This study will be a standard 3+3 design with a lead in of TGR-1202 at dose of 600mg (dose level 1) or 800mg daily (dose level 2) for 6 weeks, i.e. 2 cycles, followed by pembrolizumab at 200mg every 3 weeks for 8 cycles along with TGR-1202 for patients with relapsed/refractory B-cell NHL or CLL. If the dose of 600mg daily of TGR-1202 (dose level 1) is tolerated in the first cohort the dose will be increased to 800mg qd which is the only and final dose escalation. If TGR-1202 is not tolerated at 600mg daily the dose will be decreased to 400mg daily. The lead in of TGR-1202 was chosen to ensure clinical benefit and to minimize the occurrence of early overlapping toxicity with pembrolizumab as most toxicities were observed early on in the treatment with idelalisib, a related PI3K-inhibitor, and rituximab.
Of note, TGR-1202 has not been associated with treatment related pneumonitis, transaminitis, colitis, PCP-infection nor CMV-reactivation which distinguishes TGR-1202 from idelalisib's toxicity profile. Once the maximum tolerated dose has been safely reached the study will open an expansion cohort to enroll 18 patients with a patient group in which a clinical signal is detected. Another 7 patients (up to a total of 25 patients in the expansion cohort) may be enrolled after an interim analysis. The duration of therapy will be 2 cycles of TGR-1202 followed by 8 cycles with pembrolizumab and TGR-1202. Thereafter patient will continue on TGR-1202 at the MTD until disease progression. Subjects who experience disease progression while on TGR-1202 maintenance may be eligible for re-treatment with pembrolizumab for up to 6 cycles at the discretion of the Local Investigator if the patient experienced at least disease stabilization during the initial treatment with pembrolizumab, the subject meets the safety parameters listed in the inclusion/exclusion criteria, and the trial is still open. Subjects will resume therapy at the same dose and schedule at the time of initial discontinuation. If safety and feasibility of the combination is confirmed in this dose expansion cohort, a randomized phase II trial comparing TGR-1202 with pembrolizumab versus TGR-1202 could be considered in a larger patient population, possibly within the cooperative group setting for patients with relapsed/refractory B-cell NHL and CLL The primary objective of the dose expansion cohort will be CR rate. Secondary endpoints will include safety and feasibility, PFS, OS and clinical response (SD, PR, PD). Patients will be monitored for disease response, adverse events and survival for a minimum of 2 years following enrollment. During and after treatment, patients will be evaluated for toxicities, particularly immunologic adverse events including pneumonitis, autoimmune colitis, dermatitisetc. Peripheral blood, lymph node and bone marrow samples will be collected before and during the treatment course for the correlative studies outlined below. Complete blood counts and differential counts with a complete metabolic panel will be obtained at the time intervals. If the patients are confirmed to have disease progression or intolerable toxicities the patients will be offered alternative treatment at the physicians' discretion. All of the patients will be followed for survival. All patients will receive HSV prophylaxis with acyclovir 400mg po bid or per institutional standards.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
20
TGR-1202 will be given at a dose of 600mg (dose level 1) or 800mg (dose level 2). If the dose of 600mg is tolerated in the first cohort, then the dose will be increased to 800mg which is the only and final dose escalation. If the dose of 600mg is not tolerated, then the dose will be decreased to 400mg daily.
Pembrolizumab will be given at 200 mg every 3 weeks. The dose will not be adjusted throughout the course of the study.
Yale University
New Haven, Connecticut, United States
University of Chicago
Chicago, Illinois, United States
Memorial Sloan Kettering Cancer Center
New York, New York, United States
Number of patients with adverse events
To determine the maximally tolerated dose of TGR-1202 in combination with pembrolizumab by finding the number of patients with adverse events. This information will be used to determine the recommended phase II dose for this combination for patients with relapsed/refractory CLL/SLL and B-cell NHL.
Time frame: Up to 3 years.
proportion of patients with complete remission (CR)
The proportion of subjects who achieve a confirmed CR by the the international workshop on CLL (iwCLL) and the Lugano Response Criteria for Non-Hodgkin's Lymphoma.
Time frame: Up to 3 years
duration of response (DOR)
The interval from the first documentation of confirmed CR or PR (by IRC) to the first documentation of definitive disease progression or death from any cause. Definitive disease progression is CLL progression based on standard criteria excluding lymphocytosis alone.
Time frame: Up to 3 years
progression free survival (PFS) rate
The interval from the first dose of study drug to the first documentation of definitive disease progression or death from any cause.
Time frame: From the start of treatment until the date of first documented progression or date of death from any cause, whichever comes first, up to 100 months
MRD negativity rate
The proportion of subjects with MRD \<10-4, assessed by flow cytometry in bone marrow.
Time frame: Up to 3 years
nodal response rate
The proportion of subjects who achieve a 50% decrease from baseline in the sum of the products of the greatest perpendicular diameters (SPD) of index lesions.
Time frame: Up to 3 years
overall survival (OS) rate
The interval from the start of study treatment to death from any cause.
Time frame: From the start of treatment until the date of death from any cause, whichever comes first, up to 100 months
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