Triple Drug Therapy for Acute Lymphoblastic Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: PPIs, H2 antagonists

Disqualifiers: Ph-negative ALL, HIV, Hepatitis, others

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

Compensation: Varies

Number of Visits: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of three oral drugs to assess their safety in treating acute lymphoblastic leukemia (ALL). The drugs under study are dexamethasone (a corticosteroid), dasatinib (known as Sprycel, a cancer drug), and ruxolitinib (known as Jakafi, a cancer drug). Although these drugs have been used in people before, they have not been combined in this specific way. The trial aims to determine the right dose of ruxolitinib that can be safely combined with the other two drugs. This trial may suit individuals with Philadelphia chromosome-positive ALL (a specific genetic marker) who have not previously received dasatinib. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering a chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial requires a 'washout' period (time without taking certain medications) of at least 14 days from the last previous cytotoxic chemotherapy before starting treatment. However, no 'washout' period is needed for previous bcr-abl TKI therapy given with the mentioned chemotherapy cycles. Hydroxyurea and corticosteroids can be used as bridge therapy up until 24 hours before starting the trial treatment.

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

Research shows that the three drugs in the trial—ruxolitinib, dasatinib, and dexamethasone—have been studied in people before, each with different safety results.

Several studies have tested ruxolitinib, and it is generally well-tolerated. However, in rare cases, serious side effects like multi-organ failure occurred at higher doses. Most patients did not experience severe side effects, but caution is important as doses increase.

Dasatinib is usually well-tolerated when combined with other treatments. Serious side effects like infections have been reported in some cases, but these are uncommon. Overall, the drug has been effective and manageable for many patients.

Dexamethasone is commonly used to treat acute lymphoblastic leukemia and is favored for its ability to reduce relapses. However, it can increase the risk of treatment-related death compared to some other options.

The trial is in its early stage, focusing on finding the safest dose of these drugs when used together. This stage is crucial for understanding how the combination affects patients and how to minimize any risks. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment because it introduces Ruxolitinib, a JAK inhibitor, into the mix with Dasatinib and Dexamethasone for treating Acute Lymphoblastic Leukemia (ALL). Unlike traditional chemotherapy options that primarily target rapidly dividing cells, Ruxolitinib works by specifically inhibiting pathways that drive cancer cell growth, potentially leading to more targeted and effective suppression of the leukemia. Additionally, this combination therapy is designed to enhance remission rates and offer a more personalized treatment approach, which could improve outcomes for patients with ALL. This novel approach aims to integrate targeted therapy with existing treatments to improve efficacy and reduce side effects.

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

In this trial, participants will receive a combination of Dasatinib, Dexamethasone, and Ruxolitinib to treat acute lymphoblastic leukemia (ALL). Research has shown that each of these drugs could be effective against ALL. Dasatinib has proven effective for treating Philadelphia chromosome-positive (Ph+) ALL, with high survival rates. Dexamethasone has reduced the chances of cancer recurrence. Ruxolitinib, which blocks certain signals in leukemia cells, has shown promise, especially for Ph-like ALL cases. Together, these drugs might offer a strong approach to fighting leukemia by attacking the cancer in different ways. ^{6 7 8 9 10}

Who Is on the Research Team?

Jae Park, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults aged 40 or older with newly diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) who haven't been treated before, except for specific prior therapies. Participants must be able to consent and have acceptable organ function. It's not open to those with HIV, Hepatitis B/C, certain heart conditions, other active cancers (with exceptions), uncontrolled infections, or severe pre-existing GI disorders.

Inclusion Criteria

Patient able to give informed consent

I am 18 or older with a specific type of leukemia (Ph+ ALL, Ph-like ALL, or CML in crisis).

My cancer is confirmed to be Philadelphia chromosome positive.

Exclusion Criteria

I cannot tolerate certain medications for virus and pneumonia prevention during my initial cancer treatment.

I cannot take certain stomach medicines due to severe stomach issues or reactions.

My leukemia is identified as Mature B-cell (Burkitt's).

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Steroid Pre-Phase

Prednisone 10 mg/m2/day uptitrated to 60/mg/m2/day oral over seven days

1 week

1 visit (in-person)

Remission Induction

Dasatinib, dexamethasone, and ruxolitinib are administered to find the right dose combination

12 weeks

Multiple visits (in-person)

Post-Remission Induction Therapy

Allogeneic HSCT or consolidation therapy as determined by the treating physician

Variable

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Dasatinib
• Dexamethasone
• Ruxolitinib

Trial Overview

The study tests a new drug combo: Ruxolitinib added to Dasatinib and Dexamethasone in Ph+ ALL patients. Starting with low doses of Ruxolitinib, the amount will increase gradually if no severe side effects occur. This helps find the safest effective dose for future research.

How Is the Trial Designed?

Group I: Adding Ruxolitinib to Combination of Dasatinib + Dexamethasone Experimental Treatment 3 Interventions

Steroid Pre-Phase (Days -6 to 0) Prednisone 10 mg/m2/day uptitrated to 60/mg/m2/day oral over seven days (capped at 120 mg/day). Remission Induction (Days 1 to 84) Dasatinib 140 mg oral once daily. Days 1-84. Dexamethasone 10 mg/m2/day oral (capped at 20 mg/day). Days 1-24. Dexamethasone oral taper 10 mg/m2/day (capped at 20 mg/day) to off. Taper days 25-32. Off day 33. Ruxolitinib phase I cohort dose oral. Days 1-84. Delivered BID. Delivered per the phase I dose cohort. Methotrexate (MTX) 12 mg Intrathecal (IT) for 4 doses on days 22, 43, 64, 85; +/- 3 days. Post-Remission Induction Therapy (Starting Day 85) Allogeneic HSCT, at the discretion of the treating physician, at any point post-remission induction. Or, post-remission induction (consolidation) therapy to be determined per the treating physician

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?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Novartis Pharmaceuticals

Industry Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

In a study involving 408 children with acute lymphoblastic leukemia (ALL), dexamethasone was found to be more effective than prednisone in treatment, but it was associated with poorer performance in fluid reasoning tests among patients.

While most neuropsychological outcomes were similar between the two groups, a higher percentage of patients treated with dexamethasone required special education services (33% vs. 20% for prednisone), suggesting a need for further investigation into the long-term cognitive effects of dexamethasone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuropsychological outcomes of a randomized trial of prednisone versus dexamethasone in acute lymphoblastic leukemia: findings from Dana-Farber Cancer Institute All Consortium Protocol 00-01. Waber, DP., McCabe, M., Sebree, M., et al.[2021]

Adolescents with Acute Lymphoblastic Leukaemia (ALL) experience more severe adverse drug reactions (ADRs) from oral dexamethasone compared to younger children, with higher incidences of issues like hyperglycemia, infections, and thrombosis, based on a review of 11 studies.

The increased severity of ADRs in adolescents may be linked to age-related differences in how dexamethasone is processed in the body and the effects of puberty, highlighting the need for healthcare professionals to closely monitor this age group during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse drug reactions of oral dexamethasone in children and adolescents with childhood acute lymphoblastic leukemia: a systematic review. Hu, L., Kim Emily, AN., Juh Allen, YE.[2022]

In a mouse model of Philadelphia chromosome-positive acute lymphoblastic leukemia, the combination of dasatinib (targeting BCR-ABL kinase) and ruxolitinib (targeting JAK2) led to prolonged survival.

This combined treatment approach also helped prevent resistance to therapy, suggesting a promising strategy for improving outcomes in patients with this type of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting BCR-ABL and JAK2 in Ph+ ALL. Hantschel, O.[2021]

In a study involving 105 children with late bone marrow relapses of acute lymphoblastic leukemia (ALL), 97% achieved a second complete remission, indicating that retreatment can be effective.

The trial did not conclusively determine a superior treatment regimen between doxorubicin/prednisone and cytarabine/teniposide, but identified key prognostic factors such as age under 10, lower white blood cell count at relapse, and longer initial remission duration that are associated with better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of late bone marrow relapse in children with acute lymphoblastic leukemia: a Pediatric Oncology Group study. Sadowitz, PD., Smith, SD., Shuster, J., et al.[2021]

A clinical study involving 56 volunteers demonstrated that the generic dasatinib tablet (YiNiShu®) is bioequivalent to the branded version (Sprycel®) under both fasting and fed conditions, indicating similar pharmacokinetic profiles.

Both dasatinib formulations showed a good safety profile, confirming that patients can expect comparable efficacy and safety when using either version of the medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of dasatinib and its generic: a phase I bioequivalence study in healthy Chinese subjects. Wang, Y., Xue, J., Su, Z., et al.[2023]

Dasatinib is an effective targeted therapy for chronic myelogenous leukemia and Philadelphia positive acute lymphoblastic leukemia, showing strong hematologic, cytogenetic, and molecular responses in patients resistant or intolerant to imatinib.

Despite its efficacy, dasatinib can cause significant side effects like myelosuppression and pleural effusions, particularly in advanced-phase patients; however, recent dose optimization has reduced these adverse events without affecting the drug's effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Guidelines for the management of dasatinib (Sprycel)-induced side effects in chronic myelogenous leukemia and Philadelphia positive acute lymphoblastic leukemias]. Cony-Makhoul, P., Bergeron, A., Corm, S., et al.[2015]

In a phase I study involving 7 adults with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), the combination of the CDK4/6 inhibitor palbociclib and dexamethasone showed potential efficacy, with one patient achieving a complete response.

The treatment was well-tolerated with no dose-limiting toxicities reported, and biological markers indicated on-target effects, including reductions in specific cell populations and proteins associated with leukemic growth.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of the combination of palbociclib and dexamethasone for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia. Wilde, L., Porazzi, P., Trotta, R., et al.[2023]

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SPRYCEL® (dasatinib) Efficacy - Newly Diagnosed Patients

SPRYCEL patients achieved higher & faster cCCyR* and MMR† rates at Years 1 and 5 vs imatinib · Fatal adverse reactions occurred in 3 patients (4%), all of which ...

2.

pmc.ncbi.nlm.nih.gov

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Dasatinib in the Management of Pediatric Patients With ...

Dasatinib plus chemotherapy showed good tolerability and outcomes similar to imatinib in COG AALL0031 (5-year OS 86% ± 5% overall, 87% ± 5% for ...

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onclive.com

onclive.com/view/dasatinib-plus-car-t-cell-therapy-shows-efficacy-in-ph-acute-lymphoblastic-leukemia

Dasatinib Plus CAR T-Cell Therapy Shows Efficacy in Ph+ ...

Dasatinib plus CAR T cells led to high CMR and LFS rates with a good safety profile in Ph-positive acute lymphoblastic leukemia.

4.

news.bms.com

news.bms.com/news/details/2017/Sprycel-dasatinib-Added-to-Standard-Chemotherapy-Demonstrates-Three-Year-Survival-Benefit-in-Pediatric-Patients-with-Newly-Diagnosed-Philadelphia-Chromosome-Positive-Acute-Lymphoblastic-Leukemia/default.aspx

Sprycel (dasatinib) Added to Standard Chemotherapy ...

Showed event-free and overall survival rates of 65.5% and 91.5%, respectively 14.2% of patients treated with Sprycel induction therapy ...

5.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.23.01075

Long-Term Results of the Dasatinib-Blinatumomab ...

The initial report showed 60% of molecular responses (52% by intention to treat) at the primary end point (after two cycles of blinatumomab) and ...

6.

sprycel-hcp.com

sprycel-hcp.com/safety-newly-diagnosed

SPRYCEL® (dasatinib) Safety Profile - Newly Diagnosed ...

Fatal adverse reactions occurred in 3 patients (4%), all of which were due to infections; Eight patients (10%) experienced adverse reactions leading to ...

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC5085255/

Dasatinib and low-intensity chemotherapy in elderly patients ...

In conclusion, dasatinib combined with low-intensity chemotherapy was well-tolerated and gave long-term survival in 36% of elderly patients with Ph+ ALL.

8.

academic.oup.com

academic.oup.com/jjco/advance-article/doi/10.1093/jjco/hyaf154/8271051

Safety profiles of dasatinib in pediatric patients: a real-world ...

This study demonstrates key adverse events associated with dasatinib in pediatric patients and emphasizes the importance of enhanced ...

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news.bms.com

news.bms.com/news/details/2010/Four-Year-Follow-Up-Data-for-SPRYCEL-dasatinib-Demonstrate-82-Percent-Overall-Survival-in-Patients-with-Chronic-Myeloid-Leukemia-Who-Failed-Gleevec1/default.aspx

Four-Year Follow-Up Data for SPRYCEL® (dasatinib) ...

At four years, for all patients administered SPRYCEL 100 mg once daily, overall survival was 82% (95% CI: 76%-88%) and progression-free survival was 66% (95% CI ...

10.

fda.gov

fda.gov/media/124180/download

1. Benefit-Risk Assessment

The efficacy and safety results from clinical trial CA180372 demonstrate substantial evidence of efficacy and safety of Sprycel (dasatinib) ...