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

Trial Summary

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.

What data supports the effectiveness of the drug Ponatinib for treating Chronic Myeloid Leukemia?

Ponatinib has shown effectiveness in treating Chronic Myeloid Leukemia (CML) by achieving major responses in over half of patients with chronic-phase CML and significant responses in those with more advanced phases, even when other treatments failed. It is particularly effective against a specific mutation (T315I) that makes the disease resistant to other drugs. ^{1 2 3 4 5}

What safety information is available for Ponatinib in humans?

Ponatinib, also known as Iclusig, has been associated with serious safety concerns, including cardiovascular events (heart-related issues) and arterial occlusive events (blockages in arteries). It was temporarily withdrawn from the market due to these risks but was reintroduced with revised warnings and precautions. Common side effects include pancreatitis (inflammation of the pancreas), hypertension (high blood pressure), hyperlipidemia (high levels of fats in the blood), and liver dysfunction. ^{2 4 6 7 8}

How is the drug Ponatinib different from other treatments for chronic myeloid leukemia?

Ponatinib is unique because it is specifically designed to target the T315I mutation in the ABL kinase domain, which makes it effective against chronic myeloid leukemia that is resistant to other treatments. It is an oral medication that inhibits multiple tyrosine kinases, including BCR-ABL and FGFRs, and is used when other tyrosine kinase inhibitors are not effective or suitable. ^{1 3 9 10 11}

What is the purpose of this trial?

This phase II trial studies how well ponatinib hydrochloride works as second line therapy in treating patients with chronic myeloid leukemia in chronic phase that has not responded to initial treatment (first line) with imatinib mesylate, dasatinib, or nilotinib or cannot tolerate imatinib mesylate, dasatinib, or nilotinib. Ponatinib hydrochloride may stop or control the growth of cancer cells by blocking a protein needed for cell growth.

Research Team

Elias Jabbour, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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.

My organs are functioning well.

Exclusion Criteria

My high blood pressure is not under control.

Active, uncontrolled psychiatric disorders

My chronic myeloid leukemia is in an advanced stage.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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 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, 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]

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 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 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 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 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]

References

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

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

2. England pubmed.ncbi.nlm.nih.gov

Insights into the optimal use of ponatinib in patients with chronic phase chronic myeloid leukaemia. [2020]

3. Germany pubmed.ncbi.nlm.nih.gov

Identification, prevention and management of cardiovascular risk in chronic myeloid leukaemia patients candidate to ponatinib: an expert opinion. [2017]

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

Resistant mutations in CML and Ph(+)ALL - role of ponatinib. [2022]

5. Germany pubmed.ncbi.nlm.nih.gov

Absorption, metabolism, and excretion of [14C]ponatinib after a single oral dose in humans. [2022]

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

Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation. [2023]

7. England pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Revised Indication and Dosing Regimen for Ponatinib Based on the Results of the OPTIC Trial. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Dose optimisation of ponatinib in chronic phase chronic myeloid leukemia. [2023]

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

Efficacy of ponatinib against ABL tyrosine kinase inhibitor-resistant leukemia cells. [2013]

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

Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models. [2020]

11. Poland pubmed.ncbi.nlm.nih.gov

Management of ponatinib dosing in chronic myeloid leukemia patients. [2022]