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A Phase I, open-label, multiple-ascending dose trial to investigate the safety, tolerability, pharmacokinetics, biological and clinical activity of avelumab (MSB0010718C) in subjects with metastatic or locally advanced solid tumors and expansion to selected indications
Protocol Number:
Phase I
Leisha Emens
Johns Hopkins Kimmel Cancer Center in Baltimore
This is a Phase I, open-label, dose-escalation trial with consecutive parallel group expansion in nonsmall cell lung cancer (NSCLC), metastatic breast cancer (MBC), melanoma, and ovarian cancer. MSB0010718C is a fully human monoclonal antibody of the IgG1 isotype, a anti- PD-L1 therapeutic antibody. We are participating in the expansion phase only. After determination of the MSB0010718C dose and regimen for further investigation, enrollment in the expansion cohorts will be opened in up to 6 selected tumor indications to determine the safety and clinical activity of MSB0010781C. Subject eligibility will need to be confirmed by the contract research organization (CRO) / Sponsor before the first administration of the study drug during the expansion phase. The 6 expansion cohorts will be divided into 2 primary cohorts of NSCLC and MBC (150 subjects each) and 4 secondary cohorts of CRC, CRPC, melanoma, and ovarian cancer (20 subjects each). During enrollment of the expansion part, the Safety Monitoring Committee will monitor all safety information of the participating subjects on an ongoing basis (i.e., every 2 months). Subjects will receive MSB0010718C intravenously as a 1-hour infusion once every 2 weeks until confirmed CR, confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or study drug occurs.
Patients with advanced solid tumors, including non-small cell lung cancer, metastatic breast cancer, melanoma, and ovarian cancer.
The administration of MSB0010718C to subjects with advanced malignancies for which no approved / established treatment option exist is justified by the following:  MSB0010718C is capable of inhibiting tumor growth in vivo when applied as a monotherapy and its efficacy can be further enhanced via combination with standard-of-care therapies, though the treatment was limited for only 3 doses in the first weeks due to immunogenicity of the humanized antibody in mice.  The relevance of PD-L1 blockade has been demonstrated in Phase 1 studies performed with antibodies targeting either PD-L1 or PD-1. One Phase I trial has been reported for BMS-936559 targeting PD-L1. At the time of data cut-off, a total of 160 subjects could be evaluated for clinical efficacy, which was demonstrated in the range of 1-10 mg/kg. Objective clinical responses up to greater than 1 year were observed in 9 out of 52 subjects with melanoma, 5 out of 49 subjects with nonsmall cell lung cancer (NSCLC), 2 out of 17 subjects with renal cell carcinoma, and 1 out of 17 subjects with ovarian cancer. No response could be observed in 7 subjects with pancreatic cancer and 18 subjects with colorectal cancer (CRC). Overall, these results are suggestive of relevant clinical efficacy through inhibition of PD-L1, which is further supported by reported clinical efficacy of the anti-PD- 1 monoclonal antibodies, BMS-936558 and CT-011. The dose rationale for the MSB0010718C first-in-man study is supported by the excellent clinical safety profile of BMS- 936559. Although it is acknowledged that MSB0010718C and BMS-936559 are different with respect to some features like isotype, terminal half-life, and capability to induce effector functions, they are similar regarding specificity and mode of action. Non-clinical safety evaluation of BMS-936559 resulted in the first-in-man study NCT00729664, the design of which is highly comparable to the concept presented here. Our strategy is further supported by positive safety results from a number of Phase I clinical studies with anti-PD-1 monoclonal antibody BMS-936558, which shares some crucial aspects of the mechanism of action (MoA) with MSB0010718C and MDX-1105. The indications for the expansion cohorts have been selected based on several factors:  PD-L1 over-expression in tumors.  Clinical activity demonstrated for PD-1 / PD-L1 blocking monoclonal antibodies in solid tumors in the case of NSCLC.  Unmet medical need.  Evidence for susceptibility to cancer immunotherapy. Over-expression of PD-L1 has been described for NSCLC, metastatic breast cancer (MBC), CRC, castrate-resistant prostate cancer (CRPC), melanoma, renal cell carcinoma, hepatocellular carcinoma, squamous cell carcinoma of the head and neck, ovarian, breast, pancreatic, gastro-esophageal and bladder urothelial carcinomas as well as glioblastoma multiforme and certain type of hematopoietic malignancies. Blockade of PD-L1 led to objective clinical responses in NSCLC, melanoma, and ovarian cancer, while blockade of its counterpart PD-1 led to objective clinical responses in NSCLC and melanoma. A limited number of subjects with CRC or CRPC, which do not allow to drawing final conclusions on the potential clinical activity of PD-1 / PD-L1 checkpoint inhibitors in these indications, have been treated up to date. However, it should be noted that MSB0010718C is an IgG1 isotype based antibody that potentially exerts ADCC, which differentiates it from the other therapeutic antibodies already being explored for their use in solid tumors but lacking such effector functions. In general, the anti-tumor immunotherapy via blockade of the PD-1 / PD-L1 axis seems not to be limited to any specific tumor types, but there is recent evidence that PD-L1 tumor expression is a pre-requisite to achieve an objective response upon blockade of the PD-1 / PD-L1 axis. Six tumor types, i.e., NSCLC, MBC, CRC, CRPC, melanoma, and ovarian cancer, for which a high medical need and evidence for susceptibility to cancer immunotherapy is given, were selected to be explored in the expansion phase of this trial. The data obtained from this study will form the basis for the dose and regimen selection for further clinical studies involving MSB0010718C and will also be supportive to provide a basis for combination with standard-of-care therapies to be explored in the future.
Last Update
01/22/2017 05:03 AM

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