Maria Aiello

BACKGROUND: Patients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemotherapy. Effective therapies with acceptable side-effect profiles are needed for this patient population. METHODS: In this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta isoform of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy. RESULTS: The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P=0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab. CONCLUSIONS: The combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemotherapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512.).

Abstract BACKGROUND: PI3K-delta (δ) is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib (Zydelig, IDELA,), a potent and selective orally administered inhibitor of PI3Kδ, in combination with rituximab weekly x 8 has yielded an ORR of 97% in patients (pts) ≥65 years with previously untreated CLL or SLL (O’Brien, ASCO 2013). This report describes the preliminary experience in treating a similar cohort of pts with IDELA monotherapy. METHODS: Enrollment began in November, 2013. Treatment-naive pts ≥65 yrs with CLL or SLL, requiring treatment per IWCLL 2008 criteria, and with measurable lymphadenopathy, were treated with IDELA 150 mg bid continuously. Response assessment, at pre-determined time points, was investigator determined using either physical exam or CT scans per investigator discretion, using modified IWCLL guidelines (Hallek 2008, Cheson 2012). RESULTS: As of 21 July 2014, 37 pts were enrolled: 78% male; CLL/SLL in 92%/8%; median age 70 years; 73% Rai III or IV; WHO 0-1/2 in 97%/3%. 46% had ≥1 B-symptom. Hepatomegaly and splenomegaly were present in 14% and 57% respectively. Adverse prognostic factors: 14% del(17p) and/or TP53 mutated; 22% del(11q); 41% IGHV unmutated; β-2 microglobulin median 4.35 mg/L (range: 2.1-12.4). The median idelalisib exposure was 4.8 months (range 0.9-8.5). There has been one discontinuation at 3 mo for respiratory distress, assessed as related to a prior condition. The median absolute lymphocyte count was 59.7 K/µl (range: 0.8-294) at baseline peaking at 100 K/µl (range: 2-385) at week 4. 27 pts were evaluable for response, having reached the first evaluation time point of 8 weeks. Of these 27, the ORR was 81% with 9 (33%) PR and 13 (48%) PR with lymphocytosis. Splenomegaly has responded in 88% of 17 evaluable pts and hepatomegaly in 75% of 4 evaluable pts. The most frequent treatment emergent adverse events (TEAE) (% all Grade/% Grade ≥3) were rash (27/3), URI (16/0), constipation (14/0), cough (14/0), nausea (11/0), pyrexia (11/0), arthralgia (8/0), back pain (8/0), diarrhea (8/3), and pneumonia (8/5). Pneumonitis was observed in 2 pts (5%), Gr ≥3 in 1(3%). Gr ≥3 treatment emergent lab abnormalities included transaminase elevation (8%), anemia (5%), and neutropenia (20%); there was no Gr ≥3 thrombocytopenia. One pt had a TEAE leading to dose reduction. CONCLUSIONS: IDELA has substantial single agent activity in treatment-naïve pts with CLL or SLL. Early lymphocytosis is observed with monotherapy in this population, as opposed to an attenuation of lymphocytosis seen in the earlier cohort treated with IDELA plus weekly rituximab. IDELA was well tolerated and had a manageable safety profile in this preliminary analysis. Disclosures Zelenetz: Gilead Sciences: Research Funding. Off Label Use: Zydelig is a kinase inhibitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; 2) Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Lamanna:Gilead Sciences: Research Funding. Kipps:Gilead Sciences: Research Funding. Coutre:Gilead Sciences: Research Funding. O'Brien:Gilead Sciences: Research Funding. Aiello:Gilead Sciences: Employment, Equity Ownership. Cho:Gilead Sciences: Employment, Equity Ownership. Dubowy:Gilead Sciences: Employment, Equity Ownership. Flinn:Gilead Sciences: Research Funding.

TPS7131 Background: PI3K-delta is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues (Lannutti et al, 2011). Ofatumumab (O) is an anti-CD20 monoclonal antibody approved for the treatment of pts with CLL refractory to fludarabine and alemtuzumab. Phase 1 studies demonstrated that idelalisib, as monotherapy or combined with O, is highly active in pts with heavily pretreated CLL: pts experienced profound and rapid regression of lymphadenopathy, reductions in disease-associated chemokines, and durable clinical benefit with an acceptable safety profile (Furman et al, 2012). Methods: This study will enroll 210 pts with CLL previously treated with a purine analog and/or bendamustine, with measurable lymphadenopathy who require treatment for CLL and have disease that is not refractory to ofatumumab, and are expected to benefit from a change in therapy because of CLL progression &lt;24 months since completion of their last prior treatment. Pts are randomized in a 2:1 ratio (Arm A:Arm B). In Arm A, pts receive idelalisib at 150 mg BID continuously in combination with 12 infusions of O at 1000 mg over ~24 weeks (weekly x 8 then monthly x 4). In Arm B, pts receive 12 infusions of O at 2,000 mg over ~24 weeks. Stratification factors address IGHV mutational status, del(17p)/p53 mutation status, and refractory vs relapsed disease. The primary study endpoint is PFS. Secondary endpoints include ORR, lymph node response rate, CR rate, and OS. This is an event-driven trial and primary endpoint evaluation will be based on independent central review. For the primary efficacy analysis, the difference in PFS between the treatment arms will be assessed in the ITT analysis set using Kaplan-Meier methods and the stratified log-rank test. The study opened for enrollment in Dec 2012. Clinical trial information: NCT01659021.

Abstract Background In B-cells, phosphatidylinositol 3-kinase delta (PI3Kd) mediates a positive effect on cell survival, proliferation, growth, and metabolism. In addition, PI3Kd activity is critical for homing and retaining B cells in lymphoid tissues. In B-cell malignancies, increased activity of PI3Kd drives proliferation and survival of malignant B-cells and mediates trafficking to lymphoid tissues. GS-9820 is a second-generation, selective, small molecule inhibitor of PI3Kd under investigation for the treatment of lymphoid malignancies including non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). The primary endpoint for the dose-escalation stage is to determine the maximally tolerated dose (MTD) and to assess safety including the incidence and severity of transaminase elevation, which has been observed to varying degrees with other PI3K inhibitors. We here report safety, efficacy and pharmacokinetics (PK) for the first four dose cohorts. Methods Subjects with recurrent lymphoid malignancies with measurable lymphadenopathy who had ≥ 1 prior therapy received GS-9820 at doses of 50, 100, 200, or 400 mg, administered orally twice daily (BID). Stage 1 is a dose escalation stage with a classic 3+3 design to evaluate the safety, efficacy and pharmacology of GS-9820. Intensive PK sampling was done on Day 1 and Day 29. Antitumor activity was evaluated every 2 months (mos) using standard response criteria, with adjustment for redistribution lymphocytosis, consistent with PI3Kd inhibition. Nodal PR (nPR) is defined as a ≥50% reduction in lymphadenopathy. Safety assessments include monitoring for transaminase elevation. Subjects may continue receiving GS-9820 indefinitely as needed. Results As of July 15, 2013, 12 subjects were enrolled in 4 cohorts across the 50 to 400 mg dose range. Of the 8 subjects with CLL and 4 subjects with NHL enrolled, 9/12 remained on-study (Table 1). Reasons for discontinuation include disease progression (3). No dose-limiting toxicities have been reported. Importantly, transaminase elevation has not been observed. Among the 10 subjects with at least 1 post-baseline CT scan, 7/10 experienced reductions in lymph node (LN) size as best response and 4/10 subjects had nPR. PK GS-9820 plasma exposures were less than dose-proportional, with mean pre-dose concentrations upon multiple-dosing above the in vitro protein-binding adjusted EC50 at the doses tested, and exposure-driven trends in pharmacodynamic response (inhibition of basophil activation). Safety Severe adverse events (grade 3 or 4) occurred in 3 subjects: pneumonia, herpes, malaise, and gallbladder pain and none were considered related to study drug. Adverse events (AEs) occurring in &gt; 1 subject included cough (n=5), malaise (n=3), fatigue (n=2), diarrhea (n=2), and increased creatinine (n=2). AEs considered related to study drug by the investigator occurred in 6 subjects and included grade 1 events of footpad neuropathy, diarrhea, edema, grade 2 events of hyperkalemia and increased creatinine, and a grade 4 event of neutropenia. Serious adverse events (SAEs) included pneumonia, Morbus Bowen's disease, and herpes. None of the SAEs were considered related to study drug by the investigator. Conclusion Interim analysis of the first 4 cohorts of a dose-escalation phase 1b study of GS-9820 in patients with recurrent lymphoid malignancies demonstrates clinical activity. Doses ranging from 50 mg to 400 mg BID are not associated with disease limiting toxicity or transaminase elevation. Disclosures: Off Label Use: GS-9820 is a second-generation, selective, small molecule inhibitor of PI3Kƒ’ƒn under investigation for the treatment of lymphoid malignancies including non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Xin:Gilead Sciences: Employment. Ramanathan:Gilead Sciences: Employment. Aiello:Gilead Sciences: Employment. Jun:Gilead Sciences: Employment.

Abstract Background Idelalisib (IDELA) is a first-in-class, selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues. Phase 1 trials demonstrated that IDELA is highly active as a single agent or in combination with rituximab (R) in heavily pretreated patients (pts) with CLL. Pts in these trials experienced reductions in disease-associated chemokines, improvement of organomegaly and cytopenias, profound reductions in lymphadenopathy, and durable clinical benefit with an acceptable safety profile (Brown 2013; Barrientos 2013). Patients with early progression and significant co-morbidities have limited treatment options; single-agent rituximab is an option in these pts (NCCN 2013; Zelenetz 2013). Methods This Phase 3 study evaluated the efficacy and safety of IDELA + R vs placebo + R in pts with previously treated CLL. Eligibility criteria included the need for treatment per IWCLL guidelines, measurable lymphadenopathy, and CLL progression &lt;24 mos since the completion of last therapy. Pts were considered unfit to receive cytotoxic therapy because of comorbidities (defined as a Cumulative Illness Rating Score [CIRS] &gt; 6), renal dysfunction, or cytopenias due to poor marrow reserve. All pts received R at 375 mg/m2 [1st dose] and then 500 mg/m2q2 wks x 4, followed by q4 wks x 3 [8 doses total]) and were randomized to Arm A (n=110; IDELA 150 mg BID continuously) or Arm B (n=110; placebo BID continuously). Primary endpoint was progression-free survival (PFS). Response and progression in both arms were assessed by an independent review committee using standard criteria (Hallek 2008; Cheson 2012). Results were reviewed by an external Data Monitoring Committee (DMC). Results Results are from a pre-specified interim analysis after ∼50% of the total number of 119 planned events of CLL progression or death from any cause. Data cutoff was 30 Aug 2013. Pt characteristics (n=220) included a median age of 71 yrs (78% ≥ 65 yrs); CIRS &gt; 6 in 85%; median creatinine clearance of 63.6 mL/min; and presence of anemia (73%), thrombocytopenia (61%), neutropenia (34%). Median time since diagnosis was 8.5 yrs, median number of prior therapies was 3 (range: 1-12), 44% had del(17p)/TP53 mutation, and 84% had unmutated IGHV. PFS in the IDELA + R arm was superior to placebo +R (HR [95% CI] = 0.15 [0.08, 0.28]; p = 3.0 x 1011). Median PFS of pts treated with IDELA + R was not reached and for placebo + R was 5.5 mos. At 24 wks, the PFS rate for IDELA +R was 93% compared to 46% for placebo + R. PFS strongly favored IDELA + R in all subgroups, including those with del(17p)/TP53 or unmutated IGHV. Pts treated with IDELA + R and with ≥1 post-baseline assessment also had a superior overall response rate (ORR) relative to those in the control arm (81% vs. 13%; odds ratio 29.9; p = 3.0 x 1019) and a higher lymph node response (LNR) rate (93% vs. 4%; odds ratio 264.5; p = 1.3 x 10-30). Relative to the control group, pts treated with IDELA +R also had a significant improvement in overall survival (OS): HR (95% CI) = 0.28 (0.09, 0.86), p = 0.018. Adverse events (AEs) occurring in ≥20% of pts (any Gr/Gr ≥3) by arm were: pyrexia (IDELA + R 29%/3%; placebo + R 16%/1%), fatigue (IDELA + R 24%/3%; placebo + R 27%/2%), nausea (IDELA + R 24%/0%; placebo + R 22%/0%), chills (IDELA + R 22%/2%; placebo + R 16%/0%), infusion-related reactions (IDELA + R 16%/0%; placebo + R 28%/4%), and cough (IDELA + R 15%/0%; placebo + R 25%/2%). Other selected AEs (any Gr/Gr ≥3) included diarrhea (IDELA + R 19%/4%; placebo + R 14%/0%) and rash (IDELA + R 10%/2%; placebo + R 6%/0%). Select lab abnormalities (any Gr/Gr ≥3) included ALT elevation (IDELA + R 31%/6%; placebo + R 9%/1%), anemia (IDELA + R 26%/6%; placebo + R 30%/14%), neutropenia (IDELA + R 55%/34%; placebo + R 49%/22%), and thrombocytopenia (IDELA + R 17%/10%; placebo + R 26%/16%). The most common SAEs were pneumonia (6.4%), pyrexia (6.4%), and febrile neutropenia (4.5%) in IDELA + R, and pneumonia (8.4%), febrile neutropenia (5.6%), and dyspnea (3.7%) in placebo + R. AEs led to study drug discontinuation in 9 pts (8.2%) in IDELA + R and 11 pts (10.3%) in placebo + R. Based on a review of efficacy and safety, the DMC recommended stopping the study early. Conclusions IDELA + R demonstrated statistically significant improvement with acceptable safety over placebo + R in PFS, ORR, LNR and OS in heavily pretreated pts with relapsed CLL, including those with adverse genetic features. Disclosures: Furman: Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Consultancy, Research Funding. Coutre:Gilead Sciences: Research Funding. Cheson:Gilead Sciences: Research Funding. Pagel:Gilead Sciences: Research Funding. Hillmen:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Zelenetz:Gilead Sciences: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kipps:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Ghia:Gilead Sciences: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Eradat:Gilead Sciences: Research Funding. Ervin:Gilead Sciences: Research Funding. Lamanna:Gilead Sciences: Research Funding. Hallek:Gilead Sciences: Research Funding. Coiffier:Gilead Sciences: Research Funding. Pettitt:Gilead Sciences: Research Funding. Ma:Gilead Sciences: Research Funding. Stilgenbauer:Gilead Sciences: Honoraria, Research Funding. Aiello:Gilead Sciences: Employment. Johnson:Gilead Sciences: Employment, Equity Ownership. Miller:Gilead Sciences: Employment, Equity Ownership. Li:Gilead Sciences: Employment. Jahn:Gilead Sciences: Employment. Dansey:Gilead Sciences: Employment, Equity Ownership. O'Brien:Gilead Sciences: Research Funding.