Diffuse Large B-cell Lymphoma
Conditions
Keywords
Drug therapy
Brief summary
The purpose of this study is to assess the efficacy of TAK-659 measured by independent radiologic review committee (IRC)-assessed overall response rate (ORR) in participants with relapsed or refractory DLBCL.
Detailed description
The drug being tested is TAK-659. This study will evaluate overall response rate (ORR) in participants with relapsed or refractory DLBCL who take TAK-659. The study will enroll approximately 122 participants. Participants will be assigned to: • TAK-659 60 mg to 100 mg All participants will be asked to take the tablets of TAK-659 at the same time each day throughout the study in a 28-day cycle. This multi-center trial will be conducted in the United States, United Kingdom, Spain, Italy, France, Canada, Germany. The overall time to participate in this study is approximately 48 months. Participants will be assessed for disease response and progression during the PFS follow-up every 3 months after end of treatment (for participants who discontinue due to reasons other than disease progression) and OS follow-up every 3 months from the last dose of study drug until death or conclusion of the study, whichever occurs first.
Interventions
DRUGTAK-659
TAK-659 Tablets
Sponsors
Calithera Biosciences, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Must have histologically confirmed DLBCL, including de novo disease or transformed disease from indolent NHL. a. High-grade B-cell lymphoma (BCL) with MYC and BCL-2 and/or BCL-6 translocations (double-hit DLBCL under DLBCL, not otherwise specified \[NOS\], based on the 2008 World Health Organization \[WHO\] classification criteria) is not eligible for this study. 2. Local pathology review for histological confirmation; A formalin-fixed, paraffin-embedded (FFPE) tumor block or appropriately stained slides from a fresh biopsy is required. 3. Relapsed or refractory to greater than or equal to (\>=) 2 prior lines of chemotherapy based on standard of care with certain requirements for prior therapy. 4. Documented investigator-assessed relapse or progression after the last treatment is required if the participant responded and then progressed on the prior treatment. 5. Measurable disease per IWG 2007 criteria. 6. Eastern Cooperative Oncology Group (ECOG) performance status less than (\<) 2. 7. Life expectancy of greater than (\>) 3 months. 8. Adequate organ function, including the following: 1. Bone marrow reserve: absolute neutrophil count (ANC) \>=1000/microliter (μL), platelet count \>=75,000/μL (\>=50,000/μL for participants with bone marrow involvement), and hemoglobin \>=8 gram per deciliter (g/dL). 2. Hepatic: total bilirubin less than or equal to (\<=) 1.5 times the upper limit of the normal range (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<=2.5\*ULN. 3. Renal: creatinine clearance \>=60 milliliter per minute (mL/min). 4. Others: * Lipase \<=1.5\*ULN and amylase \<=1.5\*ULN with no clinical symptoms suggestive of pancreatitis or cholecystitis. * Blood pressure \<=Grade 1 (hypertensive participants are permitted if their blood pressure is controlled to \<=Grade 1 by hypertensive medications. * Glycosylated hemoglobin is \<=6.5% hyperglycemic participants permitted if glucose is well controlled by antihyperglycemic medication).
Exclusion criteria
1. Central nervous system (CNS) lymphoma; active brain or leptomeningeal metastases. 2. Known human immunodeficiency virus (HIV)-related malignancy. 3. Systemic anticancer treatment (including investigational agents) less than 3 weeks before the first dose of study treatment (\<=4 weeks for antibody-based therapy including unconjugated antibody, antibody-drug conjugate, and bi-specific T-cell engager agents; \<=8 weeks for cell-based therapy or anti-tumor vaccine). 4. Radiotherapy less than 3 weeks before the first dose of study treatment. If prior radiotherapy occurred \<4 to 6 weeks before study start, as radiated lesions cannot be reliably assessed by fluorodeoxyglucose-positron emission tomography (FDG-PET), nonradiated target lesions are required for eligibility, and prior radiotherapy information must be submitted to the IRC. 5. Known HIV positive, hepatitis B surface antigen positive or known or suspected active hepatitis C infection. 6. Prior autologous stem cell transplant (ASCT) within 6 months or prior ASCT at any time without full hematopoietic recovery before Cycle 1 Day 1, or allogeneic stem cell transplant any time. 7. Participants with certain cardiovascular conditions are excluded. 8. Major surgery within 14 days before the first dose of study drug or incomplete recovery from any complications from surgery. 9. Systemic infection requiring parenteral antibiotic therapy or other serious infection (bacterial, fungal, or viral) within 21 days before the first dose of study drug. 10. Treatment with high-dose corticosteroids for anticancer purposes within 7 days before the first dose of TAK-659. 11. Participants with another malignancy within 2 years of study start. Participants with nonmelanoma 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 study entry. 12. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of TAK-659. 13. Received medications, supplements, or food/beverages that are P-glycoprotein (P-gp) inhibitors or inducers or strong cytochrome P450 (CYP) 3A inhibitors or inducers within a certain timeframe prior to the first dose of study drug. Depending on the substance, the washout period for P-gp inhibitors or inducers or strong CYP3A inhibitors or inducers will be either 7 days or 5 times the half-life (half-life is related to the time required for elimination from the body). The washout period for grapefruit containing food or beverages is 5 days.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Stage 2: ORR as Assessed by Independent Radiologic Review Committee (IRRC) Based on Modified 2007 International Working Group (IWG) Criteria | Up to 12 months | ORR was defined as the percentage of participants with complete response (CR), or partial response (PR) as assessed by IRRC according to the modified 2007 IWG criteria for malignant lymphoma. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stage 2: CR Rate as Assessed by IRC Based on Modified 2007 IWG Criteria | Up to 12 months | CR rate was defined as percentage of participants with complete response as assessed by IRC according to the modified 2007 IWG. CR was defined as disappearance of all evidence of disease. |
| Stage 2: ORR as Assessed by IRRC Based on 2014 IWG-Lugano Criteria | Up to 12 months | ORR was defined as the percentage of participants with CR or PR as assessed by IRRC according to the 2014 Lugano classification, IWG criteria for malignant lymphoma. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites. |
| Stage 2: CR Rate as Assessed by IRRC Based on 2014 IWG-Lugano Criteria | Up to 12 months | CR rate was defined as percentage of participants with complete response as assessed by IRC according to the 2014 Lugano classification, IWG criteria. CR was defined as disappearance of all evidence of disease. |
| Stage 2: Duration of Response (DOR) | Up to 12 months | DOR was defined as the time from the date of first documentation of a CR/PR to the date of first documentation of tumor progression or progressive disease (PD) per IRRC assessment according to IWG criteria. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites. PD was defined as presence of any new lesion or increase by \>=50% of previously involved sites from nadir. |
| Stage 2: Duration of CR | Up to 12 months | Duration of CR was defined as the time from the date of first documentation of a CR/PR to the date of first documentation of tumor progression or PD per IRRC assessment according to IWG criteria. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites. PD was defined as presence of any new lesion or increase by \>=50% of previously involved sites from nadir. |
| Stage 2: ORR as Assessed by IRRC in Participants With Germinal Center B-cell (GCB) DLBCL | Up to 12 months | ORR was defined as the percentage of participants with CR or PR as assessed by IRRC according to the modified 2007 IWG criteria for malignant lymphoma. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites. |
| Stage 2: ORR as Assessed by IRC in Participants With DLBCL Transformed From Indolent Non-Hodgkin's Lymphoma (NHL) | Up to 12 months | ORR was defined as the percentage of participants with CR or PR as assessed by IRC according to the modified 2007 IWG criteria for malignant lymphoma. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites. |
| Stage 2: Progression Free Survival (PFS) as Assessed by IRC | Up to 18 months | PFS was defined as time from start of study treatment to first documentation of PD per IRC assessment or up to death due to any cause, whichever occurs first based on IWG criteria. PD was defined as presence of any new lesion or increase by \>=50% of previously involved sites from nadir. |
| Stage 2: Overall Survival (OS) | Up to 24 months | OS was defined as the time from start of study treatment to date of death due to any cause. |
| Stage 1: ORR as Assessed by IRRC to Select Stage 2 Dose Regimen of TAK-659 From the Lead-in Dose Exploration Phase | Up to 12 months | ORR was defined as the percentage of participants with CR or PR as assessed by IRC. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites. |
| Stage 2: ORR as Assessed by IRC at 3, 6, and 9 Cycles in Participants With DLBCL | At Cycles 3, 6 and 9 (Up to 12 months) (Each cycle of 28 days) | ORR was defined as the percentage of participants with CR or PR as assessed by IRC according to the modified 2007 IWG criteria for malignant lymphoma. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites. |
Countries
Canada, France, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 26 investigative sites in France, Great Britain, Italy, Spain, Canada, United States from 10 October 2017 to 17 December 2019. The study was terminated by the sponsor before the initiation of the stage 2 efficacy evaluation.
Pre-assignment details
Participants with a diagnosis of relapsed or refractory diffuse large B-cell lymphoma who had at least 2 prior lines of chemotherapy were enrolled in Cohorts A and B. Cohort A received a single dose and Cohort B received ramp-up doses of TAK-659 in Stage 1 of the study.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A: TAK-659 100 mg TAK-659 100 mg tablet, orally, once daily (QD), during each 28-days cycle (median exposure was 41 days). | 24 |
| Cohort B: TAK-659 Ramp-up Dosing TAK-659 60-100 mg tablet, orally, QD, dose based on safety and tolerability during each 28-days cycle (median exposure was 28 days). | 25 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Reason not Specified | 13 | 13 |
| Overall Study | Study Terminated by Sponsor | 6 | 9 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Total | Cohort A: TAK-659 100 mg | Cohort B: TAK-659 Ramp-up Dosing |
|---|---|---|---|
| Age, Continuous | 64.4 years STANDARD_DEVIATION 10.18 | 64.2 years STANDARD_DEVIATION 9.01 | 64.6 years STANDARD_DEVIATION 11.37 |
| Height | 170.1 cm STANDARD_DEVIATION 9.81 | 172.8 cm STANDARD_DEVIATION 9.55 | 167.5 cm STANDARD_DEVIATION 9.52 |
| Race/Ethnicity, Customized Hispanic or Latino | 5 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Non-Hispanic and Latino | 34 Participants | 21 Participants | 13 Participants |
| Race/Ethnicity, Customized Not Reported | 9 Participants | 2 Participants | 7 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) White | 40 Participants | 21 Participants | 19 Participants |
| Region of Enrollment Canada | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment France | 14 Participants | 3 Participants | 11 Participants |
| Region of Enrollment Italy | 8 Participants | 4 Participants | 4 Participants |
| Region of Enrollment Spain | 6 Participants | 3 Participants | 3 Participants |
| Region of Enrollment United Kingdom | 6 Participants | 3 Participants | 3 Participants |
| Region of Enrollment United States | 14 Participants | 10 Participants | 4 Participants |
| Sex: Female, Male Female | 20 Participants | 6 Participants | 14 Participants |
| Sex: Female, Male Male | 29 Participants | 18 Participants | 11 Participants |
| Weight | 82.64 kg STANDARD_DEVIATION 22.04 | 92.88 kg STANDARD_DEVIATION 21.132 | 72.81 kg STANDARD_DEVIATION 18.388 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 24 | 3 / 25 |
| other Total, other adverse events | 24 / 24 | 20 / 25 |
| serious Total, serious adverse events | 14 / 24 | 13 / 25 |
Outcome results
Primary
Stage 2: ORR as Assessed by Independent Radiologic Review Committee (IRRC) Based on Modified 2007 International Working Group (IWG) Criteria
ORR was defined as the percentage of participants with complete response (CR), or partial response (PR) as assessed by IRRC according to the modified 2007 IWG criteria for malignant lymphoma. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites.
Time frame: Up to 12 months
Population: As the study was terminated before the initiation of Stage 2, data was not collected for this outcome measure.
Secondary
Stage 1: ORR as Assessed by IRRC to Select Stage 2 Dose Regimen of TAK-659 From the Lead-in Dose Exploration Phase
ORR was defined as the percentage of participants with CR or PR as assessed by IRC. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites.
Time frame: Up to 12 months
Population: Data were not reported for this outcome measure because ORR was only assessed by the investigator on this study and not by IRRC as the study was terminated and the selection of dose for Stage 2 was not applicable.
Secondary
Stage 2: CR Rate as Assessed by IRC Based on Modified 2007 IWG Criteria
CR rate was defined as percentage of participants with complete response as assessed by IRC according to the modified 2007 IWG. CR was defined as disappearance of all evidence of disease.
Time frame: Up to 12 months
Population: As the study was terminated before the initiation of Stage 2, data was not collected for this outcome measure.
Secondary
Stage 2: CR Rate as Assessed by IRRC Based on 2014 IWG-Lugano Criteria
CR rate was defined as percentage of participants with complete response as assessed by IRC according to the 2014 Lugano classification, IWG criteria. CR was defined as disappearance of all evidence of disease.
Time frame: Up to 12 months
Population: As the study was terminated before the initiation of Stage 2, data was not collected for this outcome measure.
Secondary
Stage 2: Duration of CR
Duration of CR was defined as the time from the date of first documentation of a CR/PR to the date of first documentation of tumor progression or PD per IRRC assessment according to IWG criteria. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites. PD was defined as presence of any new lesion or increase by \>=50% of previously involved sites from nadir.
Time frame: Up to 12 months
Population: As the study was terminated before the initiation of Stage 2, data was not collected for this outcome measure.
Secondary
Stage 2: Duration of Response (DOR)
DOR was defined as the time from the date of first documentation of a CR/PR to the date of first documentation of tumor progression or progressive disease (PD) per IRRC assessment according to IWG criteria. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites. PD was defined as presence of any new lesion or increase by \>=50% of previously involved sites from nadir.
Time frame: Up to 12 months
Population: As the study was terminated before the initiation of Stage 2, data was not collected for this outcome measure.
Secondary
Stage 2: ORR as Assessed by IRC at 3, 6, and 9 Cycles in Participants With DLBCL
ORR was defined as the percentage of participants with CR or PR as assessed by IRC according to the modified 2007 IWG criteria for malignant lymphoma. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites.
Time frame: At Cycles 3, 6 and 9 (Up to 12 months) (Each cycle of 28 days)
Population: As the study was terminated before the initiation of Stage 2, data was not collected for this outcome measure.
Secondary
Stage 2: ORR as Assessed by IRC in Participants With DLBCL Transformed From Indolent Non-Hodgkin's Lymphoma (NHL)
ORR was defined as the percentage of participants with CR or PR as assessed by IRC according to the modified 2007 IWG criteria for malignant lymphoma. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites.
Time frame: Up to 12 months
Population: As the study was terminated before the initiation of Stage 2, data was not collected for this outcome measure.
Secondary
Stage 2: ORR as Assessed by IRRC Based on 2014 IWG-Lugano Criteria
ORR was defined as the percentage of participants with CR or PR as assessed by IRRC according to the 2014 Lugano classification, IWG criteria for malignant lymphoma. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites.
Time frame: Up to 12 months
Population: As the study was terminated before the initiation of Stage 2, data was not collected for this outcome measure.
Secondary
Stage 2: ORR as Assessed by IRRC in Participants With Germinal Center B-cell (GCB) DLBCL
ORR was defined as the percentage of participants with CR or PR as assessed by IRRC according to the modified 2007 IWG criteria for malignant lymphoma. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measurable disease and no new sites.
Time frame: Up to 12 months
Population: As the study was terminated before the initiation of Stage 2, data was not collected for this outcome measure.
Secondary
Stage 2: Overall Survival (OS)
OS was defined as the time from start of study treatment to date of death due to any cause.
Time frame: Up to 24 months
Population: As the study was terminated before the initiation of Stage 2, data was not collected for this outcome measure.
Secondary
Stage 2: Progression Free Survival (PFS) as Assessed by IRC
PFS was defined as time from start of study treatment to first documentation of PD per IRC assessment or up to death due to any cause, whichever occurs first based on IWG criteria. PD was defined as presence of any new lesion or increase by \>=50% of previously involved sites from nadir.
Time frame: Up to 18 months
Population: As the study was terminated before the initiation of Stage 2, data was not collected for this outcome measure.