A Phase I/Ib Safety and Efficacy Study of the PI3K-delta Inhibitor TGR-1202 and Ibrutinib in Patients With CLL or MCL

To assess the safety of TGR1202 in combination with ibrutinib relapsed or refractory CLL or MCL. DLT is based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. DLT refers to toxicities experienced at any time during the study treatment, defined as Grade 4 anemia; Grade 4 neutropenia lasting \>7 days (while receiving growth factor support); Grade 4 thrombocytopenia lasting \> 7 days; Grade ≥3 febrile neutropenia; and Grade ≥3 thrombocytopenia with Grade \>2 hemorrhage;Grade ≥ 3 non-hematologic toxicity unresponsive to standard supportive care measure with the exception of asymptomatic Grade ≥3 lab abnormalities that resolve to ≤ Grade 1 or baseline within 7 days;treatment delay of ≥14 days due to unresolved toxicity; and non-hematologic toxicity of Grade 2 (at any time during treatment) that, in the judgment of the Investigators, Study Chair, and the Medical Monitor, is dose-limiting.

Time frame: Participants were assessed every week or more often as needed during Cycle 1 or more often for up to 28 days to assess Dose-limiting toxicities (DLTs) during Phase I

Population: Patients who have been previously treated for MCL, CLL or SLL. MCL must have 1 measurable site of disease and have had received at least one prior standard therapy; CLL/SLL patients must have an indication for treatment according to 2008 ICWLL criteria and received at least one prior standard treatment regimen

Duration of Overall Response (DOR), estimated using the Kaplan Meier method, is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) per 2008 IWCLL Criteria, until the first date that recurrent or progressive disease is objectively documented. Patients without progressive disease are censored at the date of last disease assessment.

Time frame: Disease response will be evaluated at baseline, cycle 1 day 1,8,15,22 and cycle 2 day 1,15, and cycle 3-6 on day1, and every 2 cycles until cycle 12, then every 3 cycles thereafter.

Population: all the patients were pooled together from ph1 and ph1b for the final efficacy analysis

Progression-free survival based on the Kaplan-Meier method is defined as the duration between randomization and documented disease progression (PD) or death, or is censored at time of last dsease assessment.

Time frame: Disease will be evaluated at baseline, cycle 1 day 1,8,15,22 and cycle 2 day 1,15, and cycle 3-6 on day1, and every 2 cycles until cycle 12, then every 3 cycles thereafter. In long-term follow-up, survival will be followed every 3 cycles up to 2 years.

Population: all the patients were pooled together from ph1 and ph1b for the final efficacy analysis

The overall response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) based on the 2008 IW-CLL criteria for CLL (Hallek et al., 2008) by Lugano Criteria ( Cheson et al,.24) for MCL.

Time frame: At baseline, End of Cycle 2, End of Cycle 5, End of Cycle 9, End of Cycle 14 and approximately q6 months until C26, then investigator discretion thereafter

Population: all the patients were pooled together from ph1 and ph1b for the final efficacy analysis

nPR will only be evaluated in CLL patients, defined as percentage of patients achieved nodal PR. As per Cheson et al., 2012, patients who achieve a radiographic PR but continue to have a lymphocytosis with \>5,000 B-lymphocytes per μL are considered to have a nodular partial response, also known as PR with lymphocytosis, due to the fact that they appear to derive a similar clinical benefit from BCR inhibitors as patients who achieve a traditional PR.

Time frame: At baseline, End of Cycle 2, End of Cycle 5, End of Cycle 9, End of Cycle 14 and approximately q6 months until C26, then investigator discretion thereafter

Population: all the patients were pooled together from ph1 and ph1b for the final efficacy analysis