Karl Hsu

A Phase I Pharmacokinetic and Pharmacodynamic Study of Dalotuzumab (MK-0646), an Anti-Insulin-like Growth Factor-1 Receptor Monoclonal Antibody, in Patients with Advanced Solid Tumors

Purpose: Insulin-like growth factor-1 receptor (IGF-1R) mediates cellular processes in cancer and has been proposed as a therapeutic target. Dalotuzumab (MK-0646) is a humanized IgG1 monoclonal antibody that binds to IGF-1R preventing receptor activation. This study was designed to evaluate the safety and tolerability of dalotuzumab, determine the pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and identify a recommended phase II dose. Experimental Design: Patients with tumors expressing IGF-1R protein were allocated to dose-escalating cohorts of three or more patients each and received intravenous dalotuzumab weekly, every 2 or 3 weeks. Plasma was collected for PK analysis. Paired baseline and on-treatment skin and tumor biopsy samples were collected for PD analyses. Results: Eighty patients with chemotherapy-refractory solid tumors were enrolled. One dose-limiting toxicity was noted, but a maximum-tolerated dose was not identified. Grade 1 to 3 hyperglycemia, responsive to metformin, occurred in 15 (19%) patients. At dose levels or more than 5 mg/kg, dalotuzumab mean terminal half-life was 95 hours or more, mean Cmin was more than 25 μg/mL, clearance was constant, and serum exposures were approximately dose proportional. Decreases in tumor IGF-1R, downstream receptor signaling, and Ki67 expression were observed. 18F-Fluorodeoxy-glucose positron emission tomography metabolic responses occurred in three patients. One patient with Ewings sarcoma showed a mixed radiologic response. The recommended phase II doses were 10, 20, and 30 mg/kg for the weekly, every other week, and every third week schedules, respectively. Conclusions: Dalotuzumab was generally well-tolerated, exhibited dose-proportional PK, inhibited IGF-1R pathway signaling and cell proliferation in treated tumors, and showed clinical activity. The low clearance rate and long terminal half-life support more extended dosing intervals. Clin Cancer Res; 17(19); 6304–12. ©2011 AACR.

Antibody-based therapy for solid tumors.

Monoclonal antibodies have emerged as a class of novel oncology therapeutics. The selectivity and specificity, the unique pharmacokinetics, and the ability to engage and activate the immune system differentiate these biologics from traditional small molecule anticancer drugs. In this review, we focus on 4 antibodies approved for clinical use in treating solid tumors, trastuzumab (Herceptin) for breast cancer, bevacizumab (Avastin) for colorectal cancer and non-small cell lung cancer, cetuximab (Erbitux) for colorectal cancer and head and neck cancer, and panitumumab (Vectibix) for colorectal cancer. The anticancer effects of these antibodies derive from blockade of growth factor/receptor interaction and/or down-regulation of oncogenic proteins (eg, growth factor receptors) on the tumor cell surface, and for some of these antibodies from the ability to elicit effector mechanisms of the immune system, such as antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity. The mechanism behind each antibody, the registration trials for their approved indications, and emerging indications are the focus of this article. We also review clinical considerations including commonly observed and antibody-related side effects, and dosing schedules. In addition, perspectives on challenges and opportunities of oncology antibody clinical development, antibody engineering, and the use of pharmacogenomics are presented.

Abstract LB-147: Combination of the MEK inhibitor, pimasertib (MSC1936369B), and the PI3K/mTOR inhibitor, SAR245409, in patients with advanced solid tumors: Results of a phase Ib dose-escalation trial.

Background: The PI3K/mTOR and MAPK signaling pathways are frequently aberrated in tumors and interact to promote growth. This trial investigated simultaneous inhibition of these pathways using a combination of the selective uncompetitive MEK1/2 inhibitor pimasertib and the dual PI3K/mTOR inhibitor SAR245409 (ClinicalTrials.gov NCT01390818). Materials and Methods: This phase Ib, dose-escalation trial (modified 3+3 design) included patients (pts) with solid tumors with frequent activation of these pathways, no approved therapy, and ECOG performance status ≤1. Expansion in selected indications, based on activity signals, was allowed after determination of the maximum tolerated dose (MTD). Pts received 21-day cycles of pimasertib (once-daily, qd) and SAR245409 (qd) at the following dose levels (DLs): DL1, 15/30; DL2a, 30/30; DL2b, 15/50; DL3, 30/50; DL4a, 60/50; DL4b, 30/70; DL5, 60/70; DL6a, 90/70 and DL6b 60/90. The MTD of the combination was the highest dose at which ≤1/6 pts had a dose-limiting toxicity (DLT). Safety, pharmacokinetics (PK), pharmacodynamics (PD) and tumor response were investigated. Results: Of 46 pts treated, 57% were male, the median age was 58.5 years (range 31-82) and 54% had an ECOG PS of 1. The most common primary tumor types were: colorectal (CRC, n=16), pancreatic and non-small cell lung cancer (NSCLC, n=7, each). Dose escalation was stopped at DL6b as 2/3 pts had DLTs; both had grade 3 nausea and/or vomiting, which resolved after supportive care and treatment interruption. The most frequent adverse events (AEs) (all grades) were: diarrhea (54%), fatigue (50%), nausea (41%) and vomiting and dermatitis acneiform (39% each). The median number of initiated cycles was 2 (range 1-16). There were 2 partial responses (KRAS mutated [mt] CRC with neuro-endocrine features and KRAS mt/PIK3CA mt low grade ovarian cancer and another pt with low grade ovarian cancer had 29% tumor shrinkage) and 7 other pts had stable disease lasting >12 weeks (CRC [n=2, 1 KRAS wild-type (wt) and 1 KRAS mt]; KRAS mt NSCLC [n=2]; and BRAF wt melanoma, KIT mt soft palate cancer and PIK3CA mt bladder cancer [n=1, each]). The MTD was DL6a (pimasertib 90 mg / SAR 245409 70 mg). DL5 (60/70) was the recommended phase II dose (RP2D) based on pimasertib tolerability after prolonged exposure in monotherapy program. Four disease-specific expansion cohorts (CRC, triple-negative breast cancer, NSCLC and melanoma, 18 pts each) are being treated at this dose. Dose escalation with twice-daily administration is ongoing. Preliminary PK and PD data showed no apparent drug-drug interaction. Conclusions: The combination of pimasertib and SAR245409 qd is feasible. The MTD and RP2D for the combination are within the range of the active doses of each drug as monotherapy. Early signals of activity have been observed. Citation Format: Jeffrey R. Infante, Leena Gandi, Geoffrey Shapiro, Naiyer Rizvi, Howard A. Burris, Johanna C. Bendell, Jose Baselga, Karl Hsu, Oliver von Richter, Giuseppe Locatelli, Ekaterine Asatiani, Rebecca S. Heist. Combination of the MEK inhibitor, pimasertib (MSC1936369B), and the PI3K/mTOR inhibitor, SAR245409, in patients with advanced solid tumors: Results of a phase Ib dose-escalation trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-147. doi:10.1158/1538-7445.AM2013-LB-147

Abstract 4638: Anti-tumor activity of pimasertib in combination with SAR245409 or SAR245408 in human primary colorectal cancer xenograft models bearing PI3K/KRas and KRas mutations.

The PI3K/AKT/mTOR and Ras/Raf/MEK/ERK are interlinked growth and survival signaling pathways that are often constitutively activated in human tumors as a result of amplifications and/or mutations in PIK3CA, RAS and BRAF genes. In the present work, we have investigated the anti-tumor activity and documented the steady state pharmacodynamic impact of combinations between 2 selective pan PI3K Class I inhibitors, SAR245408 (XL147) and SAR245409 (XL765) with the selective allosteric inhibitor of MEK1/2, pimasertib (AS703026; MSC1936369B) against several different patient derived colorectal cancer (CRC) xenograft models harboring either KRAS mutations, dual KRAS and BRAF mutations or dual KRAS and PIK3CA mutations. In the BRAF driven CRC model, effects of the combinations were not significantly different from that of single agent treatment of pimasertib alone. In the G12V KRAS or G12D KRAS mutant CRC models, both combinations led to significantly greater anti-tumor activity than that of single agent treatment. In the dual PIK3CA/KRAS mutant tumors, combination therapies lead to a potent inhibition of both TORC1 and TORC2 pathways, in addition to inhibition of the MAPK pathway in contrast to single agent treatments. Overall, pimasertib combined with either SAR245409 or SAR245408 showed a significantly greater anti-tumor activity as compared to single agent treatment alone in primary models bearing KRAS mutations or dual PIK3CA/KRAS mutations. The combination of pimasertib and SAR245409 is currently being investigated in patients with PIK3CA/KRAS mutant colorectal cancer as part of an ongoing Phase Ib dose escalation trial of oral combination therapy with pimasertib (MSC1936369B) and SAR245409 in subjects with locally advanced or metastatic solid tumors. Citation Format: Sukhvinder S. Sidhu, Coumaran Egile, Marc Malfilatre, Celine Lefranc, Yvette Ruffin, Jianguo Ma, Karl Hsu, Joanne Lager, Stephane Marzabal, Janet A. Ogden, Loic Vincent. Anti-tumor activity of pimasertib in combination with SAR245409 or SAR245408 in human primary colorectal cancer xenograft models bearing PI3K/KRas and KRas mutations. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4638. doi:10.1158/1538-7445.AM2013-4638

Abstract P3-04-05: Identification of SAR439859, an orally bioavailable selective estrogen receptor degrader (SERD) that has strong antitumor activity in wild-type and mutant ER+ breast cancer models

Nearly 70% or more of newly diagnosed cases of breast cancer (BC) are estrogen receptor positive (ER+) where endocrine therapy is a primary treatment. However, substantial evidence describes a continued role of ER signaling in tumor progression, where approximately 40% of patients on endocrine therapy develop resistance that include mutations in the ER that drive a constitutively active receptor. Fulvestrant, an estrogen receptor degrader, is effective at shutting down ER signaling. However, fulvestrant efficacy studies report insufficient blockade of ER signaling in patients that may be a consequence of poor pharmaceutical properties. Here we describe the discovery of SAR439859, a novel, orally bioavailable SERD with potent antagonist and degradative properties against ER both in vitro and in vivo. SAR439859 has robust inhibition of ER signaling activity in multiple ER+ breast cancer cell lines including tamoxifen resistant lines harboring ER mutations. Across a large panel of ER+ cells, SAR439859 demonstrated broad and superior ER degradation activity as compared to other SERDs including improved inhibition of ER signaling and inhibition of cell growth. Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ BC models including MCF7-ESR1 mutant-Y537S model and endocrine therapy resistant patient-derived xenograft tumor transplantation. Collectively, these results showed that SAR439859 is an oral, nonsteroidal, selective estrogen receptor antagonist and degrader that could provide therapeutic benefit to ER+ breast cancer patients. SAR439859 is currently being evaluated in a phase I clinical trial. Citation Format: Maysoun Shomali, Youssef El-Ahmad, Frank Halley, Jane Cheng, Michael Weinstein, Muchun Wang, Fangxian Sun, Natalia Malkova, Mikhail Levit, Malvika Koundinya, Zhuyan Gou, Andrew Hebert, Jessica McManus, Dietmar Hoffman, Hui Cao, Joonil Jung, Jack Pollard, Sylvie Vincent, Timothy Ackerson, Francisco Adrian, Chris Winter, Victoria Richon, Hong Chen, Karl Hsu, Joanne Lager, Albane Courjaud, Rosalia Arrebola, Laurent Besret, Pierre-Yves Abecassis, Laurent Schio, Gary McCort, Michel Tabart, Victor Certal, Fabienne Thompson, Bruno Filoche-Romme, Laurent Debussche, Patrick Cohen, Carlos Garcia-Echeverria, Monsif Bouaboula. Identification of SAR439859, an orally bioavailable selective estrogen receptor degrader (SERD) that has strong anti-tumor activity in wild-type and mutant ER+ breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5775.

Abstract A48: Anti-tumor activity of the MEK inhibitor pimasertib in combination with the PI3K/mTOR inhibitor SAR245409 in low-grade serous ovarian cancer

Low-grade serous ovarian carcinoma is a distinct neoplasm from high-grade serous ovarian carcinoma and is chemo-resistant, both in the first line setting as well as in subsequent lines of therapy. Serous ovarian tumors of low malignant potential and low grade serous ovarian cancer (LGSOC) appear to be dependent, in part, on the activation of the mitogen-activated protein kinase (MAPK) survival signaling pathway, and furthermore display significantly higher prevalence of KRAS or BRAF mutations in contrast to high-grade serous carcinomas. The PI3K/AKT/mTOR and Ras/Raf/MEK/ERK (MAPK) survival pathways are interlinked survival signaling pathways, where compensatory activation of one of the pathways in response to the inhibition of the other has been observed. Given their ability to cross-talk, simultaneous inhibition of the MAPK and PI3K/PTEN signaling cascades may significantly enhance anti-tumor activity as compared with inhibition of either cascade alone. Preclinical studies have shown that the combination of MEK and PI3K inhibitors, both in vitro and in vivo, enhanced anti-tumor effects and induced apoptosis in cell lines and primary patient-derived models across a range of cancer types. In the present series of studies, we report: 1- the anti-tumor activity of the combination of two investigational drugs, a phosphatidylinositol 3-kinase (PI3K) and mTOR inhibitor, SAR245409 (XL765) with the selective allosteric inhibitor of MEK1/2, pimasertib (AS703026; MSC1936369B) against patient-derived ovarian cancer xenograft models harboring KRAS mutations from low, intermediate and high grade ovarian tumors), and 2- the preliminary clinical activity of the combination in ovarian patients. In patient-derived xenografts of low and intermediate grade ovarian cancer, the combination led to significantly greater antitumor activity than that of single agent treatments. In the high grade model of ovarian cancer, no additive effects on antitumor activity were observed in the combination as compared to pimasertib as a single agent. The combination of pimasertib and SAR245409 is currently being investigated in patients with refractory solid tumors in an ongoing Phase Ib Trial (EMR200066-006; [NCT01390818][1]), where objective responses have been reported in 2 out of 4 evaluable patients with low-grade serous ovarian carcinoma. A phase 2 study (EMR200066-012, EudraCT Number 2013-000902-40) will investigate the activity of the combination pimasertib and SAR245409 in subjects with recurrent or metastatic low grade ovarian cancer, a patient population which has a high unmet medical need. Citation Format: Sukhvinder S. Sidhu, Frank Campana, Coumaran Egile, Karl Hsu, Samantha Goodstal, Ekaterine Asatiani, Lars Damstrup, Joanne Lager, Janet Ogden, Loic Vincent. Anti-tumor activity of the MEK inhibitor pimasertib in combination with the PI3K/mTOR inhibitor SAR245409 in low-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A48. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01390818&atom=%2Fclincanres%2F19%2F19_Supplement%2FA48.atom