relapsed or ...

5. dana-farber.org dana-farber.org/clinical-trials/13-463

A Phase 2 Open-Label Study of the Efficacy of ABT-199 ... This was an open-label, multicenter, global study to determine the efficacy of ABT-199 (Venetoclax) monotherapy in participants with relapsed/refractory ...

6. abbvieclinicaltrials.com abbvieclinicaltrials.com/study/?id=M14-032

A Phase 2 Open-Label Study of the Efficacy and Safety ... This was an open-label, non-randomized, multicenter, Phase 2 study evaluating the efficacy and safety of ABT-199 in 127 participants with relapsed or refractory ...

7. jhoonline.biomedcentral.com jhoonline.biomedcentral.com/articles/10.1186/s13045-015-0224-3

ABT-199 (venetoclax) and BCL-2 inhibitors in clinical ... Preliminary data from a phase I trial of ABT-199 showed an overall response rate (ORR) of 84 % in 56 patients with relapsed/refractory CLL [81] ...