Combination Therapy for Acute Lymphoblastic Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: OHSU Knight Cancer Institute

Must not be taking: Investigational agents

Disqualifiers: Chronic myelogenous leukemia, Serious infections, Uncontrolled cardiac illness, others

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

Compensation: Varies

Number of Visits: 12

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of drugs to treat individuals with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), a type of blood cancer. The study tests the effectiveness of a medication mix, including venetoclax (a targeted therapy), dasatinib (also known as Sprycel), prednisone, rituximab, and blinatumomab, in stopping cancer growth. It seeks participants who have been newly diagnosed or have relapsed Ph+ ALL and have not been treated with dasatinib before. Those with this type of leukemia who have not previously taken dasatinib may find this trial suitable. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering a unique opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial requires that participants stop taking certain medications before starting. Specifically, if you are taking strong or moderate CYP3A inhibitors, inducers, P-glycoprotein inhibitors, or warfarin, you must wait at least 3 half-lives of the medication before starting the trial. Additionally, if you have recently received a live vaccine, you must wait at least 4 weeks before starting.

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

Research has shown that each component of the treatment—venetoclax, dasatinib, prednisone, and rituximab—has been studied for safety in other contexts. Venetoclax is generally well-tolerated but can sometimes cause low blood cell counts. Dasatinib has been used successfully to treat leukemia, though it may lead to side effects like fluid retention or low blood cell counts. Prednisone is a common anti-inflammatory drug, but long-term use can result in high blood sugar or bone thinning. Rituximab is widely used in cancer treatments and can sometimes cause reactions during infusion.

As this trial is in its early stages, the safety of using these drugs together remains under study. However, the safety of each drug individually suggests that the combination might be manageable for many patients. Discussing potential risks with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination therapy for acute lymphoblastic leukemia (ALL) because it harnesses several unique mechanisms to target the cancer. Unlike standard treatments like chemotherapy, this combination includes dasatinib, which specifically targets cancer cell growth by inhibiting certain proteins, and venetoclax, which induces cancer cell death by blocking the BCL-2 protein. Additionally, rituximab is an antibody that targets specific cancer cells, potentially enhancing the immune system's ability to fight the disease. This multi-faceted approach could offer a more effective and potentially faster response compared to traditional treatments, providing new hope for patients with ALL.

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

Research has shown that using dasatinib and prednisone together is highly effective for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), achieving a complete remission rate of 92%. In this trial, participants will receive a combination of treatments, including dasatinib, prednisone, venetoclax, and rituximab. Venetoclax blocks a protein called Bcl-2, which cancer cells need to survive, potentially stopping their growth. Rituximab is a special protein that can prevent cancer cells from growing and spreading. This combination targets different parts of the cancer cells, which may increase the chances of success. These findings suggest that this combination therapy could be promising for individuals newly diagnosed with or experiencing a return of this type of leukemia. ^{1 2 3 6 7}

Who Is on the Research Team?

Jessica T. Leonard

Principal Investigator

OHSU Knight Cancer Institute

Are You a Good Fit for This Trial?

Adults with newly diagnosed or relapsed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) can join this trial. They must have good kidney function, no prior dasatinib treatment for relapsed cases, and be able to take oral medication. Pregnant or breastfeeding individuals, those with certain heart conditions, recent other cancer treatments, or active serious infections cannot participate.

Inclusion Criteria

Alanine aminotransferase (ALT) < 2.5 x ULN

Aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN)

Unless considered due to leukemic organ involvement. Note: subjects with Gilbert's Syndrome may have a bilirubin > 1.5 x ULN per discussion between the investigator and AbbVie medical monitor

Exclusion Criteria

I haven't taken any experimental cancer treatments recently.

I am not pregnant or breastfeeding.

You have had allergic reactions to drugs similar to dasatinib or other drugs being used in the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Phase Cycle 1

Patients receive prednisone, dasatinib, venetoclax, rituximab, and methotrexate as part of the induction therapy

4 weeks

Multiple visits for drug administration and monitoring

Induction Phase Cycles 2-3

Continuation of induction therapy with dasatinib, venetoclax, rituximab, and methotrexate

8 weeks

Multiple visits for drug administration and monitoring

Consolidation Cycles 4-7

Patients receive blinatumomab, dasatinib, venetoclax, and methotrexate as part of consolidation therapy

24 weeks

Regular visits for drug administration and monitoring

Maintenance Therapy Cycles 8+

Continuation of maintenance therapy with dasatinib, venetoclax, and methotrexate

20 weeks

Regular visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Follow-up visits every 12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Dasatinib
• Prednisone
• Rituximab
• Venetoclax

Trial Overview The trial is testing a combination of venetoclax with dasatinib, prednisone, and rituximab in patients. Venetoclax targets proteins that cancer cells need to survive; dasatinib blocks enzymes for cell growth; prednisone lowers immune response; rituximab may stop cancer spread.

How Is the Trial Designed?

Group I: Treatment (prednisone, dasatinib, venetoclax, rituximab) Experimental Treatment 9 Interventions

See detailed description

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

Approved in United States as Sprycel for:

• Chronic myeloid leukemia (CML)
• Acute lymphoblastic leukemia (ALL)

Approved in European Union as Sprycel for:

• Chronic myeloid leukemia (CML)
• Acute lymphoblastic leukemia (ALL)

Approved in Canada as Sprycel for:

• Chronic myeloid leukemia (CML)
• Acute lymphoblastic leukemia (ALL)

Who Is Running the Clinical Trial?

OHSU Knight Cancer Institute

Lead Sponsor

Trials

239

Recruited

2,089,000+

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

Oregon Health and Science University

Collaborator

Trials

1,024

Recruited

7,420,000+

Published Research Related to This Trial

The combination of tyrosine kinase inhibitors (TKIs) like dasatinib and ponatinib with the BCL-2 inhibitor venetoclax shows strong synergy in reducing cell viability and inducing apoptosis in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) cells, suggesting a promising new treatment strategy.

In tests with primary Ph(+)ALL patient samples in mice, the dasatinib-venetoclax combination was well-tolerated and demonstrated superior effectiveness compared to either drug alone, indicating its potential to enhance treatment outcomes for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting BCL-2 and ABL/LYN in Philadelphia chromosome-positive acute lymphoblastic leukemia. Leonard, JT., Rowley, JS., Eide, CA., et al.[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]

In a study involving 272 patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), higher concentrations of venetoclax led to a quicker reduction in lymphocyte counts and tumor size, resulting in a high objective response rate (ORR) of 84.8% at a daily dose of 400 mg.

Importantly, increasing the dose of venetoclax did not correlate with a higher risk of serious adverse events like neutropenia or infections, suggesting that the 400 mg daily regimen is both effective and safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. Freise, KJ., Jones, AK., Eckert, D., et al.[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]

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]

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. clinicaltrials.gov clinicaltrials.gov/study/NCT04872790

Study Details | NCT04872790 | Venetoclax, Dasatinib, ... This phase Ib trial studies the effects of venetoclax in combination with dasatinib, prednisone, rituximab and blinatumomab in treating patients with ...

2. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/284915

Venetoclax, Dasatinib, Prednisone, Rituximab and ... Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Dasatinib may stop the growth of cancer cells by ...

3. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04872790/

Clinical Trial: NCT04872790 Giving venetoclax in combination with dasatinib, prednisone, and rituximab may help treat patients with newly diagnosed or relapsed Philadelphia ...

4. clinicaltrial.be clinicaltrial.be/fr/details/44362?per_page=100&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

Venetoclax, Dasatinib, Prednisone, Rituximab and Blinatum... II. Evaluate the safety of venetoclax in combination with dasatinib by assessing the frequency, type, and severity of adverse events. SECONDARY ...

5. tandfonline.com tandfonline.com/doi/full/10.1080/16078454.2024.2335856

A review of immunotargeted therapy for Philadelphia ... The induction therapy with Dasatinib and Prednisone achieved a CR in 92% of patients. The median follow-up was 2.7 years, and the 3-year OS and ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04872790?term=medi%20538&viewType=Table&rank=5&checkSpell=

Study Details | Venetoclax, Dasatinib, Prednisone, ... A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8997772/

Treatment of Philadelphia Chromosome-Positive Acute ... In three phase 2 studies in Ph+ ALL, CR rates with dasatinib or nilotinib in combination with intensive chemotherapy were 96%, 91% and 100%, respectively [41,42 ...