Venetoclax + Chemotherapy for Acute Lymphoblastic Leukemia

Overseen By Elias Jabbour, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Philadelphia chromosome-positive ALL, Active infection, CNS leukemia, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 8 cycles (each cycle is 28 days)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of venetoclax paired with low-intensity chemotherapy for treating certain types of acute lymphoblastic leukemia (ALL) that have not responded to treatment or have returned. Venetoclax may help by blocking enzymes that enable cancer cell growth. The trial combines venetoclax with chemotherapy drugs such as cyclophosphamide, dexamethasone, methotrexate, cytarabine, prednisone, and vincristine to determine if this combination is more effective against the cancer. Suitable participants have B- or T-cell ALL that is either untreated or has not responded to treatment and cannot undergo intensive chemotherapy. As a Phase 1/Phase 2 trial, it aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but you cannot take certain drugs that affect liver enzymes or blood clotting within 7 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?

Previous research has shown that venetoclax is generally well-tolerated by patients with acute lymphoblastic leukemia (ALL). Studies indicate that combining venetoclax with low-intensity chemotherapy can enhance treatment effectiveness without causing excessive additional side effects.

Earlier studies reported common side effects such as low blood cell counts, nausea, and diarrhea. However, most patients managed these side effects well. Venetoclax already has FDA approval for treating some types of leukemia, indicating a certain level of confidence in its safety for humans.

The chemotherapy drugs used in this trial—vincristine, cyclophosphamide, dexamethasone, methotrexate, cytarabine, prednisone, and rituximab—are well-established in cancer treatment. Their side effects, including fatigue, low blood cell counts, and infection risk, are well-documented, and doctors are experienced in managing these effects.

Overall, while side effects exist, venetoclax and the chemotherapy drugs in this trial have been used in many patients before and are considered safe enough for further testing. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of venetoclax with chemotherapy for treating acute lymphoblastic leukemia because it introduces a novel mechanism of action. Unlike traditional chemotherapy that mainly targets rapidly dividing cells, venetoclax specifically inhibits the BCL-2 protein, which helps cancer cells survive. By disrupting this protein, venetoclax makes leukemia cells more vulnerable to the effects of chemotherapy. This targeted approach has the potential to enhance treatment effectiveness and may lead to better outcomes for patients battling this aggressive form of leukemia.

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

Research has shown that venetoclax, one of the treatments in this trial, shows promise when combined with mild chemotherapy for treating certain leukemias, such as acute lymphoblastic leukemia (ALL). One study found that patients newly diagnosed with ALL lived without the disease for an average of 54.6 months when treated with this combination. Venetoclax blocks proteins that help cancer cells grow, effectively reducing tumor cells. Early data also showed that venetoclax had a strong response rate of 84% in patients with relapsed or hard-to-treat chronic lymphocytic leukemia (CLL), another type of blood cancer. These findings suggest that venetoclax, especially when combined with other chemotherapy drugs, could be a good option for difficult cases of ALL. ^{1 2 6 7 8}

Who Is on the Research Team?

Elias Jabbour, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with B- or T-cell acute lymphoblastic leukemia that's come back or didn't respond to treatment. They must have acceptable liver and kidney function, not be pregnant, agree to use birth control, and can't have HIV, hepatitis B/C, a weak heart, prior venetoclax treatment, other serious cancers or bleeding disorders.

Inclusion Criteria

Aspartate aminotransferase (AST) =< 3 x ULN, unless due to disease involvement of the liver or hemolysis, in which case an AST =< 10 x ULN is acceptable

Alanine aminotransferase (ALT) =< 3 x ULN, unless due to disease involvement of the liver or hemolysis, in which case an ALT =< 10 x ULN is acceptable

I am a woman who can have children and have a recent negative pregnancy test.

Exclusion Criteria

I have a serious infection that isn't getting better with antibiotics.

I have leukemia that is either Philadelphia chromosome-positive ALL or Burkitt.

I have not taken strong medication that affects liver enzymes within the last week.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive venetoclax in combination with low-intensity chemotherapy, including vincristine, cyclophosphamide, dexamethasone, methotrexate, and cytarabine, across multiple cycles

8 cycles (each cycle is 28 days)

Multiple visits per cycle for drug administration

Maintenance Therapy

Participants may receive prednisone, vincristine, and venetoclax for maintenance therapy, with adjustments for T-cell ALL patients

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

30 days initially, then every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide, Dexamethasone, Methotrexate, Cytarabine, Prednisone, Vincristine
• Rituximab
• Venetoclax

Trial Overview The study tests the effectiveness of a drug called Venetoclax combined with low-intensity chemotherapy (including drugs like vincristine and methotrexate) on patients with relapsed/refractory acute lymphoblastic leukemia. It aims to find the best dose while assessing how well it stops tumor growth.

How Is the Trial Designed?

Group I: Experimental (venetoclax, vincristine, cyclophosphamide) Experimental Treatment 10 Interventions

See Detailed Description.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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]

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]

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]

Venetoclax is an effective oral medication for treating chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), showing significant efficacy when combined with other therapies like obinutuzumab and azacitidine.

While venetoclax is associated with adverse events such as neutropenia and gastrointestinal disorders, the article emphasizes the importance of managing these side effects to ensure patient safety during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Practical Management of the Venetoclax-Treated Patient in Chronic Lymphocytic Leukemia and Acute Myeloid Leukemia. Waggoner, M., Katsetos, J., Thomas, E., 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]

In a study of 15 patients with relapsed or refractory early T-cell precursor acute lymphoblastic leukemia (R/R ETP-ALL), Venetoclax combined with multidrug chemotherapy resulted in a 67.7% overall response rate and a 60% complete response rate, indicating significant efficacy.

The treatment was found to be safe, with manageable hematological toxicities and no severe adverse reactions, suggesting that Venetoclax combined with chemotherapy could be a promising option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical efficacy and safety of venetoclax combined with multidrug chemotherapy in the treatment of 15 patients with relapsed or refractory early T-cell precursor acute lymphoblastic leukemia]. Kong, JY., Zong, LH., Pu, Y., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6499443/

Evaluating venetoclax and its potential in treatment-naïve ... Results were dramatic–venetoclax plus rituximab achieved an 84.9% progression-free survival rate at 2 years, vs the bendamustine plus rituximab arm, which ...

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

Venetoclax plus low-intensity chemotherapy for adults with ... With a median follow-up of 60 months, median disease-free survival (DFS) for patients with newly diagnosed ALL was 54.6 months (95% confidence ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4654800/

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] (Table 1). At a ...

4. nature.com nature.com/articles/s41420-022-01093-3

Effective tumor cell abrogation via Venetoclax-mediated ... We herein prove that VEN is a potent option to suppress tumor cells in KMT2A-rearranged B-ALL in vitro and in vivo.

5. aacrjournals.org aacrjournals.org/cancerdiscovery/article/6/10/1106/5537/Efficacy-and-Biological-Correlates-of-Response-in

Efficacy and Biological Correlates of Response in a Phase II ... A and B, the median leukemia-free survival was 2.3 months (range, 1.0–2.7), and the median overall survival was 4.7 months (range, 2.3–6.0), in patients with ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02203773

NCT02203773 | Study of ABT-199 (GDC-0199) in ... This is a Phase 1b, open-label, non-randomized, multicenter study to evaluate the safety and pharmacokinetics of orally administered venetoclax (ABT-199) ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118474733

Safety and Efficacy of a Combination of Venetoclax (GDC ... Safety and Efficacy of a Combination of Venetoclax (GDC-0199/ABT-199) ... Lymphocytic Leukemia - Results from a Phase 1b Study (GP28331) Ian W. Flinn ...

8. abbvie.com abbvie.com/content/dam/abbvie-dotcom/us/clinical-trials/venetoclax_M16-106.pdf

Venetoclax (ABT-199) M16-106 Clinical Study Report Based on these results, subjects in the safety expansion cohort received a 21-day of 28-day dosing schedule of venetoclax (400 mg adult equivalent dose) with 50 ...