TAK-659 + Chemotherapy for Lymphoma

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Northwestern University

Must be taking: R-CHOP

Must not be taking: SYK inhibitors

Disqualifiers: Untreated brain metastases, HIV, others

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

Compensation: Varies

Number of Visits: 12

Duration: 18 weeks

12 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this research study is to evaluate a new investigational drug, TAK-659, given in combination with standard chemotherapy, for the treatment of Diffuse Large B-cell Lymphoma (DLBCL). ?Investigational? means that TAK-659 has not been approved by the United States Food and Drug Administration (FDA) for use as a prescription or over-the-counter medication to treat a certain condition. The primary purpose of this study is to find the appropriate and safe dose of the study drug to be used in combination with standard chemotherapy for the treatment of your disease and to determine how well the drug works in treating the disease. Other objectives include measuring the amount of the study drug in the body at different times after taking the study drug. Participation in the study is expected to last for up to 3 years after receiving the last dose of the study drug. Patients will receive the study treatment for up to 18 weeks, as long as they are benefitting.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take certain medications or supplements that affect specific enzymes (CYP3A and P-gp) during the study. It's best to discuss your current medications with the study team to see if any adjustments are needed.

What data supports the effectiveness of the drug TAK-659 combined with chemotherapy for lymphoma?

Research shows that combining rituximab with chemotherapy drugs like cyclophosphamide, doxorubicin, vincristine, and prednisone (known as R-CHOP) improves treatment outcomes for aggressive B-cell lymphoma. This combination has been shown to increase response rates and progression-free survival, making it a standard treatment for certain types of lymphoma. ^{1 2 3 4 5}

Is the combination of TAK-659 and chemotherapy safe for humans?

The safety of the chemotherapy drugs cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab, which are part of the CHOP or R-CHOP regimens, has been studied in humans. These drugs are generally considered safe, but they can cause side effects like nausea and vomiting, which are often managed with additional medications. No serious adverse events were reported in the studies reviewed. ^{6 7 8 9 10}

What makes the drug TAK-659 + Chemotherapy unique for treating lymphoma?

The combination of TAK-659 with chemotherapy drugs like cyclophosphamide, doxorubicin, and rituximab is unique because it integrates a novel agent, TAK-659, which may offer a different mechanism of action compared to traditional regimens. This approach could potentially enhance the effectiveness of the treatment by targeting lymphoma cells in a new way, although specific details about TAK-659's role in this combination are not provided in the research. ^{2 4 11 12 13}

Research Team

Reem Karmali

Principal Investigator

Northwestern University

Eligibility Criteria

This trial is for patients with a confirmed diagnosis of high-risk Diffuse Large B-cell Lymphoma (DLBCL), including several subtypes and those transformed from low-grade lymphoma. Participants may have started one cycle of R-CHOP chemotherapy or plan to start it, must have measurable disease on scans, and should not have severe ongoing effects from previous cancer treatments.

Inclusion Criteria

My diagnosis is a specific type of aggressive lymphoma.

I finished my first R-CHOP cycle within the last 21 days or plan to start it after signing up.

My cancer is the ABC/non-GCB type, confirmed by specific tests.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive R-CHOP chemotherapy and TAK-659 for up to 18 weeks

18 weeks

6 cycles, every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Every 6 months

Treatment Details

Interventions

• Cyclophosphamide
• Doxorubicin Hydrochloride
• Prednisone
• Rituximab
• TAK-659
• Vincristine Sulfate

Trial Overview The study tests TAK-659 combined with standard chemotherapy (Rituximab, Prednisone, Vincristine Sulfate, Doxorubicin Hydrochloride, Cyclophosphamide) in treating DLBCL. It aims to find the safe dose level and effectiveness of TAK-659 over an up-to-18-week treatment period within a total participation time frame of up to 3 years.

Participant Groups

Group I: TAK-659 80mg + R-CHOP Experimental Treatment 6 Interventions

Patients receive rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV over 3-5 minutes, and vincristine sulfate IV on day 1, and prednisone PO on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Beginning in cycle 2, patients also receive spleen tyrosine kinase inhibitor TAK-659 Dose Level 2 PO QD on days 1-21. Treatment repeats every 21 days for up to 5 courses in the absence of disease progression or unacceptable toxicity.

Group II: TAK-659 60mg + R-CHOP Experimental Treatment 6 Interventions

Patients receive rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV over 3-5 minutes, and vincristine sulfate IV on day 1, and prednisone PO on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Beginning in cycle 2, patients also receive spleen tyrosine kinase inhibitor TAK-659 Dose Level 1 PO QD on days 1-21. Treatment repeats every 21 days for up to 5 courses in the absence of disease progression or unacceptable toxicity.

Group III: TAK-659 100mg + R-CHOP Experimental Treatment 6 Interventions

Patients receive rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV over 3-5 minutes, and vincristine sulfate IV on day 1, and prednisone PO on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Beginning in cycle 2, patients also receive spleen tyrosine kinase inhibitor TAK-659 Dose Level 3 PO QD on days 1-21. Treatment repeats every 21 days for up to 5 courses in the absence of disease progression or unacceptable toxicity.

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?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 20 patients with untreated poor prognosis diffuse large B-cell lymphoma (DLBCL), the two-weekly dose-adjusted EPOCH-like chemotherapy (DA-EDOCH14-R) showed a promising three-year progression-free survival (PFS) rate of 95%, compared to 74% in a previous trial with a three-weekly regimen.

The treatment was well-tolerated with manageable toxicity and no therapy-related deaths, highlighting its safety, especially for patients with a high-risk prognosis (age-adjusted International Prognostic Index of 3), where PFS reached 100% compared to just 30% in the previous trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two-weekly dose-adjusted (DA)-EPOCH-like chemotherapy with high-dose dexamethasone plus rituximab (DA-EDOCH14-R) in poor-prognostic untreated diffuse large B-cell lymphoma. García-Suárez, J., Flores, E., Callejas, M., et al.[2015]

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 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]

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 involving 549 patients with advanced indolent lymphoma, bendamustine plus rituximab significantly improved median progression-free survival (69.5 months) compared to R-CHOP (31.2 months), indicating it may be a more effective first-line treatment.

Bendamustine plus rituximab was better tolerated than R-CHOP, with significantly lower rates of side effects such as alopecia, hematological toxicity, infections, and peripheral neuropathy, making it a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Rummel, MJ., Niederle, N., Maschmeyer, G., et al.[2022]

In a study of 24 multiple myeloma patients undergoing high-dose melphalan treatment, a triple antiemetic regimen of palonosetron, aprepitant, and dexamethasone effectively controlled chemotherapy-induced nausea and vomiting (CINV), achieving a complete response rate of 75% overall.

The combination therapy was particularly effective in the acute phase (88% complete response) and demonstrated a strong safety profile, with no serious adverse events related to the antiemetic treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palonosetron, aprepitant, and dexamethasone for prevention of nausea and vomiting after high-dose melphalan in autologous transplantation for multiple myeloma: A phase II study. Isoda, A., Saito, R., Komatsu, F., et al.[2018]

In a study of 30 patients with advanced non-small cell lung cancer undergoing high-dose cisplatin chemotherapy, tropisetron effectively controlled acute nausea and vomiting with a complete plus major control rate of up to 86% across treatment cycles.

Tropisetron also demonstrated efficacy in preventing delayed nausea and vomiting, with control rates reaching 87%, and was generally well-tolerated, with mild side effects like headache and diarrhea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and tolerability of tropisetron in the prevention of cisplatin-induced nausea and vomiting in advanced non-small cell lung cancer. Thongprasert, S.[2019]

The ECHELON-2 trial demonstrated that the combination of brentuximab vedotin with cyclophosphamide, doxorubicin, and prednisone (A+CHP) significantly improved progression-free survival in patients with CD30-positive peripheral T-cell lymphomas, with a median of 48.2 months compared to 20.8 months for the standard CHOP regimen.

The safety profile of A+CHP was manageable, with similar rates of adverse events like febrile neutropenia and peripheral neuropathy compared to CHOP, indicating that A+CHP is a viable and effective front-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Horwitz, S., O'Connor, OA., Pro, B., et al.[2022]

In a phase 3 study involving 447 treatment-naive patients with indolent non-Hodgkin's lymphoma or mantle cell lymphoma, bendamustine plus rituximab (BR) was found to be noninferior to standard rituximab-chemotherapy regimens (R-CHOP/R-CVP) in achieving complete response rates (31% vs 25%).

While BR showed a higher overall response rate (97% vs 91%), it also had a higher incidence of vomiting and drug-hypersensitivity reactions compared to standard therapies, indicating a need to consider safety profiles when choosing treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Flinn, IW., van der Jagt, R., Kahl, BS., et al.[2022]

In a study of 91 people living with HIV and Burkitt lymphoma, adding rituximab to CODOX-M/IVAC chemotherapy did not increase severe treatment-related toxicities, indicating it is a safe option for this population.

The addition of rituximab significantly improved both overall survival (72% vs. 55%) and progression-free survival (81% vs. 55%) compared to chemotherapy alone, suggesting it enhances treatment efficacy without added risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adding rituximab to CODOX-M/IVAC chemotherapy in the treatment of HIV-associated Burkitt lymphoma is safe when used with concurrent combination antiretroviral therapy. Alwan, F., He, A., Montoto, S., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Two-weekly dose-adjusted (DA)-EPOCH-like chemotherapy with high-dose dexamethasone plus rituximab (DA-EDOCH14-R) in poor-prognostic untreated diffuse large B-cell lymphoma. [2015]

2. 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]

3. 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]

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

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

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

Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. [2022]

6. Japan pubmed.ncbi.nlm.nih.gov

Palonosetron, aprepitant, and dexamethasone for prevention of nausea and vomiting after high-dose melphalan in autologous transplantation for multiple myeloma: A phase II study. [2018]

7. England pubmed.ncbi.nlm.nih.gov

A randomized, double-blind, multicentre study comparing daily 2 and 5 mg of tropisetron for the control of nausea and vomiting induced by low-dose cisplatin- or non-cisplatin-containing chemotherapy. [2020]

8. France pubmed.ncbi.nlm.nih.gov

[A phase III trial comparing the antiemetic activity of tetracosactide with dexamethasone in combination with metoclopramide, diphenhydramine and clorazepate during chemotherapy including cisplatin]. [2013]

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

Efficacy and tolerability of tropisetron in the prevention of cisplatin-induced nausea and vomiting in advanced non-small cell lung cancer. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Granisetron plus aprepitant versus granisetron in preventing nausea and vomiting during CHOP or R-CHOP regimen in malignant lymphoma: a retrospective study. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. [2022]

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

Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. [2022]

13. England pubmed.ncbi.nlm.nih.gov

Adding rituximab to CODOX-M/IVAC chemotherapy in the treatment of HIV-associated Burkitt lymphoma is safe when used with concurrent combination antiretroviral therapy. [2022]