Safety, Pharmacodynamics, Pharmacokinetics, and Efficacy of GS-9901 in Adults With Relapsed or Refractory Follicular Lymphoma, Marginal Zone Lymphoma, Chronic Lymphocytic Leukemia, or Small Lymphocytic Lymphoma

Study Overview
=================
Brief Summary
-----------------
This study will evaluate the safety and tolerability of GS-9901 monotherapy in adults with follicular lymphoma (FL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL). The study will also characterize the pharmacokinetic (PK) profile of GS-9901, determine the appropriate dosing regimen of GS-9901 for use in future clinical trials, and to evaluate the efficacy of GS-9901 monotherapy in adults with FL, MZL, CLL, or SLL.

Official Title
-----------------
A Phase 1b Dose-escalation Study Evaluating the Safety, Pharmacodynamics, Pharmacokinetics, and Efficacy of GS-9901 in Subjects With Relapsed or Refractory Follicular Lymphoma, Marginal Zone Lymphoma, Chronic Lymphocytic Leukemia, or Small Lymphocytic Lymphoma

Conditions
-----------------
Follicular Lymphoma, Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Marginal Zone Lymphoma

Intervention / Treatment
-----------------
* Drug: GS-9901


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of FL, MZL, SLL, or CLL (meeting International Workshop on CLL [IWCLL] Criteria, 2008) as documented by medical records and with histology based on criteria established by the World Health Organization FL Grades 1, 2, or 3a SLL with absolute lymphocyte count of < 5 x 10^9/L at initial diagnosis MZL (splenic, nodal, or extra-nodal) Prior treatment for FL or CLL/SLL with ≥ 1 prior chemotherapy-based or immunotherapy-based regimen with no approved therapies available Presence of radiographically measurable lymphadenopathy or extra nodal lymphoid malignancy All acute toxic effects of any prior antitumor therapy resolved to Grade ≤1 before the start of study therapy (with the exception of alopecia [Grade 1 or 2 permitted], or bone marrow parameters [any of Grade 1, 2, or 3 permitted) Eastern Cooperative Oncology Group (ECOG) ≤ 2 Able to provide written informed consent Exclusion Criteria: History of lymphoid malignancy other than FL, MZL, SLL, or CLL History of myelodysplastic syndrome History of a non-lymphoid malignancy except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for ≥ 1 year prior to start of study therapy, or any other cancer that has been in complete remission for ≥ 5 years Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of start of study therapy Ongoing drug-induced pneumonitis Ongoing inflammatory bowel disease History of prior allogeneic bone marrow progenitor cell or solid organ transplantation History of prior therapy with any inhibitor of serine/threonine kinase (AKT), Bruton tyrosine kinase (BTK), Janus kinase (JAK), mammalian target of rapamycin (mTOR), phosphatidylinositol 3-kinase (PI3K), or spleen tyrosine kinase (SYK) Ongoing immunosuppressive therapy, including systemic corticosteroids for treatment of lymphoid malignancy

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GS-9901<br>Participants will receive one of 6 escalating doses of GS-9901 once daily until unacceptable toxicity, substantial noncompliance, disease progression, pregnancy, initiation of another anti-cancer or experimental therapy, or other protocol-specified reasons for GS-9901 discontinuation. | Drug: GS-9901<br>* GS-9901 tablets administered orally<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of adverse events (AEs) and clinical laboratory abnormalities defined as dose limiting toxicities (DLTs) | Overall safety profile will be characterized by number of participants experiencing adverse events or laboratory abnormalities. | Up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of AEs and clinical laboratory abnormalities not defined as DLTs | Overall safety profile will be characterized by number of participants experiencing adverse events or laboratory abnormalities. | Up to 2 years | 
| Overall response rate | Overall response rate (ORR) is defined as the proportion of participants who achieve a complete response (CR) or partial response (PR). | Up to 2 years | 
| Progression-free survival | Progression-free survival (PFS) is defined as the interval from the start of study therapy to the earlier of the first documentation of definitive disease progression or death from any cause. | Up to 2 years | 
| Duration of response | Duration of response (DOR) is defined as the interval from the first documentation of CR or PR to the earlier of the first documentation of definitive disease progression or death from any cause. | Up to 2 years | 
| PK profile of GS-9901 | This endpoint will measure the plasma PK profile of GS-9901. The following parameters will be measured: Cmax: maximum observed concentration of drug in plasma AUCtau: concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval) | Predose and 0.5, 1, 1.5, 2, 3, 4, 6, and 24 hours postdose on Days 1 and 15; predose and 1.5 hours postdose on Days 29, 43, 85, and 169 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Chronic lymphocytic leukemia (CLL), Follicular lymphoma (FL), Small Lymphocytic Lymphoma (SLL), Phosphatidylinositol 3 kinase (PI3K), Marginal Zone Lymphoma (MZL)