Childs, Barrett H.

AbstractCopanlisib is an intravenously administered phosphatidylinositol 3‐kinase (PI3K) inhibitor which was investigated in pediatric patients with relapsed/refractory solid tumors. A model‐informed approach was undertaken to support and confirm an empirically selected starting dose of 28 mg/m2 for pediatric patients ≥1 year old, corresponding to 80% of the adult recommended dose adjusted for body surface area. An adult physiologically based pharmacokinetic (PBPK) model was initially established using copanlisib physicochemical and disposition properties and clinical pharmacokinetics (PK) data and was shown to adequately capture clinical PK across a range of copanlisib doses in adult cancer patients. The adult PBPK model was then extended to the pediatric population through incorporation of age‐dependent anatomical and physiological changes and used to simulate copanlisib exposures in pediatric cancer patient age groups. The pediatric PBPK model predicted that the copanlisib 28 mg/m2 dose would achieve similar copanlisib exposures across pediatric ages when compared with historical adult exposures following the approved copanlisib 60 mg dose administered on Days 1, 8, and 15 of a 28‐day cycle. Clinical PK were collected from a phase I study in pediatric patients with relapsed/refractory solid tumors (aged ≥4 years). An established adult population PK model was extended to incorporate an allometrically‐scaled effect of body surface area and confirmed that the copanlisib maximum tolerated dose of 28 mg/m2 was appropriate to achieve uniform copanlisib exposures across the investigated pediatric age range and consistent exposures to historical data in adult cancer patients. The model‐informed approach successfully supported and confirmed the copanlisib pediatric dose recommendation.

1021 Background: At 5 years, AT did not improve disease free survival or overall survival and RS was a more accurate predictor of relapse than standard clinicopathologic characteristics for patients with hormone receptor (HR) positive tumors. Methods: A Phase III Intergroup trial tested adjuvant AT vs. AC. Women with 1-3 N + or N - and T-size > 1cm were randomized to 4 cycles of AT (60 mg/m2/60 mg/ m2) or AC (60 mg/m2/600 mg/m2) q 3 wk x 4. Patients(pts) with ER + and/ or PR + tumors received tam for 5 yrs. Pts were stratified by nodal, HR (ER+ PR+, ER+PR-, ER-PR+, ER-PR-, ER/PR unk) and menopausal status. The primary endpoint was DFS. A sample of 465 pts with HR + breast cancer with 0 to 3 positive axillary nodes who did (N =116) or did not have a recurrence had tumor tissue evaluated using the 21- gene assay. Grade and HR expression were evaluated locally and centrally. Results: 2952 pts were randomized between 7/30/98 and 1/21/00. 2883 were eligible and analyzable. Arms were balanced for age, HR, menopause, nodes, surgery, grade and T-size: median age 51; 64% ER +; 65% LN-; grade: 10% low, 38% int., 46% high; and median T-size - 2.0 cm. At a median follow-up of 11.5 years the DFS/OS results are shown in the table below. RS was a highly significant predictor of recurrence including node negative and node positive disease (P < .0001) and predicted recurrence more accurately than clinical variables. Conclusions: At 11.5 yrs. median follow-up, there remains no difference in DFS or OS, although there continue to be fewer events in the AT arm in the prespecified ER/PR negative subgroup. At 10 years, the RS continues to be a more accurate predictor of relapse than standard clinical features. [Table: see text]

Abstract Background: Copanlisib is a novel pan-Class I phosphatidylinositol-3-kinase (PI3K) inhibitor with potent preclinical inhibitory activity against both PI3K-δ and PI3K-α isoforms. A phase II study of copanlisib in patients with relapsed/refractory indolent or aggressive lymphoma reported promising activity in the indolent NHL group (Dreyling et al., ENA 2014). The objective of this study is to evaluate the efficacy and safety of copanlisib in patients with indolent B-cell NHL relapsed after or refractory to standard therapy. Methods: Patients meeting the following criteria are eligible for enrollment: histologically confirmed diagnosis of indolent B-cell NHL, with follicular lymphoma (FL) grade 1-2-3a, marginal zone lymphoma (MZL; splenic, nodal, or extra-nodal), small lymphocytic lymphoma (SLL) with absolute lymphocyte count &lt; 5 × 109/L at the time of diagnosis and at study entry, or lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM), and who have previously received ? 2 prior lines of therapy with rituximab and an alkylating agent and must be refractory to the last treatment with rituximab (refractory defined as progressing or not responding within 6 months of the last course of treatment). Patients will be randomized in 2:1 manner to receive 60 mg of copanlisib administered intravenously on days 1, 8 and 15 of a 28-day cycle or placebo administered on the same schedule until disease progression or intolerable toxicity. Patients in the placebo arm will be allowed to cross-over to receive follow-up treatment with copanlisib, after confirmed disease progression. Dose reductions due to toxicities will be allowed. Radiologic tumor assessment will be performed every 12, 16 or 24 weeks for years 1, 2, and 3, respectively. The primary endpoint will be progression-free survival (PFS). Secondary objectives include overall objective response rate (ORR), duration of response (DOR), time to progression (TTP), complete response rate (CRR), overall survival (OS), time to deterioration as well as time to improvement in disease-related symptoms. Exploratory objectives will include secondary PFS after first progression in placebo-treated patients who cross over to receive copanlisib and time to improvement and the time to deterioration in disease-related symptoms - physical (DRS-P) of at least 3 points as measured by the FLymSI-18 questionnaire. Approximately 189 patients who meet the eligibility criteria will be randomized 2:1, with approximately 126 patients in the copanlisib monotherapy arm and approximately 63 patients in placebo arm. The study is planned to detect a 132% increase in median PFS in copanlisib versus placebo (i.e. to detect a hazard ratio of 0.43), using a stratified log-rank test. This study is currently enrolling patients (NCT02369016). Citation Format: Grzegorz S. Nowakowski, Igor Gorbatchevsky, Florian Hiemeyer, Lisa Cupit, Barrett H. Childs. A randomized, double-blind phase III study of phosphatidylinositol-3 kinase alpha/delta inhibitor copanlisib versus placebo in patients with rituximab-refractory indolent non-Hodgkin's lymphoma (iNHL): CHRONOS-2. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT084.

Abstract Background: Copanlisib is a novel pan-Class I phosphatidylinositol-3-kinase (PI3K) inhibitor with potent preclinical inhibitory activity against both PI3K-δ and PI3K-α isoforms. A phase II study of copanlisib in patients with relapsed/refractory indolent or aggressive lymphoma reported a promising overall response rate of up to 53% for patients in the indolent NHL group (Dreyling et al., ENA 2014). The objective of this study is to evaluate the efficacy and safety of copanlisib in patients with indolent B-cell NHL relapsed after or refractory to standard therapy. Methods: In this study, patients meeting the following criteria will be eligible for enrollment: histologically confirmed diagnosis of indolent B-cell NHL, with follicular lymphoma (FL) grade 1-2-3a, marginal zone lymphoma (MZL; splenic, nodal, or extra-nodal), small lymphocytic lymphoma (SLL) with absolute lymphocyte count &lt; 5 × 109/L at the time of diagnosis and at study entry, or lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM), and who have previously received ≥ 2 prior lines of therapy with rituximab and an alkylating agent and must be refractory to the last treatment with rituximab (refractory defined as not responding or progressing within 6 months of the last course of treatment). Patients will be randomized in 2:1 manner to receive 60 mg of copanlisib administered intravenously on days 1, 8 and 15 of a 28-day cycle or placebo administered on the same schedule. Patients will be treated until disease progression or intolerable toxicity. Patients in the placebo arm will be allowed to cross-over to receive follow-up treatment with copanlisib, after confirmed disease progression. Dose reductions due to toxicities to 45 mg and 30 mg will be allowed. Radiologic tumor assessment will be performed every 12, 16 or 24 weeks for years 1, 2, and 3, respectively. The primary endpoint will be progression-free survival (PFS). Secondary objectives include overall objective response rate (ORR), duration of response (DOR), time to progression (TTP), complete response rate (CRR), overall survival (OS), time to deterioration as well as time to improvement in disease-related symptoms. Exploratory objectives will include secondary PFS after first progression in placebo-treated patients who cross over to receive copanlisib and time to improvement and the time to deterioration in disease-related symptoms-physical (DRS-P) of at least 3 points as measured by the FLymSI-18 questionnaire. Approximately 189 patients who meet the eligibility criteria will be randomized 2:1, with approximately 126 patients in the copanlisib monotherapy arm and approximately 63 patients in placebo arm. The study is planned to detect a 132% increase in median PFS in copanlisib versus placebo (i.e. to detect a hazard ratio of 0.43), using a stratified log-rank test. Citation Format: Grzegorz S. Nowakowski, Igor Gorbatchevsky, Florian Hiemeyer, Lisa Cupit, Barrett H. Childs. CHRONOS-2: A randomized, double-blind phase III study of phosphatidylinositol-3 kinase alpha/delta inhibitor copanlisib versus placebo in patients with rituximab-refractory indolent non-Hodgkin's lymphoma (iNHL). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT212. doi:10.1158/1538-7445.AM2015-CT212

Abstract Purpose: To conduct an exploratory analysis of the relationship between gene expression and recurrence in patients with operable triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin-containing chemotherapy. Experimental Design: RNA was extracted from archived tumor samples derived from 246 patients with stage I-III TNBC treated with adjuvant doxorubicin-containing chemotherapy, and was analyzed by quantitative reverse transcriptase PCR for a panel of 374 genes. The relationship between gene expression and recurrence was evaluated using weighted Cox proportional hazards model score tests. Results: Growth factor receptor bound protein 7 (GRB7) was the only gene for which higher expression was significantly associated with increased recurrence in TNBC (Korn's adjusted P value = 0.04). In a Cox proportional hazards model adjusted for clinicopathologic features, higher GRB7 expression was associated with an increased recurrence risk (HR = 2.31; P = 0.04 using the median as the split). The 5-year recurrence rates were 10.5% [95% confidence intervals (CI), 7.8–14.1] in the low and 20.4% (95% CI, 16.5–25.0) in the high GRB7 groups. External validation in other datasets indicated that GRB7 expression was not prognostic in two adjuvant trials including variable systemic therapy, but in two other trials showed that high GBR7 expression was associated with resistance to neoadjuvant doxorubicin and taxane therapy. Conclusions: GRB7 was associated with an increased risk of recurrence in TNBC, suggesting that GRB7 or GRB7-dependent pathways may serve as potential biomarkers for therapeutic targets. Therapeutic targeting of one or more factors identified which function as interaction nodes or effectors should also be considered. Clin Cancer Res; 17(22); 7194–203. ©2011 AACR.