LP-118 Combination Therapy for Lymphoblastic Leukemia-Lymphoma

Overseen By Wendy Stock, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Chicago

Disqualifiers: CNS leukemia, Hepatitis B/C, HIV, others

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

Compensation: Varies

Number of Visits: 7

Duration: 36 weeks

15 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to learn more about LP-118 (an experimental drug) and its side effects and decide on acceptable doses. The purpose of this study is to determine if LP-118 can be given safely with another medicine called ponatinib, that is FDA-approved for the treatment of acute lymphoblastic leukemia.

Do I need to stop my current medications to join the trial?

The trial information does not specify if you need to stop taking your current medications. However, there is a requirement for a washout period (time without taking certain medications) of 4 half-lives for those who participated in other investigational trials.

What data supports the effectiveness of the drug combination therapy for lymphoblastic leukemia-lymphoma?

Research shows that dexamethasone, a component of the therapy, is more effective than prednisone in treating acute lymphoblastic leukemia (ALL), although it may cause more side effects. Additionally, dexamethasone may help prevent central nervous system relapses in lymphoblastic lymphoma, but it also increases the risk of severe side effects. ^{1 2 3 4 5}

Is the LP-118 combination therapy generally safe for humans?

Dexamethasone, a component of the LP-118 combination therapy, has been shown to be more effective than prednisone in treating acute lymphoblastic leukemia (ALL) but is associated with greater toxicity, including potential impacts on neuropsychological function and quality of life in children. ^{1 6 7 8 9}

How is the LP-118 combination drug for lymphoblastic leukemia-lymphoma different from other drugs?

The LP-118 combination drug is unique because it combines multiple agents, including dexamethasone, LP-118, ponatinib, and vincristine, which may offer a novel approach by targeting different pathways in the cancer cells. This combination could potentially enhance treatment effectiveness compared to using these drugs individually. ^{1 2 4 6 10}

Eligibility Criteria

This trial is for individuals with relapsed or refractory Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL), including various types of non-Hodgkin's lymphoma and leukemia. Participants must have previously undergone treatment without success.

Inclusion Criteria

My leukemia or lymphoma has returned or didn't respond to treatment.

I have had a hysterectomy, my ovaries removed, or I am confirmed to be post-menopausal.

My blood or bone marrow has a specific level of cancer cells, or my cancer is visible on a CT scan.

Exclusion Criteria

I have hepatitis B, C, or HIV but my viral load is undetectable.

I do not have any severe uncontrolled health issues like heart or lung problems.

I have not had major surgery in the last 2 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive LP-118 and ponatinib in combination with standard chemotherapy drugs vincristine, dexamethasone, and methotrexate in 21-day cycles

36 weeks

7 visits in cycle 1, 5 visits per cycle for cycles 2-12

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Dexamethasone
• LP-118
• Ponatinib
• Vincristine

Trial Overview The study tests LP-118, an experimental drug, in combination with ponatinib, which is already approved for ALL treatment. It also includes vincristine, dexamethasone, and methotrexate to evaluate safety and determine the proper doses.

Participant Groups

Group I: All Participants (Single Arm) Experimental Treatment 5 Interventions

All study participants will receive LP-118 and ponatinib. The initial dose of LP-118 to be tested is 100 mg, and initial dose of ponatinib to be tested is 30 mg. Higher doses of LP-118 will only be tested if the study doctor feels it is safe to do so. A member of the study team will let study participants know which doses they are assigned. Study drugs will be given in 21-day cycles. There will be 7 study visits in cycle 1 (on Days 1, 5, 6, 7, 15, 22, and 28). LP-118 and ponatinib will be taken at home every day. Dexamethasone will be taken between days 1-7 and days 15-22. For Cycles 2-12, study participants will have 5 study visits per cycle (on Days 1, 8, 15, 22, and 28). On all days, study participants will take LP-118 and ponatinib at home. Participants in this group will also receive standard of care vincristine, dexamethasone, and methotrexate during study cycles.

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

Approved in European Union as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases
• Immune system disorders

Approved in United States as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders
• Neoplastic diseases
• Nervous system disorders

Approved in Canada as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases

Approved in Japan as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders

Who Is Running the Clinical Trial?

University of Chicago

Lead Sponsor

Trials

1,086

Recruited

844,000+

Findings from Research

In a study involving 408 children with acute lymphoblastic leukemia (ALL), dexamethasone was found to be more effective than prednisone in treatment, but it was associated with poorer performance in fluid reasoning tests among patients.

While most neuropsychological outcomes were similar between the two groups, a higher percentage of patients treated with dexamethasone required special education services (33% vs. 20% for prednisone), suggesting a need for further investigation into the long-term cognitive effects of dexamethasone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuropsychological outcomes of a randomized trial of prednisone versus dexamethasone in acute lymphoblastic leukemia: findings from Dana-Farber Cancer Institute All Consortium Protocol 00-01. Waber, DP., McCabe, M., Sebree, M., et al.[2021]

In a study involving 325 adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma, treatment with dexamethasone did not result in better event-free survival compared to prednisolone, with 6-year rates of 25.9% and 28.7% respectively.

Both treatments led to similar rates of complete remission (80.4% for dexamethasone and 76.5% for prednisolone), indicating that dexamethasone does not provide a significant therapeutic advantage over prednisolone in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexamethasone compared to prednisolone for adults with acute lymphoblastic leukemia or lymphoblastic lymphoma: final results of the ALL-4 randomized, phase III trial of the EORTC Leukemia Group. Labar, B., Suciu, S., Willemze, R., et al.[2021]

In a pilot study involving 34 patients with refractory acute lymphoblastic leukemia (ALL), high-dose dexamethasone combined with standard drugs achieved a complete remission (CR) rate of 47%, with a median duration of remission lasting 10 months.

For patients with late recurrences of ALL, the CR rate was notably higher at 70%, while those with primary resistant forms had a CR rate of 37.5%, indicating that high-dose dexamethasone is a promising treatment option for difficult cases of ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Superhigh doses of dexamethasone in treatment of refractory forms of acute lymphoblast leukemia of adults]. Parovichnikova, EN., Savchenko, VG., Isaev, VG., et al.[2013]

In the EURO-LB02 trial involving 319 patients with lymphoblastic lymphoma, the 5-year event-free survival rate was 82%, but the previously reported 90% rate for T-cell lymphoblastic lymphoma was not achieved, primarily due to increased toxic deaths and central nervous system relapses.

Patients receiving dexamethasone during induction experienced significantly more severe toxicities compared to those on prednisone, leading to treatment delays, although dexamethasone may be more effective in preventing central nervous system relapses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results and conclusions of the European Intergroup EURO-LB02 trial in children and adolescents with lymphoblastic lymphoma. Landmann, E., Burkhardt, B., Zimmermann, M., et al.[2018]

In a study involving 11 patients with advanced lymphocytic lymphosarcoma and chronic lymphocytic leukemia, the new drug LEO 1031 showed promising results, achieving three complete remissions and one partial remission in lymphocytic lymphosarcoma patients.

Among patients with chronic lymphocytic leukemia, three out of four experienced benefits from LEO 1031, suggesting its potential efficacy and warranting further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of chronic lymphocytic leukemia and lymphosarcoma with a new chlorambucil ester of prednisolone (Leo 1031) (NSC-134087). Aungst, CW., Mittelman, A., Murphy, GP.[2019]

The hyper-CVAD regimen shows a high complete remission rate of 90.4% after the first cycle in adults with acute lymphoblastic leukemia (ALL), indicating its efficacy as a treatment option.

The study found a low induction mortality rate of 1.9%, but highlighted the need for antiviral prophylaxis in patients with hepatitis B to prevent reactivation, as 11% experienced hepatitis flare due to HBV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcomes of patients with acute lymphoblastic leukemia receiving the hyper-CVAD regimen and assessment of the risk of hepatitis flares due to hepatitis B virus reactivation after chemotherapy. Law, MF., Chan, HN., Kong, SY., et al.[2022]

Dexamethasone (DXM) is significantly more effective than prednisolone (PDN) in treating acute lymphoblastic leukemia (ALL), showing better cytotoxicity in vitro and leading to lower rates of central nervous system relapses and improved event-free survival in children.

A recent trial indicated that DXM did not provide additional benefits over PDN in adult ALL patients, particularly those at high risk, suggesting that the effectiveness of DXM may vary significantly between pediatric and adult populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Which steroids should we choose for the treatment of adult acute lymphoblastic leukemia? Zheng, C., Liu, X., Wu, J., et al.[2019]

In a study involving 45 children with acute lymphoblastic leukemia (ALL), both dexamethasone and prednisone showed similar improvements in health-related quality of life (HRQOL) and behavior over one year, suggesting that dexamethasone does not negatively impact these outcomes compared to prednisone.

Despite concerns about the potential neuropsychological toxicity of dexamethasone, the results indicate that its use in ALL treatment is associated with significant improvements in HRQOL without significant differences in outcomes compared to traditional therapy with prednisone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HRQOL implications of treatment with dexamethasone for children with acute lymphoblastic leukemia (ALL). Eiser, C., Davies, H., Jenney, M., et al.[2016]

In a study involving 1603 children with newly diagnosed acute lymphoblastic leukaemia (ALL), substituting dexamethasone for prednisolone significantly reduced the risk of isolated central nervous system (CNS) relapse by half.

Dexamethasone treatment improved event-free survival rates to 84.2% compared to 75.6% with prednisolone over 5 years, indicating that despite its increased toxicity, dexamethasone should be considered a standard part of therapy for childhood ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. Mitchell, CD., Richards, SM., Kinsey, SE., et al.[2022]

In a randomized trial involving over 1000 children with standard-risk acute lymphoblastic leukemia (ALL), dexamethasone was found to significantly reduce the risk of central nervous system relapses compared to prednisone, with a 6-year relapse rate of 3.7% versus 7.1%.

The study also showed that dexamethasone improved event-free survival rates at 6 years (85%) compared to prednisone (77%), indicating that dexamethasone may be a more effective treatment option in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Bostrom, BC., Sensel, MR., Sather, HN., et al.[2021]

References

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

Neuropsychological outcomes of a randomized trial of prednisone versus dexamethasone in acute lymphoblastic leukemia: findings from Dana-Farber Cancer Institute All Consortium Protocol 00-01. [2021]

2. Italy pubmed.ncbi.nlm.nih.gov

Dexamethasone compared to prednisolone for adults with acute lymphoblastic leukemia or lymphoblastic lymphoma: final results of the ALL-4 randomized, phase III trial of the EORTC Leukemia Group. [2021]

3. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Superhigh doses of dexamethasone in treatment of refractory forms of acute lymphoblast leukemia of adults]. [2013]

4. Italy pubmed.ncbi.nlm.nih.gov

Results and conclusions of the European Intergroup EURO-LB02 trial in children and adolescents with lymphoblastic lymphoma. [2018]

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

Treatment of chronic lymphocytic leukemia and lymphosarcoma with a new chlorambucil ester of prednisolone (Leo 1031) (NSC-134087). [2019]

6. Poland pubmed.ncbi.nlm.nih.gov

Clinical outcomes of patients with acute lymphoblastic leukemia receiving the hyper-CVAD regimen and assessment of the risk of hepatitis flares due to hepatitis B virus reactivation after chemotherapy. [2022]

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

Which steroids should we choose for the treatment of adult acute lymphoblastic leukemia? [2019]

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

HRQOL implications of treatment with dexamethasone for children with acute lymphoblastic leukemia (ALL). [2016]

9. England pubmed.ncbi.nlm.nih.gov

Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. [2022]

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

Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. [2021]