Combination Chemotherapy +/− Bortezomib for Lymphoma

Recruiting at 224 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

847 Participants Needed

Trial Summary

What is the purpose of this trial?

This randomized phase III trial compares how well combination chemotherapy works when given with or without bortezomib in treating patients with newly diagnosed T-cell acute lymphoblastic leukemia or stage II-IV T-cell lymphoblastic lymphoma. Bortezomib may help reduce the number of leukemia or lymphoma cells by blocking some of the enzymes needed for cell growth. It may also help chemotherapy work better by making cancer cells more sensitive to the drugs. It is not yet known if giving standard chemotherapy with or without bortezomib is more effective in treating newly diagnosed T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that you should not have received any cytotoxic chemotherapy for your current diagnosis before starting the trial, except for certain allowed treatments like specific steroids and intrathecal cytarabine. It's best to discuss your current medications with the trial team to be sure.

What evidence supports the effectiveness of the drug combination chemotherapy with Bortezomib for treating lymphoma?

Research shows that similar drug combinations, like CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), have been effective in treating aggressive B-cell lymphoma, especially when combined with rituximab. Additionally, studies indicate that liposomal formulations of similar drugs can enhance effectiveness and reduce side effects, suggesting potential benefits for the combination therapy including Bortezomib. ^{1 2 3 4 5}

What safety data exists for the chemotherapy drugs used in lymphoma treatment?

Liposomal formulations of doxorubicin, used in lymphoma treatment, are associated with lower risks of heart-related side effects compared to conventional doxorubicin. However, they may still cause other side effects like myelosuppression (reduced bone marrow activity) and hand-foot syndrome (redness and swelling of the hands and feet). Cyclophosphamide, vincristine, and prednisolone, when used in combination, can lead to infections and require hospitalization in some cases. ^{4 6 7 8 9}

What makes the combination chemotherapy with bortezomib unique for lymphoma treatment?

This treatment is unique because it combines bortezomib, a proteasome inhibitor that can enhance the effectiveness of chemotherapy, with a mix of drugs like cyclophosphamide, doxorubicin, and vincristine, which are commonly used in lymphoma treatment. The addition of bortezomib may improve outcomes by increasing the cancer-killing effects of the chemotherapy regimen. ^{10 11 12 13 14}

Research Team

David T Teachey

Principal Investigator

Children's Oncology Group

Eligibility Criteria

This trial is for young patients aged 1-30 with newly diagnosed T-cell acute lymphoblastic leukemia or stage II-IV T-cell lymphoblastic lymphoma. They must not have Down syndrome, uncontrolled seizures, a history of severe reactions to bortezomib or its components, be pregnant/breastfeeding, or have used certain medications recently.

Inclusion Criteria

I have been recently diagnosed with T-ALL or T-LLy at stage II-IV.

I am between 1 and 31 years old.

T-ALL patients must be enrolled on AALL08B1 or Project:EveryChild (APEC14B1, if open for the classification of ALL patients) prior to treatment and enrollment on AALL1231

Exclusion Criteria

I've taken steroids for no more than 5 days in the last week or 14 days in the last month.

I have not had chemotherapy for my current T-ALL or T-L-Ly diagnosis before starting treatment on AALL1231.

I have received or need 600 cGy of chest radiation for medical reasons.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive initial treatment to induce remission, including chemotherapy and bortezomib for Arm B

4 weeks

Weekly visits for treatment administration

Consolidation

Patients receive intensive chemotherapy to consolidate remission

8 weeks

Bi-weekly visits for treatment administration

Interim Maintenance

Patients receive maintenance chemotherapy to maintain remission

8 weeks

Bi-weekly visits for treatment administration

Delayed Intensification

Patients receive intensified chemotherapy to eliminate residual disease

8 weeks

Bi-weekly visits for treatment administration

Maintenance Therapy

Long-term chemotherapy to prevent relapse, with different durations for male and female patients

2-3 years

Monthly visits for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

10 years

Treatment Details

Interventions

• Bortezomib
• Cyclophosphamide
• Cytarabine
• Dexamethasone
• Doxorubicin
• Methotrexate
• Pegaspargase
• Vincristine

Trial Overview The study tests if adding bortezomib to standard chemotherapy is more effective for treating T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Patients are randomly assigned to receive either the usual chemotherapy alone or with bortezomib.

Participant Groups

Group I: Arm B (combination chemotherapy, bortezomib) Experimental Treatment 19 Interventions

Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m\^2 during Induction and 4 doses at 1.3 mg/m\^2 during Delayed Intensification). See Detailed Description.

Group II: Arm A (combination chemotherapy) Active Control 18 Interventions

Patients receive combination chemotherapy without bortezomib. 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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 50 patients treated with R-CHOP-14 for aggressive B-cell lymphoma, 82% achieved a complete or improved response, indicating high efficacy of this treatment regimen.

Despite its effectiveness, R-CHOP-14 was associated with significant toxicities, including grade 3-4 neutropenia in 32% of patients and peripheral neuropathy in 45%, highlighting the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with biweekly CHOP plus rituximab chemoimmunotherapy for the treatment of aggressive B-cell non-Hodgkin lymphoma. Aguiar Bujanda, D., Aguiar Morales, J., Bohn Sarmiento, U., et al.[2021]

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]

In a study of 35 elderly patients with aggressive non-Hodgkin's lymphoma, the use of liposomal Daunorubicin (DNX) resulted in a high overall response rate of 77%, with 15 patients achieving complete remission (CR) and 5 achieving partial remission (PR).

Liposomal DNX demonstrated similar efficacy to traditional Daunorubicin while significantly reducing acute toxicity, making it a safer option for treating this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and toxicity of liposomal daunorubicin included in PVABEC regimen for aggressive NHL of the elderly. Cervetti, G., Caracciolo, F., Cecconi, N., et al.[2019]

In a study of 326 lymphoma patients treated with Myocet® (a liposomal formulation of doxorubicin), the treatment showed a comparable response rate of at least 58% to conventional therapies, indicating its efficacy in managing lymphoproliferative disorders.

Despite a high prevalence of cardiovascular comorbidities (72% of patients), the incidence of severe cardiac events was relatively low, suggesting that Myocet® may have a better safety profile regarding cardiotoxicity compared to traditional doxorubicin formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-pegylated liposomal doxorubicin in lymphoma: patterns of toxicity and outcome in a large observational trial. Wasle, I., Gamerith, G., Kocher, F., et al.[2018]

This study analyzed over 7.5 million reports from the FDA Adverse Event Reporting System and found that conventional doxorubicin (DOX) has a higher incidence of adverse events compared to liposomal formulations, particularly in terms of myelosuppression and cardiotoxicity.

Liposomal DOX, especially the PEGylated version, showed lower reporting odds ratios for serious side effects like myelosuppression and cardiotoxicity, but a higher risk for palmar-plantar erythrodysesthesia (PPE), indicating the need for careful monitoring when using these formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the adverse event profiles of conventional and liposomal formulations of doxorubicin using the FDA adverse event reporting system. Fukuda, A., Tahara, K., Hane, Y., et al.[2022]

In a phase 1 study involving 20 patients with untreated diffuse large B-cell lymphoma (DLBCL) or mantle cell lymphoma (MCL), bortezomib could be safely added to the standard R-CHOP chemotherapy regimen at a dose of 1.3 mg/m2, with acceptable levels of toxicity.

The treatment showed promising efficacy, with a 95% complete response rate among evaluable patients and a 4-year overall survival rate of 75%, indicating that this combination could be a viable option for patients with these types of lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 trial of bortezomib plus R-CHOP in previously untreated patients with aggressive non-Hodgkin lymphoma. Furman, RR., Martin, P., Ruan, J., et al.[2022]

Salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation is the standard treatment for relapsed diffuse large B-cell lymphoma, but the addition of rituximab has improved outcomes after first-line treatment and relapses.

The CORAL trial found no significant difference in response rates between two salvage regimens (R-ICE and R-DHAP), and identified that factors like early relapse and certain genetic markers significantly affect survival, indicating that over 70% of patients may not benefit from standard salvage therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is there any role for transplantation in the rituximab era for diffuse large B-cell lymphoma? Gisselbrecht, C.[2022]

The CHOEA-7 chemotherapy regimen, which includes cyclophosphamide, doxorubicin, vincristine, etoposide, and ara-C, has shown excellent results in treating patients with CD 20-positive non-Hodgkin's lymphoma.

Adding rituximab to the CHOEA-7 regimen (RCHOEA-7) further enhances treatment efficacy, indicating a promising approach for improving outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Results of dose-intense, dose-impact weekly combination chemotherapy with rituximab for patients with CD 20-positive B-cell non-Hodgkin's lymphoma]. Uzuka, Y., Saitou, Y., Saitou, K., et al.[2015]

References

1. Italy pubmed.ncbi.nlm.nih.gov

Clinical experience with biweekly CHOP plus rituximab chemoimmunotherapy for the treatment of aggressive B-cell non-Hodgkin lymphoma. [2021]

2. 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]

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

Advanced diffuse non-Hodgkin's lymphoma. Analysis of prognostic factors by the international index and by lactic dehydrogenase in an intergroup study. [2019]

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

Efficacy and toxicity of liposomal daunorubicin included in PVABEC regimen for aggressive NHL of the elderly. [2019]

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

A dose-finding study of liposomal daunorubicin with CVP (COP-X) in advanced NHL. [2020]

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

A phase II study of liposomal daunorubicin, in combination with cyclophosphamide, vincristine and prednisolone, in elderly patients with previously untreated aggressive non-Hodgkin lymphoma. [2019]

7. Germany pubmed.ncbi.nlm.nih.gov

Non-pegylated liposomal doxorubicin in lymphoma: patterns of toxicity and outcome in a large observational trial. [2018]

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

Comparison of the adverse event profiles of conventional and liposomal formulations of doxorubicin using the FDA adverse event reporting system. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

Replacement of conventional doxorubicin by pegylated liposomal doxorubicin is a safe and effective alternative in the treatment of non-Hodgkin's lymphoma patients with cardiac risk factors. [2018]

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

Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma. [2015]

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

A phase 1 dose escalation study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone for untreated follicular lymphoma and other low-grade B-cell lymphomas. [2015]

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

Phase 1 trial of bortezomib plus R-CHOP in previously untreated patients with aggressive non-Hodgkin lymphoma. [2022]

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

Is there any role for transplantation in the rituximab era for diffuse large B-cell lymphoma? [2022]

14. Japan pubmed.ncbi.nlm.nih.gov

[Results of dose-intense, dose-impact weekly combination chemotherapy with rituximab for patients with CD 20-positive B-cell non-Hodgkin's lymphoma]. [2015]