Clinical trial NCT02639182: A Study of AGS-16C3F vs. Axitinib in Metastatic Renal Cell Carcinoma
Official title: A Multi-Center, Open Label, Randomized Phase 2 Study of AGS-16C3F vs. Axitinib in Metastatic Renal Cell Carcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Renal Cell Carcinoma
Keywords: Axitinib
Metastatic Renal Cell Carcinoma
AGS-16C3F
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2015-12-24
Enrollment: 133
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Progression Free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigator Radiologic Review
timeFrame: From date of randomization to the earliest of either documented disease progression or death from any cause (up to 53 months)
Secondary outcomes:
measure: PFS Per RECIST v1.1 as Assessed by Blinded Central Radiology Assessment
timeFrame: From date of randomization to the earliest of either documented disease progression or death from any cause (up to 40 months)
measure: Objective Response Rate (ORR) Based on the Investigator's Radiographic Assessment
timeFrame: From date of randomization until data cutoff date of 21 August 2019 (up to 40 months)
measure: Duration of Response (DOR) Based on the Investigator's Radiographic Assessment
timeFrame: From date of first objective response until data cutoff date of 21 August 2019 (up to 40 months)
measure: Overall Survival (OS)
timeFrame: Date of randomization until the date of death from any cause (up to 53 months)
measure: Disease Control Rate (DCR) Based on the Investigator's Radiographic Assessment
timeFrame: Date of randomization until data cutoff date of 21 August 2019 (up to 40 months)
measure: Number of Participants With Adverse Events
timeFrame: From first dose up to 53 months
measure: Maximum Observed Serum Concentration (Cmax) of Antibody Drug Conjugate (ADC)
timeFrame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
measure: Mean Predose Serum Concentration (Ctrough) of ADC
timeFrame: Predose on cycle 2, 3, 4, 6, 14, and 18 (each cycle is 21 days)
measure: Time to Maximum Observed Serum Concentration (Tmax) of ADC
timeFrame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
measure: Area Under the Concentration Versus Time Curve From Time Zero to 21days (AUC0 to 21) of ADC
timeFrame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
measure: Terminal Elimination Half-life (t1/2) of ADC
timeFrame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
measure: Maximum Serum Concentration (Cmax) of Total Antibody (TAb)
timeFrame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
measure: Mean Predose Serum Concnetration (Ctrough) of TAb
timeFrame: Predose on cycle 2, 3, 4, 6, 14, and 18 (each cycle is 21 days)
measure: Time to Maximum Observed Serum Concentration (Tmax) of Tab
timeFrame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
measure: Area Under the Concentration Versus Time Curve From Time Zero to 21days (AUC0 to 21) of TAb
timeFrame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
measure: Terminal Elimination Half-life (t1/2) of Tab
timeFrame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
measure: Maximum Serum Concentration (Cmax) of Cysteine Adduct of Maleimidocaproyl Monomethyl Auristatin F (Cys-mcMMAF)
timeFrame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
measure: Mean Predose Serum Concnetration (Ctrough) of Cys-mcMMAF
timeFrame: Predose on cycle 2, 3, 4, 6, 14, and 18 (each cycle is 21 days)
measure: Time to Maximum Observed Serum Concentration (Tmax) of Cys-mcMMAF
timeFrame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
measure: Area Under the Concentration Versus Time Curve From Time Zero to 21days (AUC0 to 21) of Cys-mcMMAF
timeFrame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
measure: Terminal Elimination Half-life (t1/2) of Cys-mcMMAF
timeFrame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Site US01026
state: Arizona
city: La Jolla
country: United States
facility: Site US01008
state: California
city: Los Angeles
country: United States
facility: Site US01007
state: California
city: Los Angeles
country: United States
facility: Site US01020
state: California
city: Palo Alto
country: United States
facility: Site US01019
state: California
city: Atlanta
country: United States
facility: Site US01010
state: Georgia
city: Baltimore
country: United States
facility: Site US01023
state: Maryland
city: Boston
country: United States
facility: Site US01002
state: Massachusetts
city: Ann Arbor
country: United States
facility: Site US01004
state: Michigan
city: Detroit
country: United States
facility: Site US01013
state: Michigan
city: Omaha
country: United States
facility: Site US01012
state: Nebraska
city: Buffalo
country: United States
facility: Site US01006
state: New York
city: Durham
country: United States
facility: Site US01022
state: North Carolina
city: Portland
country: United States
facility: Site US01017
state: Oregon
city: Pittsburgh
country: United States
facility: Site US01021
state: Pennsylvania
city: Charleston
country: United States
facility: Site US01011
state: South Carolina
city: Houston
country: United States
facility: Site US01003
state: Texas
city: Temple
country: United States
facility: Site US01014
state: Texas
city: Seattle
country: United States
facility: Site US01001
state: Washington
city: Milwaukee
country: United States
facility: Site US01009
state: Wisconsin
city: Calgary
country: Canada
facility: Site CA02006
state: Alberta
city: Edmonton
country: Canada
facility: Site CA02004
state: Alberta
city: Kelowna
country: Canada
facility: Site CA02005
state: British Columbia
city: Vancouver
country: Canada
facility: Site CA02001
state: British Columbia
city: Hamilton
country: Canada
facility: Site CA02002
state: Ontario
city: London
country: Canada
facility: Site CA02008
state: Ontario
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Associate Medical Director
role: STUDY_DIRECTOR
References: