Metastatic Renal Cell Carcinoma
Conditions
Keywords
Axitinib, Metastatic Renal Cell Carcinoma, AGS-16C3F
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.
Interventions
DRUGAGS-16C3F
Intravenous (IV) infusion
DRUGAxitinib
Oral
Sponsors
Astellas Pharma Global Development, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigator Radiologic Review | From date of randomization to the earliest of either documented disease progression or death from any cause (up to 53 months) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PFS Per RECIST v1.1 as Assessed by Blinded Central Radiology Assessment | From date of randomization to the earliest of either documented disease progression or death from any cause (up to 40 months) | 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. |
| Objective Response Rate (ORR) Based on the Investigator's Radiographic Assessment | From date of randomization until data cutoff date of 21 August 2019 (up to 40 months) | 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. |
| Duration of Response (DOR) Based on the Investigator's Radiographic Assessment | From date of first objective response until data cutoff date of 21 August 2019 (up to 40 months) | 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. |
| Overall Survival (OS) | Date of randomization until the date of death from any cause (up to 53 months) | 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. |
| Disease Control Rate (DCR) Based on the Investigator's Radiographic Assessment | Date of randomization until data cutoff date of 21 August 2019 (up to 40 months) | 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. |
| Number of Participants With Adverse Events | From first dose up to 53 months | 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. |
| Maximum Observed Serum Concentration (Cmax) of Antibody Drug Conjugate (ADC) | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | Cmax of ADC was reported. |
| Mean Predose Serum Concentration (Ctrough) of ADC | Predose on cycle 2, 3, 4, 6, 14, and 18 (each cycle is 21 days) | Ctrough of ADC was reported. |
| Time to Maximum Observed Serum Concentration (Tmax) of ADC | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | Tmax of ADC was reported. |
| Area Under the Concentration Versus Time Curve From Time Zero to 21days (AUC0 to 21) of ADC | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | AUC (0 to 21) of ADC was reported. |
| Terminal Elimination Half-life (t1/2) of Cys-mcMMAF | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | t1/2 of Cys-mcMMAF was reported |
| Maximum Serum Concentration (Cmax) of Total Antibody (TAb) | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | Cmax of TAb was reported. |
| Mean Predose Serum Concnetration (Ctrough) of TAb | Predose on cycle 2, 3, 4, 6, 14, and 18 (each cycle is 21 days) | Ctrough of TAb was reported. |
| Time to Maximum Observed Serum Concentration (Tmax) of Tab | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | Tmax of TAb was reported. |
| Area Under the Concentration Versus Time Curve From Time Zero to 21days (AUC0 to 21) of TAb | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | AUC (0 to 21) of TAb was reporetd. |
| Terminal Elimination Half-life (t1/2) of Tab | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | t1/2 of TAb was reported. |
| Maximum Serum Concentration (Cmax) of Cysteine Adduct of Maleimidocaproyl Monomethyl Auristatin F (Cys-mcMMAF) | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | Cmax of Cys-mcMMAF was reported. |
| Mean Predose Serum Concnetration (Ctrough) of Cys-mcMMAF | Predose on cycle 2, 3, 4, 6, 14, and 18 (each cycle is 21 days) | Ctrough of Cys-mcMMAF was reported. |
| Time to Maximum Observed Serum Concentration (Tmax) of Cys-mcMMAF | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | Tmax of Cys-mcMMAF was reported. |
| Area Under the Concentration Versus Time Curve From Time Zero to 21days (AUC0 to 21) of Cys-mcMMAF | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | AUC (0 to 21) of Cys-mcMMAF was reporetd. |
| Terminal Elimination Half-life (t1/2) of ADC | Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days) | t1/2 of ADC was reported. |
Countries
Canada, United States
Participant flow
Recruitment details
Participants who were atleast 18 years of age with all histologies of confirmed renal cell carcinoma and evidence of progression on or after the last regimen received were enrolled.
Pre-assignment details
Randomization was stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1), the number of prior systemic RCC regimens (2 or \> 2) and Renal cell carcinoma (RCC), histology (clear or nonclear cell).
Participants by arm
| Arm | Count |
|---|---|
| AGS-16C3F Participants received 1.8 mg/kg of AGS-16C3F once every three weeks by single (60-minute) IV infusion. | 67 |
| Axitinib Participants received axitinib at a starting dose of 5 mg orally twice daily and then adjusted to 2 to 10 mg orally twice daily, as defined in the product label and per local institutional guidelines. | 66 |
| Total | 133 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 7 | 5 |
| Overall Study | Disease Progression | 50 | 49 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 3 | 3 |
| Overall Study | Randomized But Did Not Receive Study Drug | 1 | 1 |
| Overall Study | Sponsor Ended Study | 0 | 1 |
| Overall Study | Study Closure | 1 | 2 |
| Overall Study | Withdrew Consent | 5 | 4 |
Baseline characteristics
| Characteristic | AGS-16C3F | Axitinib | Total |
|---|---|---|---|
| Age, Continuous | 62.3 Years STANDARD_DEVIATION 9.1 | 61.1 Years STANDARD_DEVIATION 8.9 | 61.7 Years STANDARD_DEVIATION 9 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 | 19 Participants | 19 Participants | 38 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 | 48 Participants | 47 Participants | 95 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 64 Participants | 62 Participants | 126 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Histological Type Clear cell | 55 Participants | 55 Participants | 110 Participants |
| Histological Type Non-clear cell | 12 Participants | 11 Participants | 23 Participants |
| Number of Prior Systemic Renal cell carcinoma (RCC) Treatment Regimens >2 if clear cell or >1 if non-clear cell histology | 32 Participants | 33 Participants | 65 Participants |
| Number of Prior Systemic Renal cell carcinoma (RCC) Treatment Regimens 2 if clear cell or 1 if non-clear cell histology | 35 Participants | 33 Participants | 68 Participants |
| Prognostic Risk Group Favorable (0 risk factors) | 5 Participants | 10 Participants | 15 Participants |
| Prognostic Risk Group Intermediate (1-2 risk factors) | 48 Participants | 43 Participants | 91 Participants |
| Prognostic Risk Group Poor (>=3 risk factors) | 14 Participants | 13 Participants | 27 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Asian | 6 Participants | 7 Participants | 13 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Race White | 59 Participants | 56 Participants | 115 Participants |
| Sex: Female, Male Female | 18 Participants | 17 Participants | 35 Participants |
| Sex: Female, Male Male | 49 Participants | 49 Participants | 98 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 36 / 67 | 44 / 66 |
| other Total, other adverse events | 65 / 66 | 64 / 65 |
| serious Total, serious adverse events | 26 / 66 | 31 / 65 |
Outcome results
Primary
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.
Time frame: From date of randomization to the earliest of either documented disease progression or death from any cause (up to 53 months)
Population: FAS Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AGS-16C3F | Progression Free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigator Radiologic Review | 2.9 Months |
| Axitinib | Progression Free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigator Radiologic Review | 5.7 Months |
p-value: 0.983Log Rank
Secondary
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.
Time frame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
Population: PKAS Population with available data at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AGS-16C3F | Area Under the Concentration Versus Time Curve From Time Zero to 21days (AUC0 to 21) of ADC | Cycle 1 | 199.80 Day*Microgram per Milliliter (day*μg/mL) | Standard Deviation 68.821 |
| AGS-16C3F | Area Under the Concentration Versus Time Curve From Time Zero to 21days (AUC0 to 21) of ADC | Cycle 4 | 293.90 Day*Microgram per Milliliter (day*μg/mL) | Standard Deviation 100.19 |
Secondary
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.
Time frame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
Population: PKAS Population with available data at specified time point. Not calculated at cycle 4 due to an insufficient number of participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AGS-16C3F | Area Under the Concentration Versus Time Curve From Time Zero to 21days (AUC0 to 21) of Cys-mcMMAF | Cycle 1 | 9.61 day*ng/mL | Standard Deviation 10.3 |
Secondary
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.
Time frame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
Population: PKAS Population with available data at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AGS-16C3F | Area Under the Concentration Versus Time Curve From Time Zero to 21days (AUC0 to 21) of TAb | Cycle 1 | 246.06 day*μg/mL | Standard Deviation 88.815 |
| AGS-16C3F | Area Under the Concentration Versus Time Curve From Time Zero to 21days (AUC0 to 21) of TAb | Cycle 4 | 346.07 day*μg/mL | Standard Deviation 158.029 |
Secondary
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.
Time frame: Date of randomization until data cutoff date of 21 August 2019 (up to 40 months)
Population: FAS Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AGS-16C3F | Disease Control Rate (DCR) Based on the Investigator's Radiographic Assessment | 13.4 Percentage of Participants |
| Axitinib | Disease Control Rate (DCR) Based on the Investigator's Radiographic Assessment | 22.7 Percentage of Participants |
p-value: 0.15295% CI: [0.2, 1.3]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: From date of first objective response until data cutoff date of 21 August 2019 (up to 40 months)
Population: FAS Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AGS-16C3F | Duration of Response (DOR) Based on the Investigator's Radiographic Assessment | 6.8 Months |
| Axitinib | Duration of Response (DOR) Based on the Investigator's Radiographic Assessment | 6.7 Months |
p-value: 0.43995% CI: [0.031, 4.482]Log Rank
Secondary
Maximum Observed Serum Concentration (Cmax) of Antibody Drug Conjugate (ADC)
Cmax of ADC was reported.
Time frame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
Population: Pharmacokinetic Population (PKAS): (included all participants who were randomized to receive AGS-16C3F and had sufficient serum concentration data to facilitate derivation of at least 1 pharmacokinetic parameter, and for whom the time of dosing on the day of sampling was known) with available data at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AGS-16C3F | Maximum Observed Serum Concentration (Cmax) of Antibody Drug Conjugate (ADC) | Cycle 1 | 52.21 Microgram per Milliliter (μg/mL) | Standard Deviation 58.407 |
| AGS-16C3F | Maximum Observed Serum Concentration (Cmax) of Antibody Drug Conjugate (ADC) | Cycle 4 | 48.66 Microgram per Milliliter (μg/mL) | Standard Deviation 38.82 |
Secondary
Maximum Serum Concentration (Cmax) of Cysteine Adduct of Maleimidocaproyl Monomethyl Auristatin F (Cys-mcMMAF)
Cmax of Cys-mcMMAF was reported.
Time frame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
Population: PKAS Population with available data at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AGS-16C3F | Maximum Serum Concentration (Cmax) of Cysteine Adduct of Maleimidocaproyl Monomethyl Auristatin F (Cys-mcMMAF) | Cycle 1 | 6.09 ng/mL | Standard Deviation 4.08 |
| AGS-16C3F | Maximum Serum Concentration (Cmax) of Cysteine Adduct of Maleimidocaproyl Monomethyl Auristatin F (Cys-mcMMAF) | Cycle 4 | 3.78 ng/mL | Standard Deviation 1.7 |
Secondary
Maximum Serum Concentration (Cmax) of Total Antibody (TAb)
Cmax of TAb was reported.
Time frame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
Population: PKAS Population with available data at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AGS-16C3F | Maximum Serum Concentration (Cmax) of Total Antibody (TAb) | Cycle 1 | 37.49 μg/mL | Standard Deviation 12.515 |
| AGS-16C3F | Maximum Serum Concentration (Cmax) of Total Antibody (TAb) | Cycle 4 | 42.84 μg/mL | Standard Deviation 12.345 |
Secondary
Mean Predose Serum Concentration (Ctrough) of ADC
Ctrough of ADC was reported.
Time frame: Predose on cycle 2, 3, 4, 6, 14, and 18 (each cycle is 21 days)
Population: PKAS Population. Here, number of participants analyzed signifies participants who had quantifiable data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AGS-16C3F | Mean Predose Serum Concentration (Ctrough) of ADC | Cycle 2 | 3429.39 Nanogram per Milliliter (ng/mL) | Standard Deviation 1402.334 |
| AGS-16C3F | Mean Predose Serum Concentration (Ctrough) of ADC | Cycle 3 | 5194.21 Nanogram per Milliliter (ng/mL) | Standard Deviation 3602.012 |
| AGS-16C3F | Mean Predose Serum Concentration (Ctrough) of ADC | Cycle 4 | 7731.38 Nanogram per Milliliter (ng/mL) | Standard Deviation 11171.906 |
| AGS-16C3F | Mean Predose Serum Concentration (Ctrough) of ADC | Cycle 6 | 5695.13 Nanogram per Milliliter (ng/mL) | Standard Deviation 3899.222 |
| AGS-16C3F | Mean Predose Serum Concentration (Ctrough) of ADC | Cycle 14 | 8698.26 Nanogram per Milliliter (ng/mL) | Standard Deviation 4239.327 |
| AGS-16C3F | Mean Predose Serum Concentration (Ctrough) of ADC | Cycle 18 | 7213.32 Nanogram per Milliliter (ng/mL) | Standard Deviation 2082.501 |
Secondary
Mean Predose Serum Concnetration (Ctrough) of Cys-mcMMAF
Ctrough of Cys-mcMMAF was reported.
Time frame: Predose on cycle 2, 3, 4, 6, 14, and 18 (each cycle is 21 days)
Population: PKAS Population. Here, number of participants analyzed signifies participants who had quantifiable data.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| AGS-16C3F | Mean Predose Serum Concnetration (Ctrough) of Cys-mcMMAF | Cycle 6 | 0.307 ng/mL |
| Unknown | Mean Predose Serum Concnetration (Ctrough) of Cys-mcMMAF | Cycle 4 | — ng/mL |
| Unknown | Mean Predose Serum Concnetration (Ctrough) of Cys-mcMMAF | Cycle 2 | — ng/mL |
| Unknown | Mean Predose Serum Concnetration (Ctrough) of Cys-mcMMAF | Cycle 3 | — ng/mL |
| Unknown | Mean Predose Serum Concnetration (Ctrough) of Cys-mcMMAF | Cycle 14 | — ng/mL |
| Unknown | Mean Predose Serum Concnetration (Ctrough) of Cys-mcMMAF | Cycle 18 | — ng/mL |
Secondary
Mean Predose Serum Concnetration (Ctrough) of TAb
Ctrough of TAb was reported.
Time frame: Predose on cycle 2, 3, 4, 6, 14, and 18 (each cycle is 21 days)
Population: PKAS Population. Here, number of participants analyzed signifies participants who had quantifiable data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AGS-16C3F | Mean Predose Serum Concnetration (Ctrough) of TAb | Cycle 2 | 4966.69 ng/mL | Standard Deviation 2571.41 |
| AGS-16C3F | Mean Predose Serum Concnetration (Ctrough) of TAb | Cycle 3 | 6943.11 ng/mL | Standard Deviation 3666.956 |
| AGS-16C3F | Mean Predose Serum Concnetration (Ctrough) of TAb | Cycle 4 | 8660.94 ng/mL | Standard Deviation 4176.472 |
| AGS-16C3F | Mean Predose Serum Concnetration (Ctrough) of TAb | Cycle 6 | 8777.51 ng/mL | Standard Deviation 4131.388 |
| AGS-16C3F | Mean Predose Serum Concnetration (Ctrough) of TAb | Cycle 14 | 12491.90 ng/mL | Standard Deviation 6593.131 |
| AGS-16C3F | Mean Predose Serum Concnetration (Ctrough) of TAb | Cycle 18 | 11726.15 ng/mL | Standard Deviation 5572.172 |
Secondary
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.
Time frame: From first dose up to 53 months
Population: Safety Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AGS-16C3F | Number of Participants With Adverse Events | 65 Participants |
| Axitinib | Number of Participants With Adverse Events | 64 Participants |
Secondary
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.
Time frame: From date of randomization until data cutoff date of 21 August 2019 (up to 40 months)
Population: FAS Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AGS-16C3F | Objective Response Rate (ORR) Based on the Investigator's Radiographic Assessment | 7.5 Percentage of Participants |
| Axitinib | Objective Response Rate (ORR) Based on the Investigator's Radiographic Assessment | 18.2 Percentage of Participants |
p-value: 0.06295% CI: [0.1, 1.1]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: Date of randomization until the date of death from any cause (up to 53 months)
Population: FAS Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AGS-16C3F | Overall Survival (OS) | 13.1 Months |
| Axitinib | Overall Survival (OS) | 15.5 Months |
p-value: 0.746Log Rank
Secondary
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.
Time frame: From date of randomization to the earliest of either documented disease progression or death from any cause (up to 40 months)
Population: FAS Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AGS-16C3F | PFS Per RECIST v1.1 as Assessed by Blinded Central Radiology Assessment | 3.5 Months |
| Axitinib | PFS Per RECIST v1.1 as Assessed by Blinded Central Radiology Assessment | 4.5 Months |
p-value: 0.1195% CI: [0.924, 2.192]Log Rank
Secondary
Terminal Elimination Half-life (t1/2) of ADC
t1/2 of ADC was reported.
Time frame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
Population: PKAS Population with available data at specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AGS-16C3F | Terminal Elimination Half-life (t1/2) of ADC | Cycle 1 | 6.93 Days |
| AGS-16C3F | Terminal Elimination Half-life (t1/2) of ADC | Cycle 4 | 7.40 Days |
Secondary
Terminal Elimination Half-life (t1/2) of Cys-mcMMAF
t1/2 of Cys-mcMMAF was reported
Time frame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
Population: PKAS Population with available data at specified time point. Not calculated at cycle 4 due to an insufficient number of samples.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AGS-16C3F | Terminal Elimination Half-life (t1/2) of Cys-mcMMAF | Cycle 1 | 2.72 Days |
Secondary
Terminal Elimination Half-life (t1/2) of Tab
t1/2 of TAb was reported.
Time frame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
Population: PKAS Population with available data at specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AGS-16C3F | Terminal Elimination Half-life (t1/2) of Tab | Cycle 1 | 8.70 Days |
| AGS-16C3F | Terminal Elimination Half-life (t1/2) of Tab | Cycle 4 | 9.15 Days |
Secondary
Time to Maximum Observed Serum Concentration (Tmax) of ADC
Tmax of ADC was reported.
Time frame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
Population: PKAS Population with available data at specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AGS-16C3F | Time to Maximum Observed Serum Concentration (Tmax) of ADC | Cycle 1 | 0.04 Days |
| AGS-16C3F | Time to Maximum Observed Serum Concentration (Tmax) of ADC | Cycle 4 | 0.05 Days |
Secondary
Time to Maximum Observed Serum Concentration (Tmax) of Cys-mcMMAF
Tmax of Cys-mcMMAF was reported.
Time frame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
Population: PKAS Population with available data at specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AGS-16C3F | Time to Maximum Observed Serum Concentration (Tmax) of Cys-mcMMAF | Cycle 1 | 0.207 Days |
| AGS-16C3F | Time to Maximum Observed Serum Concentration (Tmax) of Cys-mcMMAF | Cycle 4 | 0.208 Days |
Secondary
Time to Maximum Observed Serum Concentration (Tmax) of Tab
Tmax of TAb was reported.
Time frame: Predose, end of infusion, 4, 24, 72, 336 hours postdose of cycle 1 and cycle 4 (each cycle is 21 days)
Population: PKAS Population with available data at specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AGS-16C3F | Time to Maximum Observed Serum Concentration (Tmax) of Tab | Cycle 1 | 0.05 Days |
| AGS-16C3F | Time to Maximum Observed Serum Concentration (Tmax) of Tab | Cycle 4 | 0.05 Days |