Chemotherapy + Ponatinib for Acute Lymphoblastic Leukemia

Overseen By Elias Jabbour, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: Tyrosine kinase inhibitors

Must not be taking: CYP3A4 inhibitors

Disqualifiers: Cardiovascular disease, Pancreatitis, Infection, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 24-32 weeks

88 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of combining chemotherapy drugs with ponatinib, a targeted therapy, for treating acute lymphoblastic leukemia (ALL), a type of blood cancer. Chemotherapy drugs kill cancer cells or stop them from growing and spreading, while ponatinib targets specific enzymes that cancer cells need to grow. Individuals diagnosed with Ph-positive ALL or certain types of chronic myelogenous leukemia (CML) who have undergone previous treatments might be suitable candidates for this trial. The researchers focus on understanding the side effects and effectiveness of this combined treatment approach. As a Phase 2 trial, the research measures how well the treatment works in an initial, smaller group of people, offering participants a chance to contribute to important advancements in cancer therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking any medications or herbal supplements that are strong inhibitors of CYP3A4 at least 14 days before starting ponatinib. If you are taking drugs that may cause a heart rhythm problem called torsades de pointes, you may need to switch to alternatives.

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

Research has shown that ponatinib hydrochloride has been studied for safety over the years. Over the past decade, its safety profile has improved, as doctors and researchers have become better at managing side effects. In earlier studies, ponatinib was used in patients with other blood cancers and demonstrated lasting benefits with manageable side effects.

Chemotherapy drugs like cyclophosphamide, vincristine, doxorubicin, and dexamethasone are well-known in cancer treatment. They have been used for many years, so doctors understand their safety and side effects well. While these drugs can cause side effects like nausea or hair loss, they are generally well-tolerated with close monitoring.

This trial combines these familiar chemotherapy drugs with ponatinib. As a Phase 2 study, the treatment has shown sufficient safety in earlier trials to continue testing in humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for acute lymphoblastic leukemia?

Researchers are excited about this treatment combination because it includes ponatinib hydrochloride, a potent drug that's not part of the standard chemotherapy regimen for acute lymphoblastic leukemia (ALL). Ponatinib is known for its ability to target specific proteins involved in cancer cell growth, particularly the BCR-ABL protein found in some leukemia cells. This targeted action could potentially enhance the effectiveness of traditional chemotherapy drugs like cyclophosphamide and doxorubicin, offering a more comprehensive attack on cancer cells. By integrating ponatinib with established treatments, there's hope for improved outcomes and a new standard in ALL therapy.

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

Research has shown that ponatinib hydrochloride effectively treats a type of acute lymphoblastic leukemia (ALL) with the Philadelphia chromosome (Ph+ ALL). In earlier studies, 98% of patients taking ponatinib survived for three years, outperforming other treatments. Ponatinib blocks certain proteins that aid cancer cell growth, making it a strong option for targeting leukemia cells. In this trial, participants will receive ponatinib combined with chemotherapy drugs such as cyclophosphamide, vincristine, doxorubicin, and prednisone. These chemotherapy drugs are known for their ability to kill cancer cells or stop them from growing. Using these treatments together might improve outcomes for people with acute lymphoblastic leukemia. ^{1 2 5 6 7}

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 untreated or previously treated Ph-positive acute lymphoblastic leukemia (ALL) or chronic myelogenous leukemia (CML) in blast phase. Participants must be physically able to perform daily activities with minimal assistance, have normal organ function, and agree to use effective contraception. Excluded are those with serious infections, active hepatitis B, severe heart conditions, uncontrolled blood pressure, a history of significant bleeding disorders unrelated to cancer, or alcohol abuse.

Inclusion Criteria

Total serum bilirubin =< 1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome

Alanine aminotransferase (ALT) =< 2 x ULN

Aspartate aminotransferase (AST) =< 2.5 x ULN

Exclusion Criteria

I have active hepatitis B but am on treatment to control it.

Pregnant and lactating women

I have another cancer besides skin cancer that may shorten my life to under a year.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive combination chemotherapy and ponatinib hydrochloride in cycles. Odd cycles include cyclophosphamide, doxorubicin, vincristine, dexamethasone, and ponatinib. Even cycles include methotrexate, ponatinib, and cytarabine. Treatment repeats every 3-4 weeks for up to 8 cycles.

24-32 weeks

Maintenance Therapy

Participants receive vincristine, prednisone, and ponatinib. Cycles repeat every 28 days for 24 months.

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs at 30 days and then every 6 months for up to 24 months.

24 months

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Doxorubicin Hydrochloride
• Methotrexate
• Ponatinib Hydrochloride
• Prednisone
• Vincristine

Trial Overview The study tests how well a combination of chemotherapy drugs like cyclophosphamide and doxorubicin hydrochloride works alongside ponatinib hydrochloride—a drug that blocks enzymes needed for cancer cell growth—in treating ALL. It's a phase II trial aiming to determine the effectiveness and side effects of this treatment regimen.

How Is the Trial Designed?

Group I: Treatment (combination chemotherapy, ponatinib hydrochloride) Experimental Treatment 13 Interventions

See Detailed Description.

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

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

In a study of 83 children with higher-risk B-lineage acute lymphoblastic leukemia (ALL), 98% achieved remission after receiving intensive intravenous methotrexate (MTX) and mercaptopurine (MP) treatment, indicating high efficacy of this regimen.

The 4-year event-free survival rate was 57.4%, and the treatment was associated with generally mild toxicities, suggesting that intensive MTX/MP is an effective and relatively safe option for postremission therapy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intensive intravenous methotrexate and mercaptopurine treatment of higher-risk non-T, non-B acute lymphocytic leukemia: A Pediatric Oncology Group study. Camitta, B., Mahoney, D., Leventhal, B., et al.[2017]

In a phase II study involving 20 heavily pretreated children with relapsed acute lymphoblastic leukemia (ALL), the combination of ifosfamide and etoposide (VP16) resulted in a 40% complete remission rate, demonstrating significant efficacy in this challenging patient population.

The treatment was generally well tolerated, with myelosuppression being the most common side effect, indicating that while the therapy is effective, careful monitoring for toxicity is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ifosfamide and etoposide in recurrent childhood acute lymphoblastic leukemia. Crooks, GM., Sato, JK.[2019]

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]

The study identified that the dual MERTK and FLT3 kinase inhibitor MRX-2843 synergizes effectively with vincristine to inhibit the growth of both B-ALL and T-ALL leukemia cells, suggesting a promising combination therapy for patients who do not respond to standard treatments.

Using lipid nanoparticle formulations to deliver MRX-2843 and vincristine in specific ratios improved anti-leukemia activity and prolonged survival in a mouse model of T-ALL, highlighting the importance of drug ratios and dosing in enhancing therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of constitutively synergistic nanoformulations to enhance chemosensitivity in T-cell leukemia. Kelvin, JM., Chimenti, ML., Zhang, DY., et al.[2023]

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 490 children with high-risk B-precursor acute lymphoblastic leukemia (ALL), two treatment regimens were compared, showing that both regimens achieved a high remission rate of 97%.

While regimen B, which involved more intensive myelosuppressive combinations, showed a higher estimated 4-year event-free survival (EFS) of 69.4% compared to 61.6% for regimen A, the difference was not statistically significant, and regimen B was associated with more frequent toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of early intensive methotrexate/mercaptopurine with early intensive alternating combination chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group phase III randomized trial. Lauer, SJ., Shuster, JJ., Mahoney, DH., et al.[2019]

In a study of 31 pediatric patients with relapsed acute lymphoblastic leukemia (ALL), topotecan administered before standard induction therapy resulted in an impressive 89.3% response rate, significantly reducing circulating blast cells.

The combination of topotecan with standard induction therapy led to a 74.2% complete response rate, indicating that this regimen is effective and well-tolerated, despite some hematologic and gastrointestinal toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of topotecan in combination with dexamethasone, asparaginase, and vincristine in pediatric patients with acute lymphoblastic leukemia in first relapse. Hijiya, N., Stewart, CF., Zhou, Y., et al.[2015]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/41027807/

Molecular Milestones and Survival Outcomes of Ponatinib ... Ponatinib demonstrated substantial real-world efficacy in pretreated patients with CML and Ph+ ALL, with MR3.0 in CML and MR5.0 in Ph+ ALL ...

2. iclusig.com iclusig.com/hcp/efficacy/ph-positive-all-pace-trial

PACE Efficacy Results in Ph+ ALL for ICLUSIG® (ponatinib) View ICLUSIG 5 year efficacy results from the PACE trial in patients with Ph+ ALL. See Important Safety Information and full Prescribing Information, ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e18531

Investigating the efficacy and safety of ponatinib in acute ... In particular, the average 3-year OS rates of ponatinib compared to imatinib was 98% vs 58% respectively; the average 3-year OS of ponatinib vs ...

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

Clinical outcomes in patients with Philadelphia chromosome ... The 5-year follow-up data of this trial showed deep and durable responses to ponatinib therapy in CP-CML patients [8]. In total, 60% of the evaluable CP-CML ...

5. iclusig.com iclusig.com/cml/how-iclusig-may-help

ICLUSIG® (ponatinib) Clinical Trial Results in CML Based on 5-year data from PACE, ICLUSIG was shown to help control CML in adult patients whose disease was considered resistant or intolerant to prior TKI ...

6. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/3816/533600/Ponatinib-Safety-Profile-An-Analysis-of-10-Years

Ponatinib Safety Profile: An Analysis of 10 Years of Real ... Conclusion: Our study findings suggest the safety profile of ponatinib has improved since it first became commercially available, with ...

7. 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 ...