PMID- 29572245 OWN - NLM STAT- MEDLINE DCOM- 20190920 LR - 20201209 IS - 1549-490X (Electronic) IS - 1083-7159 (Print) IS - 1083-7159 (Linking) VI - 23 IP - 7 DP - 2018 Jul TI - A Phase I Trial of the IGF-1R Antibody Ganitumab (AMG 479) in Combination with Everolimus (RAD001) and Panitumumab in Patients with Advanced Cancer. PG - 782-790 LID - 10.1634/theoncologist.2016-0377 [doi] AB - PURPOSE: This study evaluated the maximum tolerated dose or recommended phase II dose (RPTD) and safety and tolerability of the ganitumab and everolimus doublet regimen followed by the ganitumab, everolimus, and panitumumab triplet regimen. MATERIALS AND METHODS: This was a standard 3 + 3 dose escalation trial. Doublet therapy consisted of ganitumab at 12 mg/kg every 2 weeks; doses of everolimus were adjusted according to dose-limiting toxicities (DLTs). Panitumumab at 4.8 mg/kg every 2 weeks was added to the RPTD of ganitumab and everolimus. DLTs were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. Pretreatment and on-treatment skin biopsies were collected to assess insulin-like growth factor 1 receptor and mammalian target of rapamycin (mTOR) target modulation. RESULTS: Forty-three subjects were enrolled. In the doublet regimen, two DLTs were observed in cohort 1, no DLTs in cohort -1, and one in cohort -1B. The triplet combination was discontinued because of unacceptable toxicity. Common adverse events were thrombocytopenia/neutropenia, skin rash, mucositis, fatigue, and hyperglycemia. In the doublet regimen, two patients with refractory non-small cell lung cancer (NSCLC) achieved prolonged complete responses ranging from 18 to >60 months; one treatment-naive patient with chondrosarcoma achieved prolonged stable disease >24 months. In dermal granulation tissue, the insulin-like growth factor receptor and mTOR pathways were potently and specifically inhibited by ganitumab and everolimus, respectively. CONCLUSION: The triplet regimen of ganitumab, everolimus, and panitumumab was associated with unacceptable toxicity. However, the doublet of ganitumab at 12 mg/kg every 2 weeks and everolimus five times weekly had an acceptable safety profile and demonstrated notable clinical activity in patients with refractory NSCLC and sarcoma. IMPLICATIONS FOR PRACTICE: This trial evaluated the maximum tolerated dose or recommended phase II dose and safety and tolerability of the ganitumab and everolimus doublet regimen followed by the ganitumab, everolimus, and panitumumab triplet regimen. Although the triplet regimen of ganitumab, everolimus, and panitumumab was associated with unacceptable toxicity, the doublet of ganitumab at 12 mg/kg every 2 weeks and everolimus at five times weekly had an acceptable safety profile and demonstrated notable clinical activity in patients with refractory non-small cell lung cancer and sarcoma. CI - (c) AlphaMed Press 2018. FAU - Vlahovic, Gordana AU - Vlahovic G AD - Duke Cancer Institute, Durham, North Carolina, USA. FAU - Meadows, Kellen L AU - Meadows KL AD - Duke Cancer Institute, Durham, North Carolina, USA. FAU - Hatch, Ace J AU - Hatch AJ AD - Duke Cancer Institute, Durham, North Carolina, USA. FAU - Jia, Jingquan AU - Jia J AD - Duke Cancer Institute, Durham, North Carolina, USA. FAU - Nixon, Andrew B AU - Nixon AB AD - Duke Cancer Institute, Durham, North Carolina, USA. FAU - Uronis, Hope E AU - Uronis HE AD - Duke Cancer Institute, Durham, North Carolina, USA. FAU - Morse, Michael A AU - Morse MA AD - Duke Cancer Institute, Durham, North Carolina, USA. FAU - Selim, M Angelica AU - Selim MA AD - Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA. FAU - Crawford, Jeffrey AU - Crawford J AD - Duke Cancer Institute, Durham, North Carolina, USA. FAU - Riedel, Richard F AU - Riedel RF AD - Duke Cancer Institute, Durham, North Carolina, USA. FAU - Zafar, S Yousuf AU - Zafar SY AD - Duke Cancer Institute, Durham, North Carolina, USA. FAU - Howard, Leigh A AU - Howard LA AD - Duke Cancer Institute, Durham, North Carolina, USA. FAU - O'Neill, Margot AU - O'Neill M AD - Duke Cancer Institute, Durham, North Carolina, USA. FAU - Meadows, Jennifer J AU - Meadows JJ AD - Duke Cancer Institute, Durham, North Carolina, USA. FAU - Haley, Sherri T AU - Haley ST AD - Duke Cancer Institute, Durham, North Carolina, USA. FAU - Arrowood, Christy C AU - Arrowood CC AD - Duke Cancer Institute, Durham, North Carolina, USA. FAU - Rushing, Christel AU - Rushing C AD - Duke Cancer Institute, Durham, North Carolina, USA. FAU - Pang, Herbert AU - Pang H AD - Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina, USA. FAU - Hurwitz, Herbert I AU - Hurwitz HI AD - Duke Cancer Institute, Durham, North Carolina, USA hurwi004@mc.duke.edu. LA - eng GR - P30 CA014236/CA/NCI NIH HHS/United States GR - R01 CA112252/CA/NCI NIH HHS/United States GR - K24 CA113755/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180323 PL - England TA - Oncologist JT - The oncologist JID - 9607837 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Biomarkers, Tumor) RN - 0 (IGF1R protein, human) RN - 0 (Receptors, Somatomedin) RN - 6A901E312A (Panitumumab) RN - 9HW64Q8G6G (Everolimus) RN - CK1441RCZ8 (ganitumab) RN - EC 2.7.10.1 (Receptor, IGF Type 1) SB - IM MH - Adult MH - Aged MH - Antibodies, Monoclonal/administration & dosage MH - Antibodies, Monoclonal, Humanized MH - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use MH - Biomarkers, Tumor/metabolism MH - Dose-Response Relationship, Drug MH - Everolimus/administration & dosage MH - Female MH - Humans MH - Male MH - Middle Aged MH - Neoplasms/*drug therapy/genetics/metabolism/pathology MH - Panitumumab/administration & dosage MH - Receptor, IGF Type 1 MH - Receptors, Somatomedin/immunology PMC - PMC6058343 OTO - NOTNLM OT - Advanced cancer OT - Everolimus OT - Ganitumab OT - Panitumumab OT - Phase I COIS- Disclosures of potential conflicts of interest may be found at the end of this article. EDAT- 2018/03/25 06:00 MHDA- 2019/09/21 06:00 PMCR- 2019/07/01 CRDT- 2018/03/25 06:00 PHST- 2016/09/30 00:00 [received] PHST- 2017/08/17 00:00 [accepted] PHST- 2018/03/25 06:00 [pubmed] PHST- 2019/09/21 06:00 [medline] PHST- 2018/03/25 06:00 [entrez] PHST- 2019/07/01 00:00 [pmc-release] AID - theoncologist.2016-0377 [pii] AID - ONCO12411 [pii] AID - 10.1634/theoncologist.2016-0377 [doi] PST - ppublish SO - Oncologist. 2018 Jul;23(7):782-790. doi: 10.1634/theoncologist.2016-0377. Epub 2018 Mar 23.