Tazemetostat + CHOP for T-Cell Lymphoma

Recruiting at 2 trial locations

Overseen By Eric Jacobsen, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Eric Jacobsen, MD

Must not be taking: Investigational agents

Disqualifiers: CNS involvement, Organ transplant, Pregnancy, 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: 2

24 Participants Needed

Trial Summary

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

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that participants should not be on other investigational agents and should not have had prior chemotherapy for T-cell lymphoma, except for one cycle of CHOP/CHOEP or a short course of corticosteroids. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Tazemetostat + CHOP for T-Cell Lymphoma?

Research shows that combining doxorubicin, a component of CHOP, with other drugs like histone deacetylase inhibitors can enhance its effectiveness in treating certain cancers, such as sarcomas. This suggests that similar combinations might improve outcomes in T-Cell Lymphoma. ^{1 2 3 4 5}

Is the combination of Tazemetostat and CHOP safe for treating T-Cell Lymphoma?

The safety of Tazemetostat and CHOP for T-Cell Lymphoma isn't directly addressed in the provided studies, but some components like Vincristine (part of CHOP) have been studied for other conditions. Vincristine is known to be effective in inhibiting cell growth, but the safety profile for this specific combination in T-Cell Lymphoma isn't detailed here. ^{6 7 8 9 10}

What makes the drug Tazemetostat + CHOP unique for T-Cell Lymphoma?

The combination of Tazemetostat with CHOP (Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) is unique because Tazemetostat is a histone deacetylase inhibitor, which can enhance the effectiveness of chemotherapy by promoting cancer cell death. This approach may offer a novel mechanism of action compared to traditional chemotherapy regimens for T-Cell Lymphoma. ^{1 11 12 13 14}

What is the purpose of this trial?

This research is being done to evaluate tazemetostat in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy as a possible treatment for peripheral T-Cell Lymphoma (PTCL). The name of the study drugs involved in this study are: * Tazemetostat (a type of inhibitor for Enhancer of Zeste Homolog 2 (EZH2)) * Standard of care CHOP therapy: * Cyclophosphamide (a type of alkylating agent) * Doxorubicin (a type of anthracycline antibiotic) * Vincristine (a type of vinca alkaloid) * Prednisone (a type of corticosteroid) * Standard of care BEAM conditioning regimen for autologous stem cell transplant: * Carmustine (a type of alkylating agent) * Etoposide (a type of Topoisomerase II inhibitor) * Cytarabine (a type of antineoplastic) * Melphalan (a type of alkylating agent)

Research Team

Eric Jacobsen, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

This trial is for individuals with various types of T-cell lymphoma, including peripheral and intestinal forms. Participants should be suitable for chemotherapy. Specific eligibility criteria are not provided, but typically include factors like age, disease stage, and overall health.

Inclusion Criteria

My organs and bone marrow are working well.

Ability to understand and sign a written informed consent document

Agree to use adequate contraception

Exclusion Criteria

I have had an organ transplant.

I have nerve damage affecting my movements or sensations that is mild or worse.

I have not had major surgery in the last 4 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Prephase

Participants receive a predetermined dose of Tazemetostat twice daily

2 weeks

1 visit (in-person)

Induction

Participants receive CHOP chemotherapy and Tazemetostat over 6 cycles of 21 days each

18 weeks

Multiple visits (in-person) for each cycle

Maintenance

Participants receive Tazemetostat daily for 6 cycles of 28 days each

24 weeks

Regular visits (in-person) for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 years

Periodic visits (in-person)

Treatment Details

Interventions

• Doxorubicin
• Melphalan
• Tazemetostat
• Vincristine

Trial Overview The study is testing the effectiveness of tazemetostat (an EZH2 inhibitor) combined with CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) against T-cell lymphoma. Some patients may also receive BEAM conditioning before a stem cell transplant.

Participant Groups

Group I: Tazemetostat + CHOP Therapy + Transplant Not Elected Experimental Treatment 5 Interventions

Enrolled participants will complete: * Baseline visit * Prephase Period: Days -14 through -1: Predetermined dose of Tazemetost 2x daily * Induction Period: Cycles 1 through 6 (21 day cycles): * Cycle 1 Day 1: tumor biopsy and CT scan * Day 1: Predetermined dose of Cyclophosphamide once, Doxorubicin once, and Vincristine once * Days 1 through 5: Predetermined dose of Prednisone 1x daily * Days 2 through 21: Predetermined dose of Tazemetost 2x daily * Prior to Cycle 4 Day 1: Pet-CT scan * Note, treatment will stop if participants do not respond to the drugs after the first 3 cycles * Pet-CT scan at end of Cycle 6. * Maintenance Period: * Cycles 1 through 6 (28 day cycles): --Days 1 through 28: Predetermined dose of Tazemetost 2x daily. * After Cycle 3: CT scan * Cycle 4 Day 1: CT scan * End of treatment visit * Follow up is for 4 years

Group II: Tazemetostat + CHOP Therapy + Transplant Elected Experimental Treatment 9 Interventions

Enrolled participants will complete: * Baseline visit * Prephase Period: Days -14 through -1: Predetermined dose of Tazemetost 2x daily * Induction Period: Cycles 1 through 6 (21 day cycles): * Cycle 1 Day 1: tumor biopsy and CT scan * Day 1: Predetermined dose of Cyclophosphamide once, Doxorubicin once, and Vincristine once * Days 1 through 5: Predetermined dose of Prednisone 1x daily * Days 2 through 21: Predetermined dose of Tazemetost 2x daily * Prior to Cycle 4 Day 1: Pet-CT scan * Note, treatment will stop if participants do not respond to the drugs after the first 3 cycles * Bone marrow biopsy and Pet-CT scan at end of Cycle 6 * Maintenance Period: * Day 0: autologous stem cell transplant with BiCNU, Etoposide, Cytarabine, and Melphalan (BEAM) * Day 100: PET-CT scan * Cycles 1 through 6 (28 day cycles): --Days 1 through 28: Predetermined dose of Tazemetost 2x daily * After Cycle 3: CT scan * Cycle 4 Day 1: CT scan * End of treatment visit * Follow up is for 4 years

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

Approved in United States as Adriamycin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in European Union as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in Canada as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in Japan as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Who Is Running the Clinical Trial?

Eric Jacobsen, MD

Lead Sponsor

Trials

1

Recruited

20+

Ipsen

Industry Sponsor

Trials

358

Recruited

74,600+

David Loew

Ipsen

Chief Executive Officer since 2020

BA in Business Administration and MBA from the University of St. Gallen, Switzerland

Sandra Silvestri

Ipsen

Chief Medical Officer since 2023

MD, PhD

Findings from Research

Targeted therapies combined with doxorubicin showed significant effectiveness against small cell sarcoma cell lines, with dual combinations of vorinostat and 17-DMAG achieving synergistic effects that enhanced cell killing by 60% compared to doxorubicin alone.

The study found that while vorinostat and 17-DMAG synergized with doxorubicin, sorafenib did not, and the combination of all three agents did not show synergy but increased apoptosis, indicating potential for improved treatment strategies in advanced sarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted polytherapy in small cell sarcoma and its association with doxorubicin. Dumont, SN., Yang, D., Dumont, AG., et al.[2021]

Belinostat, when combined with doxorubicin, was well tolerated in a study of 41 patients, with a maximum tolerated dose established at 1000 mg/m² for belinostat and 75 mg/m² for doxorubicin, despite common side effects like fatigue and nausea.

The combination therapy showed a moderate response rate of 13% in soft tissue sarcomas, with a median time to progression of 6.0 months, suggesting it may be more effective than doxorubicin alone in some cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I/II Clinical Trial of Belinostat (PXD101) in Combination with Doxorubicin in Patients with Soft Tissue Sarcomas. Vitfell-Rasmussen, J., Judson, I., Safwat, A., et al.[2020]

In a study of 101 lymphoma patients undergoing autologous stem cell transplantation, the mitoxantrone-melphalan (Mx-Mel) regimen showed similar efficacy to the BEAM regimen while being less toxic, making it a promising alternative for patients who cannot tolerate high cytotoxic treatments.

Although the BEAM regimen resulted in a statistically shorter time to neutrophil engraftment (10 days) compared to Mx-Mel (12 days), both regimens did not lead to significant differences in transplant-related complications, indicating that Mx-Mel is a safe option with effective outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Mitoxantrone-Melphalan and BEAM Conditioning Regimens in Patients with Lymphoma. Gunes, AK., Serin, I., Demir, I., et al.[2023]

In a study testing 11 anti-cancer agents on 4 pediatric ALCL cell lines, vinblastine was found to be the most effective, significantly inhibiting cell growth in a time- and dose-dependent manner, with effective doses as low as 0.0002 microM/L after 24 hours.

Vinblastine treatment not only inhibited cell growth but also induced apoptosis and disrupted mitotic spindle formation, supporting its use as a first-line treatment in high-risk pediatric ALCL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antineoplastic agents for pediatric anaplastic large cell lymphoma: Vinblastine is the most effective in vitro. Muto, A., Nakagawa, A., Shimomura, Y., et al.[2019]

In a study of 93 children with acute lymphoblastic leukemia, both the Capizzi regimen (escalating doses of methotrexate) and high-dose methotrexate (HD-MTX) showed similar overall toxicity rates, with 28.7% for Capizzi and 29.8% for HD-MTX, indicating that both regimens are associated with significant toxicities.

Mucositis was more prevalent in the HD-MTX group (14.6%) compared to the Capizzi group (5.5%), suggesting that while both regimens are effective, HD-MTX may carry a higher risk for this specific toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse effects with intravenous methotrexate in children with acute lymphoblastic leukemia/lymphoma: a retrospective study. Mandal, P., Samaddar, S., Chandra, J., et al.[2021]

In a study involving 23 patients with previously untreated peripheral T-cell lymphoma, the combination of belinostat and CHOP was well tolerated, with the maximum tolerated dose (MTD) established at 1000 mg/m2 over a Day 1-5 schedule.

The treatment showed a high overall response rate (ORR) of 86%, with 71% of patients achieving a complete response (CR) at the MTD, indicating its efficacy in treating this type of lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belinostat in combination with standard cyclophosphamide, doxorubicin, vincristine and prednisone as first-line treatment for patients with newly diagnosed peripheral T-cell lymphoma. Johnston, PB., Cashen, AF., Nikolinakos, PG., et al.[2021]

References

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

Phase 1 study of oral abexinostat, a histone deacetylase inhibitor, in combination with doxorubicin in patients with metastatic sarcoma. [2021]

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

Targeted polytherapy in small cell sarcoma and its association with doxorubicin. [2021]

3. Egypt pubmed.ncbi.nlm.nih.gov

A Phase I/II Clinical Trial of Belinostat (PXD101) in Combination with Doxorubicin in Patients with Soft Tissue Sarcomas. [2020]

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

The histone deacetylase inhibitor vorinostat selectively sensitizes fibrosarcoma cells to chemotherapy. [2021]

5. Saudi Arabia pubmed.ncbi.nlm.nih.gov

Comparison of Mitoxantrone-Melphalan and BEAM Conditioning Regimens in Patients with Lymphoma. [2023]

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

Antineoplastic agents for pediatric anaplastic large cell lymphoma: Vinblastine is the most effective in vitro. [2019]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Topotecan, Ara-C, cisplatin and prednisolone (TOPOSHAP) for patients with refractory and relapsing lymphomas: results of a phase I trial. [2013]

8. Turkey pubmed.ncbi.nlm.nih.gov

Stevens-Johnson Syndrome-Like Exanthema Secondary to Methotrexate. [2016]

9. Italy pubmed.ncbi.nlm.nih.gov

A phase I study of idarubicin dose escalation with amisfostine and high-dose cytarabine in patients with relapsed acute myelogenous leukemia and myelodysplastic syndromes. [2013]

10. India pubmed.ncbi.nlm.nih.gov

Adverse effects with intravenous methotrexate in children with acute lymphoblastic leukemia/lymphoma: a retrospective study. [2021]

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

Effective treatment of a murine model of adult T-cell leukemia using depsipeptide and its combination with unmodified daclizumab directed toward CD25. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Belinostat in combination with standard cyclophosphamide, doxorubicin, vincristine and prednisone as first-line treatment for patients with newly diagnosed peripheral T-cell lymphoma. [2021]

13. Thailand pubmed.ncbi.nlm.nih.gov

CHOEP-21 chemotherapy for newly diagnosed nodal peripheral T-cell lymphomas (PTCLs) in Maharaj Nakorn Chiang Mai Hospital. [2022]

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

Novel therapies for cutaneous T-cell lymphomas. [2018]