Lymphoma
Conditions
Keywords
Diffuse large B-cell lymphoma, Relapsed Diffuse large B-cell lymphoma, Refractory Diffuse large B-cell lymphoma, activated B cell, germinal center B-cell, non-Hodgkin lymphoma, JAK1 inhibitor, Bruton's tyrosine kinase (BTK) inhibitor
Brief summary
The purpose of this study is to evaluate the safety/tolerability and efficacy of itacitinib in combination with ibrutinib in subjects with relapsed or refractory diffuse large B-cell lymphoma (DLBCL)
Interventions
DRUGitacitinib
Phase 1 will evaluate itacitinib at the protocol-specified starting dose, with a possible increase or decrease depending on tolerability. Phase 2 will evaluate the recommended dose determined in Phase 1.
DRUGibrutinib
Sponsors
Incyte Corporation
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically documented diagnosis of DLBCL. * Phase 1: any DLBCL subtype. * Phase 2: activated B-cell or unclassifiable subtypes confirmed by immunohistochemistry using the Hans algorithm * Relapsed or refractory DLBCL, defined as having received at least 1 but no more than 3 prior treatment regimens and ineligible for high-dose chemotherapy/autologous stem cell transplant. * Fluorodeoxyglucose-avid disease (based on local evaluation) per the Lugano Classification. Fluorodeoxyglucose-avid disease is defined as disease with a 5-point scale score of 4 or 5. * Archived tumor tissue (block or 15-20 unstained slides) available, or be willing to undergo an incisional or excisional lymph node biopsy of accessible adenopathy (or, in less accessible lymph nodes, 4 to 8 core biopsies). * At least 1 measurable (≥ 2 cm in longest dimension) lesion on CT scan or magnetic resonance imaging (MRI). * Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
Exclusion criteria
* Transformed DLBCL or DLBCL with coexistent histologies (eg, follicular or mucosa-associated lymphoid tissue lymphoma). * Primary mediastinal (thymic) large B-cell lymphoma. * Known central nervous system lymphoma (either primary or metastatic). * Allogeneic stem cell transplant within the previous 6 months, or active graft versus host disease following allogeneic transplant. * Use of immunosuppressive therapy within 28 days of starting study treatment. Immunosuppressive therapy includes but is not limited to cyclosporine A, tacrolimus, or high-dose corticosteroids. Subjects receiving corticosteroids must be at a dose level ≤ 10 mg/day within 7 days of initiating study treatment. * Prior or concurrent therapy with a Janus kinase inhibitor or Bruton's tyrosine kinase inhibitor
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | up to 285 days | An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. Abnormal laboratory values or test results occurring after informed consent constituted AEs only if they induced clinical signs or symptoms, were considered clinically meaningful, required therapy (e.g., hematologic abnormality that required transfusion), or required changes in the study drug(s). A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of study drug and until 30 days after the last dose of study drug. |
| Phase 1: Number of Participants With Any Grade 3 or Higher TEAE | up to 285 days | An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. Abnormal laboratory values or test results occurring after informed consent constituted AEs only if they induced clinical signs or symptoms, were considered clinically meaningful, required therapy (e.g., hematologic abnormality that required transfusion), or required changes in the study drug(s). A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of study drug and until 30 days after the last dose of study drug. Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4: life-threatening consequences; urgent intervention indicated. |
| Phase 1: Number of Participants With Any Dose-limiting Toxicity (DLT) | up to Day 28 | A DLT was defined as the occurrence of any protocol-defined toxicities occurring up to and including Study Day 28, except those with a clear alternative explanation (e.g., disease progression) or transient (≤72 hours) abnormal laboratory values without associated clinically significant signs or symptoms based on investigator determination. All DLTs were assessed by the investigator using Common Terminology Criteria for Adverse Events (CTCAE) v4.03 criteria. In order to be included in the tolerability review, subjects must have received the cohort-specific dose of INCB039110 and ibrutinib for at least 75% of the days during the 28-day surveillance period or have experienced a DLT. |
| Phase 2: Objective Response Rate (ORR), Defined as the Percentage of Participants Achieving Either a Complete Response (CR) or a Partial Response (PR), Per the Modified Lugano Classification for Diffuse Large B-cell Lymphoma (DLBCL) | up to 1538 days | CR: (1) target nodes/nodal masses of lymph nodes/extralymphatic sites regressed to ≤1.5 centimeters (cm) in the longest dimension transverse diameter of lesion (LDi); (2) absence of non-measured lesions; (3) organ enlargement regressed to normal; (4) no new lesions; (5) normal bone marrow morphology; if indeterminate, immunohistochemistry negative. PR: (1) lymph nodes/extralymphatic sites: ≥50% decrease in the sum of the product of perpendicular diameters for multiple lesions of up to 6 target measurable nodes/extranodal sites; if lesion is too small to measure on computed tomography, assign 5 millimeters (mm) × 5 mm as default; if no longer visible, 0 mm × 0 mm. For node \>5 mm × 5 mm but smaller than normal, use actual measurement; (2) absent/regressed non-measured lesions, no increase; (3) organ enlargement; spleen regressed by \>50% in length beyond normal; (4) no new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Number of Participants With Any TEAE | up to 1573 days | An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. Abnormal laboratory values or test results occurring after informed consent constituted AEs only if they induced clinical signs or symptoms, were considered clinically meaningful, required therapy (e.g., hematologic abnormality that required transfusion), or required changes in the study drug(s). A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of study drug and until 30 days after the last dose of study drug. |
| Phase 1: ORR, Defined as the Percentage of Participants Achieving Either a CR or a PR, Per the Modified Lugano Classification for DLBCL | up to 250 days | CR: (1) target nodes/nodal masses of lymph nodes/extralymphatic sites regressed to ≤1.5 cm in the LDi; (2) absence of non-measured lesions; (3) organ enlargement regressed to normal; (4) no new lesions; (5) normal bone marrow morphology; if indeterminate, immunohistochemistry negative. PR: (1) lymph nodes/extralymphatic sites: ≥50% decrease in the sum of the product of perpendicular diameters for multiple lesions of up to 6 target measurable nodes/extranodal sites; if lesion is too small to measure on computed tomography, assign 5 mm × 5 mm as default; if no longer visible, 0 mm × 0 mm. For node \>5 mm × 5 mm but smaller than normal, use actual measurement; (2) absent/regressed non-measured lesions, no increase; (3) organ enlargement; spleen regressed by \>50% in length beyond normal; (4) no new lesions. |
| Phase 2: Number of Participants With Any Grade 3 or Higher TEAE | up to 1573 days | An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. Abnormal laboratory values or test results occurring after informed consent constituted AEs only if they induced clinical signs or symptoms, were considered clinically meaningful, required therapy (e.g., hematologic abnormality that required transfusion), or required changes in the study drug(s). A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of study drug and until 30 days after the last dose of study drug. Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4: life-threatening consequences; urgent intervention indicated. |
| Phase 2: Duration of Response (DOR): Time From the First Overall Response Contributing to an Objective Response (CR or PR) to the Earlier of the Participant's Death and the First Overall Response of Progressive Disease, Per the Lugano Classification | up to 947 days | Disease progression requires ≥1 of the following: (1) an abnormal individual node/lesion with all of the following: (a) LDi \> 1.5 cm; (b) increase by ≥50% from cross product of the LDi and the perpendicular diameter (PPD) nadir; (c) increase in LDi or the shortest axis perpendicular to the LDi (SDi) from nadir: (i) 0.5 cm for lesions ≤2 cm; (ii) 1.0 cm for lesions \> 2 cm. (2) For splenomegaly, the splenic length must increased by 50% of the extent of its prior increase beyond baseline. If no prior splenomegaly, must increase by at least 2 cm from baseline. (3) New/recurrent splenomegaly. (4) New/clear progression of preexisting nonmeasured lesions. (5) Regrowth of previously resolved lesions. (6) A new node \> 1.5 cm in any axis. (7) A new extranodal site \> 1.0 cm in any axis; if \< 1.0 cm in any axis, its presence must be unequivocal/attributable to lymphoma. (8) Assessable disease of any size unequivocally attributable to lymphoma. (9) New or recurrent involvement of the bone marrow. |
| Phase 2: Durable Response Rate (DRR) | up to 1538 days | DRR=percentage of participants with a CR or PR, per Lugano Classification, for ≥16 weeks since the time from the first overall response contributing to an objective response (CR or PR). CR: (1) target nodes/nodal masses of lymph nodes/extralymphatic sites regressed to ≤1.5 cm in the LDi; (2) absence of non-measured lesions; (3) organ enlargement regressed to normal; (4) no new lesions; (5) normal bone marrow morphology; if indeterminate, immunohistochemistry negative. PR: (1) lymph nodes/extralymphatic sites: ≥50% decrease in the sum of the product of perpendicular diameters for multiple lesions of up to 6 target measurable nodes/extranodal sites; if lesion is too small to measure on computed tomography, assign 5 mm × 5 mm as default; if no longer visible, 0 mm × 0 mm. For node \>5 mm × 5 mm but smaller than normal, use actual measurement; (2) absent/regressed non-measured lesions, no increase; (3) organ enlargement; spleen regressed by \>50% in length beyond normal; (4) no new lesions. |
| Phase 2: Progression-free Survival (PFS), Defined as the Time From the First Dose to the Earlier Date of Death Due to Any Cause or Disease Progression Determined by Objective Radiographic Disease Assessments | up to 1538 days | Disease progression requires ≥1 of the following: (1) an abnormal individual node/lesion with all of the following: (a) LDi \> 1.5 cm; (b) increase by ≥50% from cross product of the LDi and the perpendicular diameter (PPD) nadir; (c) increase in LDi or the shortest axis perpendicular to the LDi (SDi) from nadir: (i) 0.5 cm for lesions ≤2 cm; (ii) 1.0 cm for lesions \> 2 cm. (2) For splenomegaly, the splenic length must increased by 50% of the extent of its prior increase beyond baseline. If no prior splenomegaly, must increase by at least 2 cm from baseline. (3) New/recurrent splenomegaly. (4) New/clear progression of preexisting nonmeasured lesions. (5) Regrowth of previously resolved lesions. (6) A new node \> 1.5 cm in any axis. (7) A new extranodal site \> 1.0 cm in any axis; if \< 1.0 cm in any axis, its presence must be unequivocal/attributable to lymphoma. (8) Assessable disease of any size unequivocally attributable to lymphoma. (9) New or recurrent involvement of the bone marrow. |
Countries
United States
Participant flow
Pre-assignment details
This study was conducted at 12 study centers in the United States.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1; Cohort 1: Itacitinib 300 mg QD + Ibrutinib 560 mg QD Participants received oral itacitinib 300 milligrams (mg) once daily (QD) plus oral ibrutinib 560 mg QD until treatment discontinuation criteria were met. | 6 |
| Phase 1; Cohort 2: Itacitinib 400 mg QD + Ibrutinib 560 mg QD Participants received oral itacitinib 400 mg QD plus oral ibrutinib 560 mg QD until treatment discontinuation criteria were met. | 7 |
| Phase 2: Itacitinib 400 mg QD + Ibrutinib 560 mg QD Participants received oral itacitinib 400 mg QD plus oral ibrutinib 560 mg QD until treatment discontinuation criteria were met. | 19 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Phase 1 | Amendment Removed Survival Follow-up | 0 | 1 | 0 |
| Phase 1 | Death | 3 | 6 | 0 |
| Phase 1 | Progressive Disease | 1 | 0 | 0 |
| Phase 1 | Unknown; Did Not Complete End-of-Study Visit | 1 | 0 | 0 |
| Phase 1 | Withdrawal by Subject | 2 | 0 | 0 |
| Phase 2 | Death | 0 | 0 | 12 |
| Phase 2 | Progressive Disease | 0 | 0 | 1 |
| Phase 2 | Unknown; Did Not Complete End-of-Study Visit | 0 | 0 | 3 |
| Phase 2 | Withdrawal by Subject | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | Phase 2: Itacitinib 400 mg QD + Ibrutinib 560 mg QD | Phase 1; Cohort 1: Itacitinib 300 mg QD + Ibrutinib 560 mg QD | Total | Phase 1; Cohort 2: Itacitinib 400 mg QD + Ibrutinib 560 mg QD |
|---|---|---|---|---|
| Age, Continuous | 72.1 years STANDARD_DEVIATION 14.25 | 70.3 years STANDARD_DEVIATION 10.42 | 70.6 years STANDARD_DEVIATION 13.2 | 67.0 years STANDARD_DEVIATION 13.39 |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Black/African-American | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Captured as Other | 3 Participants | 0 Participants | 4 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 2 Participants | 1 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized Missing | 1 Participants | 0 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 13 Participants | 4 Participants | 20 Participants | 3 Participants |
| Race/Ethnicity, Customized Not Reported | 3 Participants | 1 Participants | 4 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 0 Participants | 5 Participants | 4 Participants |
| Race/Ethnicity, Customized White/Caucasian | 13 Participants | 6 Participants | 23 Participants | 4 Participants |
| Sex: Female, Male Female | 6 Participants | 2 Participants | 13 Participants | 5 Participants |
| Sex: Female, Male Male | 13 Participants | 4 Participants | 19 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 6 | 19 / 26 | 21 / 32 |
| other Total, other adverse events | 6 / 6 | 26 / 26 | 32 / 32 |
| serious Total, serious adverse events | 4 / 6 | 18 / 26 | 22 / 32 |
Outcome results
Primary
Phase 1: Number of Participants With Any Dose-limiting Toxicity (DLT)
A DLT was defined as the occurrence of any protocol-defined toxicities occurring up to and including Study Day 28, except those with a clear alternative explanation (e.g., disease progression) or transient (≤72 hours) abnormal laboratory values without associated clinically significant signs or symptoms based on investigator determination. All DLTs were assessed by the investigator using Common Terminology Criteria for Adverse Events (CTCAE) v4.03 criteria. In order to be included in the tolerability review, subjects must have received the cohort-specific dose of INCB039110 and ibrutinib for at least 75% of the days during the 28-day surveillance period or have experienced a DLT.
Time frame: up to Day 28
Population: Safety Run-In Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1; Cohort 1: Itacitinib 300 mg QD + Ibrutinib 560 mg QD | Phase 1: Number of Participants With Any Dose-limiting Toxicity (DLT) | 0 Participants |
| Phase 1; Cohort 2: Itacitinib 400 mg QD + Ibrutinib 560 mg QD | Phase 1: Number of Participants With Any Dose-limiting Toxicity (DLT) | 1 Participants |
Primary
Phase 1: Number of Participants With Any Grade 3 or Higher TEAE
An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. Abnormal laboratory values or test results occurring after informed consent constituted AEs only if they induced clinical signs or symptoms, were considered clinically meaningful, required therapy (e.g., hematologic abnormality that required transfusion), or required changes in the study drug(s). A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of study drug and until 30 days after the last dose of study drug. Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4: life-threatening consequences; urgent intervention indicated.
Time frame: up to 285 days
Population: Safety Run-In Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1; Cohort 1: Itacitinib 300 mg QD + Ibrutinib 560 mg QD | Phase 1: Number of Participants With Any Grade 3 or Higher TEAE | 5 Participants |
| Phase 1; Cohort 2: Itacitinib 400 mg QD + Ibrutinib 560 mg QD | Phase 1: Number of Participants With Any Grade 3 or Higher TEAE | 5 Participants |
Primary
Phase 1: Number of Participants With Any Treatment-emergent Adverse Event (TEAE)
An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. Abnormal laboratory values or test results occurring after informed consent constituted AEs only if they induced clinical signs or symptoms, were considered clinically meaningful, required therapy (e.g., hematologic abnormality that required transfusion), or required changes in the study drug(s). A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of study drug and until 30 days after the last dose of study drug.
Time frame: up to 285 days
Population: Safety Run-In Population: all participants enrolled in the Phase 1 portion of the study who received at least 1 dose of study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1; Cohort 1: Itacitinib 300 mg QD + Ibrutinib 560 mg QD | Phase 1: Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 6 Participants |
| Phase 1; Cohort 2: Itacitinib 400 mg QD + Ibrutinib 560 mg QD | Phase 1: Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 7 Participants |
Primary
Phase 2: Objective Response Rate (ORR), Defined as the Percentage of Participants Achieving Either a Complete Response (CR) or a Partial Response (PR), Per the Modified Lugano Classification for Diffuse Large B-cell Lymphoma (DLBCL)
CR: (1) target nodes/nodal masses of lymph nodes/extralymphatic sites regressed to ≤1.5 centimeters (cm) in the longest dimension transverse diameter of lesion (LDi); (2) absence of non-measured lesions; (3) organ enlargement regressed to normal; (4) no new lesions; (5) normal bone marrow morphology; if indeterminate, immunohistochemistry negative. PR: (1) lymph nodes/extralymphatic sites: ≥50% decrease in the sum of the product of perpendicular diameters for multiple lesions of up to 6 target measurable nodes/extranodal sites; if lesion is too small to measure on computed tomography, assign 5 millimeters (mm) × 5 mm as default; if no longer visible, 0 mm × 0 mm. For node \>5 mm × 5 mm but smaller than normal, use actual measurement; (2) absent/regressed non-measured lesions, no increase; (3) organ enlargement; spleen regressed by \>50% in length beyond normal; (4) no new lesions.
Time frame: up to 1538 days
Population: Intent-to-Treat (ITT) Population: all participants enrolled in the Phase 2 portion of the study. The confidence interval was calculated based on the exact method for binomial distribution.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: Itacitinib 400 mg QD + Ibrutinib 560 mg QD | Phase 2: Objective Response Rate (ORR), Defined as the Percentage of Participants Achieving Either a Complete Response (CR) or a Partial Response (PR), Per the Modified Lugano Classification for Diffuse Large B-cell Lymphoma (DLBCL) | 26.3 percentage of participants |
Secondary
Phase 1: ORR, Defined as the Percentage of Participants Achieving Either a CR or a PR, Per the Modified Lugano Classification for DLBCL
CR: (1) target nodes/nodal masses of lymph nodes/extralymphatic sites regressed to ≤1.5 cm in the LDi; (2) absence of non-measured lesions; (3) organ enlargement regressed to normal; (4) no new lesions; (5) normal bone marrow morphology; if indeterminate, immunohistochemistry negative. PR: (1) lymph nodes/extralymphatic sites: ≥50% decrease in the sum of the product of perpendicular diameters for multiple lesions of up to 6 target measurable nodes/extranodal sites; if lesion is too small to measure on computed tomography, assign 5 mm × 5 mm as default; if no longer visible, 0 mm × 0 mm. For node \>5 mm × 5 mm but smaller than normal, use actual measurement; (2) absent/regressed non-measured lesions, no increase; (3) organ enlargement; spleen regressed by \>50% in length beyond normal; (4) no new lesions.
Time frame: up to 250 days
Population: Safety Run-in Population. The confidence interval was calculated based on the exact method for binomial distribution.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1; Cohort 1: Itacitinib 300 mg QD + Ibrutinib 560 mg QD | Phase 1: ORR, Defined as the Percentage of Participants Achieving Either a CR or a PR, Per the Modified Lugano Classification for DLBCL | 33.3 percentage of participants |
| Phase 1; Cohort 2: Itacitinib 400 mg QD + Ibrutinib 560 mg QD | Phase 1: ORR, Defined as the Percentage of Participants Achieving Either a CR or a PR, Per the Modified Lugano Classification for DLBCL | 57.1 percentage of participants |
Secondary
Phase 2: Durable Response Rate (DRR)
DRR=percentage of participants with a CR or PR, per Lugano Classification, for ≥16 weeks since the time from the first overall response contributing to an objective response (CR or PR). CR: (1) target nodes/nodal masses of lymph nodes/extralymphatic sites regressed to ≤1.5 cm in the LDi; (2) absence of non-measured lesions; (3) organ enlargement regressed to normal; (4) no new lesions; (5) normal bone marrow morphology; if indeterminate, immunohistochemistry negative. PR: (1) lymph nodes/extralymphatic sites: ≥50% decrease in the sum of the product of perpendicular diameters for multiple lesions of up to 6 target measurable nodes/extranodal sites; if lesion is too small to measure on computed tomography, assign 5 mm × 5 mm as default; if no longer visible, 0 mm × 0 mm. For node \>5 mm × 5 mm but smaller than normal, use actual measurement; (2) absent/regressed non-measured lesions, no increase; (3) organ enlargement; spleen regressed by \>50% in length beyond normal; (4) no new lesions.
Time frame: up to 1538 days
Population: ITT Population. Participants who achieved a CR or a PR per Lugano Classification were analyzed. The confidence interval was calculated based on the exact method for binomial distribution.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: Itacitinib 400 mg QD + Ibrutinib 560 mg QD | Phase 2: Durable Response Rate (DRR) | 60.0 percentage of participants |
Secondary
Phase 2: Duration of Response (DOR): Time From the First Overall Response Contributing to an Objective Response (CR or PR) to the Earlier of the Participant's Death and the First Overall Response of Progressive Disease, Per the Lugano Classification
Disease progression requires ≥1 of the following: (1) an abnormal individual node/lesion with all of the following: (a) LDi \> 1.5 cm; (b) increase by ≥50% from cross product of the LDi and the perpendicular diameter (PPD) nadir; (c) increase in LDi or the shortest axis perpendicular to the LDi (SDi) from nadir: (i) 0.5 cm for lesions ≤2 cm; (ii) 1.0 cm for lesions \> 2 cm. (2) For splenomegaly, the splenic length must increased by 50% of the extent of its prior increase beyond baseline. If no prior splenomegaly, must increase by at least 2 cm from baseline. (3) New/recurrent splenomegaly. (4) New/clear progression of preexisting nonmeasured lesions. (5) Regrowth of previously resolved lesions. (6) A new node \> 1.5 cm in any axis. (7) A new extranodal site \> 1.0 cm in any axis; if \< 1.0 cm in any axis, its presence must be unequivocal/attributable to lymphoma. (8) Assessable disease of any size unequivocally attributable to lymphoma. (9) New or recurrent involvement of the bone marrow.
Time frame: up to 947 days
Population: ITT Population. Participants who achieved a CR or a PR per Lugano Classification for DLBCL were analyzed. The 90% confidence interval was calculated using the Brookmeyer and Crowley's method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: Itacitinib 400 mg QD + Ibrutinib 560 mg QD | Phase 2: Duration of Response (DOR): Time From the First Overall Response Contributing to an Objective Response (CR or PR) to the Earlier of the Participant's Death and the First Overall Response of Progressive Disease, Per the Lugano Classification | 8.80 months |
Secondary
Phase 2: Number of Participants With Any Grade 3 or Higher TEAE
An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. Abnormal laboratory values or test results occurring after informed consent constituted AEs only if they induced clinical signs or symptoms, were considered clinically meaningful, required therapy (e.g., hematologic abnormality that required transfusion), or required changes in the study drug(s). A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of study drug and until 30 days after the last dose of study drug. Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4: life-threatening consequences; urgent intervention indicated.
Time frame: up to 1573 days
Population: Safety Evaluable Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 2: Itacitinib 400 mg QD + Ibrutinib 560 mg QD | Phase 2: Number of Participants With Any Grade 3 or Higher TEAE | 16 Participants |
Secondary
Phase 2: Number of Participants With Any TEAE
An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. Abnormal laboratory values or test results occurring after informed consent constituted AEs only if they induced clinical signs or symptoms, were considered clinically meaningful, required therapy (e.g., hematologic abnormality that required transfusion), or required changes in the study drug(s). A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of study drug and until 30 days after the last dose of study drug.
Time frame: up to 1573 days
Population: Safety Evaluable Population: all participants enrolled in the Phase 2 portion of the study who received at least 1 dose of study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 2: Itacitinib 400 mg QD + Ibrutinib 560 mg QD | Phase 2: Number of Participants With Any TEAE | 19 Participants |
Secondary
Phase 2: Progression-free Survival (PFS), Defined as the Time From the First Dose to the Earlier Date of Death Due to Any Cause or Disease Progression Determined by Objective Radiographic Disease Assessments
Disease progression requires ≥1 of the following: (1) an abnormal individual node/lesion with all of the following: (a) LDi \> 1.5 cm; (b) increase by ≥50% from cross product of the LDi and the perpendicular diameter (PPD) nadir; (c) increase in LDi or the shortest axis perpendicular to the LDi (SDi) from nadir: (i) 0.5 cm for lesions ≤2 cm; (ii) 1.0 cm for lesions \> 2 cm. (2) For splenomegaly, the splenic length must increased by 50% of the extent of its prior increase beyond baseline. If no prior splenomegaly, must increase by at least 2 cm from baseline. (3) New/recurrent splenomegaly. (4) New/clear progression of preexisting nonmeasured lesions. (5) Regrowth of previously resolved lesions. (6) A new node \> 1.5 cm in any axis. (7) A new extranodal site \> 1.0 cm in any axis; if \< 1.0 cm in any axis, its presence must be unequivocal/attributable to lymphoma. (8) Assessable disease of any size unequivocally attributable to lymphoma. (9) New or recurrent involvement of the bone marrow.
Time frame: up to 1538 days
Population: ITT Population. The 90% confidence interval was calculated using the Brookmeyer and Crowley's method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: Itacitinib 400 mg QD + Ibrutinib 560 mg QD | Phase 2: Progression-free Survival (PFS), Defined as the Time From the First Dose to the Earlier Date of Death Due to Any Cause or Disease Progression Determined by Objective Radiographic Disease Assessments | 3.17 months |