A Study of Itacitinib (INCB039110) in Combination With Ibrutinib in Subjects With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Study Overview
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Brief Summary
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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)

Official Title
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An Open-Label Phase 1/2 Study of Itacitinib (INCB039110) in Combination With Ibrutinib in Subjects With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Conditions
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Lymphoma

Intervention / Treatment
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* Drug: itacitinib
* Drug: ibrutinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: itacitinib + ibrutinib<br> | Drug: itacitinib<br>* 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.<br>* Other names: INCB039110;Drug: ibrutinib<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | up to 285 days | 
| 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. | up to 285 days | 
| 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. | up to Day 28 | 
| 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. | up to 1538 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | up to 250 days | 
| 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. | up to 947 days | 
| 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. | up to 1538 days | 
| 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. | up to 1538 days | 
| 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. | up to 1573 days | 
| 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. | up to 1573 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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