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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how a combination of chemotherapy drugs, including nelarabine, works against T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma. The goal is to determine how effectively these drugs stop cancer cells from growing, spreading, or dividing. The trial is open to patients who have not received prior treatment or whose cancer has not responded to initial treatment. Patients with T-cell leukemia or lymphoma who have experienced ineffective treatment might be suitable for this study. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Research has shown that nelarabine, one of the drugs being tested, caused some side effects in past studies. Neurotoxicity, affecting the nervous system, occurred in about 72% of cases and often limited the drug's dosage. Additionally, about 29% of patients experienced neutropenia, a drop in white blood cells, and around 32% had thrombocytopenia, low platelet counts affecting blood clotting.

Many other drugs in this trial, such as cyclophosphamide, vincristine, and doxorubicin, are already used in chemotherapy. These drugs have known side effects, which are generally well understood due to their long-term use. For example, they can cause hair loss, nausea, and fatigue, but these effects are well-documented.

Overall, while nelarabine presents some significant side effects, past studies provide a good understanding of what to expect. The safety profile relies on previous research, and doctors use this information to monitor patients closely. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard chemotherapy options for leukemia and lymphoma, which often rely on traditional medications like cyclophosphamide and methotrexate, the study treatment includes nelarabine, which specifically targets and disrupts the growth of cancerous T-cells. Researchers are excited about this because nelarabine provides a more targeted approach, potentially reducing harm to healthy cells and leading to fewer side effects. Additionally, the treatment combines nelarabine with a powerful lineup of other chemotherapy drugs, offering a comprehensive attack on the cancer, which could improve overall effectiveness and outcomes for patients.

What evidence suggests that this trial's treatments could be effective for leukemia and lymphoma?

Research has shown that nelarabine, one of the treatments in this trial, yields promising results for treating T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma. In earlier studies, nelarabine alone enabled over half of the patients to achieve a complete response, meaning their cancer was no longer detectable after treatment. Nelarabine has also significantly improved survival rates, particularly in younger patients, with some having a 91% chance of being disease-free for four years. This trial will evaluate nelarabine in combination with other chemotherapy drugs, which could effectively stop cancer from growing and spreading in people with these conditions. ^{1 3 5 6 7}

Who Is on the Research Team?

Farhad Ravandi-Kashani

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 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

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

Exclusion Criteria

Pregnant or nursing women

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

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 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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39792179/

The efficacy and safety of nelarabine in relapsed or ... The pooled analysis revealed a CR rate of 37.9% (95% CI: 20.5-55.4%, p < 0.001) for Nelarabine monotherapy. Significant adverse events included ...

2. ashpublications.org ashpublications.org/bloodadvances/article/8/1/23/496638/Nelarabine-when-and-how-to-use-in-the-treatment-of

Nelarabine: when and how to use in the treatment of T-cell ... Here, we review current data on nelarabine and present our approach to the use of nelarabine in the treatment of patients with T-ALL/LBL.

3. link.springer.com link.springer.com/article/10.1007/s00277-024-06121-z

The efficacy and safety of nelarabine in relapsed or ... Nelarabine yielded favorable patient outcomes in terms of MRD, OS, DFS, and EFS. It was observed that 6/52 (11.53%) cases of MRD negative were ...

4. cancer.gov cancer.gov/news-events/cancer-currents-blog/2018/leukemia-nelarabine-improves-survival

Nelarabine Improves Survival in Young Patients with T-Cell ... This group of patients had a 4-year disease-free survival rate of 91%, which “is spectacular for pediatric T-ALL,” Dr. Smith said. Patients with ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S2473952922008151

Nelarabine combination therapy for relapsed or refractory T ... Nelarabine is approved as a single agent based on the results of previous studies which showed CR rates of 27% to 55% and 31% in pediatric and ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36448227/

A phase 1 study to evaluate the safety, pharmacology, and ... The overall response rate was 31%, including 27% complete remission (CR) or CR with incomplete platelet recovery (CRp). Peripheral neuropathy ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2025/021877Orig1s014lbl.pdf

ARRANON® (nelarabine) injection, for intravenous use Adult Patient: The safety profile of ARRANON is based on data from 103 adult patients treated with the recommended dose and schedule in 2 studies: an adult T- ...