Venetoclax + Vyxeos for Leukemia

Overseen By Site Pulblic Contact

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Children's Hospital Medical Center, Cincinnati

Must not be taking: Investigational drugs, Anti-cancer agents

Disqualifiers: APML, CNS status 3, Ph+ leukemia, 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: 3

Duration: 3-4 weeks

21 Participants Needed

Trial Summary

What is the purpose of this trial?

This study evaluates the safety and tolerability of combining venetoclax with Vyxeos (CPX-351) in pediatric and young adult patients with acute leukemia that has come back or not responded to treatment.

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 be on other anti-cancer agents, except for certain exceptions like intrathecal agents or hydroxyurea.

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 prolonging progression-free survival when used alone or in combination with other drugs. It has also been studied in combination with low-dose cytarabine for acute myeloid leukemia, showing a trend towards improved survival. ^{1 2 3 4 5}

Is the combination of Venetoclax and Vyxeos safe for humans?

Venetoclax has been shown to have an acceptable safety profile in patients with chronic lymphocytic leukemia and acute myeloid leukemia, with common side effects including low potassium levels, vomiting, and constipation. The safety of Vyxeos (a combination of daunorubicin and cytarabine) is not specifically detailed in the provided research, but Venetoclax has been studied in combination with other treatments and found to be manageable. ^{1 2 3 6 7}

What makes the drug combination of Venetoclax and Vyxeos unique for treating leukemia?

The combination of Venetoclax and Vyxeos is unique because Venetoclax is a targeted therapy that inhibits a protein helping cancer cells survive, while Vyxeos is a liposomal formulation of two chemotherapy drugs, daunorubicin and cytarabine, designed to improve delivery and effectiveness. This combination aims to enhance treatment outcomes by using both targeted and traditional chemotherapy approaches. ^{1 8 9 10 11}

Research Team

John Perentesis, MD

Principal Investigator

Children's Hospital Medical Center, Cincinnati

Eligibility Criteria

This trial is for young patients aged 1-39 with acute leukemia that's relapsed or hasn't responded to treatment. They should have recovered from previous therapies and not have certain other health conditions like Fanconi Anemia or Wilson's Disease, be pregnant, breastfeeding, or unable to swallow pills.

Inclusion Criteria

I am between 1 and 39 years old.

I've recovered from previous cancer treatments and it's been enough time since my last major therapy.

My leukemia has returned or didn't respond to treatment.

Exclusion Criteria

You have been diagnosed with certain types of leukemia, genetic disorders, or other medical conditions. You are pregnant or breastfeeding, have an uncontrolled infection, have received a high amount of radiation to the chest area, cannot swallow pills, have recently received certain medications or treatments, are currently taking experimental drugs or other anti-cancer medications (with a few exceptions), or are unable to follow the safety monitoring requirements of the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single course of venetoclax and Vyxeos. Venetoclax is given daily with a 3-day ramp-up, and Vyxeos is administered intravenously on Days 1, 3, and 5.

3-4 weeks

3 visits (in-person) for Vyxeos administration

Follow-up

Participants are monitored for safety, tolerability, and response to treatment, including pharmacokinetic analysis and cardiac function assessment.

60 days

Treatment Details

Interventions

• Venetoclax
• Vyxeos

Trial Overview The study tests combining Venetoclax with Vyxeos (CPX-351) in pediatric and young adult patients. It aims to assess the safety of this combination therapy in those whose acute leukemia has returned or is resistant to standard treatments.

Participant Groups

Group I: Venetoclax and Vyxeos combination Experimental Treatment 2 Interventions

Venetoclax will be given orally on Days per the assigned dose level. A single course consisting of 3 doses of Vyxeos and 7-21 doses of venetoclax depending on the assigned dose level will be administered to participants in this study. Vyxeos will be administered by central venous catheter over 90 minutes on Day 1, 3, and 5. Venetoclax is given daily by mouth per assigned dose level.

Venetoclax is already approved in United States, European Union for the following indications:

Approved in United States as Venclexta for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Acute myeloid leukemia (AML)

Approved in European Union as Venclyxto for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Acute myeloid leukemia (AML)

Who Is Running the Clinical Trial?

Children's Hospital Medical Center, Cincinnati

Lead Sponsor

Trials

844

Recruited

6,566,000+

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]

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]

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 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 subgroup of 27 Japanese patients with newly diagnosed acute myeloid leukaemia, venetoclax combined with low-dose cytarabine showed a higher complete remission rate (44.4%) compared to placebo (11.1%), indicating potential efficacy in this population.

Despite the higher remission rate, the median overall survival was similar between the venetoclax (4.7 months) and placebo (8.1 months) groups, suggesting limited survival benefit, which may be influenced by small sample size and baseline health differences among patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus low-dose cytarabine in Japanese patients with untreated acute myeloid leukaemia ineligible for intensive chemotherapy. Yamauchi, T., Yoshida, C., Usuki, K., et al.[2022]

In a study involving 15 Chinese patients with acute myeloid leukemia (AML) who could not tolerate intensive chemotherapy, venetoclax combined with low-dose cytarabine (LDAC) showed a 38% reduction in the risk of death compared to placebo, with a median overall survival of 9.0 months versus 4.1 months for the placebo group.

The treatment resulted in a complete remission rate of 33% among those receiving venetoclax, while no patients in the placebo group achieved remission, indicating that venetoclax with LDAC is an effective option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Venetoclax with low-dose cytarabine for patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy: results from the Chinese cohort of a phase three randomized placebo-controlled trial]. Hu, Y., Jin, J., Zhang, Y., et al.[2021]

In a study of 211 patients with untreated acute myeloid leukemia (AML) who were not eligible for intensive chemotherapy, venetoclax combined with low-dose cytarabine (LDAC) showed a median overall survival of 8.4 months compared to 4.1 months for the placebo group, indicating a 30% reduction in the risk of death.

The treatment with venetoclax + LDAC also resulted in significantly higher complete response rates (48.3% vs. 13.2%) and improved event-free survival (4.9 months vs. 2.1 months), while maintaining a similar safety profile to the placebo group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

6-month follow-up of VIALE-C demonstrates improved and durable efficacy in patients with untreated AML ineligible for intensive chemotherapy (141/150). Wei, AH., Panayiotidis, P., Montesinos, P., et al.[2022]

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]

In a Phase 3 clinical trial, venetoclax combined with low-dose cytarabine showed improved response rates and overall survival in patients with newly diagnosed acute myeloid leukemia who couldn't undergo intensive chemotherapy, supporting its efficacy.

In an expanded access study in Japan involving 14 patients, the safety profile of venetoclax was consistent with previous findings, with neutropenia being the most common serious side effect, indicating that careful management of adverse events is crucial in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy: an expanded access study in Japan. Asada, N., Ando, J., Takada, S., et al.[2023]

In a study comparing treatment regimens for relapsed/refractory acute myeloid leukemia (R/R AML), the venetoclax (VEN) combination therapy showed a comparable overall response rate (59.3%) to intensive chemotherapy (IC) (44.0%), suggesting it is an effective alternative for patients who have failed previous treatments.

Patients receiving the VEN combination had a significantly higher percentage of successful stem cell transplants at blast clearance (86.5% vs. 62.3% for IC), indicating better disease control and potentially lower treatment-related mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective comparison of salvage intensive chemotherapy versus venetoclax-combined regimen in patients with relapsed/refractory acute myeloid leukemia (AML). Park, S., Kwag, D., Kim, TY., 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]

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: First Global Approval. [2018]

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

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

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

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

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

Venetoclax plus low-dose cytarabine in Japanese patients with untreated acute myeloid leukaemia ineligible for intensive chemotherapy. [2022]

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

[Venetoclax with low-dose cytarabine for patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy: results from the Chinese cohort of a phase three randomized placebo-controlled trial]. [2021]

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

6-month follow-up of VIALE-C demonstrates improved and durable efficacy in patients with untreated AML ineligible for intensive chemotherapy (141/150). [2022]

8. England pubmed.ncbi.nlm.nih.gov

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

9. England pubmed.ncbi.nlm.nih.gov

Venetoclax plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy: an expanded access study in Japan. [2023]

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

A retrospective comparison of salvage intensive chemotherapy versus venetoclax-combined regimen in patients with relapsed/refractory acute myeloid leukemia (AML). [2022]

11. England pubmed.ncbi.nlm.nih.gov

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