A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours
| العنوان: | A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours |
|---|---|
| المؤلفون: | Jonathan D. Cheng, Lainie P. Martin, J. Fiorica, Raanan Berger, Paul Haluska, William S. Dalton, M. B. Jones, Shannon N. Westin, Lillian L. Siu, Talia Golan, J. Stephenson, Jhanelle E. Gray, Khaldoun Almhanna, R. M. Wenham, P. Hanjani, Alexandra Gunchenko, Daniel M. Sullivan, J. Edenfield, Irene Brana |
| المصدر: | British Journal of Cancer |
| بيانات النشر: | Nature Publishing Group, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Male, Cancer Research, Akt inhibitor, Pharmacology, Receptor, IGF Type 1, Cohort Studies, chemistry.chemical_compound, MK-0752, Neoplasms, Antineoplastic Combined Chemotherapy Protocols, Benzene Derivatives, Medicine, Tissue Distribution, Sulfones, Randomized Controlled Trials as Topic, Aged, 80 and over, biology, Receptors, Notch, TOR Serine-Threonine Kinases, Antibodies, Monoclonal, Middle Aged, Discovery and development of mTOR inhibitors, Prognosis, ovarian cancer, Oncology, MK-2206, Female, Antibody, Heterocyclic Compounds, 3-Ring, Adult, colorectal cancer, Antibodies, Monoclonal, Humanized, Ridaforolimus, Clinical Trials, Phase II as Topic, ridaforolimus, Biomarkers, Tumor, Humans, In patient, Aged, Neoplasm Staging, dalotuzumab, Sirolimus, business.industry, Dalotuzumab, chemistry, Clinical Trials, Phase III as Topic, biology.protein, Clinical Study, Propionates, business, Proto-Oncogene Proteins c-akt, Follow-Up Studies |
| الوصف: | Background: Two strategies to interrogate the insulin growth factor 1 receptor (IGF-1R) pathway were investigated: vertical inhibition with dalotuzumab and MK-2206 or ridaforolimus to potentiate PI3K pathway targeting and horizontal cross-talk inhibition with dalotuzumab and MK-0752 to exert effects against cellular proliferation, angiogenesis, and stem cell propagation. Methods: A phase I, multi-cohort dose escalation study was conducted in patients with advanced solid tumours. Patients received dalotuzumab (10 mg kg–1) and escalating doses of MK-2206 (90–200 mg) or escalating doses of dalotuzumab (7.5–10 mg kg–1) and MK-0752 (1800 mg) weekly. Upon maximum tolerated dose determination, patients with low-RAS signature, high-IGF1 expression ovarian cancer were randomised to dalotuzumab/MK-2206 versus dalotuzumab/ridaforolimus, whereas patients with high IGF1/low IGF2 expression colorectal cancer received dalotuzumab/MK-0752. Results: A total of 47 patients were enrolled: 29 in part A (18 in the dalotuzumab/MK-2206 arm and 11 in the dalotuzumab/MK-0752 arm) and 18 in part B (6 in each arm). Dose-limiting toxicities (DLTs) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction, maculopapular rash, and gastrointestinal inflammation. For dalotuzumab/MK-0752, DLTs included grade 3 dehydration, rash, and diarrhoea. Seven patients remained on study for >4 cycles. Conclusions: Dalotuzumab/MK-2206 and dalotuzumab/MK-0752 combinations were tolerable. Further developments of prospectively validated predictive biomarkers to aid in patient selection for anti-IGF-1R therapies are needed. |
| اللغة: | English |
| تدمد: | 1532-1827 0007-0920 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6f49b7b9125e9a40ceec15ef2e49d7c9Test http://europepmc.org/articles/PMC4229637Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....6f49b7b9125e9a40ceec15ef2e49d7c9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15321827 00070920 |
|---|