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

Trial Summary

What is the purpose of this trial?

This phase II trial studies the side effects and how well combination chemotherapy and ponatinib hydrochloride work in treating patients with acute lymphoblastic leukemia. Drugs used in chemotherapy, such as cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Ponatinib hydrochloride may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving combination chemotherapy and ponatinib hydrochloride may be an effective treatment for acute lymphoblastic leukemia.

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.

What data supports the effectiveness of the drug combination used in the Chemotherapy + Ponatinib for Acute Lymphoblastic Leukemia trial?

Research shows that combinations of drugs like vincristine, prednisone, and doxorubicin can induce remission in patients with relapsed acute lymphoblastic leukemia (ALL). Additionally, methotrexate and mercaptopurine have been used effectively in post-remission treatment to help prevent relapse in high-risk ALL patients. ^{1 2 3 4 5}

Is the combination of chemotherapy drugs, including vincristine, generally safe for treating acute lymphoblastic leukemia?

The combination of chemotherapy drugs, including vincristine, has been studied in various regimens for treating acute lymphoblastic leukemia (ALL). Some studies have shown that these combinations can be effective, but they may also lead to side effects like infections and other non-blood-related issues. It's important to discuss potential risks and benefits with your healthcare provider. ^{2 6 7 8 9}

What makes the chemotherapy and ponatinib treatment unique for acute lymphoblastic leukemia?

This treatment combines chemotherapy with ponatinib, a third-generation tyrosine kinase inhibitor, which has shown promising results in improving survival rates for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia, especially when compared to earlier treatments like imatinib. Ponatinib is particularly effective in achieving complete molecular responses, making it a novel option for this condition. ^{10 11 12 13 14}

Research Team

Elias Jabbour, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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.

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

I do not have severe heart failure.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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]

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 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]

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]

References

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

Ifosfamide and etoposide in recurrent childhood acute lymphoblastic leukemia. [2019]

2. United States 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. [2017]

3. 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]

4. England 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. [2019]

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

Cyclic combination chemotherapy for acute lymphoblastic leukemia recurring after elective cessation of therapy. [2019]

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

Comparison of two regimens for the treatment of elderly patients with acute lymphoblastic leukaemia (ALL). [2019]

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

Adult Acute Lymphoblastic Leukemia: Limitations of Intensification of Therapy in a Developing Country. [2020]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Development of constitutively synergistic nanoformulations to enhance chemosensitivity in T-cell leukemia. [2023]

9. United States 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. [2015]

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

INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph+ acute lymphoblastic leukemia. [2022]

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

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

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

Efficacy of Ponatinib Versus Earlier Generation Tyrosine Kinase Inhibitors for Front-line Treatment of Newly Diagnosed Philadelphia-positive Acute Lymphoblastic Leukemia. [2023]

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

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