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Macrophages can be co-opted to contribute to neoplastic, neurologic, and inflammatory diseases. Colony-stimulating factor 1 receptor (CSF1R)-dependent macrophages and other inflammatory cells can suppress the adaptive immune system in cancer and contribute to angiogenesis, tumor growth, and metastasis. CSF1R-expressing osteoclasts mediate bone degradation in osteolytic cancers and cancers that metastasize to bone. In the rare disease tenosynovial giant cell tumor (TGCT), aberrant CSF1 expression and production driven by a gene translocation leads to the recruitment and growth of tumors formed by CSF1R-dependent inflammatory cells. Small molecules and antibodies targeting the CSF1/CSF1R axis have shown promise in the treatment of TGCT and cancer, with pexidartinib recently receiving FDA approval for treatment of TGCT. Many small-molecule kinase inhibitors of CSF1R also inhibit the closely related kinases KIT, PDGFRA, PDGFRB, and FLT3, thus CSF1R suppression may be limited by off-target activity and associated adverse events. Vimseltinib (DCC-3014) is an oral, switch control tyrosine kinase inhibitor specifically designed to selectively and potently inhibit CSF1R by exploiting unique features of the switch control region that regulates kinase conformational activation. In preclinical studies, vimseltinib durably suppressed CSF1R activity in vitro and in vivo, depleted macrophages and other CSF1R-dependent cells, and resulted in inhibition of tumor growth and bone degradation in mouse cancer models. Translationally, in a phase I clinical study, vimseltinib treatment led to modulation of biomarkers of CSF1R inhibition and reduction in tumor burden in TGCT patients.

Background: P is a small molecule tyrosine kinase inhibitor that selectively inhibits VEGFR1-3, PDGFR-α, PDGFR-β, c-kit, and FGFR 1-3 and is approved for renal cancer and STS. T is a potent, highly selective, allosteric inhibitor of MEK1/2 approved for BRAF-mutated advanced melanoma. Increased signaling of growth factor receptor tyrosine kinases have been shown to be important to cell survival in multiple tumor types, and their inhibition has been effective therapeutically in STS, DTC, and ChCa. In addition, increased RAS/RAF/MEK/ERK signaling plays a critical role in the development of many different types of cancers, including ChCA and DTC. We hypothesized that combination therapy with P and T would be tolerable and effective for this range of tumor types. Methods: We designed a phase I, open label, dose escalation trial with P+T open to patients with advanced solid tumors. The study was a standard 3+3 design with an expansion cohort of 25 pts each for advanced DTC, STS, and ChCA for correlative endpoints and PK studies. Pts were treated with T held constant at 1 mg QD and P at 400 mg QD (DL1), 600 mg QD (DL2)and 800 mg QD (DL3); T was then escalated to 1.5 mg QD (DL4) and 2 mg QD (DL5). Eligibility included adequate end organ function, PS 0-1, and PD within 6 months in the expansion cohort of DTC. The primary objective was to determine the safety and tolerability of P+T and to find the MTD. Secondary objectives include assessing preliminary efficacy and exploration of PK/PD endpoints with tumor biopsies. Results: We report the results of the dose escalation component of the study. 26 pts were accrued to 5 dose levels and treated for a median of 3 cycles (range Conclusions: P+T is a tolerable combination with some preliminary signs of efficacy. Accrual to expansion cohorts in DTC, STS, and ChCA for further exploration of efficacy and correlative endpoints is ongoing. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support provided by GlaxoSmithKline. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B279. Citation Format: Nilofer Azad, Douglas Ball, Steven Sherman, Michelle Rudek, Gerald Falchook, Barry Nelkin, Filip Janku, Nicholas Papadopoulos, Ashley O'Conner, Shabina Ahmed, Breelyn Wilky, Susan Markus, Jing Gong, David Cosgrove, Marianna Zahurak, Ralph Zinner, Razelle Kurzrock. A phase I study determining the safety and tolerability of combination therapy with Pazopanib (P), a VEGFR/PDGFR/Raf inhibitor, and GSK1120212 (Trametinib: T), a MEK inhibitor, in advanced solid tumors with expansion cohorts in advanced differentiated thyroid cancer (DTC), cholangiocarcinoma (ChCA), and soft tissue sarcoma (STS). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B279.

Background: The IGF1 receptor activates key pro-survival signaling pathways critical in cancer including the RAS/RAF/MEK/ERK and PI3K/mTOR/AKT pathways. Despite this, clinical trials of single-agent IGF1-R antibodies have shown modest clinical benefit. In vitro data suggests that dual inhibition of IGF1-R and MEK synergistically decreases downstream pathway activation and increases apoptosis. Therefore, we performed a phase I clinical trial to test the safety and toxicity of combined IMC-A12 (anti-IGF1-R antibody) and AZD6244 (MEK 1/2 inhibitor). Methods: Patients were required to have advanced solid tumors refractory to standard therapy with adequate performance status and end-organ function. Treatment consisted of AZD6244 hydrogen sulfate capsules orally twice daily, and IMC-A12 intravenously on days 1 and 15 of each 28-day cycle. The study was a 3+3 design, with a dose-finding cohort and an expansion cohort treated at the maximally tolerated dose. Pharmacokinetic studies were performed on all patients, while pre- and post-treatment biopsies for pharmacodynamic assessment of pathway activity were obtained from patients on the expansion cohort. Results: 30 patients were enrolled on the study, 16 in the dose-finding cohort and 14 patients in the expansion cohort. The regimen was well-tolerated in most patients, and the most common study-drug related adverse events included rash, nausea/vomiting, diarrhea, and poor appetite/weight loss. Grade 3 or greater toxicities included nausea and vomiting, anemia, CVA, hypertension, hyperglycemia, and ophthalmologic symptoms (blurry vision, floaters, flashing lights, black dots/lines in field of vision, retinopathy). Three patients treated at dose level 2 (AZD6244 75 mg / IMC-A12 12 mg) developed dose-limiting toxicity of ophthalmologic symptoms; therefore the maximally tolerated combination dose was AZD6244 50 mg / IMC-A12 12 mg. 19 patients remained on study for at least 8 weeks and were evaluable for radiographic response. Two patients achieved a partial response (one unconfirmed), and 6 patients achieved progression-free survival of greater than 6 months. Two of the three patients with BRAF mutations showed prolonged progression-free survival on therapy. Pharmacokinetic analysis is ongoing. Paired pre- and on-treatment biopsies obtained in 5 patients showed significant suppression of phospho-ERK activity with treatment. Conclusions: Vertical inhibition of IGF1-R mediated signaling aims to avoid compensatory escape mechanisms by inhibiting additional downstream targets within the RAS/RAF/MEK/ERK and/or PI3K/mTOR/AKT pathways. Our study of IMC-A12 and AZD6244 showed that the drug combination is safe and well-tolerated, with decreased phosphorylation of ERK indicating effective target inhibition. Further study is necessary to identify biomarkers for patients likely to benefit from this treatment approach, particularly with regards to patients possessing BRAF mutations. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B74. Citation Format: Breelyn A. Wilky, Michelle Rudek, Daniel Laheru, David Cosgrove, Ross Donehower, Barry Nelkin, Douglas Ball, L. Austin Doyle, Helen Chen, Xiaobu Ye, Nilofer Azad. A Phase I trial of vertical inhibition of IGF signaling using IMC-A12, an IGF1-R inhibitor, and AZD6244, a MEK 1/2 inhibitor, in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B74.