A Study of AGS-16C3F vs. Axitinib in Metastatic Renal Cell Carcinoma

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the progression free survival (PFS), based on investigator radiologic review, of AGS-16C3F compared to axitinib in subjects with metastatic renal cell carcinoma.

Official Title
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A Multi-Center, Open Label, Randomized Phase 2 Study of AGS-16C3F vs. Axitinib in Metastatic Renal Cell Carcinoma

Conditions
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Metastatic Renal Cell Carcinoma

Intervention / Treatment
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* Drug: AGS-16C3F
* Drug: Axitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis of RCC Non-clear subjects must be ENPP3 positive, defined as IHC H-score ≥15 Has evidence of progression on or after the last regimen received: Clear cell subject: must have received at least 2 prior systemic regimens, one of which is an anti-VEGF agent. Non-clear cell subject: must have received at least one prior anti-VEGF regimen Has measurable disease according to Response Criteria for Solid Tumors (RECIST v.1.1) Has Eastern Cooperative Group (ECOG) performance status of 0 or 1 Has archive tumor tissue from primary tumor or metastatic site (excluding bone), for which the source and availability have been confirmed. If no archive tissue is available, the subject may elect to have a biopsy performed to obtain tissue. Has adequate organ function including: Hematopoietic function as follows: Absolute neutrophil count (ANC) ≥ 1.5 x 10 9/L Platelet count ≥ 100 x 10 9/L Hemoglobin ≥ 9 g/dL (transfusions are allowed) Renal Function as follows: 1. Creatinine ≤ 1.5 x upper limit of normal (ULN), or calculated glomerular filtration rate (GFR) > 40 mL/min (Cockcroft-Gault) if creatinine > 1.5x ULN Hepatic function, as follows: Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 x ULN or ≤ 5x ULN if known liver metastases Total bilirubin ≤ 1.5 x ULN Prothrombin time (PT) and activated partial thromboplastin time (aPTT) levels ≤1.5 x ULN. If institution does not report PT value, the international normalization ratio (INR) must be ≤ ULN. If subject is receiving Coumadin (warfarin), a stable international normalization ratio (INR) of 2-3 is required. No clinical symptoms of hypothyroidism Urine Protein to Creatinine Ratio (uPCR) < 2.0 If uPCR ≥ 2.0 then a 24-hour urine collection can be performed to qualify. If this is performed to qualify, the protein result must be < 2 g per 24 hours. Female subject must either: Be of non-childbearing potential: post-menopausal (defined as at least 1 year without any menses) prior to Screening, or documented surgically sterile Or, if of childbearing potential, Agree not to try to become pregnant during the study and for 6 months after the final study drug administration And have a negative serum pregnancy test ≤ 10 days of cycle 1, day 1 (C1D1) And, if heterosexually active, agree to consistently use 2 forms of highly effective birth control* (at least one of which must be a barrier method) starting at Screening and throughout the study period and for 6 months after the final study drug administration. Female subject must agree not to breastfeed starting at Screening and throughout the study period, and for 6 months after the final study drug administration. Female subject must not donate ova starting at Screening and throughout the study period, and for 6 months after the final study drug administration. Male subject and their female spouse/partners who are of childbearing potential must be using highly effective contraception* consisting of 2 forms of birth control (at least one of which must be a barrier method) starting at Screening and continue throughout the study period, and for 6 months after the final study drug administration Male subject must not donate sperm starting at Screening and throughout the study period and, for 6 months after the final study drug administration Note: *Highly effective forms of birth control include: Consistent and correct usage of established oral contraception. Established intrauterine device (IUD) or intrauterine system (IUS). Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository Exclusion Criteria: Has previously been treated with axitinib, AGS-16C3F, or AGS-16M8F Has untreated brain metastasis. In the case of a solitary brain metastasis which has been resected, there must be evidence of a disease-free interval of at least 3 months post-surgery. For brain metastases treated with whole brain or stereotactic radiation therapy, brain imaging must be stable > 3 months. All subjects previously treated for brain metastases must be stable off corticosteroid therapy for at least 28 days prior to C1D1. Has uncontrolled hypertension defined as blood pressure > 150/90 on medication(s) by 2 blood pressure readings taken at least 1 hour apart. Has gastrointestinal abnormalities including: inability to take oral medication; requirement for intravenous alimentation; prior surgical procedures affecting absorption including total gastric resection; active gastrointestinal bleeding, unrelated to cancer, as evidenced by hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy; malabsorption syndromes such as celiac disease, cystic fibrosis, inflammatory bowel disease, systemic sclerosis, and carcinoid syndrome Has ocular conditions such as: Active infection or corneal ulcer Monocularity Visual acuity of 20/70 or worse in both eyes History of corneal transplantation Contact lens dependent (if using contact lens, must be able to switch to glasses during the entire study duration) Uncontrolled glaucoma (topical medications allowed) Uncontrolled or active ocular problems (e.g., retinopathy, macular edema, active uveitis, wet macular degeneration) requiring surgery, laser treatment, or intravitreal injections Papilledema or other active optic nerve disorder Has used any investigational drug (including marketed drugs not approved for this indication) ≤ 14 days of C1D1. No time limit applies to the use of marketed drugs approved for this indication provided that the subject has progressed on the treatment and all toxicities attributable to the drug have resolved, returned to baseline or stabilized. Has known sensitivity to any of the ingredients of: investigational product AGS-16C3F and/or, Inlyta® (axitinib) and/or, 1% prednisolone acetate ophthalmic suspension and any other corticosteroids. Is currently using (i.e., within 14-days prior to first dose) drugs that are known strong CYP3A4/5 inhibitors / inducers. Thromboembolic event (e.g., deep vein thrombosis [DVT] and pulmonary embolism [PE]) ≤ 4 weeks of C1D1. Subjects who had a thromboembolic event ≤ 4 weeks of C1D1 must be receiving adequate anticoagulation treatment for at least 2 weeks before C1D1 and must continue as clinically indicated post first dose Has history bleeding disorders (e.g., pulmonary hemorrhage, significant hemoptysis, menometrorrhagia not responding to hormonal treatment) ≤ 2 months before C1D1 Has active angina or Class III or IV Congestive Heart Failure (New York Heart Association CHF Functional Classification System) or clinically significant cardiac disease within 6 months of randomization, including myocardial infarction, unstable angina, Grade 2 or greater peripheral vascular disease, congestive heart failure, or arrhythmias not controlled by medication. Had major surgery ≤ 4 weeks of C1D1 Is pregnant (confirmed by positive serum pregnancy test) or lactating Has active infection requiring treatment with systemic (intravenous or oral) anti-infectives (antibiotic, antifungal, or antiviral agent) ≤ 10 days of C1D1 Is unwilling or unable to comply with study requirements Has any medical or psychiatric disorder that compromises the ability of the subject to give written informed consent, and/or comply with the study procedures.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AGS-16C3F<br>Participants received 1.8 milligram per kilogram (mg/kg) of AGS-16C3F once every three weeks by single intravenous (IV) infusion. | Drug: AGS-16C3F<br>* Intravenous (IV) infusion<br>|
| Active Comparator: Axitinib<br>Participants received 2 to 10 milligram (mg) of axitinib twice daily by oral administration as defined in the product label and per local institutional guidelines. | Drug: Axitinib<br>* Oral<br>* Other names: Inlyta®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigator Radiologic Review | PFS was defined as the time from the date of randomization to the earliest of documented disease progression as defined by RECIST v.1.1 or death from any cause. PFS was analysed using Kaplan-Meier estimates. Progressive disease (PD) was defined as at least a 20% increase in the sum of diameters (longest for non-nodal lesions, short axis for nodal lesions) of the target lesions taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeter (mm). The appearance of 1 or more new lesions is also considered progression. Participants were censored if there were 2 or more than 2 consecutive missing assesments immediately prior to death or progression; or no death and no postebaseline assesments; or if ininitiated non protocol anticancer treatment prior to death or prior to documentation of disease progression; or alive and not progressed. | From date of randomization to the earliest of either documented disease progression or death from any cause (up to 53 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS Per RECIST v1.1 as Assessed by Blinded Central Radiology Assessment | PFS was defined as the time from the date of randomization to the earliest of documented disease progression as defined by RECIST v.1.1 or death from any cause. PFS was analysed using Kaplan-Meier estimates. PD was defined as at least a 20% increase in the sum of diameters (longest for non-nodal lesions, short axis for nodal lesions) of the target lesions taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. The appearance of 1 or more new lesions is also considered progression. Participants were censored if there were 2 or more than 2 consecutive missing assessments immediately prior to death or progression; or no death and no postebaseline assessments; or if initiated non protocol anticancer treatment prior to death or prior to documentation of disease progression; or alive and not progressed. | From date of randomization to the earliest of either documented disease progression or death from any cause (up to 40 months) | 
| Objective Response Rate (ORR) Based on the Investigator's Radiographic Assessment | ORR was defined as the percentage of participants who had a best overall response of complete response (CR) or partial response (PR). CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) with reduction in short axis to <10mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters. | From date of randomization until data cutoff date of 21 August 2019 (up to 40 months) | 
| Duration of Response (DOR) Based on the Investigator's Radiographic Assessment | DOR was defined as the time from the date of the first response of CR or PR (whichever was first recorded) to the first date of documented PD or death due to any cause. DOR was analysed using Kaplan-Meier estimates. CR and PR were defined in outcome measure 3 and PD was defined in outcome measures 1 and 2. Participants were censored if there were 2 or more than 2 consecutive missing assesments immediately prior to death or progression; or no death and no postebaseline assesments; or if ininitiated non protocol anticancer treatment prior to death or prior to documentation of disease progression; or alive and not progressed. | From date of first objective response until data cutoff date of 21 August 2019 (up to 40 months) | 
| Overall Survival (OS) | OS was defined as the time from the date of randomization until the date of death from any cause. OS was analysed using Kaplan-Meier estimates. Participants were censored if there was no death and no postbaseline contact or no death and at least one postbaseline follow-up. | Date of randomization until the date of death from any cause (up to 53 months) | 
| Disease Control Rate (DCR) Based on the Investigator's Radiographic Assessment | DCR was defined as the percentage of patients who had a best overall response of CR, PR or at least 6 months with stable disease (SD). CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) with reduction in short axis to <10mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters. SD was defined as neither sufficient decrease to qualify for PR nor sufficient increase to qualify for progressive disease taking as reference the smallest sum of diameters while on study drug. | Date of randomization until data cutoff date of 21 August 2019 (up to 40 months) | 
| Number of Participants With Adverse Events | AE was defined as any untoward medical occurrence in a participant administered a study drug or has undergone study procedures and which did not necessarily have a causal relationship with this treatment. An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG data, and physical exam) was defined as an AE only if the abnormality induces clinical signs or symptoms or requires active intervention or requires interruption or discontinuation of study medication or the abnormality or investigational value is clinically significant in the opinion of the investigator. AE was considered serious if it results in death or is life threatening results in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions or results in congenital anomaly, or birth defect requires inpatient hospitalization or leads to prolongation of hospitalization or other medically important events. | From first dose up to 53 months | 
| Maximum Observed Serum Concentration (Cmax) of Antibody Drug Conjugate (ADC) | Cmax of ADC was reported. | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | 
| Mean Predose Serum Concentration (Ctrough) of ADC | Ctrough of ADC was reported. | Predose on cycle 2, 3, 4, 6, 14, and 18 (each cycle is 21 days) | 
| Time to Maximum Observed Serum Concentration (Tmax) of ADC | Tmax of ADC was reported. | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | 
| Area Under the Concentration Versus Time Curve From Time Zero to 21days (AUC0 to 21) of ADC | AUC (0 to 21) of ADC was reported. | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | 
| Terminal Elimination Half-life (t1/2) of ADC | t1/2 of ADC was reported. | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | 
| Maximum Serum Concentration (Cmax) of Total Antibody (TAb) | Cmax of TAb was reported. | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | 
| Mean Predose Serum Concnetration (Ctrough) of TAb | Ctrough of TAb was reported. | Predose on cycle 2, 3, 4, 6, 14, and 18 (each cycle is 21 days) | 
| Time to Maximum Observed Serum Concentration (Tmax) of Tab | Tmax of TAb was reported. | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | 
| Area Under the Concentration Versus Time Curve From Time Zero to 21days (AUC0 to 21) of TAb | AUC (0 to 21) of TAb was reporetd. | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | 
| Terminal Elimination Half-life (t1/2) of Tab | t1/2 of TAb was reported. | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | 
| Maximum Serum Concentration (Cmax) of Cysteine Adduct of Maleimidocaproyl Monomethyl Auristatin F (Cys-mcMMAF) | Cmax of Cys-mcMMAF was reported. | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | 
| Mean Predose Serum Concnetration (Ctrough) of Cys-mcMMAF | Ctrough of Cys-mcMMAF was reported. | Predose on cycle 2, 3, 4, 6, 14, and 18 (each cycle is 21 days) | 
| Time to Maximum Observed Serum Concentration (Tmax) of Cys-mcMMAF | Tmax of Cys-mcMMAF was reported. | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | 
| Area Under the Concentration Versus Time Curve From Time Zero to 21days (AUC0 to 21) of Cys-mcMMAF | AUC (0 to 21) of Cys-mcMMAF was reporetd. | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | 
| Terminal Elimination Half-life (t1/2) of Cys-mcMMAF | t1/2 of Cys-mcMMAF was reported | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Axitinib, Metastatic Renal Cell Carcinoma, AGS-16C3F