Richard Gedrich

A phase I study of continuous oral dosing of OSI-906, a dual inhibitor of insulin-like growth factor-1 and insulin receptors, in patients with advanced solid tumors

Purpose: OSI-906 is a potent inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR). The purpose of this study was to determine the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906 in patients with advanced solid tumors. Patients and Methods: This was a nonrandomized, open-label, phase I, dose-escalation study in patients with advanced solid tumors. The study also included a diabetic expansion cohort and a biomarker expansion cohort of patients with colorectal cancer. Patients were treated with OSI-906 by once- or twice-daily continuous dosing schedules. Results: Of 95 patients enrolled in the study, 86 received at least one dose of OSI-906. Dose-limiting toxicities included QTc prolongation, grade 2 abdominal pain and nausea, hyperglycemia, and elevation of aspartate aminotransferase and alanine aminotransferase (all grade 3). The MTDs were established to be 400 mg once daily and 150 mg twice daily. The recommended phase II dose was determined as 150 mg twice daily. OSI-906 was rapidly absorbed with a half-life of 5 hours, and steady-state plasma concentrations were achieved by day 8. Pharmacodynamic effects on IGF1R and IR phosphorylation were levels observed and correlated with plasma concentrations of OSI-906. Thirty-one patients had stable disease as their best response. One patient with melanoma had a radiographic partial response and underwent resection, during which only melanocytic debris but no viable tumor tissue was identified. Conclusions: At the established MTD, OSI-906 was well tolerated and antitumor activity was observed. These results support further evaluation of OSI-906 in solid tumors. Clin Cancer Res; 21(4); 701–11. ©2014 AACR. See related commentary by Yee, p. 667

Phase I Study of Intermittent Oral Dosing of the Insulin-like Growth Factor-1 and Insulin Receptors Inhibitor OSI-906 in Patients With Advanced Solid Tumors

Purpose: We determined the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906, a potent, oral, dual inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR), in patients with advanced solid tumors. Experimental Design: This was a multicenter, open-label, dose escalation phase I study evaluating three intermittent dosing schedules of once-daily OSI-906 [schedule (S) 1, days 1–3 every 14 days; S2, days 1–5 every 14 days; S3, days 1–7 every 14 days]. A fed-fasting expansion cohort was included in the study. Results: Seventy-nine patients were enrolled: 62 in S1, 4 in S2, and 13 in S3. S2 was discontinued. Dose-limiting toxicity comprised grade 3–4 hyperglycemia, vomiting, fatigue, and prolonged QTc interval. The MTD and recommended phase II dose of OSI-906 was 600 mg for both S1 and S3 schedules. Other common adverse events were grade 1–2 nausea, vomiting, fatigue, and diarrhea. The pharmacokinetics of OSI-906 was dose linear, and the terminal half-life ranged between 2 and 6 hours. High-fat meals had a moderate effect on the pharmacokinetics of OSI-906. At the MTD, inhibition of IGF1R and IR was observed in peripheral blood mononuclear cells. An increase in plasma IGF1 concentrations, an indirect measure of IGF1R signaling inhibition, was seen at doses ≥ 450 mg. Two patients with adrenocortical carcinoma achieved partial responses. Conclusion: The MTD of 600 mg was well tolerated and associated with preliminary antitumor activity. These data support further evaluation of OSI-906 in solid tumors. Clin Cancer Res; 21(4); 693–700. ©2014 AACR. See related commentary by Yee, p. 667

Sorafenib Inhibits Imatinib-Resistant KIT and Platelet-Derived Growth Factor Receptor β Gatekeeper Mutants

Purpose: Targeting of KIT and platelet-derived growth factor receptor (PDGFR) tyrosine kinases by imatinib is an effective anticancer strategy. However, mutations of the gatekeeper residue (T670 in KIT and T681 in PDGFRβ) render the two kinases resistant to imatinib. The aim of this study was to evaluate whether sorafenib (BAY 43-9006), a multitargeted ATP-competitive inhibitor of KIT and PDGFR, was active against imatinib-resistant KIT and PDGFRβ kinases. Experimental Design: We used in vitro kinase assays and immunoblot with phosphospecific antibodies to determine the activity of sorafenib on KIT and PDGFRβ kinases. We also exploited reporter luciferase assays to measure the effects of sorafenib on KIT and PDGFRβ downstream signaling events. The activity of sorafenib on interleukin-3–independent proliferation of Ba/F3 cells expressing oncogenic KIT or its imatinib-resistant T670I mutant was also tested. Results: Sorafenib efficiently inhibited gatekeeper mutants of KIT and PDGFRβ (IC50 for KIT T670I, 60 nmol/L; IC50 for PDGFRβ T681I, 110 nmol/L). Instead, it was less active against activation loop mutants of the two receptors (IC50 for KIT D816V, 3.8 μmol/L; IC50 for PDGFRβ D850V, 1.17 μmol/L) that are also imatinib-resistant. Sorafenib blocked receptor autophosphorylation and signaling of KIT and PDGFRβ gatekeeper mutants in intact cells as well as activation of AP1-responsive and cyclin D1 gene promoters, respectively. Finally, the compound inhibited KIT-dependent proliferation of Ba/F3 cells expressing the oncogenic KIT mutant carrying the T670I mutation. Conclusions: Sorafenib might be a promising anticancer agent for patients carrying KIT and PDGFRβ gatekeeper mutations.

Phase I Dose Escalation Study of Linsitinib (OSI-906) and Erlotinib in Patients with Advanced Solid Tumors

Purpose: Cross-talk between type I IGF receptor (IGF1R), insulin receptor (INSR), and epidermal growth factor receptor (EGFR) mediates resistance to individual receptor blockade. This study aimed to determine the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of linsitinib, a potent oral IGF1R/INSR inhibitor, with EGFR inhibitor erlotinib. Experimental Design: This open-label, dose-escalation study investigated linsitinib schedules S1: once daily intermittent (days 1–3 weekly); S2, once daily continuous; S3, twice-daily continuous; each with erlotinib 100–150 mg once daily; and a non–small cell lung cancer (NSCLC) expansion cohort. Results: Ninety-five patients were enrolled (S1, 44; S2, 24; S3, 12; expansion cohort, 15) and 91 treated. Seven experienced dose-limiting toxicities: QTc prolongation (3), abnormal liver function (2), hyperglycemia (1), and anorexia (1). Common adverse events included drug eruption (84%), diarrhea (73%), fatigue (68%), nausea (58%), vomiting (40%). MTDs for linsitinib/erlotinib were 450/150 mg (S1), 400/100 mg (S2). On the basis of prior monotherapy data, S3 dosing at 150 mg twice daily/150 mg once daily was the recommended phase II dose for the expansion cohort. There was no evidence of drug–drug interaction. Pharmacodynamic data showed IGF-1 elevation and reduced IGF1R/INSR phosphorylation, suggesting pathway inhibition. Across schedules, 5/75 (7%) evaluable patients experienced partial responses: spinal chordoma (268+ weeks), rectal cancer (36 weeks), three NSCLCs including 2 adenocarcinomas (16, 72 weeks), 1 squamous wild-type EGFR NSCLC (36 weeks). Disease control (CR+PR+SD) occurred in 38 of 75 (51%), and 28 of 91 (31%) patients were on study >12 weeks. Conclusions: The linsitinib/erlotinib combination was tolerable with preliminary evidence of activity, including durable responses in cases unlikely to respond to erlotinib monotherapy. Clin Cancer Res; 22(12); 2897–907. ©2016 AACR.

Targeting KIT on innate immune cells to enhance the antitumor activity of checkpoint inhibitors

Innate immune cells such as mast cells and myeloid-derived suppressor cells are key components of the tumor microenvironment. Recent evidence indicates that levels of myeloid-derived suppressor cells in melanoma patients are associated with poor survival to checkpoint inhibitors. This suggests that targeting both the innate and adaptive suppressive components of the immune system will maximize clinical benefit and elicit more durable responses in cancer patients. Preclinical data suggest that targeting signaling by the receptor tyrosine kinase KIT, particularly on mast cells, may modulate innate immune cell numbers and activity in tumors. Here, we review data highlighting the importance of the KIT signaling in regulating antitumor immune responses and the potential benefit of combining selective KIT inhibitors with immune checkpoint inhibitors.

Anti-KIT Monoclonal Antibody Treatment Enhances the Antitumor Activity of Immune Checkpoint Inhibitors by Reversing Tumor-Induced Immunosuppression

The receptor tyrosine kinase KIT is an established oncogenic driver of tumor growth in certain tumor types, including gastrointestinal stromal tumors, in which constitutively active mutant forms of KIT represent an actionable target for small-molecule tyrosine kinase inhibitors. There is also considerable potential for KIT to influence tumor growth indirectly based on its expression and function in cell types of the innate immune system, most notably mast cells. We have evaluated syngeneic mouse tumor models for antitumor effects of an inhibitory KIT mAb, dosed either alone or in combination with immune checkpoint inhibitors. Anti-KIT mAb treatment enhanced the antitumor activity of anti–CTLA-4 and anti–PD-1 mAbs, and promoted immune responses by selectively reducing the immunosuppressive monocytic myeloid-derived suppressor cell population and by restoring CD8+ and CD4+ T-cell populations to levels observed in naïve mice. These data provide a rationale for clinical investigation of the human KIT-specific mAb KTN0158 in novel immuno-oncology combinations with immune checkpoint inhibitors and other immunotherapeutic agents across a range of tumor types. Mol Cancer Ther; 16(4); 671–80. ©2017 AACR.

KTN0158, a Humanized Anti-KIT Monoclonal Antibody, Demonstrates Biologic Activity against both Normal and Malignant Canine Mast Cells

Purpose: KTN0158 is a novel anti-KIT antibody that potently inhibits wild-type and mutant KIT. This study evaluated the safety, biologic activity, and pharmacokinetic/pharmacodynamics profile of KTN0158 in dogs with spontaneous mast cell tumors (MCT) as a prelude to human clinical applications. Experimental Design: Cell proliferation, KIT phosphorylation, and mast cell degranulation were evaluated in vitro. KTN0158 was administered to 4 research dogs to assess clinical effects and cutaneous mast cell numbers. Thirteen dogs with spontaneous MCT were enrolled into a prospective phase I dose-escalating open-label clinical study of KTN0158 evaluating 3 dose levels and 2 schedules and with weekly assessments for response and clinical toxicities. Results: KTN0158 was a potent inhibitor of human and dog KIT activation and blocked mast cell degranulation in vitro. In dogs, KTN0158 was well tolerated and reduced cutaneous mast cell numbers in a dose-dependent manner. Clinical benefit of KTN0158 administration in dogs with MCT (n = 5 partial response; n = 7 stable disease) was observed regardless of KIT mutation status, and decreased KIT phosphorylation was demonstrated in tumor samples. Histopathology after study completion demonstrated an absence of neoplastic cells in the primary tumors and/or metastatic lymph nodes from 4 dogs. Reversible hematologic and biochemical adverse events were observed at doses of 10 and 30 mg/kg. The MTD was established as 10 mg/kg. Conclusions: KTN0158 inhibits KIT phosphorylation, demonstrates an acceptable safety profile in dogs, and provides objective responses in canine MCT patients with and without activating KIT mutations, supporting future clinical evaluation of KTN0158 in people. Clin Cancer Res; 23(10); 2565–74. ©2016 AACR.

Targeting KIT on innate immune cells enhances the antitumor activity of checkpoint inhibitors in vivo

Mast cell infiltrates are associated with tumors, though their role in the tumor microenvironment remains unclear. Mast cells express high levels of KIT throughout differentiation and as mature cells. Mast cells in tumors have been shown to release proinflammatory cytokines and promote angiogenesis, increasing tumor growth and metastasis. KIT signaling and mast cells also appear to modulate myleloid-derived suppressor cell (MDSC) development, recruitment and activity in tumors. Furthermore, treatment of tumor-bearing mice or cancer patients with small molecule KIT inhibitors or an anti-mouse KIT antibody decreased tumoral MDSCs and other immunosuppressive cells including regulatory T cells. KTN0158 is a humanized anti-KIT IgG1 monoclonal antibody that specifically binds KIT and is being developed as a potential therapy for cancer and mast cell-related diseases such as neurofibromatosis type 1 (NF1). It binds canine, feline, non-human primate and human KIT with high affinity, but does not bind mouse or rat KIT. KTN0158 inhibits KIT signaling and function in vitro and in vivo and has shown antitumor activity in dogs with mast cell tumors expressing either wild-type or mutant KIT. Immune checkpoint inhibitors targeting the CTLA-4 and PD-1 pathways have demonstrated single agent efficacy in cancer patients, and the combinations have shown superior efficacy in some preclinical and clinical settings. To test the effects of KIT inhibition on immune tolerance in syngeneic mouse tumor models, the anti-mouse KIT monoclonal antibody ACK2 was used as a surrogate for KTN0158 and tested alone and in combination with CTLA-4 and PD-1 inhibitors. In the Colon26 model, single agent treatment with the anti-KIT antibody had little antitumor activity. However, the combination of anti-KIT and anti-CTLA-4 had substantial antitumor effects, comparable to those observed for anti-CTLA-4 plus anti-PD1. These antitumor effects were dose-dependent. Pharmacodynamic assessments will also be presented. Collectively, these data suggest that the combination of immunotherapies targeting KIT on innate immune cells and checkpoint pathway inhibitors may have clinical benefit.

Abstract 4020: Inhibition of KIT in vivo modifies immune cell populations to improve the efficacy of checkpoint inhibitors in syngeneic mouse tumor models

The KIT receptor tyrosine kinase plays critical roles in GIST and a range of other tumor types, and when activated by somatic mutation serves as a potent oncogenic driver in these neoplasms. Whereas small molecule inhibitors of the tyrosine kinase domain of KIT have demonstrated considerable success in treatment of GIST patients with some KIT mutations, there remains a need to develop additional KIT-directed therapies for treatment of GIST patients that fail to respond to these agents, or that develop resistance during therapy. Furthermore, KIT is prominently expressed on mast cells, which promote an immune evasive environment within the tumor microenvironment by influencing the function of other immune cells, such as myeloid derived suppressor cells (MDSC’s). However, the potential impact of KIT inhibition on anti-tumor immunity has not been studied extensively to date. KTN0158 is a humanized anti-KIT IgG1 monoclonal antibody that specifically binds to the extracellular domain of KIT, and is being developed as a potential therapy for cancer and other mast cell-related diseases such as neurofibromatosis type 1 (NF1). KTN0158 inhibits KIT signaling and function in vitro and in vivo and has demonstrated anti-tumor activity in dogs with mast cell tumors expressing either wild-type or mutant KIT. In order to explore the potentially broad anti-tumor benefit of KIT inhibition by an antibody, a series of syngeneic tumor models were evaluated for sensitivity and immune cell profile changes in response to a surrogate antibody that recognizes mouse KIT (ACK2), dosed as either a single agent or in combination with T cell checkpoint inhibitors. Within this panel of tumor models, ACK2 strongly enhanced the anti-tumor activity provided by an anti-CTLA4 antibody in the colon26 model, while exhibiting no anti-tumor activity when dosed as a single agent. The colon26 cell line does not express detectable levels of KIT, and does not exhibit sensitivity to ACK2 or SCF treatment in proliferation assays performed in vitro, suggesting that this effect of ACK2 is not due to a direct effect on the tumor cells. Strikingly, ACK2 treatment was associated with pronounced effects on immune cell populations, including a profound decrease in both intra-tumoral and splenic monocytic MDSC counts. These observations suggest that KIT inhibition in vivo has the potential to modulate immune cell populations including MDSC9s and mast cells, thereby targeting immune suppressive innate immune cells in the tumor and sensitizing the tumor to immune checkpoint inhibitors. Furthermore, the data provide a rationale to investigate KTN0158 in combination with immune checkpoint inhibitors across a range of human tumor types. Citation Format: Andrew J. Garton, Lori Lopresti-Morrow, Scott Seibel, Theresa LaVallee, Richard Gedrich. Inhibition of KIT in vivo modifies immune cell populations to improve the efficacy of checkpoint inhibitors in syngeneic mouse tumor models. [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 4020.

Abstract C167: KTN0158, a humanized anti-KIT monoclonal antibody, demonstrates antitumor activity in dogs with mast cell tumors

Background: KTN0158 is a novel humanized anti-KIT IgG1 monoclonal antibody that binds canine, feline, non-human primate and human KIT with high affinity. KTN0158 potently inhibits wild-type and some oncogenic variants of KIT in vitro and modulates canine mast cell function and survival in vivo. A clinical trial was conducted in dogs with spontaneous mast cell tumors (MCT) where KIT is known to be widely expressed and where activating mutations in the form of internal tandem duplications (ITDs) in exon 11 are found in 30% of tumors. The purpose of this study was to evaluate the safety, biologic activity and pharmacokinetic/pharmacodynamic (PK/PD) profile associated with KTN0158 administration in dogs with MCT. Methods: Twelve dogs with measurable MCT were enrolled into this open-label phase 1 dose-escalating clinical trial. Three dose levels and 2 schedules were evaluated (10 or 30 mg/kg given on Day 0 only; 1 or 10 mg/kg given on Days 0 and 21). Serial tumor biopsies and blood samples for PK and PD analysis were collected pre- and post-treatment throughout the study. Dogs were assessed weekly with physical examination and standard laboratory tests (serum chemistries, hematology profiles, and urinalyses) for clinical toxicities and response. Adverse events (AEs) were recorded and graded according to published common terminology criteria for AEs in dogs. Determination of antitumor efficacy was based on objective tumor assessments made according to established RECIST criteria for solid tumors in dogs. Results: Of the 12 dogs entered in this study, 3 had tumors with exon 11 ITDs and 6 had evidence of metastasis to the local lymph node. All dogs treated with a single dose of KTN0158 at 10 or 30 mg/kg or two doses of KTN0158 at 1 or 10 mg/kg experienced clinical benefit. Partial responses were observed in 5 dogs (n = 1 KIT ITD) and stable disease was observed in 7 dogs (n = 2 KIT ITD). Upon study completion, 11 dogs underwent surgical removal of the MCT with or without extirpation of the draining lymph node. Histopathology failed to identify neoplastic mast cells in tumor samples from 2 dogs (patients 2 and 4) and 3 draining lymph nodes from 3 dogs (patients 2, 3 and 11) classified as metastatic at study entry. The most common adverse events associated with KTN0158 administration were reversible dose-dependent hematologic changes including anemia, neutropenia, and thrombocytopenia, generally occurring 7-14 days post-treatment. Doses of 30 mg/kg KTN0158 resulted in clinically significant toxicities not observed at other dosing levels, including evidence of edema/erythema, grade 4 neutropenia, and grade 3 thrombocytopenia. Evaluation of PK and PD biomarkers is ongoing. Conclusions: KTN0158 given at 1 and 10 mg/kg demonstrated an acceptable adverse event profile and single agent biologic activity in a relevant spontaneous large animal model of KIT driven malignancy (MCT). The objective responses observed in tumors with and without activating KIT mutation suggest that KTN0158 may provide clinical benefit to patients with GIST and other KIT-driven tumors and human clinical studies are planned. Citation Format: Cheryl London, Sarah Rippy, Heather Gardner, William Kisseberth, Gerald Post, Neal Janson, Linda Crew, Theresa LaVallee, Richard Gedrich. KTN0158, a humanized anti-KIT monoclonal antibody, demonstrates antitumor activity in dogs with mast cell tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C167.