Combination Chemotherapy + Nelarabine for Leukemia and Lymphoma

Overseen By Farhad Ravandi-Kashani, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Disqualifiers: Pregnant, Nursing women

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: 8 courses, each 21 days

160 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 nelarabine work in treating patients with T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma. Drugs used in chemotherapy, such as cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine, mercaptopurine, prednisone, pegaspargase, nelarabine, and venetoclax 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.

Do I need to stop my current medications for this trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug combination chemotherapy with nelarabine for leukemia and lymphoma?

Research shows that a combination of nelarabine with other drugs like etoposide and cyclophosphamide led to complete remission in five out of seven children with relapsed or refractory T-cell leukemia or lymphoma. Additionally, the hyper-CVAD regimen, which includes some of the same drugs, has shown significant activity in adult acute lymphocytic leukemia and other blood cancers. ^{1 2 3 4 5}

Is the combination chemotherapy with venetoclax generally safe for humans?

The combination of venetoclax with other chemotherapy drugs has been studied for safety in various conditions, including aggressive B-cell lymphoma and acute myeloid leukemia. Common side effects include blood-related issues like low white blood cell counts, which can lead to infections, and some patients experienced serious adverse reactions, including febrile neutropenia (fever with low white blood cell count). ^{6 7 8 9 10}

What makes the combination chemotherapy with nelarabine unique for leukemia and lymphoma?

This treatment is unique because it combines nelarabine, which specifically targets cancerous T-cells, with a variety of other chemotherapy drugs to enhance effectiveness against leukemia and lymphoma. Nelarabine is particularly used for cases that are resistant to other treatments, and the combination aims to improve remission rates, although it requires careful monitoring for side effects like neurotoxicity. ^{1 11 12 13 14}

Research Team

Farhad Ravandi-Kashani

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for patients with T-cell acute lymphoblastic leukemia or lymphoma who haven't been treated before, or those who didn't respond to one chemo treatment but are now in remission after up to two courses. They must have acceptable levels of bilirubin and creatinine, liver enzymes no more than four times the normal limit, and be able to perform daily activities (ECOG status ≤3). Pregnant or nursing women can't participate.

Inclusion Criteria

I have T cell ALL or lymphoma and haven't been treated, or only had one chemotherapy course.

Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) less than or equal to 4 x upper limit of normal (ULN)

Serum bilirubin less than or equal to 2.0 mg/dL unless considered due to involvement by tumor when an upper limit of 5.0 mg/dL is acceptable

Exclusion Criteria

Pregnant or nursing women

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive hyper-CVAD and methotrexate/cytarabine courses, along with nelarabine, pegaspargase, and venetoclax

8 courses, each 21 days

Maintenance

Participants receive POMP maintenance therapy with mercaptopurine, vincristine, methotrexate, prednisone, and venetoclax

30 months

Intensification

Participants receive nelarabine, pegaspargase, and venetoclax during intensification courses

4 courses, each 21-35 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 3-6 months

Treatment Details

Interventions

• Cyclophosphamide
• Cytarabine
• Dexamethasone
• Doxorubicin Hydrochloride
• Mercaptopurine
• Methotrexate
• Nelarabine
• Pegaspargase
• Prednisone
• Venetoclax
• Vincristine Sulfate

Trial Overview The study tests how well a combination of chemotherapy drugs works against certain blood cancers. It includes Prednisone, Nelarabine, Cyclophosphamide, Cytarabine, Dexamethasone, Methotrexate, Doxorubicin Hydrochloride, Pegaspargase, Mercaptopurine,Venetoclax,and Vincristine Sulfate.

Participant Groups

Group I: Treatment (nelarabine and combination chemotherapy) Experimental Treatment 11 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+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study involving seven children with refractory or relapsed T-cell leukemia or lymphoma, a combination therapy of nelarabine, etoposide, and cyclophosphamide showed promising results, with five out of seven patients achieving complete remission after treatment.

While the combination therapy was effective, it was associated with increased hematological toxicity and neurological side effects, such as sensory and motor neuropathy, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Salvage therapy with nelarabine, etoposide, and cyclophosphamide in relapsed/refractory paediatric T-cell lymphoblastic leukaemia and lymphoma. Commander, LA., Seif, AE., Insogna, IG., et al.[2021]

The COG AALL0434 trial, involving 299 patients aged 1-31, demonstrated that the Capizzi-based methotrexate/pegaspargase regimen resulted in a high response rate, with 98.8% of participants achieving at least a partial response by the end of induction.

The trial reported impressive 4-year event-free survival (EFS) of 84.7% and overall survival (OS) of 89.0%, indicating that this treatment is effective for newly diagnosed pediatric T-cell lymphoblastic lymphoma without the need for prophylactic cranial radiation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Outcomes of Newly Diagnosed T Lymphoblastic Lymphoma: Results From Children's Oncology Group AALL0434. Hayashi, RJ., Winter, SS., Dunsmore, KP., et al.[2023]

The hyper-CVAD regimen, which includes cyclophosphamide, vincristine, doxorubicin, and dexamethasone, has shown significant effectiveness in treating adult lymphocytic leukemia and other blood cancers, such as Burkitt's disease and multiple myeloma.

Clinical trials conducted at the University of Texas M. D. Anderson Cancer Center have provided strong evidence for the efficacy of hyper-CVAD, leading to ongoing discussions about strategies to enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The hyper-CVAD regimen in adult acute lymphocytic leukemia. Garcia-Manero, G., Kantarjian, HM.[2019]

In a study comparing treatments for Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL), patients receiving hyper-CVAD with ofatumumab had a median event-free survival of 65 months, compared to 33 months for those treated with hyper-CVAD plus rituximab.

The overall survival for the ofatumumab group was not reached, indicating potentially better long-term outcomes, while the rituximab group had a median overall survival of 52 months, suggesting that ofatumumab may offer superior efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyper-CVAD plus ofatumumab versus hyper-CVAD plus rituximab as frontline therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: A propensity score analysis. Sasaki, K., Kantarjian, HM., Morita, K., et al.[2022]

In a study of 56 untreated childhood acute lymphoblastic leukemia (ALL) patients, the complete remission rates were similar across three treatment regimens, indicating that adding anthracyclines (daunorubicin or adriamycin) did not significantly improve remission outcomes compared to vincristine and prednisone alone.

However, the anthracycline regimens led to increased granulocytopenia and a higher rate of infectious complications, suggesting that while they may offer some theoretical benefits, their use could result in greater morbidity without improving long-term remission or survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and cytokinetic aspects of remission induction of childhood acute lymphoblastic leukemia (ALL): addition of an anthracycline to vincristine and prednisone. Sallan, SE., Camitta, BM., Frei, E., et al.[2019]

In a phase 1 study involving 30 patients with aggressive B-cell lymphomas, the combination of venetoclax and dose-adjusted EPOCH-R demonstrated a high overall response rate of 96.7%, with 93.3% achieving a complete response, indicating strong efficacy in this high-risk population.

The maximum tolerated dose of venetoclax was determined to be 800 mg for 10 days, with a recommended phase 2 dose of 600 mg for 5 days, showing an acceptable safety profile despite common adverse events like cytopenias and febrile neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax with dose-adjusted EPOCH-R as initial therapy for patients with aggressive B-cell lymphoma: a single-arm, multicentre, phase 1 study. Rutherford, SC., Abramson, JS., Bartlett, NL., et al.[2021]

The combination of fludarabine, cytarabine, granulocyte colony-stimulating factor, idarubicin, and venetoclax showed a high overall response rate of 75% in relapsed/refractory acute myeloid leukemia (R/R-AML) and 97% in newly diagnosed acute myeloid leukemia (ND-AML), indicating its efficacy as a treatment option.

Patients with ND-AML and R/R-AML who underwent allogeneic hematopoietic stem-cell transplantation after this treatment had significantly improved overall survival rates, with 1-year survival rates of 94% for ND-AML and 78% for R/R-AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax Combined With FLAG-IDA Induction and Consolidation in Newly Diagnosed and Relapsed or Refractory Acute Myeloid Leukemia. DiNardo, CD., Lachowiez, CA., Takahashi, K., et al.[2022]

In a real-world study of 24 patients with acute myeloid leukemia (AML) treated with the oral BCL2 inhibitor venetoclax (VEN) combined with hypomethylating agents (HMAs), 52% achieved complete remission, indicating significant efficacy for patients unfit for intensive chemotherapy.

However, the treatment was associated with a high rate of adverse drug reactions, with 79% of patients experiencing serious side effects, including a notable incidence of febrile neutropenia, which led to 3 deaths, highlighting the need for careful monitoring of safety in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Off-Label Use of Venetoclax in Patients With Acute Myeloid Leukemia: Single Center Experience and Data From Pharmacovigilance Database. Gozzo, L., Vetro, C., Brancati, S., et al.[2021]

Coadministration of azithromycin with venetoclax resulted in a modest reduction in venetoclax levels (25% lower maximum concentration and 35% lower area under the curve), but did not require any dose adjustments, indicating that azithromycin is a safe option for patients taking venetoclax.

The study involved 12 healthy female subjects and found that venetoclax was well tolerated with no serious adverse events, suggesting that azithromycin can be used as an alternative antibiotic without significantly impacting venetoclax pharmacokinetics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Azithromycin on Venetoclax Pharmacokinetics in Healthy Volunteers: Implications for Dosing Venetoclax with P-gp Inhibitors. Agarwal, SK., Tong, B., Bueno, OF., et al.[2019]

The study successfully replaced toxic chemotherapy drugs vincristine and doxorubicin with vindesine and epirubicin hydrochloride in the EPOCH regimen, aiming to reduce neurovirulence and cardiotoxicity in patients with relapsed or refractory non-Hodgkin's lymphoma.

In vitro tests showed that the new drug combinations were stable and compatible in a 0.9% NaCl solution for at least 24 hours, maintaining over 96% of their initial concentrations, which supports their potential for safe clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro compatibility and stability of admixtures containing etoposide, epirubicin hydrochloride and vindesine sulphate in a single infusion bag. Li, J., Yao, C., Xu, Y., et al.[2022]

In a phase I pilot study involving 18 patients with refractory lymphoid malignancies, the MILD chemotherapy regimen (methotrexate, ifosfamide, l-asparaginase, and dexamethasone) demonstrated a 57% overall response rate, with complete responses in 3 patients and partial responses in 4 patients.

The treatment was generally feasible with acceptable toxicity, although one patient experienced treatment-related death from systemic mucormycosis, and significant hematologic toxicities were observed, particularly in patients with T/NK-cell malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity and safety of combination chemotherapy with methotrexate, ifosfamide, l-asparaginase and dexamethasone (MILD) for refractory lymphoid malignancies: a pilot study. Tsukune, Y., Isobe, Y., Yasuda, H., et al.[2013]

Nelarabine is an effective treatment for adult and pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL) that has not responded to at least two prior chemotherapy regimens, highlighting its role in managing refractory cases.

As a prodrug that converts to ara-GTP in cancerous T-cells, nelarabine shows a targeted mechanism of action, but its use is limited by dose-dependent toxicities such as neurotoxicity and myelosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nelarabine in the treatment of refractory T-cell malignancies. Roecker, AM., Stockert, A., Kisor, DF.[2021]

In a study of 21 patients with advanced non-Hodgkin's lymphoma treated with the VINAP chemotherapy regimen, 76% showed a response, with 23% achieving complete remission, indicating significant efficacy for this heavily pretreated group.

The VINAP regimen had an acceptable safety profile, with manageable side effects like myelosuppression and mucositis, but no severe neurological issues or skin reactions were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Vindesine, CCNU, high-dosage ara-C, and prednisolone (VINAP regimen) in the treatment of relapsing or refractory non-Hodgkin's lymphomas]. Domingo Albós, A., Callís, M., Juliá, A., et al.[2013]

The ESHAOx regimen, which replaces cisplatin with oxaliplatin, showed a 63% overall response rate in 27 patients with refractory or relapsed aggressive non-Hodgkin's lymphoma, indicating its potential effectiveness as a treatment option.

While the treatment resulted in significant hematologic toxicities like neutropenia (56%) and thrombocytopenia (35%), it did not cause severe renal or neurotoxicity, suggesting a favorable safety profile for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter phase II trial of etoposide, methylprednisolone, high-dose cytarabine, and oxaliplatin for patients with primary refractory/relapsed aggressive non-Hodgkin's lymphoma. Sym, SJ., Lee, DH., Kang, HJ., et al.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Salvage therapy with nelarabine, etoposide, and cyclophosphamide in relapsed/refractory paediatric T-cell lymphoblastic leukaemia and lymphoma. [2021]

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

Successful Outcomes of Newly Diagnosed T Lymphoblastic Lymphoma: Results From Children's Oncology Group AALL0434. [2023]

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

The hyper-CVAD regimen in adult acute lymphocytic leukemia. [2019]

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

Hyper-CVAD plus ofatumumab versus hyper-CVAD plus rituximab as frontline therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: A propensity score analysis. [2022]

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

Clinical and cytokinetic aspects of remission induction of childhood acute lymphoblastic leukemia (ALL): addition of an anthracycline to vincristine and prednisone. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Venetoclax with dose-adjusted EPOCH-R as initial therapy for patients with aggressive B-cell lymphoma: a single-arm, multicentre, phase 1 study. [2021]

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

Venetoclax Combined With FLAG-IDA Induction and Consolidation in Newly Diagnosed and Relapsed or Refractory Acute Myeloid Leukemia. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Off-Label Use of Venetoclax in Patients With Acute Myeloid Leukemia: Single Center Experience and Data From Pharmacovigilance Database. [2021]

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

Effect of Azithromycin on Venetoclax Pharmacokinetics in Healthy Volunteers: Implications for Dosing Venetoclax with P-gp Inhibitors. [2019]

10. England pubmed.ncbi.nlm.nih.gov

In vitro compatibility and stability of admixtures containing etoposide, epirubicin hydrochloride and vindesine sulphate in a single infusion bag. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Activity and safety of combination chemotherapy with methotrexate, ifosfamide, l-asparaginase and dexamethasone (MILD) for refractory lymphoid malignancies: a pilot study. [2013]

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

Nelarabine in the treatment of refractory T-cell malignancies. [2021]

13. Spain pubmed.ncbi.nlm.nih.gov

[Vindesine, CCNU, high-dosage ara-C, and prednisolone (VINAP regimen) in the treatment of relapsing or refractory non-Hodgkin's lymphomas]. [2013]

14. Germany pubmed.ncbi.nlm.nih.gov

A multicenter phase II trial of etoposide, methylprednisolone, high-dose cytarabine, and oxaliplatin for patients with primary refractory/relapsed aggressive non-Hodgkin's lymphoma. [2018]