A Study of IMC-RON8 in Advanced Solid Tumors

Study Overview
=================
Brief Summary
-----------------
A dose escalation study to determine the maximum tolerated dose of IMC-RON8 in participants with solid tumors. Participants can either be dosed once a week, or once every other week.

Official Title
-----------------
Phase 1 Study of the Anti-Ron Receptor Monoclonal Antibody IMC-RON8 in Patients With Advanced Solid Tumors Who No Longer Respond to Standard Therapy or for Whom No Standard Therapy is Available

Conditions
-----------------
Cancer

Intervention / Treatment
-----------------
* Biological: IMC-RON8
* Biological: IMC-RON8
* Biological: IMC-RON8
* Biological: IMC-RON8
* Biological: IMC-RON8
* Biological: IMC-RON8
* Biological: IMC-RON8
* Biological: IMC-RON8


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The participant has histologically-confirmed advanced primary or recurrent solid tumors that have not responded to standard therapy or for which no standard therapy is available The participant has measurable or non-measurable disease The participant has not received major surgery, prior chemotherapy, prior treatment with an investigational agent or device, or prior radiation therapy within 28 days prior to the first dose of study therapy The participant has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0-2 The participant has adequate hematologic function The participant has adequate renal function as defined by serum creatinine ≤1.5 times the institutional upper limit of normal (ULN) The participant has a life expectancy >3 months Exclusion Criteria: The participant has received chemotherapy or therapeutic radiation therapy within 28 days prior to the first dose of study therapy The participant has ongoing toxicities of >Grade 1 associated with any prior treatment The participant has a known sensitivity to monoclonal antibodies or other therapeutic agents, or to agents of similar biologic composition as IMC-RON8 The participant has received treatment with any monoclonal antibodies within 6 weeks prior to first dose of study therapy The participant has received treatment with agents specifically targeting the RON ligand or receptor within 6 weeks prior to first dose of study therapy The participant has undergone a major surgical procedure, open biopsy, or experienced a significant traumatic injury within 28 days prior to the first dose of study therapy The participant has an ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia (well controlled atrial fibrillation is permitted), psychiatric illness/social situations, active bleeding, or any other serious uncontrolled medical disorders in the opinion of the investigator The participant has known or suspected brain or leptomeningeal metastases (participants with a history of brain metastases must have received definitive surgery or radiotherapy, be clinically stable, and may not be taking steroids; participants receiving anticonvulsants are eligible) The participant has a serious or nonhealing active wound, ulcer, or bone fracture The participant is currently using or has received a thrombolytic agent within 28 days prior to first dose of study therapy The participant is receiving full-dose warfarin (participants receiving low-dose warfarin to maintain the patency of permanent, indwelling intravenous catheters are eligible if the international normalized ratio is <1.5) The participant is receiving intravenous heparin

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IMC-RON8<br>A monoclonal antibody to human macrophage-stimulating 1-receptor-8 (RON8). | Biological: IMC-RON8<br>* 5 milligrams per kilogram (mg/kg) intravenously (IV) Once a week for each 4-week treatment cycle, for a total of four doses per cycle. The initial 4-week treatment cycle will be followed by a 2-week observation period. Cohort 1<br>* Other names: LY3012219;Biological: IMC-RON8<br>* 10 mg/kg IV Once a week for each 4-week treatment cycle, for a total of four doses per cycle. The initial 4-week treatment cycle will be followed by a 2-week observation period. Cohort 2<br>* Other names: LY3012219;Biological: IMC-RON8<br>* 15 mg/kg IV Once a week for each 4-week treatment cycle, for a total of four doses per cycle. The initial 4-week treatment cycle will be followed by a 2-week observation period. Cohort 3<br>* Other names: LY3012219;Biological: IMC-RON8<br>* 15 mg/kg IV Once every 2 weeks for each 4-week treatment cycle, for a total of two doses per cycle. Cohort 4<br>* Other names: LY3012219;Biological: IMC-RON8<br>* 20 mg/kg IV Once every 2 weeks for each 4-week treatment cycle, for a total of two doses per cycle. Cohort 5<br>* Other names: LY3012219;Biological: IMC-RON8<br>* 25 or 30 mg/kg IV Once every 2 weeks for each 4-week treatment cycle, for a total of two doses per cycle. Cohort 6<br>* Other names: LY3012219;Biological: IMC-RON8<br>* 30, 35, or 40 mg/kg IV Once every 2 weeks for each 4-week treatment cycle, for a total of two doses per cycle. Cohort 7<br>* Other names: LY3012219;Biological: IMC-RON8<br>* 20 or 25 mg/kg IV Once every week for each 4-week treatment cycle, for a total of four doses per cycle. Cohort 8<br>* Other names: LY3012219;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of IMC-RON8 | The MTD was the previous dose level to that in which 2 of 6 participants experienced dose-limiting toxicities (DLTs). DLTs were defined as any of the following events: Grade 4 neutropenia lasting >7 days; any Grade 3 or 4 neutropenia complicated by fever ≥38.5 degrees Celsius or infection, Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia complicated by hemorrhage; Grade 3 hepatic toxicity; or any Grade 3 or 4 nonhematologic toxicity (excluding alopecia, fatigue, anorexia, nausea, and vomiting that is controlled with antiemetics). | Baseline through end of study treatment (up to 48 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Maximum Concentration (Cmax) of IMC-RON8 | The Cmax of IMC-RON8 following the first and multiple IV infusions (the fourth infusion for the qw treatment regimen and the fifth infusion for the q2w treatment regimen) is reported. PK samples were collected per protocol and individual sampling times varied depending on the treatment arm and infusion (first or multiple). The geometric mean and geometric coefficient of variation (%CV) were calculated for treatment arms that had ≥3 participants who had evaluable PK samples for Cmax. | First and fourth or fifth infusion: Predose, immediately postdose through 168 or 336 hours postdose | 
| PK: Area Under the Curve (AUC) of IMC-RON8 | The AUC from time 0 to the last quantifiable concentration [AUC(0-tlast)] of IMC-RON8 following the first IV infusion is reported along with the AUC for 1 dosing interval (AUC tau). Tau = fourth infusion through 168 hours post infusion for the qw regimen and the fifth infusion through 336 hours post infusion for the q2w regimen. PK samples were collected per protocol and individual sampling times varied depending on the treatment arm and infusion (first or multiple). The geometric mean and geometric coefficient of variation (%CV) were calculated for treatment arms that had ≥3 participants who had evaluable PK samples for AUC(0-tlast) or AUC tau. | First and fourth or fifth infusion: Predose, immediately postdose through 168 or 336 hours postdose | 
| Immunogenicity of IMC-RON8 | An immunogenicity assay for IMC-RON8 was not developed due to the decision to not further develop IMC-RON8 based on preliminary results of this study. | Prior to first infusion through study completion (up to 52 weeks) | 
| Pharmacodynamics: H-Score of Macrophage-Stimulating 1-Receptor-8 (RON8) | The expression of RON8 was measured in cell membrane/cytoplasm by immunohistochemistry (IHC) methods that incorporated both intensity and distribution of staining. The H-Score was calculated by summing the percentage of cell staining at each intensity multiplied by the weighted intensity of staining: 0 (no staining), 1+ (weak staining), 2+ (medium staining), 3+ (strongest staining). H-Scores could range from a minimum score of 0 to a maximum score of 300; the maximum score indicated the strongest expression. Pharmacodynamic samples were collected per protocol and individual sampling times varied depending on the treatment group. | Prior to first infusion through 1 hour post last infusion (end of study treatment, up to 48 weeks) | 
| Best Overall Tumor Response (Antitumor Activity of IMC-RON8 in the Treatment of Solid Tumors) | Response was defined using Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST, v 1.1) criteria. CR was the disappearance of all target and nontarget lesions; and any pathological lymph node (whether target or nontarget) must have had a reduction in short axis to <10 millimeters (mm) and normalization of tumor marker level of nontarget lesions. The disappearance of any intratumoral arterial enhancement in all target lesions was also required. PR was having at least a 30% decrease in sum of longest diameter of target lesions. PD was having at least 20% increase in sum of longest diameter of target lesions and minimum 5 mm increase above nadir and the unequivocal progression of existing nontarget lesions. SD was small changes that did not meet the above criteria. | Baseline to measured PD (up to 48 weeks) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Tumors, Macrophage stimulating 1 receptor, human, RON protein, RON receptor protein tyrosine kinase