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)

Phase 2CompletedNCT02018861

Incyte Corporation88 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

B-Cell Malignancies

Interventions

ParsaclisibDRUG

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (7)

University of Alabama At Birmingham Comprehensive Cancer Center

Birmingham, Alabama, United States

University of Michigan Cancer Center

Ann Arbor, Michigan, United States

Karmanos Cancer Institute

Detroit, Michigan, United States

Nyu Langone Laura and Isaac Perlmutter Cancer Center

New York, New York, United States

University Hospitals Case Medical Center

Cleveland, Ohio, United States

Greenville Health System Cancer Institute

Greenville, South Carolina, United States

Baylor Charles A. Sammons Cancer Center

Dallas, Texas, United States

Outcomes

Primary Outcomes

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.

Time frame: Up to approximately 53 months (4.4 years)

Secondary Outcomes

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.

Time frame: Up to approximately 53 months (4.4 years)

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.

Time frame: Up to approximately 44 months (3.7 years)

Part 6: Overall Response Rate (Percentage of Participants With CR and PR) Based on IWCLL Criteria for CLL for Participants With CLL

Time frame: Up to approximately 4 months

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.

Time frame: Up to approximately 53 months (4.4 years)

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.

Time frame: Up to approximately 44 months (3.7 years)

Part 6: ORR Based on the VIth International Workshop on WM Response Assessment for Participants With WM

Time frame: Up to approximately 4 months

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.

Time frame: Up to approximately 53 months (4.4 years)

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.

Time frame: Up to approximately 44 months (3.7 years)

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

Time frame: Up to approximately 4 months

Cmax of Itacitinib in Combination With Parsaclisib

Cmax is defined as the maximum observed plasma or serum concentration of itacitinib.

Time frame: Cycle 1 Day 15; pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose

Tmax of Itacitinib in Combination With Parsaclisib

tmax is defined as the time to the maximum concentration of itacitinib.

Time frame: Cycle 1 Day 15; pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose

Cmin of Itacitinib in Combination With Parsaclisib

Cmin is defined as the minimum observed plasma or serum concentration over the dose interval of itacitinib.

Time frame: Cycle 1 Day 15; pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose

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.

Time frame: Cycle 1 Day 15; pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose

AUC0-τ of Itacitinib in Combination With Parsaclisib

Time frame: Cycle 1 Day 15; pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose

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.