Combination Chemotherapy +/− Bortezomib for Lymphoma

Not currently recruiting at 235 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Dexamethasone

Disqualifiers: Down syndrome, Pregnancy, Seizure disorder, others

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if adding bortezomib (Velcade) to standard chemotherapy is more effective for treating newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) and stage II-IV T-cell lymphoblastic lymphoma (T-LLy). Bortezomib may enhance chemotherapy effectiveness by increasing cancer cells' sensitivity and blocking enzymes essential for cancer cell growth. Ideal candidates for this trial are individuals diagnosed with T-ALL or T-LLy who have not yet started cytotoxic chemotherapy. As a Phase 3 trial, this study represents the final step before FDA approval, offering patients the opportunity to contribute to potentially groundbreaking treatment advancements.

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.

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

Research has shown that bortezomib, a drug tested with standard chemotherapy, has a known safety record from earlier studies. In trials with patients who have different types of cancer, about 77% experienced serious side effects, similar to those seen in past studies with bortezomib. Common issues included heart problems, such as heart failure or reduced heart function.

Despite these side effects, past patients generally tolerated bortezomib well. Its use for other conditions has helped researchers better understand its safety. The chemotherapy drugs used in combination (cyclophosphamide, cytarabine, dexamethasone, doxorubicin, methotrexate, pegaspargase, and vincristine) are also well-known from previous use, though they have their own risks.

Researchers will closely monitor participants in the trial to manage any side effects. Anyone considering joining the trial should discuss potential risks and benefits with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for lymphoma because they explore the potential of adding bortezomib to a standard chemotherapy regimen. Unlike traditional chemotherapy that targets rapidly dividing cells in general, bortezomib specifically inhibits a protein complex called the proteasome, which can lead to increased cancer cell death. This targeted approach could make the chemotherapy more effective and potentially improve outcomes for patients. Additionally, incorporating bortezomib might enhance treatment effects without significantly increasing toxicity, offering a promising new avenue for managing lymphoma.

What evidence suggests that this trial's treatments could be effective for T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma?

Research has shown that bortezomib may help treat certain cancers, such as T-cell lymphoblastic lymphoma. In earlier studies, newly diagnosed patients treated with bortezomib achieved a 100% overall response rate, meaning all patients responded to the treatment. Within two years, some patients became completely cancer-free. The survival rate reached 84.6%, and 76.9% of patients lived without their cancer worsening. Bortezomib blocks enzymes that cancer cells need to grow, potentially enhancing the effectiveness of chemotherapy. In this trial, participants in Arm B will receive combination chemotherapy with bortezomib, while Arm A will receive combination chemotherapy without it. Although researchers are still studying its effectiveness in combination with other treatments, these results are promising for those considering this treatment. ^{6 7 8 9 10}

Who Is on the Research Team?

David T Teachey

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.23.00033

Differential Efficacy From the Addition of Bortezomib to R- ... Primary analysis at a median follow-up of 30 months found no effect of bortezomib on progression-free survival (PFS) or overall survival (OS).

2. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/6152/506246/The-Final-Results-of-a-Phase-I-Study-Using

The Final Results of a Phase I Study Using Bortezomib ... Two relapsed patients experienced disease progression after received two cycles of treatment and died in 5 and 7 months. Another patient died in ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39737396/

A phase I study using bortezomib (Velcade), cladribine ... The median follow-up time was 43 (9-60) months. Low-grade hematological toxicity and mild fatigue were observed. No severe systemic toxicity was ...

4. clinical-lymphoma-myeloma-leukemia.com clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(22)01715-3/abstract

Real-world Outcomes With Cumulative Bortezomib Dose ... The higher-dose group showed a trend for higher rate of complete response (14.3% vs. 5.7%, P = .225) and significantly higher rate of very good ...

5. frontiersin.org frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1449401/full

A phase I study using bortezomib (Velcade), cladribine, ... In the newly diagnosed subject cohort, the OR and CR were 100%, the 2-year overall survival rate was 84.6%, and the progression-free survival rate was 76.9%.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4856151/

Bortezomib for the treatment of non-Hodgkin's lymphoma In a large Phase II trial in heavily pretreated subjects with MM, bortezomib yielded responses in 35% of patients that lasted a median of 12 months, leading to ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118465573

Safety and Efficacy of Bortezomib (VELCADE™) in 104 ... Overall, 76.9% of the pts experienced Grade 3 & 4 adverse events. Safety profile observed is similar to past trial results with bortezomib. Conclusion: In this ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10903519/

Real-world incidence and risk factors of bortezomib-related ... A meta-analysis of clinical trials defined cardiovascular outcomes as heart failure, cardiomyopathy, left ventricular ejection fraction decline, ...

9. ashpublications.org ashpublications.org/blood/article/104/11/2638/54983/Safety-and-Efficacy-of-Bortezomib-Velcade-for-the

Safety and Efficacy of Bortezomib (Velcade) for the Treatment ... All patients received at least one dose of bortezomib and are evaluable for treatment toxicity. Treatment was reasonably well tolerated with the ...

10. e-crt.org e-crt.org/DOIx.php?id=10.4143/crt.2024.479

Assessing the Efficacy of Bortezomib and Dexamethasone ... The median progression-free survival (PFS) was 5.8 months, with responders showing a median PFS of 14.0 months. Treatment-emergent adverse events were generally ...