TAK-659 + Chemotherapy for Lymphoma

No longer 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of a new drug, TAK-659, combined with standard chemotherapy for treating Diffuse Large B-cell Lymphoma (DLBCL), a type of blood cancer. The main goal is to determine a safe and effective dose of TAK-659 and assess its impact on the disease. Participants will be divided into groups to receive varying doses of the drug along with chemotherapy. This trial may suit individuals with DLBCL who have at least one high-risk feature, such as specific gene expressions or previous treatments. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

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.

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

Research has shown that TAK-659, also known as mivavotinib, may help treat diffuse large B-cell lymphoma (DLBCL). In studies with patients who had already tried other treatments, researchers tested TAK-659 to assess its safety. Although the drug is still under study and has not received FDA approval, it has been used with standard chemotherapy drugs like rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, collectively known as R-CHOP.

Previous patients demonstrated that TAK-659 can be tolerated when combined with these chemotherapy drugs. However, as with any new treatment, determining the safest doses and monitoring for side effects is crucial. The study aims to identify the right dose to ensure safety and effectiveness when combined with R-CHOP.

Since this trial is in its early stages, it primarily focuses on understanding how the drug works in the body and identifying any side effects. Researchers closely monitor participants to manage potential risks. The trial provides a controlled setting to ensure safety while exploring the benefits of TAK-659 for DLBCL. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about TAK-659 combined with R-CHOP for treating lymphoma because it introduces a new approach by targeting spleen tyrosine kinase, a key player in cancer cell survival and growth. Unlike traditional treatments like R-CHOP alone, which work by attacking rapidly dividing cells, TAK-659 aims to disrupt specific signaling pathways essential for cancer cell survival. This could potentially enhance the effectiveness of chemotherapy and improve outcomes for patients. By offering a targeted mechanism of action, TAK-659 may lead to more precise and effective lymphoma treatment options.

What evidence suggests that this trial's treatments could be effective for Diffuse Large B-cell Lymphoma?

Research shows that TAK-659, a new drug tested in this trial, may help treat diffuse large B-cell lymphoma (DLBCL). Previous studies have demonstrated that TAK-659, which targets a specific protein in the body, benefits patients who have not succeeded with other treatments. In this trial, participants will receive TAK-659 combined with R-CHOP—a common chemotherapy treatment consisting of five drugs—in varying dosages. R-CHOP alone cures about 60% of patients with this condition. Early evidence suggests that adding TAK-659 could improve outcomes for those who haven't responded well to other treatments. ^{1 3 4 6 7}

Who Is on the Research Team?

Reem Karmali

Principal Investigator

Northwestern University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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 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 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 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 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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9882996/

updated data with mivavotinib (TAK-659/CB-659) - PMC Although first-line R-CHOP treatment (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is curative for an estimated 60 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9928783/

Phase I study of novel SYK inhibitor TAK‐659 (mivavotinib) in ... TAK‐659, a novel oral SYK inhibitor, has demonstrated efficacy in heavily pretreated diffuse large B‐cell lymphoma (DLBCL).

3. clinicaltrials.gov clinicaltrials.gov/study/NCT01855750

NCT01855750 | A Study of the Bruton's Tyrosine Kinase ... The purpose of this study is to evaluate if ibrutinib administered in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone ...

4. ncoda.org ncoda.org/pes/rituximab-cyclophosphamide-doxorubicin-vincristine-and-prednisone/

Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, ... The combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is used for certain types of lymphoma. Supported by: PES ...

5. researchgate.net researchgate.net/publication/264049627_Combination_of_ibrutinib_with_rituximab_cyclophosphamide_doxorubicin_vincristine_and_prednisone_R-CHOP_for_treatment-naive_patients_with_CD20-positive_B-cell_non-Hodgkin_lymphoma_A_non-randomised_phas

Combination of ibrutinib with rituximab, cyclophosphamide ... Pharmacodynamic data showed Bruton's tyrosine kinase was fully occupied (>90% occupancy) at the recommended phase 2 dose. Interpretation ...

6. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/full/10.1002/jha2.625

Phase I study of novel SYK inhibitor TAK‐659 (mivavotinib) ... TAK-659, a novel oral SYK inhibitor, has demonstrated efficacy in heavily pretreated diffuse large B-cell lymphoma (DLBCL).

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5576035/

Promising Novel Agents for Aggressive B-Cell Lymphoma In a recent study, 68 patients with relapsed or refractory DLBCL, fostamatinib treatment resulted in a 3% response rate. None of the patients with clinical ...