A Phase 1/2, Open-Label, Dose Escalation, Safety and Tolerability Study of INCB050465 and Itacitinib in Subjects With Previously Treated B-Cell Malignancies (CITADEL-101)

B-Cell Malignancies Clinical Trial

Official title:

A Phase 1/2, Open-Label, Dose Escalation, Safety and Tolerability Study of INCB050465 and Iitacitinib in Subjects With Previously Treated B-Cell Malignancies (CITADEL-101)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02018861
• Other study ID #: INCB 50465-101 (CITADEL-101)
• Secondary ID: Parsaclisib
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: September 22, 2016
• Est. completion date: April 12, 2021

Study information

• Verified date: September 2023
• Source: Incyte Corporation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Open-label, dose-escalation study in subjects with previously treated B-cell malignancies to find maximum tolerated dose (MTD) or pharmacologic active dose of a PI3Kδ inhibitor, parsaclisib, as monotherapy and in combination with: itacitinib (INCB039110), a JAK1 inhibitor; rituximab; and rituximab, ifosfamide, carboplatin, and etoposide. Parsaclisib inhibits PI3Kδ, a protein involved in growth and survival of B-cell cancer cells.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 88
• Est. completion date: April 12, 2021
• Est. primary completion date: April 12, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Aged 18 years or older, with lymphoid malignancies of B-cell origin including:

1. Indolent / aggressive B-cell non-Hodgkin's lymphoma (NHL)

• EXCLUDING: Burkitt's lymphoma and precursor B lymphoblastic leukemia/lymphoma
• INCLUDING: any non-Hodgkin's B cell malignancy such as chronic lymphocytic leukemia (CLL) and rare non-Hodgkin's B- cell subtypes such as hairy cell leukemia, Waldenström macroglobulinemia (WM), mantle cell leukemia (MCL), and transformed NHL histologies

2. Hodgkin's lymphoma (HL)

• Life expectancy of 12 weeks or longer
• Subject must have received = 1 prior treatment regimen(s)
• The subject must not be a candidate for potentially curative therapy including hematopoietic stem cell transplantation, except where one of the standard therapy regimen combinations may be used prior to transplantation per standard medical practice

Exclusion Criteria:

• Has history of brain metastasis, spinal cord compression (unless treated, asymptomatic, and stable on most recent imaging and enrolling in expansion cohort), or lymphoma involving the central nervous system (CNS)
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of = 3 (= 2 during dose escalation)
• Received allogeneic hematopoietic stem cell transplant within the last 6 months, or has active graft versus host disease (GVHD) following allogeneic transplant, or currently receiving immunosuppressive therapy following allogeneic transplant
• Received autologous hematopoietic stem cell transplant within the last 3 months
• Inadequate marrow reserve assessed by hematologic laboratory parameters
• Inadequate renal or liver function
• Known HIV infection, or hepatitis B virus (HBV) or hepatitis C virus (HCV) viremia or at risk for HBV reactivation

Related Conditions & MeSH terms

• B-Cell Malignancies
• Neoplasms

Intervention

Drug:
• Parsaclisib

• Itacitinib

• Rituximab

• Ifosfamide

• Carboplatin

• Etoposide

Locations

Country	Name	City	State
United States	University of Michigan Cancer Center	Ann Arbor	Michigan
United States	University of Alabama At Birmingham Comprehensive Cancer Center	Birmingham	Alabama
United States	University Hospitals Case Medical Center	Cleveland	Ohio
United States	Baylor Charles A. Sammons Cancer Center	Dallas	Texas
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	Greenville Health System Cancer Institute	Greenville	South Carolina
United States	Nyu Langone Laura and Isaac Perlmutter Cancer Center	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Incyte Corporation

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An adverse event (AE) is defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occur after a participant provides informed consent. Abnormal laboratory values or test results occurring after informed consent constitute AEs only if they induce clinical signs or symptoms, are considered clinically meaningful, require therapy (e.g., hematologic abnormality that requires transfusion), or require changes in the study drug(s). A TEAE is defined as an event that was reported for the first time, or the worsening of a pre-existing event, after the first dose of study drug.	Up to approximately 53 months (4.4 years)
Secondary	Part 1: Overall Response Rate (Percentage of Participants With Complete Response [CR] and Partial Response [PR]) Based on International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria for Chronic Lymphocytic Leukemia (CLL) for CLL Participants	CR: (a) peripheral blood lymphocytes <4 x 10^9/Liter (L); (b) no significant lymphadenopathy and lymph nodes <1.5 centimeters (cm) in longest diameter; (c) no splenomegaly/hepatomegaly; (d) no disease-related constitutional symptoms; (e) neutrophils =1.5 x 10^9/L; (f) platelets =100 x 10^9/L; (g) hemoglobin =11.0 grams/deciliter (g/dL) (without transfusion); (h) minimal residual disease assessment; (i) normocellular marrow, with no CLL cells/no B-lymphoid nodules. PR (improvement in =2 Group A parameters and =1 Group B parameter if previously abnormal. If only 1 parameter of both Groups A and B was abnormal before therapy, only 1 needs to improve): Group A: (a) decrease of =50% (from Baseline) in lymph nodes, liver/spleen size, and circulating lymphocyte count; (b) any constitutional symptoms. Group B: (a) platelets =100 x 10^9/L or increase =50% over Baseline; (b) hemoglobin =11 g/dL or increase =50% over Baseline; (c) presence of CLL cells or B-lymphoid nodules.	Up to approximately 53 months (4.4 years)
Secondary	Part 2: Overall Response Rate (Percentage of Participants With CR and PR) Based on IWCLL Criteria for CLL for Participants With CLL	CR: (a) peripheral blood lymphocytes <4 x 10^9/L; (b) no significant lymphadenopathy and lymph nodes <1.5 cm in longest diameter; (c) no splenomegaly/hepatomegaly; (d) no disease-related constitutional symptoms; (e) neutrophils =1.5 x 10^9/L; (f) platelets =100 x 10^9/L; (g) hemoglobin =11.0 g/dL (without transfusion); (h) minimal residual disease assessment; (i) normocellular marrow, with no CLL cells/no B-lymphoid nodules. PR (improvement in =2 Group A parameters and =1 Group B parameter if previously abnormal. If only 1 parameter of both Groups A and B was abnormal before therapy, only 1 needs to improve): Group A: (a) decrease of =50% (from Baseline) in lymph nodes, liver/spleen size, and circulating lymphocyte count; (b) any constitutional symptoms. Group B: (a) platelets =100 x 10^9/L or increase =50% over Baseline; (b) =11 g/dL or increase =50% over Baseline; (c) presence of CLL cells or B-lymphoid nodules.	Up to approximately 44 months (3.7 years)
Secondary	Part 6: Overall Response Rate (Percentage of Participants With CR and PR) Based on IWCLL Criteria for CLL for Participants With CLL	CR: (a) peripheral blood lymphocytes <4 x 10^9/L; (b) no significant lymphadenopathy and lymph nodes <1.5 cm in longest diameter; (c) no splenomegaly/hepatomegaly; (d) no disease-related constitutional symptoms; (e) neutrophils =1.5 x 10^9/L; (f) platelets =100 x 10^9/L; (g) hemoglobin =11.0 g/dL (without transfusion); (h) minimal residual disease assessment; (i) normocellular marrow, with no CLL cells/no B-lymphoid nodules. PR (improvement in =2 Group A parameters and =1 Group B parameter if previously abnormal. If only 1 parameter of both Groups A and B was abnormal before therapy, only 1 needs to improve): Group A: (a) decrease of =50% (from Baseline) in lymph nodes, liver/spleen size, and circulating lymphocyte count; (b) any constitutional symptoms. Group B: (a) platelets =100 x 10^9/L or increase =50% over Baseline; (b) =11 g/dL or increase =50% over Baseline; (c) presence of CLL cells or B-lymphoid nodules.	Up to approximately 4 months
Secondary	Part 1: ORR Based on the VIth International Workshop on Waldenström Macroglobulinemia (WM) Response Assessment for Participants With WM	ORR: sum of participants achieving minor response (MR), PR, very good partial response (VGPR), and CR. CR: (a) no serum monoclonal IgM protein by immunofixation; (b) normal serum IgM level; (c) complete resolution of extramedullary disease, i.e., lymphadenopathy/splenomegaly if present at Baseline (BL); (d) morphologically normal bone marrow aspirate and trephine biopsy. VGPR: (a) detectable monoclonal IgM protein; (b) =90% reduction in serum IgM level from BL; (c) complete resolution of extramedullary disease, i.e., lymphadenopathy/splenomegaly if present at BL; (d) no new signs/symptoms of active disease. PR: (a) detectable monoclonal IgM protein; (b) =50% but <90% reduction in serum IgM level from BL; (c) reduction in extramedullary disease, i.e., lymphadenopathy/splenomegaly if present at BL; (d) no new signs/symptoms of active disease. MR: (a) detectable monoclonal IgM protein; (b) =25% but <50% reduction in serum IgM level from BL; (d) no new signs/symptoms of active disease.	Up to approximately 53 months (4.4 years)
Secondary	Part 2: ORR Based on the VIth International Workshop on WM Response Assessment for Participants With WM	ORR: sum of participants achieving MR, PR, VGPR, and CR. CR: (a) no serum monoclonal IgM protein by immunofixation; (b) normal serum IgM level; (c) complete resolution of extramedullary disease, i.e., lymphadenopathy/splenomegaly if present at BL; (d) morphologically normal bone marrow aspirate and trephine biopsy. VGPR: (a) detectable monoclonal IgM protein; (b) =90% reduction in serum IgM level from BL; (c) complete resolution of extramedullary disease, i.e., lymphadenopathy/splenomegaly if present at BL; (d) no new signs/symptoms of active disease. PR: (a) detectable monoclonal IgM protein; (b) =50% but <90% reduction in serum IgM level from BL; (c) reduction in extramedullary disease, i.e., lymphadenopathy/splenomegaly if present at BL; (d) no new signs/symptoms of active disease. MR: (a) detectable monoclonal IgM protein; (b) =25% but <50% reduction in serum IgM level from BL; (d) no new signs/symptoms of active disease.	Up to approximately 44 months (3.7 years)
Secondary	Part 6: ORR Based on the VIth International Workshop on WM Response Assessment for Participants With WM	ORR: sum of participants achieving MR, PR, VGPR, and CR. CR: (a) no serum monoclonal IgM protein by immunofixation; (b) normal serum IgM level; (c) complete resolution of extramedullary disease, i.e., lymphadenopathy/splenomegaly if present at BL; (d) morphologically normal bone marrow aspirate and trephine biopsy. VGPR: (a) detectable monoclonal IgM protein; (b) =90% reduction in serum IgM level from BL; (c) complete resolution of extramedullary disease, i.e., lymphadenopathy/splenomegaly if present at BL; (d) no new signs/symptoms of active disease. PR: (a) detectable monoclonal IgM protein; (b) =50% but <90% reduction in serum IgM level from BL; (c) reduction in extramedullary disease, i.e., lymphadenopathy/splenomegaly if present at BL; (d) no new signs/symptoms of active disease. MR: (a) detectable monoclonal IgM protein; (b) =25% but <50% reduction in serum IgM level from BL; (d) no new signs/symptoms of active disease.	Up to approximately 4 months
Secondary	Part 1: ORR (Sum of Participants With CR and PR) Based on the Revised Response Criteria for Hodgkin's Lymphoma (HL) and Non-Hodgkin's Lymphoma (NHL), Using Positron Emission Tomography-computed Tomography (PET-CT) and CT	CR, PET-CT: (a) complete metabolic response (MR); (b) lymph nodes and extralymphatic sites (LNs/ELSs): score 1, 2, or 3, with/without residual mass; (c) no new lesions (NNLs); (d) no evidence of fluorodeoxyglucose-avid disease in marrow. CT: complete radiologic response: (a) regression of target nodes/nodal masses to = 1.5 cm in longest transverse lesion diameter; (b) no ELSs of disease; (c) absence of nonmeasured lesions; (d) regression to normal organ size; (e) NNLs; (f) normal morphological bone marrow. PR, PET-CT: (a) partial MR; (b) LNs/ELSs: score 4 or 5, with reduced uptake compared with Baseline and residual mass of any size; (c) NNLs; (d) residual uptake higher than uptake in normal marrow but reduced compared with Baseline. CT: partial remission: (a) LNs/ELSs: = 50% decrease in the sum of the product of the perpendicular diameters for multiple lesions of up to 6 target measurable sites; (b) spleen must have regressed by > 50% in length beyond normal; (c) NNLs.	Up to approximately 53 months (4.4 years)
Secondary	Part 2: ORR (Sum of Participants With CR and PR) Based on the Revised Response Criteria for HL and NHL, Using PET-CT and CT	CR, PET-CT: (a) complete MR; (b) LNs/ELSs: score 1, 2, or 3, with/without residual mass; (c) NNLs; (d) no evidence of fluorodeoxyglucose-avid disease in marrow. CT: complete radiologic response: (a) regression of target nodes/nodal masses to = 1.5 cm in longest transverse lesion diameter; (b) no ELSs of disease; (c) absence of nonmeasured lesions; (d) regression to normal organ size; (e) NNLs; (f) normal morphological bone marrow. PR, PET-CT: (a) partial MR; (b) LNs/ELSs: score 4 or 5, with reduced uptake compared with Baseline and residual mass of any size; (c) NNLs; (d) residual uptake higher than uptake in normal marrow but reduced compared with Baseline. CT: partial remission: (a) LNs/ELSs: = 50% decrease in the sum of the product of the perpendicular diameters for multiple lesions of up to 6 target measurable sites; (b) spleen must have regressed by > 50% in length beyond normal; (c) NNLs.	Up to approximately 44 months (3.7 years)
Secondary	Part 6: ORR (Sum of Participants With CR and PR) Based on the Revised Response Criteria for HL and NHL, Using PET-CT and CT	CR, PET-CT: (a) complete MR; (b) LNs/ELSs: score 1, 2, or 3, with/without residual mass; (c) NNLs; (d) no evidence of fluorodeoxyglucose-avid disease in marrow. CT: complete radiologic response: (a) regression of target nodes/nodal masses to = 1.5 cm in longest transverse lesion diameter; (b) no ELSs of disease; (c) absence of nonmeasured lesions; (d) regression to normal organ size; (e) NNLs; (f) normal morphological bone marrow. PR, PET-CT: (a) partial MR; (b) LNs/ELSs: score 4 or 5, with reduced uptake compared with Baseline and residual mass of any size; (c) NNLs; (d) residual uptake higher than uptake in normal marrow but reduced compared with Baseline. CT: partial remission: (a) LNs/ELSs: = 50% decrease in the sum of the product of the perpendicular diameters for multiple lesions of up to 6 target measurable sites; (b) spleen must have regressed by > 50% in length beyond normal; (c) NNLs.	Up to approximately 4 months
Secondary	Cmax of Itacitinib in Combination With Parsaclisib	Cmax is defined as the maximum observed plasma or serum concentration of itacitinib.	Cycle 1 Day 15; pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
Secondary	Tmax of Itacitinib in Combination With Parsaclisib	tmax is defined as the time to the maximum concentration of itacitinib.	Cycle 1 Day 15; pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
Secondary	Cmin of Itacitinib in Combination With Parsaclisib	Cmin is defined as the minimum observed plasma or serum concentration over the dose interval of itacitinib.	Cycle 1 Day 15; pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
Secondary	AUC0-t of Itacitinib in Combination With Parsaclisib	AUC0-t is defined as the area under the plasma or serum concentration-time curve from time = 0 to the last measurable concentration at time = t of itacitinib.	Cycle 1 Day 15; pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
Secondary	AUC0-t of Itacitinib in Combination With Parsaclisib	AUC0-t is defined as the area under the steady-state plasma or serum concentration-time curve over 1 dose interval (i.e., from hour 0 to 12 for once every 12 hours [q12h] administration or from hour 0 to 24 for once every 24 hours [q24h] administration) of itacitinib.	Cycle 1 Day 15; pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
Secondary	Parts 1 and 2: Cmax of Parsaclisib as Monotherapy and in Combination With Itacitinib	Cmax is defined as the maximum observed plasma or serum concentration of parsaclisib. PK samples collected in Part 2, the combination dose escalation study, and in Part 3, Cohort E expansion group, were analyzed for both parsaclisib and itacitinib.	Cycle 1 Days 1 and 15; pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
Secondary	Parts 1 and 2: Tmax of Parsaclisib as Monotherapy and in Combination With Itacitinib	tmax is defined as the time to the maximum concentration of parsaclisib. PK samples collected in Part 2, the combination dose escalation study, and in Part 3, Cohort E expansion group, were analyzed for both parsaclisib and itacitinib.	Cycle 1 Days 1 and 15; pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
Secondary	Parts 1 and 2: Cmin of Parsaclisib as Monotherapy and in Combination With Itacitinib	Cmin is defined as the minimum observed plasma or serum concentration over the dose interval of parsaclisib. PK samples collected in Part 2, the combination dose escalation study, and in Part 3, Cohort E expansion group, were analyzed for both parsaclisib and itacitinib.	Cycle 1 Days 1 and 15; pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
Secondary	Parts 1 and 2: AUC0-t of Parsaclisib as Monotherapy and in Combination With Itacitinib	AUC0-t is defined as the area under the plasma or serum concentration-time curve from time = 0 to the last measurable concentration at time = t of parsaclisib. PK samples collected in Part 2, the combination dose escalation study, and in Part 3, Cohort E expansion group, were analyzed for both parsaclisib and itacitinib.	Cycle 1 Days 1 and 15; pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
Secondary	Parts 1 and 2: AUC0-t of Parsaclisib as Monotherapy and in Combination With Itacitinib	AUC0-t is defined as the area under the steady-state plasma or serum concentration-time curve over 1 dose interval (i.e., from hour 0 to 12 for q12h administration or from hour 0 to 24 for q24h administration) of parsaclisib. PK samples collected in Part 2, the combination dose escalation study, and in Part 3, Cohort E expansion group, were analyzed for both parsaclisib and itacitinib.	Cycle 1 Days 1 and 15; pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
Secondary	Part 3: Cmax of Parsaclisib Monotherapy	Cmax is defined as the maximum observed plasma or serum concentration of parsaclisib. PK samples for parsaclisib monotherapy were collected and analyzed from the Part 3 dose expansion (different participant populations). Cohort A: B-cell malignancies; Cohort B: Hodgkin's lymphoma; Cohort C: diffuse large B-cell lymphoma; Cohort D: indolent lymphoma.	Cycle 1 Days 1 and 15; pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
Secondary	Part 3: Tmax of Parsaclisib Monotherapy	tmax is defined as the time to the maximum concentration of parsaclisib. PK samples for parsaclisib monotherapy were collected and analyzed from the Part 3 dose expansion (different participant populations). Cohort A: B-cell malignancies; Cohort B: Hodgkin's lymphoma; Cohort C: diffuse large B-cell lymphoma; Cohort D: indolent lymphoma.	Cycle 1 Days 1 and 15; pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
Secondary	Part 3: Cmin of Parsaclisib Monotherapy	Cmin is defined as the minimum observed plasma or serum concentration over the dose interval of parsaclisib. PK samples for parsaclisib monotherapy were collected and analyzed from the Part 3 dose expansion (different participant populations). Cohort A: B-cell malignancies; Cohort B: Hodgkin's lymphoma; Cohort C: diffuse large B-cell lymphoma; Cohort D: indolent lymphoma.	Cycle 1 Days 1 and 15; pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
Secondary	Part 3: AUC0-t of Parsaclisib Monotherapy	AUC0-t is defined as the area under the plasma or serum concentration-time curve from time = 0 to the last measurable concentration at time = t of of parsaclisib. PK samples for parsaclisib monotherapy were collected and analyzed from the Part 3 dose expansion (different participant populations). Cohort A: B-cell malignancies; Cohort B: Hodgkin's lymphoma; Cohort C: diffuse large B-cell lymphoma; Cohort D: indolent lymphoma.	Cycle 1 Days 1 and 15; pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
Secondary	Part 3: AUC0-t of Parsaclisib Monotherapy	AUC0-t is defined as the area under the steady-state plasma or serum concentration-time curve over 1 dose interval (i.e., from hour 0 to 12 for once every 12 hours [q12h] administration or from hour 0 to 24 for once every 24 hours [q24h] administration) of parsaclisib. PK samples for parsaclisib monotherapy were collected and analyzed from the Part 3 dose expansion (different participant populations). Cohort A: B-cell malignancies; Cohort B: Hodgkin's lymphoma; Cohort C: diffuse large B-cell lymphoma; Cohort D: indolent lymphoma.	Cycle 1 Days 1 and 15; pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose

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