Study to Assess the Efficacy and Safety of Umbralisib in Participants With Non-Follicular Indolent Non-Hodgkin's Lymphoma

Study Overview
=================
Brief Summary
-----------------
This research study will evaluate the safety and efficacy of a study drug called Umbralisib (also known as TGR-1202) alone as a possible treatment for Waldenstrom's Macroglobulinemia that has come back or that has not responded to standard treatment.

Official Title
-----------------
A Phase 2 Study to Assess the Efficacy and Safety of TGR-1202 (Umbralisib) Monotherapy in Patients With Non-Follicular Indolent Non-Hodgkin's Lymphoma

Conditions
-----------------
Marginal Zone Lymphoma, Waldenstrom Macroglobulinemia, Non Follicular Indolent Non-Hodgkin Lymphoma

Intervention / Treatment
-----------------
* Drug: Umbralisib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed diagnosis of Waldenstroms Macroglobulinemia Relapsed or refractory after at least one prior treatment regimen Eastern Cooperative Oncology Group (ECOG) score of 0 to 2 Exclusion Criteria: Any major surgery, chemotherapy or immunotherapy within the last 21 days Evidence of hepatitis B virus, hepatitis C virus or known HIV infection Prior autologous stem cell transplant within 6 months of study entry

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Marginal Zone Lymphoma (MZL): Umbralisib<br>Participants with non-follicular indolent non-Hodgkin's lymphoma (iNHL) with MZL as the histology type received umbralisib, 800 milligrams (mg), orally, once daily (QD), until disease progression, unacceptable toxicity, or withdrawal from the study whichever occurred first. | Drug: Umbralisib<br>* Oral Daily Dose<br>* Other names: TGR-1202;|
| Experimental: Waldenstrom's Macroglobulinemia (WM): Umbralisib<br>Participants with non-follicular iNHL with WM as the histology type received umbralisib, 800 mg, orally, QD, until disease progression, unacceptable toxicity, or withdrawal from the study whichever occurred first. | Drug: Umbralisib<br>* Oral Daily Dose<br>* Other names: TGR-1202;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) as Assessed by Revised Response Criteria for Non- Hodgkin's Lymphoma (Lugano Classification) and Consensus-Based 6th International Workshop on Waldenstrom's Macroglobulinemia (IWWM) | ORR for MZL=percentage of participants with complete response (CR)/partial response (PR). ORR for WM=CR/PR/very good partial response (VGPR)/minor response (MR). Response assessed per revised Lugano Classification for MZL &per IWWM for WM participants. Per Lugano criteria CR=complete disappearance of all evidence of disease & disease-related symptoms. PR=regression of measurable disease & no new disease sites. Regression=≥50% decrease in the sum of the products of the diameters (SPD) of index lesions, with no increase in size of other lymph nodes/liver/spleen.Per IWWM criteria CR=disappearance of serum monoclonal immunoglobulin M (IgM) protein by immunofixation with a normal serum IgM level. VGPR=reduction of monoclonal IgM protein >90% from baseline. PR=reduction of monoclonal IgM protein between 50-90% from baseline with regression of measurable disease. Regression defined in similar manner as Lugano Classification. MR=reduction of monoclonal IgM protein >25% but <50% from baseline. | Every 3 cycles (1 Cycle = 28 days) from Day 1 Cycle 1 up to approximately 4.2 years | 
| Duration of Response (DOR) | DOR is defined as the time from documentation of a response to treatment to the first documentation of tumor progression or death due to any cause, whichever comes first. | From the first demonstration of response to umbralisib till disease progression/death (up to approximately 4.2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) Rate | CR rate is defined as percentage of participants who achieved CR. CR was assessed using Revised Response Criteria for Non- Hodgkin's Lymphoma (Lugano Classification) for participants with MZL and Consensus-Based 6th IWWM for participants with WM. Per Lugano Classification, CR= the complete disappearance of all evidence of disease and disease-related symptoms i.e., liver/spleen non palpable and normal in size and disappearance of nodules related to lymphoma. Per IWWM criteria, CR=disappearance of serum monoclonal IgM protein by immunofixation with a normal serum IgM level, liver/spleen non palpable and normal in size and disappearance of nodes related to WM. | Every 3 cycles (1 Cycle = 28 days) from Day 1 Cycle 1 up to approximately 4.2 years | 
| Progression-Free Survival (PFS) | PFS is defined as the interval from Cycle 1 (1 cycle = 28 days) Day 1 to the earlier of the first documentation of definitive disease progression or death from any cause. Assessment of progressive disease (PD) was based on Revised Response Criteria for non-Hodgkin's lymphoma, Lugano Classification for participants with MZL and consensus-based 6th IWWM for participants with WM. Per Lugano Classification, PD was defined as the appearance of any new lesion more than 1.5 centimeters (cm) in any axis, even if other lesions are decreasing in size. At least a 50% increase from nadir in one of the following: SPD of index lesions, greatest transverse diameter (GTD) of any individual previously involved node, or GTD of any previously involved node provided that the GTD of that node is now ≥ 1.5 cm. Per IWWM criteria participants, PD was defined as more than 25% increase in serum IgM level from lowest nadir and/or progression in clinical features attributable to the disease. | From date of randomization until the date of first documented progression (up to approximately 4.2 years) | 
| Time to Treatment Failure (TTF) | TTF is defined as a composite endpoint measuring time from Cycle 1/Day 1 to discontinuation of treatment for any reason, including disease progression, treatment toxicity, and death. PD was assessed based on Revised Response Criteria for non-Hodgkin's lymphoma, Lugano Classification for participants with MZL and consensus-based 6th IWWM for participants with WM. Per Lugano Classification, PD was defined as the appearance of any new lesion more than 1.5 cm in any axis, even if other lesions are decreasing in size. At least a 50% increase from nadir in one of the following: SPD of index lesions, GTD of any individual previously involved node, or GTD of any previously involved node provided that the GTD of that node is now ≥ 1.5 cm. Per IWWM criteria PD was defined as more than 25% increase in serum IgM level from lowest nadir and/or progression in clinical features attributable to the disease. | From first dose on Day 1 of Cycle 1 (28 days = 1 cycle) up to discontinuation of treatment (up to approximately 4.2 years) | 
| Number of Participants With at Least One Adverse Event (AE) | An AE is any untoward medical occurrence in a participant that does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. | From first dose of study treatment up to end of study (up to approximately 4.2 years) |