Phase 1b study of safety, tolerability and efficacy of R1507, a monoclonal antibody to IGF-1R in combination with multiple standard oncology regimens in patients with advanced solid malignancies

Mahadevan, Daruka; Sutton, G.; Arteta-Bulos, Rafael; Bowden, Chris; Miller, Paul J.; Swart, Rachel; Walker, Mark S.; Haluska, Paul; Münster, Pamela N.; Marshall, John L.; Hamid, Omid; Kurzrock, Razelle

doi:10.1007/s00280-013-2372-x

Cited by 34 publications

(26 citation statements)

References 24 publications

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“…Two of the PRs achieved were among 5 patients with adenoid cystic carcinoma or salivary gland cancer, which is in line with recent descriptions of EGFR family members (HER1 and HER2) found to be overexpressed in salivary gland carcinoma (29), although specific molecular abnormalities in adenoid cystic carcinoma are unknown. However, recurrent mutations have been identified in the FGF/IGF/PI3K pathway in adenoid cystic carcinoma tumor samples (30), and in a previous phase Ib study, one patient with adenoid cystic carcinoma who received the IGF-1R mAb R1507 plus sorafenib had a response of greater than 1 year (31).…”

Section: Discussionmentioning

confidence: 99%

A Phase I Clinical Trial and Independent Patient-Derived Xenograft Study of Combined Targeted Treatment with Dacomitinib and Figitumumab in Advanced Solid Tumors

Calvo

Soria

Wee

et al. 2017

Clinical Cancer Research

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Purpose: This phase I, open-label, single-arm trial assessed the safety and tolerability of dacomitinib-figitumumab combination therapy in patients with advanced solid tumors.Experimental Design: A standard 3 þ 3 dose escalation/deescalation design was utilized. Starting doses were figitumumab 20 mg/kg administered intravenously once every 3 weeks and dacomitinib 30 mg administered orally once daily. We also performed an independent study of the combination in patient-derived xenograft (avatar mouse) models of adenoid cystic carcinoma.Results: Of the 74 patients enrolled, the most common malignancies were non-small cell lung cancer (24.3%) and colorectal cancer (14.9%). The most common treatment-related adverse events in the 71 patients who received treatment across five dose levels were diarrhea (59.2%), mucosal inflammation (47.9%), and fatigue and acneiform dermatitis (45.1% each). The most common dose-limiting toxicity was mucosal inflammation. Dosing schedules of dacomitinib 10 or 15 mg daily plus figitumumab 20 mg/kg every 3 weeks after a figitumumab loading dose were tolerated by patients over multiple cycles and considered recommended doses for further evaluation. Objective responses were seen in patients with adenoid cystic carcinoma, ovarian carcinoma, and salivary gland cancer. Pharmacokinetic analysis did not show any significant drugÀ-drug interaction. In the adenoid cystic carcinoma xenograft model, figitumumab exerted significant antitumor activity, whereas dacomitinib did not. Figitumumab-sensitive tumors showed downregulation of genes in the insulin-like growth factor receptor 1 pathway.Conclusions: DacomitinibÀfigitumumab combination therapy was tolerable with significant dose reductions of both agents to less than the recommended single-agent phase II dose of each drug. Preliminary clinical activity was demonstrated in the potential target tumor adenoid cystic carcinoma.

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Section: Discussionmentioning

confidence: 99%

A Phase I Clinical Trial and Independent Patient-Derived Xenograft Study of Combined Targeted Treatment with Dacomitinib and Figitumumab in Advanced Solid Tumors

Calvo

Soria

Wee

et al. 2017

Clinical Cancer Research

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“…In a phase 1 trial, R1507, a humanized IGF1R mAb, has been shown to be tolerable in combination with chemotherapy plus the VEGF-A inhibitor bevacizumab (Table 2) (Mahadevan et al 2014). Similarly, a phase 2 trial tested the safety and PK of AMG479 in conjunction with bevacizumab for advanced solid tumors (Tables 1 and 2: Ref #20, NCT00974896).…”

Section: :11mentioning

confidence: 99%

“…The safety and tolerability of the IGF1R monoclonal antibody R1507 in combination with several standard oncology regimens have been shown to be manageable in a variety of advanced solid malignancies including breast (Table 2) (Mahadevan et al 2014). Different combination therapies including cixutumumab have been studied in a phase 1b trial to test the tolerability in solid cancers with the following therapies: (1) gemcitabine plus erlotinib; (2) paclitaxel plus bevacizumab; (3) carboplatin plus etoposide; (4) mFOLFOX6 (combination chemotherapy) plus bevacizumab; (5) capecitabine plus trastuzumab and (6) sorafenib.…”

Section: All Breast Cancer Molecular Subtypesmentioning

confidence: 99%

“…Different combination therapies including cixutumumab have been studied in a phase 1b trial to test the tolerability in solid cancers with the following therapies: (1) gemcitabine plus erlotinib; (2) paclitaxel plus bevacizumab; (3) carboplatin plus etoposide; (4) mFOLFOX6 (combination chemotherapy) plus bevacizumab; (5) capecitabine plus trastuzumab and (6) sorafenib. Based on the findings that they were well tolerated, with some individuals presenting with a lasting response for a median of 29 weeks, the combination treatments are potentially viable for a subset of cancers (Mahadevan et al 2014).…”

Section: All Breast Cancer Molecular Subtypesmentioning

confidence: 99%

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Combination therapy approaches to target insulin-like growth factor receptor signaling in breast cancer

Ochnik

Baxter

2016

Endocrine-Related Cancer

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Insulin-like growth factor receptor (IGF1R) signaling as a therapeutic target has been widely studied and clinically tested. Despite the vast amount of literature supporting the biological role of IGF1R in breast cancer, effective clinical translation in targeting its activity as a cancer therapy has not been successful. The intrinsic complexity of cancer cell signaling mediated by many tyrosine kinase growth factor receptors that work together to modulate each other and intracellular downstream mediators in the cell highlights that studying IGF1R expression and activity as a prognostic factor and therapeutic target in isolation is certainly associated with problems. This review discusses the current literature and clinical trials associated with IGF-1 signaling and attempts to look at new ways of designing novel IGF1R-directed breast cancer therapy approaches to target its activity and/or intracellular downstream signaling pathways in IGF1R-expressing breast cancers. 23:11 Review A M Ochnik and R C BaxterDual IGF-directed breast cancer therapies

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“…However, while high circulating serum levels of IGF-1 are a risk factor for developing breast cancer [29] there is conflicting epidemiological data on whether IGF-1 is associated with breast cancer survival or recurrence [30,31]. Given the active development of inhibitory IGF-1 receptor monoclonal antibodies and small molecule receptor inhibitors as a novel cancer therapeutic strategy [32], identifying breast cancer patients with genetic susceptibility to increased signaling via the IGF-1 receptor may play an important role in personalizing treatment.…”

Section: Discussionmentioning

confidence: 99%

Association between germline single nucleotide polymorphisms in the PI3K-AKT-mTOR pathway, obesity, and breast cancer disease-free survival

Pande

Bondy

Anh

et al. 2014

Breast Cancer Res Treat

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Purpose Obesity-related hormones and cytokines alter PI3K-AKT-mTOR pathway activation in breast tumors contributing to poorer disease-free survival (DFS) and decreased responsiveness to tamoxifen and trastuzumab. We hypothesized that single nucleotide polymorphisms (SNPs) in candidate genes in the PI3K-AKT-mTOR signaling pathway may act as genetic modifiers of breast cancer DFS. Methods We analyzed the association of 106 tagging SNPs in 13 genes (ADIPOQ, IGF1, INS, IRS1, LEP, LEPR, LEPROT, PIK3CA, PIK3R5, PTEN, TSC1, TSC2, and AKT1) in the P13K-AKT-mTOR pathway with DFS in a sample of 1,019 women with stage I–II breast cancer. SNPs significantly associated with DFS in any genetic model (additive, dominant or recessive) after correcting for false discovery rate (FDR=0.10) were included in Cox proportional hazards multivariable analyses. Results After adjusting for race/ethnicity, age at diagnosis, tumor stage and treatment, rs1063539 in ADIPOQ, rs11585329 in LEPR, and rs2519757 in TSC1 were associated with improved DFS and rs1520220 in IGF1 and rs2677760 in PIK3CA were associated with worse DFS. The associations were not significantly modified by type of systemic treatment received or body mass index. The SNPs were not associated with tumor characteristics such as tumor size, lymph node status, nuclear grade, or hormone receptor status. Conclusion In this study, germline SNPs in the PI3K-AKT-mTOR pathway were associated with breast cancer DFS and may be potential prognostic markers. Future studies are needed to replicate our results and to evaluate the relationship between these polymorphisms and activation of the PI3K-AKT-mTOR pathway in breast tumors.

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Phase 1b study of safety, tolerability and efficacy of R1507, a monoclonal antibody to IGF-1R in combination with multiple standard oncology regimens in patients with advanced solid malignancies

Abstract: R1507 added to six standard oncology regimens was well tolerated with an ORR of 36 %.

Cited by 34 publications

References 24 publications

A Phase I Clinical Trial and Independent Patient-Derived Xenograft Study of Combined Targeted Treatment with Dacomitinib and Figitumumab in Advanced Solid Tumors

A Phase I Clinical Trial and Independent Patient-Derived Xenograft Study of Combined Targeted Treatment with Dacomitinib and Figitumumab in Advanced Solid Tumors

Combination therapy approaches to target insulin-like growth factor receptor signaling in breast cancer

Association between germline single nucleotide polymorphisms in the PI3K-AKT-mTOR pathway, obesity, and breast cancer disease-free survival

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