Ponatinib vs Imatinib for Acute Lymphoblastic Leukemia

Recruiting at 126 trial locations

Overseen By Takeda Call center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Takeda

Must be taking: Ponatinib, Imatinib

Must not be taking: QTc drugs, CYP3A4 drugs

Disqualifiers: CML, HIV, Hepatitis, CNS pathology, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

245 Participants Needed

Trial Summary

What is the purpose of this trial?

In this study, adults with newly-diagnosed Philadelphia Chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) will receive first-line therapy of ponatinib or imatinib. The main aim of this study is to compare the number of participants on each treatment that show no signs of disease. Participants will take tablets of either ponatinib or imatinib at the same time each day combined with reduced-intensity chemotherapy for up to 20 months. Then, they will continue with single-agent therapy (ponatinib or imatinib) until they meet the discontinuation criteria from the study.

Do I have to stop taking my current medications for the trial?

You may need to stop taking certain medications, especially if they are known to affect heart rhythm or interact with the trial drugs. It's best to discuss your current medications with the trial team to see if any changes are needed.

What data supports the effectiveness of the drugs Ponatinib and Imatinib for treating acute lymphoblastic leukemia?

Research shows that Ponatinib, a potent tyrosine kinase inhibitor, has improved outcomes for patients with acute lymphoblastic leukemia, especially those with the Philadelphia chromosome. Additionally, early results from a clinical trial indicate that Ponatinib, when combined with another drug called blinatumomab, can lead to complete remissions in most patients with this type of leukemia. ^{1 2 3 4 5}

What safety data exists for Imatinib and Ponatinib in humans?

Imatinib, also known as Gleevec, has been shown to be generally well-tolerated in treating chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST), with mild side effects like muscle pain and swelling. In children with CML, it has a good safety profile with manageable side effects such as nausea and pain. Ponatinib, marketed as Iclusig, is not specifically mentioned in the provided research articles, so no safety data is available from this information. ^{6 7 8 9 10}

How does the drug ponatinib differ from imatinib for treating acute lymphoblastic leukemia?

Ponatinib is a newer drug designed to overcome resistance mutations that can occur with other treatments like imatinib, making it effective even in cases where the T315I mutation is present. It has shown promising results when combined with chemotherapy, leading to better survival rates compared to imatinib, but it carries a higher risk of serious vascular side effects. ^{2 5 11 12 13}

Research Team

Study Director

Principal Investigator

Takeda

Eligibility Criteria

Adults newly diagnosed with Philadelphia Chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who are in good enough health to perform daily activities with slight limitations (ECOG <=2). They can't join if they have HIV, hepatitis B or C, recent major surgery, certain heart diseases, other cancers within the last 5 years, severe nervous system conditions, or are taking specific drugs that affect liver enzymes or cause heart rhythm problems.

Inclusion Criteria

My leukemia is newly diagnosed and positive for Philadelphia chromosome or BCR-ABL1.

I can take care of myself but might not be able to do heavy physical work.

Exclusion Criteria

I have no history of major brain-related health issues like epilepsy, stroke, or dementia.

I have HIV or active hepatitis B or C.

Uncontrolled hypertriglyceridemia (triglycerides >450 milligram per deciliter [mg/dL])

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Participants receive ponatinib or imatinib with reduced-intensity chemotherapy for up to 3 cycles

3 months

Multiple visits per cycle

Consolidation

Participants continue with ponatinib or imatinib and additional chemotherapy agents for cycles 4 to 9

6 months

Multiple visits per cycle

Maintenance

Participants receive ponatinib or imatinib as a single agent for cycles 10 to 20

11 months

Monthly visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 6 years

Every 3 months

Treatment Details

Interventions

• Imatinib
• Ponatinib

Trial Overview The trial is testing Ponatinib against Imatinib in adults with Ph+ ALL. Participants will take one of these drugs as a pill every day along with less intense chemotherapy for up to 20 months and then continue just the pills unless they need to stop according to study rules.

Participant Groups

Group I: Cohort A: Ponatinib 30 milligram (mg) Experimental Treatment 6 Interventions

Ponatinib 30 mg, tablets, orally, once daily (QD), with vincristine 1.4 mg/m\^2 (max 2 mg) intravenous (IV), on Days 1 and 14 and dexamethasone 40 mg (\<60 years \[yrs\]) and 20 mg (≥60 yrs), orally, once on Days 1 to 4, Days 11 to 14 for up to 3 cycles (each cycle=28 days) in induction phase (reduced dose of ponatinib 15 mg upon achievement of MRD-negative CR at end of induction) followed by ponatinib last induction phase dose with cytarabine, 1000 mg/m\^2 as 2-hour IV infusion (\<60 yrs) and 250 mg/m\^2 (≥60 yrs) every 12 hours, IV on Days 1, 3, 5 of Cycles 2,4,6 and methotrexate, 1000 mg/m\^2 (\<60 yrs) and 250 mg/m\^2 (≥60 yrs), IV infusion, on Day 1 of cycles 1, 3, 5 in consolidation phase followed by ponatinib last consolidation phase dose with vincristine 1.4 mg/m\^2 (max 2 mg), IV, on Day 1 and prednisone 200 mg (\<60 yrs), 100 mg (≥60-69 yrs) and 50 mg(≥70 yrs) on Days 1 to 5 for up to 11 cycles in maintenance phase up to data cut-off date: 12 August 2022.

Group II: Cohort B: Imatinib 600 mg Active Control 6 Interventions

Imatinib 600 mg, tablets, orally, QD, with vincristine 1.4 mg/m\^2 (max 2 mg), IV, on Days 1 and 14 and dexamethasone 40 mg (\<60 yrs) and 20 mg (≥60 yrs), orally, once on Days 1 to 4 and Days 11 to 14 in each 28-day cycle for up to 3 cycles in the induction phase followed by imatinib 600 mg, tablets, orally, QD, with cytarabine, 1000 mg/m\^2 every 12 hours as a 2-hour-IV infusion (\<60 yrs) and 250 mg/m\^2 every 12 hours (≥60 yrs), IV on Days 1, 3, and 5 of each 28-day even cycles (Cycles 2, 4, and 6), and methotrexate, 1000 mg/m\^2 (\<60 yrs) and 250 mg/m\^2 (≥60 yrs), IV infusion, on Day 1 of each 28-day odd cycles (Cycle 1, 3, and 5) in consolidation phase followed by imatinib 600 mg, tablets, orally, QD, along with vincristine 1.4 mg/m\^2 (max 2 mg), IV, on Day 1 and prednisone 200 mg (\<60 yrs), 100 mg (≥60-69 yrs) and 50 mg (≥70 yrs) on Days 1 through 5 in each 28-day cycle up to 11 cycles in maintenance phase up to data cut-off date: 12 August 2022.

Imatinib is already approved in European Union, United States, Canada, Japan, Switzerland for the following indications:

Approved in European Union as Gleevec for:

• Chronic myeloid leukemia
• Gastrointestinal stromal tumors
• Dermatofibrosarcoma protuberans
• Systemic mastocytosis
• Hypereosinophilic syndrome

Approved in United States as Gleevec for:

• Chronic myeloid leukemia
• Gastrointestinal stromal tumors
• Dermatofibrosarcoma protuberans
• Systemic mastocytosis
• Hypereosinophilic syndrome

Approved in Canada as Glivec for:

• Chronic myeloid leukemia
• Gastrointestinal stromal tumors
• Dermatofibrosarcoma protuberans
• Systemic mastocytosis
• Hypereosinophilic syndrome

Approved in Japan as Glivec for:

• Chronic myeloid leukemia
• Gastrointestinal stromal tumors
• Dermatofibrosarcoma protuberans
• Systemic mastocytosis
• Hypereosinophilic syndrome

Approved in Switzerland as Gleevec for:

• Chronic myeloid leukemia
• Gastrointestinal stromal tumors
• Dermatofibrosarcoma protuberans
• Systemic mastocytosis
• Hypereosinophilic syndrome

Who Is Running the Clinical Trial?

Takeda

Lead Sponsor

Trials

1,255

Recruited

4,219,000+

Dr. Naoyoshi Hirota

Takeda

Chief Medical Officer since 2020

MD from University of Tokyo

Christophe Weber

Takeda

Chief Executive Officer since 2015

PhD in Molecular Biology from Université de Montpellier

Findings from Research

Recent advancements in treatments for acute lymphoblastic leukemia (ALL), including inotuzumab ozogamicin, blinatumomab, and CAR T-cell therapy, have significantly improved patient outcomes for both younger and older adults.

The review emphasizes the need for optimal combinations and sequences of these new therapies, as well as their integration into standard treatment regimens, to enhance the effectiveness of ALL management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing the treatment of acute lymphoblastic leukemia in younger and older adults: new drugs and evolving paradigms. Short, NJ., Kantarjian, H., Jabbour, E.[2022]

In a phase II clinical trial, the combination of ponatinib, a third-generation tyrosine kinase inhibitor, and blinatumomab, a bispecific T-cell engager, achieved complete molecular remissions in most patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.

These early results suggest a promising therapeutic strategy for this challenging type of leukemia, highlighting the potential efficacy of combining targeted therapies with immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TKI-BiTE Combo Produces CMRs in Most with ALL. [2022]

Blinatumomab represents a significant advancement in immunotherapy for relapsed or refractory acute lymphoblastic leukemia (ALL), demonstrating unprecedented efficacy by stimulating a strong T-cell response, which is a departure from traditional chemotherapy.

While blinatumomab offers promising benefits, it also presents unique immunological toxicities and complex administration requirements, necessitating careful consideration of its use compared to other emerging therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blinatumomab: enlisting serial killer T-cells in the war against hematologic malignancies. Rogala, B., Freyer, CW., Ontiveros, EP., et al.[2023]

Imatinib, a tyrosine kinase inhibitor, has significantly improved the prognosis for patients with chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GIST), showing high rates of cytogenetic and molecular responses across all phases of CML.

The drug is well tolerated, with only mild adverse effects such as joint pain and gastrointestinal symptoms, primarily occurring in the first two years of treatment, making it a safe and effective oral option for these cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A benefit-risk assessment of imatinib in chronic myeloid leukaemia and gastrointestinal stromal tumours. Wolf, D., Rumpold, H.[2021]

In the phase 3 TOWER study, blinatumomab showed a significant overall survival benefit compared to standard-of-care chemotherapy in adults with relapsed or refractory Philadelphia chromosome-negative B-precursor acute lymphoblastic leukemia, involving 267 patients who received a median of 2 cycles of treatment.

After adjusting for treatment duration, blinatumomab had lower exposure-adjusted event rates for serious adverse events compared to standard chemotherapy, particularly for infections and cytopenias, indicating it is a well-tolerated treatment option despite a higher rate of cytokine-release syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure-adjusted adverse events comparing blinatumomab with chemotherapy in advanced acute lymphoblastic leukemia. Stein, AS., Larson, RA., Schuh, AC., et al.[2020]

Blinatumomab, a bispecific T-cell engager, has been successfully used in 11 pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL) after they experienced severe chemotherapy-induced toxicity, leading to recovery in all cases.

This treatment offers a nonmyelotoxic alternative for patients who cannot tolerate traditional cytotoxic therapies, suggesting it could be a valuable option in managing severe toxicity during leukemia treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blinatumomab as a bridge to further therapy in cases of overwhelming toxicity in pediatric B-cell precursor acute lymphoblastic leukemia: Report from the Israeli Study Group of Childhood Leukemia. Elitzur, S., Arad-Cohen, N., Barzilai-Birenboim, S., et al.[2020]

References

1. England pubmed.ncbi.nlm.nih.gov

Optimizing the treatment of acute lymphoblastic leukemia in younger and older adults: new drugs and evolving paradigms. [2022]

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

TKI-BiTE Combo Produces CMRs in Most with ALL. [2022]

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

Update on developmental therapeutics for acute lymphoblastic leukemia. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Blinatumomab: enlisting serial killer T-cells in the war against hematologic malignancies. [2023]

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

Ponatinib vs. Imatinib as Frontline Treatment for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Matching Adjusted Indirect Comparison. [2023]

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

A benefit-risk assessment of imatinib in chronic myeloid leukaemia and gastrointestinal stromal tumours. [2021]

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

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

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

Exposure-adjusted adverse events comparing blinatumomab with chemotherapy in advanced acute lymphoblastic leukemia. [2020]

9. China pubmed.ncbi.nlm.nih.gov

[A retrospective analysis of the efficacy and safety of imatinib in children with chronic myeloid leukemia during chronic phase]. [2019]

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

Blinatumomab as a bridge to further therapy in cases of overwhelming toxicity in pediatric B-cell precursor acute lymphoblastic leukemia: Report from the Israeli Study Group of Childhood Leukemia. [2020]

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

Ponatinib, chemotherapy, and transplant in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. [2022]

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

Blinatumomab + ponatinib for relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia in adults. [2021]

13. England pubmed.ncbi.nlm.nih.gov

The role of ponatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia. [2023]