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Diffuse Large B-Cell LymphomaPhase 1NCT03742258

Combination Chemotherapy and TAK-659 as Front-Line Treatment in Treating Patients With High-Risk Diffuse Large B Cell Lymphoma

A Phase 1 study testing Cyclophosphamide, Doxorubicin Hydrochloride and Prednisone in people with Diffuse Large B-Cell Lymphoma and Diffuse Large B-Cell Lymphoma Activated B-Cell Type, run by Northwestern University at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Cyclophosphamide, Doxorubicin Hydrochloride and Prednisone
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
12 participants
Where
2 sitesUnited States
Study dates
13 Mar 2019to 8 Feb 2024
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients must have a pathologically confirmed diagnosis of DLBCL (including DLBCL not otherwise specified [NOS], DLBCL germinal center B-cell [GCB] type, DLBCL activated B cell [ABC]/non-GCB type, T cell/histiocyte-rich large B cell lymphoma, high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, and high-grade B cell lymphoma NOS). NOTE: DLBCL transformed from low-grade lymphoma among treatment-naive patients or patients previously treated with a non-anthracycline containing regimen are permitted
  • Patients may have completed the first cycle of R-CHOP (off study not combined with TAK-659) =< 21 days prior to the first dose of TAK-659 or plan to receive the first cycle of R-CHOP after registration
  • Patients must have at least one high-risk feature, including:
  • ABC/non-GCB subtype determined by gene expression profiling or Hans algorithm by immunohistochemistry per treating institution standards
  • High-intermediate or high-risk group by National Comprehensive Cancer Network - International Prognostic Index (NCCN-IPI) with score >= 4, at time of diagnosis
  • MYC gene rearrangement (by [fluorescent in situ hybridization] FISH)
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  • MYC overexpression by immunohistochemistry (IHC) (>= 40%) and BLC2 overexpression by IHC (>= 50%) or
  • Previously treated transformed low-grade lymphoma to large B cell lymphoma with prior treatment not including an anthracycline
  • NOTE: BCL2 and/or BCL6 aberrancy are not required for enrollment, but assessment for rearrangement by FISH and overexpression by IHC are required if there is presence of MYC rearranged by FISH
  • Patients must have measurable disease (defined as >= 1.5 cm in diameter) with correlated fluorodeoxyglucose (FDG)-avidity on positron emission tomography (PET) scan with Deauville score of 4 or 5 at time of diagnosis
  • Patients must have recovered (i.e., =< grade 1 toxicity) from the reversible effects of prior anticancer therapy, if applicable
  • Life expectancy of greater than 3 months
  • Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
  • Absolute neutrophil count >= 1000/mcL (within 14 days prior to registration)
  • Platelets >= 75,000/mcl (NOTE: Patients with bone marrow involvement may be eligible with platelets >= 50,000) (within 14 days prior to registration)
  • Hemoglobin >= 8 g/dL (within 14 days prior to registration)
  • NOTE: Red blood cell (RBC) and platelet transfusion allowed >= 14 days prior to registration
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 14 days prior to registration)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x institutional ULN (within 14 days prior to registration)
  • Creatinine clearance >= 60 mL/min either as estimated by the Cockcroft-Gault equation or based on urine collection (12 or 24 hours) (within 14 days prior to registration)
  • Lipase =< 1.5 x ULN with no clinical symptoms suggestive of pancreatitis or cholecystitis (within 14 days prior to registration)
  • Amylase =< 1.5 x ULN with no clinical symptoms suggestive of pancreatitis or cholecystitis (within 14 days prior to registration)
  • Patients must have blood pressure =< grade 1
  • NOTE: Hypertensive patients are permitted if their blood pressure is controlled to =< grade 1 by hypertensive medications
  • Female patients must meet at least one of the following criteria:
  • Are postmenopausal with last menstrual period at least 1 year before registration OR
  • Are surgically sterile, OR
  • If they are of childbearing potential
  • Agree to practice 1 highly effective method of contraception and one additional effective (barrier) method at the same time, from the time of signing the informed consent through 180 days after the last dose of study drug, or
  • Agree to practice true abstinence, when is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together
  • Agree not to donate eggs (ova) during the course of this study or 180 days after receiving their last dose of study drug
  • Male patients, even if surgically sterilized (i.e., status post-vasectomy), must:
  • Agree to practice effective barrier contraception during the entire study treatment period and through 180 days after the last dose of study drug, or
  • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception. Female and male condoms should not be used together.)
  • Agree not to donate sperm during the course of this study or within 180 days after receiving their last dose of study drug
  • Female of childbearing potential (FOCBP) must have a negative pregnancy test =< 7 days prior to registration on study
  • Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care
  • Patients must have the ability to swallow oral medication
  • Patients must be willing and able to complete study-required procedures

Who cannot join

  • Patients with exposure to chemotherapy or immunotherapy =< 30 days prior to starting study treatment are not eligible
  • NOTE: Patients may receive at most 1 cycle of R-CHOP, rituximab, or systemic corticosteroids within this timeframe
  • NOTE: If patient is registered prior to completion of washout, start date of treatment will need to be confirmed prior to registration
  • Patients with prior exposure to a SYK inhibitor are not eligible
  • NOTE: Examples of SYK inhibitors include fostamatinib (R788), entospletinib (GS-9973), cerdulatinib (PRT062070), and TAK-659
  • Patients with untreated brain metastases or leptomeningeal metastases are not eligible
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  • Patients with known hypersensitivity (e.g. anaphylactic and anaphylactoid reactions) to TAK-659 or components of R-CHOP are not eligible
  • Patients with history of drug-induced pneumonitis requiring treatment with steroids; history of idiopathic pulmonary fibrosis, organizing pneumonia, or evidence of active pneumonitis on screening imaging are not eligible
  • NOTE: A history of radiation pneumonitis in the radiation field (fibrosis) is permitted
  • Patients with known hepatitis B surface antigen positive, or known or suspected active hepatitis C infection are not eligible
  • Patients who are known to be human immunodeficiency virus (HIV) positive are not eligible
  • Patients must not have had autologous stem cell transplant within 6 months prior to registration
  • Patients must have not had allogeneic stem cell transplant at any time
  • Patients who have received systemic anticancer treatment (including investigational agents) or radiotherapy less than 3 weeks before the first dose of study treatment (=< 5 times half-life for large molecule agents or =< 4 weeks with evidence of disease progression if 5 times half-life is > 4 weeks) are not eligible
  • NOTE: Patients may receive R-CHOP cycle 1
  • NOTE: If patient is registered prior to completion of washout, start date of treatment will need to be confirmed prior to registration
  • Use or consumption of the following substances is not permitted:
  • Medications or supplements that are known to be inhibitors of P-gp and/or strong reversible inhibitors of CYP3A within 5 times the inhibitor half-life (if a reasonable half-life estimate is known), or within 7 days (if a reasonable half-life estimate is unknown), before the first dose of study drug. The use of these agents is not permitted during the study
  • Medications or supplements that are known to be strong CYP3A mechanism-based inhibitors or strong CYP3A inducers and/or P-gp inducers within 7 days, or within 5 times the inhibitor or inducer half-life (whichever is longer), before the first dose of study drug. The use of these agents is not permitted during the study
  • Grapefruit-containing food or beverages within 5 days before the first dose of study drug. Note that grapefruit-containing food and beverages are prohibited during the study
  • Patients who have major surgery, per principal investigator (PI) discretion, =< 14 days before the first dose of study drug and those who have not recovered fully from any complications from surgery are not eligible
  • Patients who have systemic infection requiring parenteral antibiotic therapy or other serious infection (bacterial, fungal or viral) =< 21 days before the first dose of study drug are not eligible
  • NOTE: Patients who are at substantial risk of developing an infection may receive prophylaxis at the start of study treatment per investigator?s discretion
  • Patients with an active secondary malignancy that requires treatment are not eligible
  • NOTE: Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection and are considered disease-free at the time of registration
  • Patients with known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of TAK-659 are not eligible (this may include difficulty swallowing tablets or diarrhea > grade 1 despite supportive therapy)
  • Patients who received treatment with high-dose corticosteroids for anticancer purposes =< 7 days before the first dose of TAK-659 are not eligible
  • NOTE: Prednisone and other steroids given as part of the R-CHOP regimen and as pre-medications are exceptions throughout the study. Patients may also receive steroids prior to starting chemotherapy to improve performance status. In other contexts, daily dose equivalent to 10 mg oral prednisone or less is permitted. Corticosteroids for topical use or in nasal spray or inhalers are allowed
  • Patients who have known central nervous system (CNS) lymphomatous involvement are not eligible
  • Patients who have an uncontrolled intercurrent illness, in the opinion of the investigator, including, but not limited to any of the following, are not eligible:
  • Uncontrolled pulmonary disease
  • Active CNS disease that would interfere with study participation
  • Active infection requiring parenteral systemic treatment
  • Psychiatric illness/social situations that would limit compliance with study requirements
  • Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient?s safety or study endpoints
  • Patients with any of the following cardiovascular conditions are excluded:
  • Acute myocardial infarction within 6 months before starting study drug
  • Current or history of New York Heart Association class III or IV heart failure
  • Evidence of current, uncontrolled cardiovascular conditions including cardiac arrhythmias, angina, pulmonary hypertension, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
  • Fridericia corrected QT interval (QTcF) > 450 milliseconds (msec) (men) or > 475 msec (women) on a 12-lead electrocardiography (ECG) during the screening period
  • Abnormalities on 12-lead ECG including, but not limited to, changes in rhythm and intervals that, in the opinion of the investigator, are considered to be clinically significant
  • Abnormal left ventricular function (ejection fraction [EF] < 50%, as indicated by baseline echocardiography [ECHO])
  • Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on day 1 before first dose of TAK-659

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • Northwestern University

    Chicago, Illinois, 60611

  • Northwestern Lake Forest Hospital

    Lake Forest, Illinois, 60045

Other trials in United States

About this study

Official title: A Phase 1 Study of R-CHOP Plus SYK Inhibitor TAK-659 for the Front-Line Treatment of High-Risk Diffuse Large B Cell Lymphoma (DLBCL)

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine the safety, tolerability, and maximum tolerated dose of TAK-659 when combined with R-CHOP in the front-line treatment of high-risk diffuse large B cell lymphoma (DLBCL).

SECONDARY OBJECTIVES:

  1. To assess preliminary efficacy of TAK-659 combined with R-CHOP in the front-line treatment of high-risk DLBCL.

EXPLORATORY OBJECTIVES:

  1. To characterize the pharmacokinetics (PK) of TAK-659 in combination with R-CHOP.

OUTLINE: This is a dose-escalation study of spleen tyrosine kinase inhibitor TAK-659.

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

After completion of study treatment, patients are followed up every 6 months for up to 3 years.

Being tested
Cyclophosphamide, Doxorubicin Hydrochloride, Prednisone, Rituximab, Spleen Tyrosine Kinase Inhibitor TAK-659
Medical subject headings
Lymphoma, Large B-Cell, Diffuse

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CyclophosphamideDrug

    Also called (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida

    Given IV

  • Doxorubicin HydrochlorideDrug

    Also called 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin

    Given IV

  • PrednisoneDrug

    Also called .delta.1-Cortisone, 1, 2-Dehydrocortisone, Adasone, Cortancyl

    Given PO

  • RituximabBiological

    Also called ABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody

    Given IV

  • Spleen Tyrosine Kinase Inhibitor TAK-659Drug

    Also called Spleen Tyrosine Kinase Inhibitor TAK659, syk Inhibitor TAK-659, syk Inhibitor TAK659, syk-Inhibitor TAK-659

    Given PO

  • Vincristine SulfateDrug

    Also called Kyocristine, Leurocristine sulfate, Leurocristine, sulfate, Oncovin

    Given IV

Study groups in NCT03742258
Study groupRoleWhat they receive
TAK-659 60mg + R-CHOPExperimentalPatients 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.
Receives: Drug: Cyclophosphamide; Drug: Doxorubicin Hydrochloride; Drug: Prednisone; Biological: Rituximab; Drug: Spleen Tyrosine Kinase Inhibitor TAK-659; Drug: Vincristine Sulfate
TAK-659 80mg + R-CHOPExperimentalPatients 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.
Receives: Drug: Cyclophosphamide; Drug: Doxorubicin Hydrochloride; Drug: Prednisone; Biological: Rituximab; Drug: Spleen Tyrosine Kinase Inhibitor TAK-659; Drug: Vincristine Sulfate
TAK-659 100mg + R-CHOPExperimentalPatients 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.
Receives: Drug: Cyclophosphamide; Drug: Doxorubicin Hydrochloride; Drug: Prednisone; Biological: Rituximab; Drug: Spleen Tyrosine Kinase Inhibitor TAK-659; Drug: Vincristine Sulfate

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum Tolerated Dose (MTD)

    Determine the safety and establish the maximum tolerated dose of TAK-659 when combined with R-CHOP in the front-line treatment of high-risk DLBCL using only patients who are evaluable for dose limiting (DLT) toxicities. MTD for TAK-659 will be determined using a 3+3 dose escalation method. The starting dose was 60 mg with possible escalation to 80 mg and 100 mg. Patients may be de-escalated to 40 mg if DLT's were met at dose level 1.

    Measured: The first 21 days after the participant received their first dose of TAK-695

Secondary outcomes (2)

  1. Overall Response Rate (ORR)

    Using Lugano criteria (2014), ORR will be defined as the percentage of subjects with a confirmed complete response (CR) or partial response (PR) as assessed by the investigators. Response will be assessed by positron emission tomography (PET)/computed tomography (CT).

    Measured: PET/CT after the completion of Cycle 3

  2. Progression Free Survival (PFS)

    PFS will be assessed using Kaplan-Meier curves at 12 month and 18 months during survival follow-up.

    Measured: Up to 18 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 Nov 2018
  2. Study start13 Mar 2019
  3. Primary completion12 Mar 2021
  4. Study completion8 Feb 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
12 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03742258
Sponsor's protocol ID
NU 18H02
Other IDs
STU00207880, NU 18H02, P30CA060553, NCI-2018-01917
Status last verified
Jun 2025
First submitted
12 Nov 2018
Last updated
18 Jun 2025
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Cyclophosphamide, Doxorubicin Hydrochloride and Prednisone in people with Diffuse Large B-Cell Lymphoma and Diffuse Large B-Cell Lymphoma Activated B-Cell Type, run by Northwestern University at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 39 inclusion and 43 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 18 Jun 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 29 Jan 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum Tolerated Dose (MTD) (time frame: The first 21 days after the participant received their first dose of TAK-695). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03742258.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jun 2025.

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