Chemoimmunotherapy + Stem Cell Transplant for NK T-cell Lymphoma/Leukemia

Recruiting at 5 trial locations

Overseen By Lauren Harrison

Age: < 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: New York Medical College

Must not be taking: CYP3A4 substrates, inhibitors, inducers

Disqualifiers: Down syndrome, Active CNS disease, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

40 Participants Needed

Trial Summary

What is the purpose of this trial?

Patients are in 2 cohorts: Cohort 1: dexamethasone, methotrexate, ifosfamide, pegaspargase, and etoposide (modified SMILE) chemotherapy regimen alone and pembrolizumab in children, adolescents, and young adults with advanced stage NK lymphoma and leukemia Cohort 2: combining pralatrexate (PRX) (Cycles 1, 2, 4, 6) and brentuximab vedotin (BV) (Cycles 3, 5) to cyclophosphamide, doxorubicin, and prednisone in children, adolescent, and young adults with advanced peripheral T-cell lymphoma (non-anaplastic large cell lymphoma or non-NK lymphoma/leukemia) . Both groups proceed to allogeneic stem cell transplant with disease response.

Will I have to stop taking my current medications?

If you are in Cohort 2 and taking medications that affect CYP3A4, you may need to stop them before joining the trial. Specifically, you should not take CYP3A4 inhibitors within 7 days or CYP3A4 inducers within 12 days before enrolling. The trial does not specify other medication restrictions.

What data supports the effectiveness of the treatment for NK T-cell Lymphoma/Leukemia?

Research shows that treatments involving components like pegaspargase, dexamethasone, and etoposide have been effective in treating NK/T-cell lymphoma. For example, a study using the MEDA regimen (which includes methotrexate, etoposide, dexamethasone, and pegaspargase) showed a high response rate and improved long-term survival when followed by stem cell transplantation. ^{1 2 3 4 5}

What safety data exists for Brentuximab Vedotin in humans?

Brentuximab Vedotin has been shown to be generally safe in humans, but it can cause side effects like peripheral neuropathy (nerve damage causing tingling or numbness), fatigue, nausea, and fever. Serious side effects, though rare, include severe nerve damage and blood-related issues, and it carries a warning for a rare brain infection. Overall, it is considered to have a manageable safety profile in treating certain types of lymphoma. ^{6 7 8 9 10}

What makes the chemoimmunotherapy and stem cell transplant treatment for NK T-cell lymphoma/leukemia unique?

This treatment is unique because it combines chemoimmunotherapy with a stem cell transplant, using a mix of drugs like Brentuximab Vedotin and Calaspargase Pegol, which are not typically used together in standard treatments for NK T-cell lymphoma/leukemia. This combination aims to enhance the immune response and improve outcomes for patients with this rare and aggressive cancer. ^{1 2 3 11 12}

Research Team

Mitchell Cairo, MD

Principal Investigator

New York Medical College

Eligibility Criteria

This trial is for children, adolescents, and young adults with advanced T-cell or NK-cell leukemia/lymphoma. They must weigh at least 10 kg, have good heart and lung function, and not be pregnant or breastfeeding. Prior chemotherapy for the current diagnosis disqualifies participation.

Inclusion Criteria

My lymphoma is at an advanced stage (III or IV).

I have been recently diagnosed with a specific type of blood cancer.

Adequate cardiac function defined as: Shortening fraction of ≥ 27% by echocardiogram, or Ejection fraction of ≥ 50% by radionuclide angiogram

Exclusion Criteria

I have only used steroids or radiation in emergencies.

I have an active brain or spinal cord disease.

My condition is ALK positive or negative Anaplastic Large Cell Lymphoma.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Chemoimmunotherapy

Participants receive induction chemoimmunotherapy with either modified SMILE regimen and pembrolizumab or pralatrexate and brentuximab vedotin, depending on cohort

6 cycles

Allogeneic Stem Cell Transplant

Participants proceed to allogeneic stem cell transplant if a donor is available and they are not in progressive disease

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Treatment Details

Interventions

• Brentuximab Vedotin
• Calaspargase Pegol
• Cyclophosphamide
• Dexamethasone
• Doxorubicin
• Etoposide
• Ifosfamide
• Methotrexate
• Pralatraxate
• Prednisone

Trial Overview The study tests two chemoimmunotherapy regimens: modified SMILE plus pembrolizumab (Cohort 1) for NK cell cancers; PRX/BV combined with other drugs (Cohort 2) for peripheral T-cell lymphomas. Successful participants will proceed to allogeneic stem cell transplant.

Participant Groups

Group I: Cohort 2 Experimental Treatment 5 Interventions

Patients with stage III or IV peripheral T-cell lymphoma-NOS, angioimmunoblastic T-cell lymphoma, hepatosplenic T-cell lymphoma, or enteropathy-associated T-cell lymphoma (other histologies will be considered after case-by-case discussion with Study Chairs and Executive Vice-Chairs). Chemotherapy Regimen: Cycle 1 \& 2: Pralatrexate Days 1, 8, and 15, cyclophosphamide Day 1, DOXOrubicin Day 1, predniSONE days 1-5 Cycle 3 \& 5: Brentuximab vedotin Day 1, cyclophosphamide Day 1, DOXOrubicin Day 1, predniSONE days 1-5 Cycle 4 \& 6: Pralatrexate Days 1, 8, and 15, cyclophosphamide Day 1, DOXOrubicin Day 1, predniSONE days 1-5 Allogeneic Stem Cell Transplant if donor available and not in PD.

Group II: Cohort 1 Experimental Treatment 5 Interventions

Patients with aggressive NK cell leukemia or stage III or IV extranodal NK/T-cell lymphoma, nasal type. Chemotherapy Regimen: mSMILE: Methotrexate Day 1, Ifosfamide Days 2-4, Dexamethasone Days 2-4, Etoposide Days 2-4, calaspargase pegol Day 8. For patients in CR and no available allogeneic SCT can receive up to 2 additional cycles of mSMILE. Pembrolizumab: For patients in PR/MR/NR/PD after 2 cycles of mSMILE. Allogeneic Stem Cell Transplant if donor available and not in PD.

Brentuximab Vedotin is already approved in United States, European Union for the following indications:

Approved in United States as Adcetris for:

• Hodgkin lymphoma
• Systemic anaplastic large cell lymphoma
• Primary cutaneous anaplastic large cell lymphoma
• CD30-expressing mycosis fungoides
• Peripheral T-cell lymphoma

Approved in European Union as Adcetris for:

• Hodgkin lymphoma
• Systemic anaplastic large cell lymphoma
• Cutaneous T-cell lymphoma

Who Is Running the Clinical Trial?

New York Medical College

Lead Sponsor

Trials

73

Recruited

8,700+

University of Alabama at Birmingham

Collaborator

Trials

1,677

Recruited

2,458,000+

Findings from Research

The P-GDP chemotherapy regimen (pegaspargase, gemcitabine, dexamethasone, and cisplatin) demonstrated a high overall response rate of 89.5% in 57 patients with newly diagnosed extranodal NK/T-cell lymphoma, with a complete response rate of 70.2%.

The treatment showed promising safety, with no treatment-related deaths reported, although common severe side effects included neutropenia (42.1%) and thrombocytopenia (38.6%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pegaspargase, gemcitabine, dexamethasone, and cisplatin (P-GDP) combined chemotherapy is effective for newly diagnosed extranodal NK/T-cell lymphoma: a retrospective study. Liu, T., Zhu, F., Xiao, Y., et al.[2022]

The SVILE regimen, which includes dexamethasone, vindesine, ifosfamide, pegaspargase, and etoposide, showed a 70% overall response rate and a 45% complete response rate in 20 patients with relapsed/refractory extranodal natural killer/T-cell lymphoma, indicating its effectiveness as a treatment option.

Patients in earlier stages (I/II) had significantly better outcomes, with a 100% complete response rate and three-year progression-free survival of 100%, compared to lower rates in later stages (III/IV), highlighting the importance of early intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SVILE regimen, a combination of dexamethasone, vindesine, ifosfamide, pegaspargase, and etoposide, for treating relapsed/refractory extranodal natural killer/T-cell lymphoma, nasal type. Wei, L., Wang, L., Cong, J., et al.[2020]

In a phase 2 study of 53 patients with stage IV natural killer/T-cell lymphoma, the MEDA chemotherapy regimen resulted in a high overall response rate of 75.5% and a complete response rate of 56.6%, indicating its effectiveness as an induction treatment.

Patients who underwent autologous hematopoietic stem cell transplantation (Auto-HSCT) after achieving complete response had significantly improved long-term survival rates, with a 4-year overall survival rate of 92.0% and progression-free survival rate of 80.0%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction with MEDA regimen and consolidation with Auto-HSCT for stage IV NKTCL patients: A prospective multicenter study. Liu, C., Ding, H., Zhu, Q., et al.[2022]

In a study of 62 patients with acute lymphoblastic leukemia (ALL) and T cell non-Hodgkin's lymphoma (T-NHL), combined chemotherapy with pegasparaginase (PEG-Asp) showed a slightly higher overall response rate (90.91%) compared to standard chemotherapy with L-asparaginase (L-Asp) (87.5%), although the difference was not statistically significant.

The PEG-Asp group experienced lower drug toxicity and completed treatment without severe adverse effects, suggesting that PEG-Asp could be a safer and more effective alternative to L-Asp for treating ALL and T-NHL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Comparison of the Effectiveness and Safety of Combined Chemotherapy with PEG-Asp for Treatment of ALL and T-NHL Patients]. Xu, Y., Wang, J., Yang, N., et al.[2018]

In a study of 40 newly diagnosed patients with early NK/T-cell lymphoma, the treatment regimen of DDGP (pegaspargase, gemcitabine, cisplatin, and dexamethasone) followed by radiotherapy resulted in a significantly higher complete response rate (85% vs 50%) and overall response rate (95% vs 65%) compared to the VIPD regimen (etoposide, ifosfamide, cisplatin, and dexamethasone).

Patients receiving DDGP followed by radiotherapy also experienced better 5-year progression-free survival rates (83.3% vs 44.4%), although there was no significant difference in overall survival rates between the two treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DDGP followed by radiotherapy vs VIPD followed by radiotherapy in newly diagnosed early NK/T-cell lymphoma. Zhang, L., Shangguan, C., Li, X., et al.[2022]

Brentuximab vedotin (Adcetris®) is an effective targeted therapy for relapsed refractory systemic anaplastic large-cell lymphoma, showing a high response rate and durable remissions in patients.

While generally well-tolerated, brentuximab vedotin can cause side effects such as peripheral neuropathy and has a serious risk of progressive multifocal leukoencephalopathy, leading to a black box warning from the FDA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin: treatment role for relapsed refractory systemic anaplastic large-cell lymphoma. Lai, CM., Horowitz, S.[2019]

Brentuximab vedotin demonstrated a high overall response rate of 70.7% in a study of 65 heavily pretreated patients with relapsed or refractory Hodgkin's lymphoma, indicating its efficacy in a real-world clinical setting.

The treatment was generally well tolerated, with manageable toxicities; however, peripheral neuropathy was the most common side effect, affecting 21.5% of patients, which led to some treatment discontinuations and dose reductions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin in relapsed/refractory Hodgkin's lymphoma: the Italian experience and results of its use in daily clinical practice outside clinical trials. Zinzani, PL., Viviani, S., Anastasia, A., et al.[2021]

Brentuximab vedotin showed an overall response rate of 67% and a complete remission rate of 26% in patients with relapsed/refractory Hodgkin lymphoma, while in systemic anaplastic large-cell lymphoma, the response rate was 75% with a high complete remission rate of 74%.

The treatment was generally well-tolerated, with low incidences of severe neurologic (6%) and hematologic (12%) toxicities, and only 5% of patients discontinued treatment due to toxicity, indicating a favorable safety profile in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experience of brentuximab vedotin in relapsed/refractory Hodgkin lymphoma and relapsed/refractory systemic anaplastic large-cell lymphoma in the Named Patient Program: Review of the literature. Zinzani, PL., Sasse, S., Radford, J., et al.[2019]

In a review of 2225 lymphoma patients from 4 randomized controlled trials, brentuximab vedotin was found to significantly increase the risk of all-grade adverse events (AEs) and high-grade AEs compared to non-brentuximab vedotin treatments.

Specific AEs associated with brentuximab vedotin included a higher risk of peripheral sensory neuropathy, pyrexia, nausea, vomiting, diarrhea, and alopecia, with particularly high risks for high-grade sensory neuropathy and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of adverse events in lymphoma patients treated with brentuximab vedotin: a systematic review and meta-analysis. Gao, S., Zhang, M., Wu, K., et al.[2021]

Brentuximab vedotin is an effective treatment for relapsed or refractory Hodgkin lymphoma and other CD30-positive cancers, showing durable antitumor activity with a manageable safety profile.

The main side effect of brentuximab vedotin is peripheral sensory neuropathy, which is dose-related and cumulative, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin. van de Donk, NW., Dhimolea, E.[2023]

In a study of 32 patients with nasal NK/T-cell lymphoma, an intensive combined therapy led to a complete response in 65% of cases, demonstrating significant efficacy in treating this rare and aggressive cancer.

The treatment, which included high-dose chemotherapy and radiotherapy, resulted in a 100% event-free survival rate at 5 years for those who responded completely, indicating a promising therapeutic approach for improving outcomes in a disease with historically poor prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nasal NK/T-cell lymphoma with disseminated disease treated with aggressive combined therapy. Avilés, A., Neri, N., Fernández, R., et al.[2018]

The combination of pegaspargase, cyclophosphamide, vincristine, etoposide, and prednisone (COEPL) with radiotherapy showed a high efficacy in treating newly diagnosed extra-nodal NK/T-cell lymphoma (ENKTL), achieving a complete response rate of 75.9% and an overall response rate of 87.3% among 80 patients studied.

With a median follow-up of 41.4 months, the 3-year progression-free survival (PFS) and overall survival (OS) rates were 71.3% and 73.3%, respectively, indicating that this treatment regimen is both effective and safe, with no treatment-related deaths reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Prospective Phase II Study of Pegaspargase-COEP Plus Radiotherapy in Patients With Newly Diagnosed Extra-Nodal NK/T-Cell Lymphoma. Hu, S., Lin, N., Liu, J., et al.[2022]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Pegaspargase, gemcitabine, dexamethasone, and cisplatin (P-GDP) combined chemotherapy is effective for newly diagnosed extranodal NK/T-cell lymphoma: a retrospective study. [2022]

2. England pubmed.ncbi.nlm.nih.gov

SVILE regimen, a combination of dexamethasone, vindesine, ifosfamide, pegaspargase, and etoposide, for treating relapsed/refractory extranodal natural killer/T-cell lymphoma, nasal type. [2020]

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

Induction with MEDA regimen and consolidation with Auto-HSCT for stage IV NKTCL patients: A prospective multicenter study. [2022]

4. China pubmed.ncbi.nlm.nih.gov

[Comparison of the Effectiveness and Safety of Combined Chemotherapy with PEG-Asp for Treatment of ALL and T-NHL Patients]. [2018]

5. England pubmed.ncbi.nlm.nih.gov

DDGP followed by radiotherapy vs VIPD followed by radiotherapy in newly diagnosed early NK/T-cell lymphoma. [2022]

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

Brentuximab vedotin: treatment role for relapsed refractory systemic anaplastic large-cell lymphoma. [2019]

7. Italy pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin in relapsed/refractory Hodgkin's lymphoma: the Italian experience and results of its use in daily clinical practice outside clinical trials. [2021]

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

Experience of brentuximab vedotin in relapsed/refractory Hodgkin lymphoma and relapsed/refractory systemic anaplastic large-cell lymphoma in the Named Patient Program: Review of the literature. [2019]

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

Risk of adverse events in lymphoma patients treated with brentuximab vedotin: a systematic review and meta-analysis. [2021]

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

Brentuximab vedotin. [2023]

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

Nasal NK/T-cell lymphoma with disseminated disease treated with aggressive combined therapy. [2018]

12. Switzerland pubmed.ncbi.nlm.nih.gov

A Prospective Phase II Study of Pegaspargase-COEP Plus Radiotherapy in Patients With Newly Diagnosed Extra-Nodal NK/T-Cell Lymphoma. [2022]