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

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

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.

Study Overview

• Status: Completed
• Conditions: Metastatic Renal Cell Carcinoma
• Intervention / Treatment: Drug: AGS-16C3F; Drug: Axitinib

• Study Type: Interventional
• Enrollment (Actual): 133
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Site CA02006
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Site CA02004
  • British Columbia
    • Kelowna, British Columbia, Canada, V1Y 5L3
      • Site CA02005
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • Site CA02001
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Site CA02002
    • London, Ontario, Canada, N6A 5W9
      • Site CA02008
• United States
  • Arizona
    • Tucson, Arizona, United States, 85719
      • Site US01026
  • California
    • La Jolla, California, United States, 92093
      • Site US01008
    • Los Angeles, California, United States, 90033
      • Site US01007
    • Los Angeles, California, United States, 90095
      • Site US01020
    • Palo Alto, California, United States, 94305
      • Site US01019
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Site US01010
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Site US01023
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Site US01002
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Site US01004
    • Detroit, Michigan, United States, 48202
      • Site US01013
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • Site US01012
  • New York
    • Buffalo, New York, United States, 14263
      • Site US01006
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Site US01022
  • Oregon
    • Portland, Oregon, United States, 97213
      • Site US01017
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • Site US01021
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Site US01011
  • Texas
    • Houston, Texas, United States, 77030
      • Site US01003
    • Temple, Texas, United States, 76508
      • Site US01014
  • Washington
    • Seattle, Washington, United States, 98109
      • Site US01001
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Site US01009

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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:

    1. Absolute neutrophil count (ANC) ≥ 1.5 x 10 9/L
    2. Platelet count ≥ 100 x 10 9/L
    3. 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:

    1. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 x ULN or ≤ 5x ULN if known liver metastases
    2. 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:

    1. post-menopausal (defined as at least 1 year without any menses) prior to Screening, or
    2. documented surgically sterile

  • Or, if of childbearing potential,

    1. Agree not to try to become pregnant during the study and for 6 months after the final study drug administration
    2. 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AGS-16C3F; Participants received 1.8 milligram per kilogram (mg/kg) of AGS-16C3F once every three weeks by single intravenous (IV) infusion.	Drug: AGS-16C3F; Intravenous (IV) infusion
Active Comparator: Axitinib; 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; Oral; Other Names: Inlyta®

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Astellas Pharma Global Development, Inc.
• Investigators: Study Director: Associate Medical Director, Astellas Pharma Global Development, Inc.

Publications and helpful links

Helpful Links

• Link to results and other applicable study documents on the Astellas Clinical Trials website
• Link to plain language summary of the study on the Trial Results Summaries website

Study record dates

Study Major Dates

• Study Start (Actual): May 3, 2016
• Primary Completion (Actual): October 2, 2020
• Study Completion (Actual): October 2, 2020

Study Registration Dates

• First Submitted: December 21, 2015
• First Submitted That Met QC Criteria: December 23, 2015
• First Posted (Estimated): December 24, 2015

Study Record Updates

• Last Update Posted (Actual): November 18, 2024
• Last Update Submitted That Met QC Criteria: October 30, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Axitinib; Metastatic Renal Cell Carcinoma; AGS-16C3F
• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Urologic Neoplasms; Kidney Neoplasms; Carcinoma; Carcinoma, Renal Cell; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Axitinib
• Other Study ID Numbers: AGS-16C3F-15-3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as products terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.
• IPD Sharing Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• IPD Sharing Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No