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

12 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to test the safety of a new combination of three oral drugs in Ph+ ALL. These drugs are dexamethasone, dasatinib, and ruxolitinib. All three drugs have been studied before in humans. This is a phase I study in which ruxolitinib dose will start low for the first patient together with dexamethasone plus dasatinib. If this dose does not cause a bad side effect, the ruxolitinib dose will slowly be made higher as new patients take part in the study. This will help the investigators find the right dose of ruxolitinib to give together with dexamethasone and dasatinib that will be used in future studies

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.

What data supports the effectiveness of the drugs Dasatinib, Dexamethasone, and Ruxolitinib for treating acute lymphoblastic leukemia?

Research shows that combining Dasatinib and Ruxolitinib can significantly extend survival in a mouse model of a specific type of leukemia (Ph+ ALL) by targeting different pathways. Additionally, the combination of Dasatinib, Ruxolitinib, and Dexamethasone has been shown to provide more durable remissions, suggesting these drugs work well together to treat this leukemia. ^{1 2 3 4 5}

Is the triple drug therapy for acute lymphoblastic leukemia safe for humans?

Dasatinib, one of the drugs in the therapy, has been shown to have mostly mild to moderate side effects that are usually manageable, but it can cause serious issues like pleural effusions (fluid around the lungs) and myelosuppression (reduced bone marrow activity). Dexamethasone can cause adverse reactions, especially in adolescents, and requires careful monitoring. Ruxolitinib's safety profile is not detailed here, but it is used in combination with dasatinib in research. ^{5 6 7 8 9}

What makes the triple drug therapy for acute lymphoblastic leukemia unique?

This triple drug therapy is unique because it combines dasatinib and ruxolitinib to target specific proteins (BCR-ABL kinase and JAK2) involved in Philadelphia chromosome-positive acute lymphoblastic leukemia, potentially preventing resistance and improving survival, while also using dexamethasone, which is more effective than prednisone for this condition. ^{5 10 11 12 13}

Research Team

Jae Park, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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 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]

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]

References

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

Successful use of trametinib and dasatinib combined with chemotherapy in the treatment of Ph-positive B-cell acute lymphoblastic leukemia: A case report. [2023]

2. Italy pubmed.ncbi.nlm.nih.gov

Glucocorticoids and selumetinib are highly synergistic in RAS pathway-mutated childhood acute lymphoblastic leukemia through upregulation of BIM. [2023]

3. England 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. [2023]

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

Janus kinase inhibition by ruxolitinib extends dasatinib- and dexamethasone-induced remissions in a mouse model of Ph+ ALL. [2021]

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

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

6. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of dasatinib and its generic: a phase I bioequivalence study in healthy Chinese subjects. [2023]

7. Australia pubmed.ncbi.nlm.nih.gov

Adverse drug reactions of oral dexamethasone in children and adolescents with childhood acute lymphoblastic leukemia: a systematic review. [2022]

8. France 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]. [2015]

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

Dasatinib, a multikinase inhibitor: therapy, safety, and appropriate management of adverse events. [2015]

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

New developments in acute lymphoblastic leukemia. [2017]

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

Treatment of late bone marrow relapse in children with acute lymphoblastic leukemia: a Pediatric Oncology Group study. [2021]

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

Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. [2018]

13. United States 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. [2021]