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

Macaulay, Valentine M.; Middleton, Mark R.; Eckhardt, S. Gail; Rudin, Charles M.; Juergens, Rosalyn A.; Gedrich, Richard; Gogov, Sven; McCarthy, Sean P.; Poondru, Srinivasu; Stephens, Andrew; Gadgeel, Shirish M.

doi:10.1158/1078-0432.ccr-15-2218

Cited by 51 publications

(49 citation statements)

References 49 publications

(77 reference statements)

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“…NCT00739453 A phase 1 dose-escalation study of OSI-906 and erlotinib (Tarceva) (Macaulay et al 2016) 1 Dec-2011 Advanced solid tumors Drug doses: linsitinib schedules (S): S1 = 50-600 mg/QD; S2 = 50-400 mg/ QD; S3 = 100/150 mg/BID in conjunction with 100-150 mg/QD erlotinib. Linsitinib/erlotinib combination was well tolerated.…”

Section: #17mentioning

confidence: 99%

“…A phase 1 clinical trial completed in 2011 reports that co-treatment with OSI-906 and erlotinib is tolerable leading to effective IGF-1R/InsR phosphorylation reduction in advanced solid cancers such as non-small-cell lung cancer, pancreatic, colorectal and prostate (Tables 1 and 2; Ref #17, NCT00739453) (Macaulay et al 2016). Based on the indirect effects of metformin on IGF1R/ EGFR activity (Rozengurt et al 2010, Liu et al 2011, there may be value in testing novel metformin combination therapies.…”

Section: Igf1r and Egfrmentioning

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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Section: #17mentioning

confidence: 99%

Section: Igf1r and Egfrmentioning

confidence: 99%

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

Ochnik

Baxter

2016

Endocrine-Related Cancer

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“…43,44 This suggests no significant effect of linsitinib on erlotinib PK, consistent with findings in the phase I combination trial. 38 …”

Section: Resultsmentioning

confidence: 99%

“…26–28 Previously, phase I results in a 91-patient advanced solid tumor study showed acceptable tolerability for combined linsitinib plus erlotinib, with no evidence of significant drug-drug interaction, as well as initial evidence of efficacy in patients with advanced solid tumors. 38 …”

Section: Discussionmentioning

confidence: 99%

“…19,31,37 Phase I results showed that linsitinib could be combined with a therapeutic dose of erlotinib, resulting in unaltered plasma concentrations of either drug, a tolerable safety profile, and clinical activity consisting of 5 PRs (including 3 patients with NSCLC) and disease control (PR plus stable disease) in 51% of patients (n = 75). 38 …”

Section: Introductionmentioning

confidence: 99%

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Phase 2 Study of Erlotinib in Combination With Linsitinib (OSI-906) or Placebo in Chemotherapy-Naive Patients With Non–Small-Cell Lung Cancer and Activating Epidermal Growth Factor Receptor Mutations

Leighl

Rizvi

Lima

et al. 2017

Clinical Lung Cancer

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This was a phase II study of linsitinib plus erlotinib versus placebo plus erlotinib in chemotherapy-naive patients with epidermal growth factor receptor-mutation positive, advanced, non—small-cell lung cancer. Linsitinib plus erlotinib resulted in inferior outcomes compared with erlotinib alone. Linsitinib combination was associated with increased adverse events that led to decreased erlotinib exposure. Results highlight the complexity of targeting insulin-like growth factor-1 receptor signaling. Introduction First-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment of advanced non—small-cell lung cancer with EGFR-activating mutations improves outcomes compared with chemotherapy, but resistance develops in most patients. Compensatory signaling through type 1 insulin-like growth factor 1 receptor (IGF-1R) may contribute to resistance; dual blockade of IGF-1R and EGFR may improve outcomes. Patients and Methods We performed a randomized, double-blind, placebo-controlled phase II study of linsitinib, a dual IGF-1R and insulin receptor tyrosine kinase inhibitor, plus erlotinib versus placebo plus erlotinib in chemotherapy-naive patients with EGFR-mutation positive, advanced non—small-cell lung cancer. Patients received linsitinib 150 mg twice daily or placebo plus erlotinib 150 mg once daily on continuous 21-day cycles. The primary end point was progression-free survival. Results After randomization of 88 patients (44 each arm), the trial was unblinded early owing to inferiority in the linsitinib arm. The median progression-free survival for the linsitinib versus the placebo group was 8.4 months versus 12.4 months (hazard ratio, 1.37; P = .29). Overall response rate (47.7% vs. 75.0%; P = .02) and disease control rate (77.3% vs. 95.5%; P = .03) were also inferior. Whereas most adverse events were ≤ grade 2, linsitinib plus erlotinib was associated with increased adverse events that led to decreased erlotinib exposure (median days, 228 vs. 305). No drug-drug interaction was suggested by pharmacokinetic and pharmacodynamic results. Conclusion Adding linsitinib to erlotinib resulted in inferior outcomes compared with erlotinib alone. Further understanding of the signaling pathways and a biomarker that can predict efficacy is needed prior to further clinical development of IGF-1R inhibitors in lung cancer.

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Recent Advances of Second‐Line Targeted Biopharmaceutical Therapies in Thyroid Associated Ophthalmopathy

Liu,

Cao,

et al. 2024

Advanced Therapeutics

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Intravenous glucocorticoids are the clinically preferred treatment for moderate‐to‐severe thyroid‐associated ophthalmopathy. However, the serious adverse effects following intravenous glucocorticoids and the risks posed by the cumulative doses cannot be overlooked. Moreover, it is found to be ineffective in the treatment of many patients with severe thyroid‐associated ophthalmopathy. Consequently, the development of superior alternative therapies is imminent. Recent advancements in the identification of multiple autoimmune‐related targets have led to the utilization of novel antibodies such as rituximab, teprotumumab, tocilizumab, and batocliumab in clinical settings. They have shown great potential in enhancing the therapeutic effect of thyroid‐associated ophthalmopathy, minimizing adverse effects, and shortening treatment duration. Additionally, small molecule targeted drugs, such as single or double aptamers are rapidly developed to target the inflammatory microenvironment. In this review, the advancements in second‐line targeted therapeutic options for thyroid‐associated ophthalmopathy, providing a clinical rationale for immune mechanism‐based treatment of thyroid‐associated ophthalmopathy in the era of precision medicine are reported.

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

Cited by 51 publications

References 49 publications

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

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

Phase 2 Study of Erlotinib in Combination With Linsitinib (OSI-906) or Placebo in Chemotherapy-Naive Patients With Non–Small-Cell Lung Cancer and Activating Epidermal Growth Factor Receptor Mutations

Recent Advances of Second‐Line Targeted Biopharmaceutical Therapies in Thyroid Associated Ophthalmopathy

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