Venetoclax Combination Therapy for Leukemia

Recruiting in Palo Alto (17 mi)

Overseen by Ibrahim Aldoss, MD

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: City of Hope Medical Center

Must not be taking: CYP3A4 inducers, Live vaccines

Disqualifiers: T cell ALL, Active infection, Others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This phase I trial tests the safety, side effects, and best dose of venetoclax in combination with a pediatric-inspired chemotherapy regimen known as C10403 in treating patients with newly diagnosed B cell acute lymphoblastic leukemia. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. The C10403 regimen is composed of the chemotherapy drugs cytarabine, cyclophosphamide, daunorubicin, mercaptopurine, pegaspargase, vincristine, and methotrexate, all which work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It also consists of prednisone, which is an anti-inflammatory drug that lowers the body's immune response and is used with other drugs in the treatment of some types of some types of cancer. This study may help researchers learn if adding venetoclax to the pediatric-inspired C10403 regimen can be tolerated and help treat older patients.

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.

What data supports the effectiveness of the drug Venetoclax for leukemia?

Venetoclax has shown effectiveness in treating chronic lymphocytic leukemia (CLL), achieving high response rates and longer progression-free survival when used in combination with other drugs like obinutuzumab and rituximab. It is also being developed for use in acute myeloid leukemia and other blood cancers, indicating its potential effectiveness in various types of leukemia. ^{1 2 3 4 5}

What safety data exists for Venetoclax combination therapy in humans?

Venetoclax, also known as Venclexta, has been shown to have an acceptable safety profile in patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Common side effects include myelosuppression (a decrease in bone marrow activity) and neutropenia (low levels of a type of white blood cell), which can be managed with supportive care and dose adjustments. No new safety concerns were identified in children and adolescents with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL). ^{1 2 5 6 7}

What makes Venetoclax combination therapy unique for treating leukemia?

Venetoclax is unique because it specifically targets and inhibits a protein called BCL-2, which helps cancer cells survive, making it different from traditional chemotherapy that targets rapidly dividing cells. This targeted approach can potentially lead to fewer side effects and improved effectiveness in treating leukemia. ^{8 9 10 11 12}

Research Team

Ibrahim Aldoss, MD

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

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

My leukemia involves the bone marrow.

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.

Trial Timeline

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

Treatment Details

Interventions

• C10403 (Chemotherapy)
• Venetoclax (Bcl-2 Inhibitor)

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.

Participant Groups

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+

Robert Stone

City of Hope Medical Center

Chief Executive Officer since 2014

Juris Doctorate from the University of Chicago, Bachelor's degree in Political Science from the University of Redlands

Sumanta (Monty) Pal

City of Hope Medical Center

Chief Medical Officer since 2023

MD

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

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]

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 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 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]

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]

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]

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]

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]

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 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]

References

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

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

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

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

3. France pubmed.ncbi.nlm.nih.gov

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

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

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

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

Venetoclax: First Global Approval. [2018]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Venetoclax for Children and Adolescents with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma. [2022]

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

Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma With Venetoclax: A Single-Center Evaluation of Off-Label Use. [2020]

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

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

9. Greece pubmed.ncbi.nlm.nih.gov

Phase II trial of irinotecan and raltitrexed in chemotherapy-naive advanced colorectal cancer. [2018]

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

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

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

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

12. England pubmed.ncbi.nlm.nih.gov

Toxicity study of cytosine arabinoside and methotrexate in the maintenance therapy of childhood leukemia. A Southwest Oncology Group study. [2019]