A Study of INCB050465 in Relapsed or Refractory Mantle Cell Lymphoma Previously Treated With or Without a Bruton's Tyrosine Kinase (BTK) Inhibitor

Study Overview
=================
Brief Summary
-----------------
This is a Phase 2, open-label, 2-cohort study designed to evaluate the efficacy and safety of 2 parsaclisib treatment regimens in participants with relapsed or refractory mantle cell lymphoma (MCL) previously treated either with or without a Bruton's tyrosine kinase (BTK) inhibitor.

Official Title
-----------------
A Phase 2, Open-Label, 2-Cohort, Multicenter Study of INCB050465, a PI3Kδ Inhibitor, in Relapsed or Refractory Mantle Cell Lymphoma Previously Treated With or Without a BTK Inhibitor (CITADEL-205)

Conditions
-----------------
Lymphoma

Intervention / Treatment
-----------------
* Drug: Parsaclisib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men and women, aged 18 years or older. Documented failure to achieve at least partial response (PR) with, or documented disease progression after, the most recent treatment regimen. Radiographically measurable lymphadenopathy or extranodal lymphoid malignancy. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. Exclusion Criteria: History of central nervous system lymphoma (either primary or metastatic). Prior treatment with idelalisib, other selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitors, or a pan PI3K inhibitor. Allogeneic stem cell transplant within the last 6 months, or autologous stem cell transplant within the last 3 months before the date of first dose of study treatment. Active graft-versus-host disease. Liver disease: Participants positive for hepatitis B surface antigen or hepatitis B core antibody will be eligible if they are negative for hepatitis B virus-deoxyribonucleic acid (HBV-DNA). Participants positive for anti-hepatitis C virus (HCV) antibody will be eligible if they are negative for HCV-ribonucleic acid (RNA).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Treatment A (Exposed to Ibrutinib)<br>Participants received parsaclisib 20 mg tablets, orally, once daily (QD) for 8 weeks followed by 20 mg once weekly (QW) for up to 52 weeks. Participants who were exposed to ibrutinib before enrollment were included in this group. | Drug: Parsaclisib<br>* Parsaclisib tablets administered orally with water and without regard to food.<br>* Other names: INCB050465;|
| Experimental: Cohort 1: Treatment B (Exposed to Ibrutinib)<br>Participants received parsaclisib 20 mg tablets, orally, QD for 8 weeks followed by 2.5 mg QD for up to 116 weeks. Participants who were exposed to ibrutinib before enrollment were included in this group. | Drug: Parsaclisib<br>* Parsaclisib tablets administered orally with water and without regard to food.<br>* Other names: INCB050465;|
| Experimental: Cohort 2: Treatment A (Bruton's Tyrosine Kinase Inhibitor Naïve)<br>Participants received parsaclisib 20 mg tablets, orally, QD for 8 weeks followed by 20 mg QW for up to approximately 145 weeks. Participants who had not received a BTK inhibitor previously were included in this group. | Drug: Parsaclisib<br>* Parsaclisib tablets administered orally with water and without regard to food.<br>* Other names: INCB050465;|
| Experimental: Cohort 2: Treatment B (Bruton's Tyrosine Kinase Inhibitor Naïve)<br>Participants received parsaclisib 20 mg tablets, orally, QD for 8 weeks followed by 2.5 mg QD for up to approximately 136 weeks. Participants who had not received a BTK inhibitor previously were included in this group. | Drug: Parsaclisib<br>* Parsaclisib tablets administered orally with water and without regard to food.<br>* Other names: INCB050465;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR=percentage of participants with complete response(CR) or partial response(PR) per revised response criteria for lymphomas,determined by independent review committee(IRC).Criteria for CR:1.Target nodes/nodal masses of lymph nodes,extralymphatic sites regressed to≤1.5cm in longest dimension transverse diameter of lesion(LDi);2.Absence of non-measured lesion;3.Organ enlargement regressed to normal;4.No new lesions;5.Normal bone marrow morphology;if indeterminate,immunohistochemistry negative.Criteria for PR:1.Lymph nodes,extralymphatic sites- ≥50%decrease in sum of product of perpendicular diameters for multiple lesions(SPD)of up to 6 target measurable nodes,extranodal sites;if lesion is too small to measure on computed tomography(CT),assign5mm×5mm as default;if no longer visible,0×0mm.Node>5mm×5mm 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 approximately 165 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) | DOR=time from first documented evidence of CR or PR until disease progression or death from any cause among participants who achieve an objective response as determined by IRC. Criteria for CR: 1.Target nodes/nodal masses of lymph nodes and extralymphatic sites must regress to ≤ 1.5 cm in LDi; 2. Absence of non-measured lesion; 3.Organ enlargement regressed to normal; 4.No new lesions; 5.Bone marrow must be normal by morphology; if indeterminate, immunohistochemistry negative. The criteria for PR included: 1.Lymph nodes and extralymphatic sites- a. ≥50% decrease in SPD of up to 6 target measurable nodes and extranodal sites; b. when a lesion is too small to measure on CT, assign 5 mm×5 mm as the default; c.when no longer visible, 0×0 mm. For a node >5 mm×5 mm but smaller than normal, use actual measurement. 2.Non-measured lesions- Absent/regressed, but no increase. 3. Organ enlargement-Spleen must have regressed by >50% in length beyond normal. 4.No new lesions. | Up to approximately 165 weeks | 
| Complete Response Rate (CRR) | CRR is defined as the percentage of participants with a CR as defined by response criteria for lymphomas, as determined by an IRC. The criteria for CR included: 1.Target nodes/nodal masses of lymph nodes and extralymphatic sites must regress to ≤ 1.5 cm in LDi; 2. Absence of non-measured lesion; 3.Organ enlargement regressed to normal; 4.No new lesions; 5.Bone marrow must be normal by morphology; if indeterminate, immunohistochemistry negative. | Up to approximately 165 weeks | 
| Progression-Free Survival (PFS) | PFS is defined as the time from the date of the first dose of study treatment until the earliest date of disease progression as determined by radiographic disease assessment provided by an IRC, or death from any cause. | Up to approximately 165 weeks | 
| Overall Survival (OS) | OS is defined as the time from the date of the first dose of study treatment until death from any cause. | Up to approximately 165 weeks | 
| Best Percent Change From Baseline in Target Lesion Size | Target lesion size is measured by the sum of the product of diameters of all target lesion sizes and is determined by the IRC. The best percent change from Baseline is defined as the largest decrease, or smallest increase if no decrease available, from Baseline in target lesion sizes on/before new (next-line) anti-lymphoma therapy during the study. Baseline is the last nonmissing measurement obtained before the first administration of study drug. A negative percent change from Baseline indicates improvement. | Up to approximately 165 weeks | 
| Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | An adverse event (AE) is any untoward medical occurrence associated with use of a drug in humans, whether or not considered drug related, that occurs after a participant provides informed consent. A TEAE is any AE either reported for the first time or worsening of a pre-existing event after first dose of study drug and within 30 days of the last administration of study drug regardless of starting new anti-lymphoma therapy. A SAE is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect or is considered to be an important medical event that may not result in death, be immediately life-threatening, or require hospitalization but may be considered serious when, based on appropriate medical judgment, the event may jeopardize the participant or may require medical or surgical intervention. | From first dose of study drug up to approximately 165 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Mantle cell lymphoma, non-Hodgkin lymphoma, Bruton's tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K)