Antineoplastic Agents

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Etoposide

Rituximab

Ifosfamide

Etoposide phosphate

Isophosphamide mustard

Antineoplastic Agents, Immunological

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Enzyme Inhibitors

Antineoplastic Agents, Alkylating

Alkylating Agents

Parsaclisib 5 milligrams (mg) as an oral tablet once a day (QD) in 21-day treatment cycles

Parsaclisib 10 mg as oral tablets QD in 21-day treatment cycles

Parsaclisib 15 mg as oral tablets QD in 21-day treatment cycles

Parsaclisib 30 mg as oral tablets QD in 21-day treatment cycles

Parsaclisib 45 mg as oral tablets QD in 21-day treatment cycles

Parsaclisib 20 mg as oral tablets QD and itacitinib (INCB039110) 300 mg as oral tablets QD in 21-day treatment cycles

Parsaclisib 30 mg as oral tablets QD and itacitinib (INCB039110) 300 mg as oral tablets QD in 21-day treatment cycles

Parsaclisib 15 mg as oral tablets QD in 21-day treatment cycles. R-ICE was a standard-of-care chemotherapy combination administered at the following doses: rituximab 375 milligrams per meters squared (mg/m\^2) intravenously (IV) on Day 1 and Day 2 of Cycle 1 and on Day 1 of Cycles 2 and 3, ifosfamide 5000 mg/m\^2 IV on Day 3 of each cycle, carboplatin area under the curve (AUC) = 5 (maximum dose 800 mg) IV on Day 3 of each cycle, and etoposide 100 mg/m\^2 or at doses consistent with institutional practice with approval from the medical monitor on Days 3 and 5 of each cycle. Each cycle was 21 days in duration

20 mg as oral tablets QD in 21-day treatment cycles. R-ICE was a standard-of-care chemotherapy combination administered at the following doses: rituximab 375 mg/m\^2 IV on Day 1 and Day 2 of Cycle 1 and on Day 1 of Cycles 2 and 3, ifosfamide 5000 mg/m\^2 IV on Day 3 of each cycle, carboplatin AUC = 5 (maximum dose 800 mg) IV on Day 3 of each cycle, and etoposide 100 mg/m\^2 or at doses consistent with institutional practice with approval from the medical monitor on Days 3 and 5 of each cycle. Each cycle was 21 days in duration.

Parsaclisib

Itacitinib

Claudia Corrado, M.D.

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.

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)

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)

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.

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.

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.

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.

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.

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.

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.

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

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

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

AUC0-τ 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.

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.

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.

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.

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.

AUC0-τ 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.

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.

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.

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.

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.

AUC0-τ 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.

Incyte Corporation

Treatment-emergent adverse events (TEAEs), defined as events that were reported for the first time, or the worsening of a pre-existing event, after the first dose of study drug, are reported for the Safety Population, defined as all participants enrolled in the study who received at least 1 dose of parsaclisib, itacitinib, rituximab, ifosfamide, carboplatin, and/or etoposide.

Participants self-administered parsaclisib 5 milligrams (mg) as an oral tablet once a day (QD) in 21-day treatment cycles.

Parsaclisib 5 mg QD

Participants self-administered parsaclisib 10 mg as oral tablets QD in 21-day treatment cycles.

Parsaclisib 10 mg QD

Participants self-administered parsaclisib 15 mg as oral tablets QD in 21-day treatment cycles.

Parsaclisib 15 mg QD

Participants self-administered parsaclisib 20 mg as oral tablets QD in 21-day treatment cycles.

Parsaclisib 20 mg QD

Participants self-administered parsaclisib 30 mg as oral tablets QD in 21-day treatment cycles.

Parsaclisib 30 mg QD

Participants self-administered parsaclisib 45 mg as oral tablets QD in 21-day treatment cycles.

Parsaclisib 45 mg QD

Participants self-administered parsaclisib 20 mg as oral tablets QD and itacitinib 300 mg as oral tablets QD in 21-day treatment cycles.

Parsaclisib 20 mg + Itacitinib 300 mg

Participants self-administered parsaclisib 30 mg as oral tablets QD and itacitinib 300 mg as oral tablets QD in 21-day treatment cycles.

Parsaclisib 30 mg + Itacitinib 300 mg

Participants self-administered parsaclisib 15 mg as oral tablets QD in 21-day treatment cycles. R-ICE was a standard-of-care chemotherapy combination administered at the following doses: rituximab 375 milligrams per meters squared (mg/m\^2) intravenously (IV) on Day 1 and Day 2 of Cycle 1 and on Day 1 of Cycles 2 and 3, ifosfamide 5000 mg/m\^2 IV on Day 3 of each cycle, carboplatin area under the curve (AUC) = 5 (maximum dose 800 mg) IV on Day 3 of each cycle, and etoposide 100 mg/m\^2 or at doses consistent with institutional practice with approval from the medical monitor on Days 3 and 5 of each cycle. Each cycle was 21 days in duration.

Parsaclisib 15 mg QD + R-ICE

Participants self-administered parsaclisib 20 mg as oral tablets QD in 21-day treatment cycles. R-ICE was a standard-of-care chemotherapy combination administered at the following doses: rituximab 375 mg/m\^2 IV on Day 1 and Day 2 of Cycle 1 and on Day 1 of Cycles 2 and 3, ifosfamide 5000 mg/m\^2 IV on Day 3 of each cycle, carboplatin AUC = 5 (maximum dose 800 mg) IV on Day 3 of each cycle, and etoposide 100 mg/m\^2 or at doses consistent with institutional practice with approval from the medical monitor on Days 3 and 5 of each cycle. Each cycle was 21 days in duration.

Parsaclisib 20 mg QD + R-ICE

All participants in all treatment arms combined.

Total

Age, Continuous

Female

Male

Sex/Gender, Customized

Black or African American

White

Unknown or Not Reported

Race/Ethnicity, Customized

Study Director

Safety Population: all participants enrolled in the study who received at least 1 dose of parsaclisib, itacitinib, rituximab, ifosfamide, carboplatin, and/or etoposide

Number of Participants With Treatment-emergent Adverse Events (TEAEs)

Intent-to-Treat (ITT) Population: all participants with CLL enrolled in the study who received at least 1 dose of parsaclisib, itacitinib, rituximab, ifosfamide, carboplatin, and/or etoposide. Confidence intervals were calculated based on the exact method for binomial distributions.

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

ITT Population: all participants with CLL. Confidence intervals were calculated based on the exact method for binomial distributions.

Part 2: Overall Response Rate (Percentage of Participants With CR and PR) Based on IWCLL Criteria for CLL for Participants With CLL

ITT Population: all participants with CLL

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

ITT Population: all participants with WM. Confidence intervals were calculated based on the exact method for binomial distributions.

Part 1: ORR Based on the VIth International Workshop on Waldenström Macroglobulinemia (WM) Response Assessment for Participants With WM

Part 2: ORR Based on the VIth International Workshop on WM Response Assessment for Participants With WM

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

Diffuse large B-cell lymphoma

Follicular lymphoma

Mantle cell lymphoma

Marginal zone lymphoma

Extranodal marginal zone lymphoma of mucosa-associated lymphatic tissue

Nodal marginal zone B-cell lymphoma

Splenic marginal zone lymphoma

Classical Hodgkin's lymphoma

Nodular lymphocytic-predominant Hodgkin's lymphoma

ITT Population: all participants with the indicated types of HL and NHL. Confidence intervals were calculated based on the exact method for binomial distributions.

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

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

ITT Population: all participants with the indicated types of HL and NHL

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

Participants self-administered parsaclisib 20 mg or 30 mg as oral tablets QD and itacitinib 300 mg as oral tablets QD in 21-day treatment cycles.

Parsaclisib 20/30 mg + Itacitinib 300 mg

Pharmacokinetic (PK)/Pharmacodynamics (PD) Population: participants in the ITT/Safety Population who had PK/PD data. Data from the parsaclisib 20 mg + itacitinib 300 mg and the parsaclisib 30 mg + itacitinib 300 mg arms were pooled for analysis because all participants received 300 mg itacitinib and there is no drug-drug interaction between parsaclisib and itacitinib to affect the PK of either drug.

Cmax of Itacitinib in Combination With Parsaclisib

Participants self-administered parsaclisib 20 or 30 mg as oral tablets QD and itacitinib 300 mg as oral tablets QD in 21-day treatment cycles.

PK/PD Population. Data from the parsaclisib 20 mg + itacitinib 300 mg and the parsaclisib 30 mg + itacitinib 300 mg arms were pooled for analysis because all participants received 300 mg itacitinib and there is no drug-drug interaction between parsaclisib and itacitinib to affect the PK of either drug.

Tmax of Itacitinib in Combination With Parsaclisib

Cmin of Itacitinib in Combination With Parsaclisib

AUC0-t of Itacitinib in Combination With Parsaclisib

AUC0-τ of Itacitinib in Combination With Parsaclisib

Cycle 1 Day 1

Cycle 1 Day 15

PK/PD Population. Only participants with available data were analyzed. In the combination therapy arms, data are reported for the Part 3 Cohort E population (participants with B-cell malignancies).

Spots Global Cancer Trial Database for 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)

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