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A Study of Dalotuzumab + MK-2206, Dalotuzumab + MK-0752, and Dalotuzumab + Ridaforolimus Combination Therapies in Participants With Advanced Cancer (MK-0646-027)

ABSTRACT: This is an open-label, two-part study to evaluate the safety and tolerability of combination treatment with dalotuzumab + MK-2206, dalotuzumab + MK-0752, or dalotuzumab + ridaforolimus (MK-8669). Part 1 of the study will determine the dose-limiting toxicities (DLTs) observed after administration of each of the combinations at various doses and define the maximum tolerated dose (MTD) of each combination. Part 2 of the study will assess preliminary anti-tumor activity of these combinations (at MTD) in two groups of participants with selected tumor biomarkers: one group with metastatic or recurrent platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer and one group with metastatic or recurrent colorectal cancer. The dalotuzumab + ridaforolimus and dalotuzumab + MK-2206 arms will be enriched with female platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer participants. The dalotuzumab + MK-0752 arm will be enriched with metastatic or recurrent wild-type kirsten rat sarcoma (KRAS) colorectal cancer participants. The primary hypothesis is that the DLTs observed in adult patients with locally advanced or metastatic solid tumors after administration of each of the MK-MK doublets will be dose-dependent to allow for definition of a MTD within each MK-MK doublet.

DISEASE(S): Ovarian Cancer,Neoplasms Malignant,Colorectal Cancer,Neoplasms,Solid Tumors

PROVIDER: 2098289 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Introduction: Mammalian target of rapamycin (mTOR) represents a key downstream intermediate for a myriad of oncogenic receptor tyrosine kinases. In the case of the insulin-like growth factor (IGF) pathway, the mTOR complex (mTORC1) mediates IGF-1 receptor (IGF-1R)-induced estrogen receptor alpha (ERÎ±) phosphorylation/activation and leads to increased proliferation and growth in breast cancer cells. As a result, the prevalence of mTOR inhibitors combined with hormonal therapy has increased in recent years. Conversely, activated mTORC1 provides negative feedback regulation of IGF signaling via insulin receptor substrate (IRS)-1/2 serine phosphorylation and subsequent proteasomal degradation. Thus, the IGF pathway may provide escape (e.g. de novo or acquired resistance) from mTORC1 inhibitors. It is therefore plausible that combined inhibition of mTORC1 and IGF-1R for select subsets of ER-positive breast cancer patients presents as a viable therapeutic option. Methods: Using hormone-sensitive breast cancer cells stably transfected with the aromatase gene (MCF-7/AC-1), works presented herein describe the in vitro and in vivo antitumor efficacy of the following compounds: dalotuzumab (DALO; âMK-0646â; anti-IGF-1R antibody), ridaforolimus (RIDA; âMK-8669â; mTORC1 small molecule inhibitor) and letrozole (âLETâ, aromatase inhibitor). Results: With the exception of MK-0646, all single agent and combination treatment arms effectively inhibited xenograft tumor growth, albeit to varying degrees. Correlative tissue analyses revealed MK-0646 alone and in combination with LET induced insulin receptor alpha A (InsR-A) isoform upregulation (both mRNA and protein expression), thereby further supporting a triple therapy approach. Conclusion: These data provide preclinical rationalization towards the combined triple therapy of LET plus MK-0646 plus MK-8669 as an efficacious anti-tumor strategy for ER-positive breast tumors. 46 samples, 28 days post treatment

Dataset Information

A Study of Dalotuzumab + MK-2206, Dalotuzumab + MK-0752, and Dalotuzumab + Ridaforolimus Combination Therapies in Participants With Advanced Cancer (MK-0646-027)

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