Ponatinib for Chronic Myeloid Leukemia

Overseen By Elias Jabbour, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Other TKIs

Disqualifiers: Heart disease, Psychiatric disorders, Hypertension, Diabetes, others

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

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 5 years

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of ponatinib hydrochloride (also known as Iclusig) for individuals with chronic myeloid leukemia (CML) who haven't responded to or can't tolerate other treatments. The researchers aim to determine if ponatinib can stop or control cancer cell growth by blocking a necessary protein. This trial suits individuals diagnosed with CML in the chronic phase who have not succeeded with previous treatments like imatinib, dasatinib, or nilotinib. Participants must stop other CML therapies at least 48 hours before starting this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

Participants must stop taking bosutinib, dasatinib, nilotinib, or other anti-leukemia therapies (except hydroxyurea) at least 48 hours before starting the study treatment.

Is there any evidence suggesting that ponatinib hydrochloride is likely to be safe for humans?

Research has shown that ponatinib hydrochloride is generally safe for patients with chronic myeloid leukemia (CML). In one study, 94% of patients used ponatinib because their disease returned or did not respond to other treatments, indicating its use when other options have failed.

Ponatinib is usually well-tolerated, though some individuals may experience side effects. Common side effects include rash, high blood pressure, and stomach pain, while serious side effects are less common. Monitoring any side effects and consulting a doctor if concerns arise is important.

Ponatinib is being tested in this trial as a second-choice treatment, meaning its safety and effectiveness are already somewhat known, particularly for those who cannot tolerate other treatments. For those considering joining this trial, it may be reassuring to know that the treatment has been used in other studies with careful follow-up, enhancing understanding of its long-term safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for chronic myeloid leukemia?

Unlike the standard treatments for chronic myeloid leukemia, which primarily include drugs like imatinib, dasatinib, and nilotinib that target the BCR-ABL protein, ponatinib hydrochloride is a next-generation tyrosine kinase inhibitor. Researchers are excited about ponatinib because it can target a specific mutation known as T315I, which makes the leukemia resistant to other drugs. This means ponatinib has the potential to be effective even when other treatments have failed, offering hope to patients who have limited options.

What evidence suggests that ponatinib hydrochloride might be an effective treatment for chronic myeloid leukemia?

Research has shown that ponatinib hydrochloride can help patients with chronic myeloid leukemia (CML) who haven't responded to other treatments. One study found that 55% of patients with chronic-phase CML experienced a major reduction in cancer cells within 12 months of taking ponatinib. Long-term results from other studies indicate that ponatinib provides strong, lasting benefits for patients who have undergone many previous treatments. This drug blocks a protein that cancer cells need to grow, helping to control the disease. Ponatinib has also demonstrated good results as an initial treatment, working well for newly diagnosed patients too. ^{3 4 6 7 8}

Who Is on the Research Team?

Elias Jabbour, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with chronic myeloid leukemia in the chronic phase who didn't respond to or can't tolerate initial treatments like imatinib mesylate, dasatinib, or nilotinib. Participants must have normal organ function tests, be able to consent, and not be pregnant or breastfeeding. They should also have no severe heart disease, uncontrolled high blood pressure, psychiatric disorders, history of certain cardiovascular events, pancreatitis or more than one prior treatment with FDA-approved TKIs.

Inclusion Criteria

I can care for myself and perform daily activities.

My leukemia is in the early stage and tests positive for specific genetic markers.

Signed informed consent

Exclusion Criteria

Active, uncontrolled psychiatric disorders

My high blood pressure is not under control.

Presence of 30% blasts or more in the peripheral blood or bone marrow for blastic phase

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ponatinib hydrochloride as second line therapy for chronic myeloid leukemia in chronic phase

Up to 5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ponatinib Hydrochloride

Trial Overview

The trial is testing ponatinib hydrochloride as a second line therapy for chronic myeloid leukemia that's resistant or intolerant to first-line drugs. It includes laboratory biomarker analysis and quality-of-life assessments to see if this drug can control cancer cell growth by blocking proteins needed for their proliferation.

How Is the Trial Designed?

Group I: Ponatinib hydrochloride Experimental Treatment 3 Interventions

Patients receive ponatinib hydrochloride PO QD. Treatment continues for up to 5 years in the absence of disease progression or unacceptable toxicity.

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

Approved in United States as Iclusig for:

• Chronic myeloid leukemia
• Philadelphia chromosome-positive acute lymphoblastic leukemia

Approved in European Union as Iclusig for:

• Chronic myeloid leukemia
• Philadelphia chromosome-positive acute lymphoblastic leukemia

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Ponatinib effectively inhibits the growth of chronic myeloid leukemia cells that are resistant to other ABL tyrosine kinase inhibitors like imatinib and nilotinib, demonstrating its potential as a treatment option for resistant cases.

The mechanism of action for ponatinib involves reducing the activity of key kinases, including ABL and Lyn, which are associated with leukemia cell proliferation, indicating its therapeutic relevance in managing resistant leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of ponatinib against ABL tyrosine kinase inhibitor-resistant leukemia cells. Okabe, S., Tauchi, T., Tanaka, Y., et al.[2013]

Ponatinib has been approved for use in patients with chronic-phase chronic myeloid leukemia (CP-CML) who have resistance or intolerance to at least two prior kinase inhibitors, expanding its treatment options for this population.

The OPTIC trial demonstrated that ponatinib is effective at a modified dose of 45 mg, achieving a major molecular response (MR2) in 42% of patients at 12 months, although it carries risks of serious side effects like arterial occlusive events, particularly in older patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Revised Indication and Dosing Regimen for Ponatinib Based on the Results of the OPTIC Trial. Pulte, ED., Chen, H., Price, LSL., et al.[2022]

Ponatinib is a highly effective treatment for chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL), particularly for patients with resistance to other therapies or specific mutations like T315I.

While ponatinib is potent, it carries a dose-dependent risk of cardiovascular toxicity, highlighting the importance of starting with a risk-adjusted dose and monitoring for side effects throughout treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of ponatinib dosing in chronic myeloid leukemia patients. Sacha, T., Szczepanek, E.[2022]

Ponatinib is a potent inhibitor of all four fibroblast growth factor receptors (FGFR1-4), showing strong efficacy in inhibiting FGFR-mediated signaling and cell viability in engineered cells and various tumor types, with IC(50) values under 40 nmol/L.

In mouse models, daily oral dosing of ponatinib significantly reduced tumor growth and inhibited signaling across multiple cancer types, suggesting its potential as a treatment for cancers driven by FGFR dysregulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models. Gozgit, JM., Wong, MJ., Moran, L., et al.[2020]

Ponatinib is an effective treatment for Philadelphia chromosome-positive leukemias that are resistant or intolerant to other therapies, but its use is associated with significant cardiovascular risks, including hypertension and thrombotic events.

To safely use ponatinib, especially in high-risk patients, collaboration between hematologists and cardiologists is essential for monitoring and risk mitigation strategies, ensuring the best outcomes for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification, prevention and management of cardiovascular risk in chronic myeloid leukaemia patients candidate to ponatinib: an expert opinion. Breccia, M., Pregno, P., Spallarossa, P., et al.[2017]

Ponatinib is effectively absorbed in the body, with 86.6% of the administered dose recovered in feces and only 5.4% in urine, indicating that it is primarily eliminated through the gastrointestinal tract.

The study found that ponatinib has a long elimination half-life of approximately 66.4 hours, and its major metabolites, including M14, also have significant half-lives, suggesting prolonged activity in the body.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Absorption, metabolism, and excretion of [14C]ponatinib after a single oral dose in humans. Ye, YE., Woodward, CN., Narasimhan, NI.[2022]

Ponatinib is a unique and effective treatment for resistant chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL), specifically targeting the T315I mutation that causes resistance in about 20% of CML cases.

Despite its efficacy, ponatinib has been associated with serious side effects in nearly 12% of patients, leading to a temporary suspension of sales; it has since resumed with an expanded black box warning, indicating the need for careful patient selection and monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Resistant mutations in CML and Ph(+)ALL - role of ponatinib. Miller, GD., Bruno, BJ., Lim, CS.[2022]

Ponatinib is an effective treatment for adults with T315I-positive chronic myeloid leukaemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL), showing major cytogenetic responses in over 50% of chronic-phase CML patients within 12 months and significant responses in accelerated and blast phases as well.

Despite its efficacy, ponatinib carries serious risks, including vascular occlusion and heart failure, leading to FDA warnings, so clinicians must carefully weigh the benefits against these potential adverse effects before prescribing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ponatinib: a review of its use in adults with chronic myeloid leukaemia or Philadelphia chromosome-positive acute lymphoblastic leukaemia. Hoy, SM.[2021]

Ponatinib is an effective third-generation tyrosine kinase inhibitor for chronic myeloid leukaemia (CML) patients who are resistant or intolerant to other treatments, showing efficacy even in heavily treated patients.

While ponatinib can induce cardiovascular events, a potential reduction in the starting dose to 15 mg/day may enhance safety without compromising its effectiveness, highlighting the importance of careful patient management during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insights into the optimal use of ponatinib in patients with chronic phase chronic myeloid leukaemia. Molica, M., Scalzulli, E., Colafigli, G., et al.[2020]

Ponatinib is a potent treatment for chronic myeloid leukemia, effectively inhibiting both wild-type and most mutated forms of the BCR:ABL1 kinase, but it carries a risk of significant cardiovascular toxicity.

A proposed decision-tree for dose selection suggests starting doses of 45 mg for highly resistant patients, 30 mg for less-resistant patients, and 15 mg for intolerant patients, allowing for dose adjustments based on individual patient responses and safety profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose optimisation of ponatinib in chronic phase chronic myeloid leukemia. Huguet, F., Réa, D., Cayssials, E., et al.[2023]

Ponatinib, a treatment for chronic myelogenous leukemia patients with the T315I mutation, has been identified as the most cardiotoxic tyrosine kinase inhibitor, with a mechanism involving excessive cardiac inflammation.

The study revealed that ponatinib activates the S100A8/A9-TLR4-NLRP3-IL-1β signaling pathway, leading to cardiac dysfunction, and suggests that immunosuppressive treatments like dexamethasone could help manage this cardiotoxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation. Tousif, S., Singh, AP., Umbarkar, P., et al.[2023]

Citations

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NCT01207440 | Ponatinib for Chronic Myeloid Leukemia ...

The purpose of this study is to determine the efficacy of ponatinib in patients with chronic myeloid leukemia (CML) in chronic phase (CP), accelerated phase ...

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC6071555/

final 5-year results of the phase 2 PACE trial - PubMed Central

Ponatinib continued to provide deep, durable responses in heavily pretreated patients with CP-CML. Tolerability was acceptable in this heavily pretreated ...

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iclusig.com

iclusig.com/hcp/efficacy/cml-pace-trial

ICLUSIG (ponatinib) Pace Trial

Achieved MCyR by 12 months%^1. 55% of the total CP-CML patient population achieved MCyR by 12 months.

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sciencedirect.com

sciencedirect.com/science/article/abs/pii/S2152265025028939

Molecular Milestones and Survival Outcomes of Ponatinib ...

Among 52 patients (27 CML and 25 Ph+ ALL; median follow-up: 50.7 months), 94% received ponatinib due to relapsed or refractory disease. Among ...

5.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/38804723/

Results of ponatinib as frontline therapy for chronic myeloid ...

Ponatinib yielded high cytogenetic and molecular responses in newly diagnosed chronic myeloid leukemia in chronic phase.

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iclusig.com

iclusig.com/hcp

ICLUSIG® (ponatinib) for US Healthcare Professionals

Find efficacy, safety profile, dosing, and support information for ICLUSIG in CML and Ph+ ALL. See Important Safety Information and full Prescribing ...

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8195783/

Clinical outcomes in patients with Philadelphia chromosome ...

By 12 months, 56% of chronic phase (CP)-CML patients achieved a major cytogenetic response (MCyR; primary endpoint) [7]. The 5-year follow-up data of this trial ...

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ashpublications.org

ashpublications.org/blood/article/144/Supplement%201/3148/529348/5-Year-Follow-up-of-the-Phase-2-Optic-Study-in

5-Year Follow-up of the Phase 2 Optic Study in Patients with ...

Conclusion: Long-term results from OPTIC highlight the clinical benefits of ponatinib in patients with CP-CML resistant to ≥2 TKIs or harboring a T315I mutation ...