A Study of Avelumab With Axitinib Versus Sunitinib In Advanced Renal Cell Cancer (JAVELIN Renal 101)
- Conditions
- Renal Cell Cancer
- Interventions
- Registration Number
- NCT02684006
- Lead Sponsor
- Pfizer
- Brief Summary
This is a phase 3 randomized trial evaluating the anti-tumor activity and safety of avelumab in combination with axitinib and of sunitinib monotherapy, administered as first-line treatment, in patients with advanced renal cell carcinoma
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 886
- Histologically or cytologically confirmed advanced or metastatic RCC with clear cell component
- Availability of a formalin-fixed, paraffin-embedded (FFPE) tumor tissue block from a de novo tumor biopsy during screening (biopsied tumor lesion should not be a RECIST target lesion). Alternatively, a recently obtained archival FFPE tumor tissue block (not cut slides) from a primary or metastatic tumor resection or biopsy can be provided if the following criteria are met: 1) the biopsy or resection was performed within 1 year of randomization AND 2) the patient has not received any intervening systemic anti-cancer treatment from the time the tissue was obtained and randomization onto the current study. If an FFPE tissue block cannot be provided as per documented regulations then, 15 unstained slides (10 minimum) will be acceptable
- Availability of an archival FFPE tumor tissue from primary tumor resection specimen (if not provided per above). If an FFPE tissue block cannot be provided as per documented regulations 15 unstained slides (10 minimum) will be acceptable
- At least one measurable lesion as defined by RECIST version 1.1 that has not been previously irradiated
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- Adequate bone marrow function, renal and liver functions
- Prior systemic therapy directed at advanced or metastatic RCC
- Prior adjuvant or neoadjuvant therapy for RCC if disease progression or relapse has occurred during or within 12 months after the last dose of treatment.
- Prior immunotherapy with IL-2, IFN-α, or anti PD 1, anti PD L1, anti PD L2, anti CD137, or anti cytotoxic T lymphocyte associated antigen 4 (CTLA 4) antibody (including ipilimumab), or any other antibody or drug specifically targeting T cell co stimulation or immune checkpoint pathways
- Prior therapy with axitinib and/or sunitinib as well as any prior therapies with other VEGF pathway inhibitors
- Newly diagnosed or active brain metastasis
- Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥3), any history of anaphylaxis, or uncontrolled asthma (ie, 3 or more features of partially controlled asthma Global Initiative for Asthma 2011)
- Any of the following in the previous 12 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, LVEF less than LLN, clinically significant pericardial effusion, cerebrovascular accident, transient ischemic attack
- Any of the following in the previous 6 months: deep vein thrombosis or symptomatic pulmonary embolism
- Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines (for example, inactivated influenza vaccines)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Avelumab in combination with axitinib Axitinib (AG-013736) Avelumab administered at 10 mg/kg IV every two weeks in combination with axitinib, 5 mg PO BID. Avelumab in combination with axitinib Avelumab (MSB0010718C) Avelumab administered at 10 mg/kg IV every two weeks in combination with axitinib, 5 mg PO BID. Sunitinib Sunitinib Sunitinib given at 50 mg PO QD on schedule 4/2
- Primary Outcome Measures
Name Time Method Progression Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) in Programmed Death-Ligand 1 (PD-L1) Positive Participants From date of randomization to the first documentation of PD or death due to any cause or censoring date, whichever occurred first (maximum up to approximately 26 months) PFS: time from the date of randomization to the date of the first documentation of progressive disease (PD) according to Response Evaluation Criteria in Solid Tumours (RECIST version \[v\] 1.1) or death due to any cause, whichever occurred first as assessed by BICR. PFS data was censored on date of last adequate tumor assessment for participants who did not have an event (PD or death), who started new anti-cancer therapy prior to an event or for participants with an event after 2 or more missing tumor assessments. PD was defined as at least a 20 percent (%), increase in the sum of all the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to relative increase of 20 %, sum must have also demonstrated an absolute more than (\>) of at least 5 millimeter (mm). The appearance of one or more new lesions was also considered progression.
Overall Survival (OS) in PD-L1 Positive Participants From the date of randomization to the date of death due to any cause or censoring date, whichever occurred first (maximum up to approximately 89 months) OS was defined as the time from the date of randomization to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method.
- Secondary Outcome Measures
Name Time Method PFS as Assessed by BICR in Participants Irrespective of PD-L1 Expression From date of randomization to the first documentation of PD or death due to any cause or censoring date, whichever occurred first (maximum up to approximately 26 months) PFS: time from the date of randomization to the date of the first documentation of PD or death due to any cause, whichever occurred first as assessed by BICR. PFS data was censored on date of last adequate tumor assessment for participants who did not have an event (PD or death), who started new anti-cancer therapy prior to an event or for participants with an event after 2 or more missing tumor assessments. PD was defined as at least a 20% increase in the sum of all the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to relative increase of 20 %, sum must have also demonstrated an absolute \> of at least 5 mm. The appearance of one or more new lesions was also considered progression.
OS in Participants Irrespective of PD-L1 Expression From the date of randomization to the date of death due to any cause or censoring date, whichever occurred first (maximum up to approximately 89 months) OS was defined as the time (in months) from the date of randomization to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method.
Percentage of Participants With Objective Response (OR) as Assessed by BICR Irrespective of PD-L1 Expression From date of randomization until PD (maximum up to approximately 26 months) OR was defined as best overall response of complete response (CR) or partial response (PR) according to RECIST v1.1 as assessed by BICR recorded from date of randomization until disease progression. CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis\<10 mm). All target lesions must be assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed. 95% CI was based on Clopper-Pearson method.
Percentage of Participants With OR as Assessed by Investigator Irrespective of PD-L1 Expression From date of randomization until PD (maximum up to approximately 89 months) OR was defined as best overall response of CR or PR according to RECIST v1.1 as assessed by investigator recorded from date of randomization until disease progression. CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis\<10 mm). All target lesions must be assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed. 95% CI was based on Clopper-Pearson method.
Percentage of Participants With Disease Control (DC) as Assessed by BICR Irrespective of PD-L1 Expression From date of randomization until PD (maximum up to approximately 26 months) DC was defined as a best overall response of CR, PR, non-CR/non-PD or stable disease (SD) according to RECIST v1.1 as assessed by BICR. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. All lymph nodes must decrease to normal size (short axis\<10mm). PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. Non-CR/Non-PD was defined as persistence of any non-target lesions and/or tumor marker level above the normal limits. SD was defined as not to qualify for CR, PR or PD for target lesions and followed PR only if the sum increased by less than 20% from the nadir (smallest sum of diameters consider baseline and all assessments prior to the time point under evaluation), but enough that a previously documented 30% decrease no longer holds.
Percentage of Participants With DC as Assessed by Investigator Irrespective of PD-L1 Expression From date of randomization until PD (maximum up to approximately 89 months) DC was defined as a best overall response of CR, PR, non-CR/non-PD or SD according to RECIST v1.1 as assessed by investigator. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. All lymph nodes must decrease to normal size (short axis\<10mm). PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. Non-CR/Non-PD was defined as persistence of any non-target lesions and/or tumor marker level above the normal limits. SD was defined as not to qualify for CR, PR or PD for target lesions and followed PR only if the sum increased by less than 20% from the nadir (smallest sum of diameters consider baseline and all assessments prior to the time point under evaluation), but enough that a previously documented 30% decrease no longer holds.
Time to Tumor Response (TTR) as Assessed by BICR in Participants Irrespective of PD-L1 Expression From the date of randomization to the first documentation of objective response (CR or PR) (maximum up to approximately 26 months) TTR was defined as the time from randomization to the first documentation of objective tumor response according to RECIST v1.1 as assessed by BICR (CR or PR) which is subsequently confirmed. CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis\<10 mm). All target lesions must be assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed.
TTR as Assessed by Investigator in Participants Irrespective of PD-L1 Expression From the date of randomization to the first documentation of objective response (CR or PR) (maximum up to approximately 89 months) TTR was defined as the time from randomization to the first documentation of objective tumor response according to RECIST v1.1 as assessed by investigator (CR or PR) which is subsequently confirmed. CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis\<10 mm). All target lesions must be assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed.
Duration of Response (DR) as Assessed by BICR in Participants Irrespective of PD-L1 Expression From documentation of OR until date of first documentation of PD or death due to any cause, whichever occurred first (maximum up to approximately 26 months) BICR assessed DR: time from first documentation of OR (confirmed CR or PR) to date of first documentation of objective tumor progression assessed by BICR or death due to any cause whichever occurred first. As per RECIST v1.1. CR: complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis\<10 mm). All target lesions must be assessed. PR: \>=30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed. PD: at least a 20% increase in the sum of all the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to relative increase of 20%, sum must have also demonstrated an absolute \> of at least 5 mm. The appearance of one or more new lesions was also considered progression.
DR as Assessed by Investigator in Participants Irrespective of PD-L1 Expression From documentation of OR until date of first documentation of PD or death due to any cause, whichever occurred first (maximum up to approximately 89 months) Investigator assessed DR: time from first documentation of OR (confirmed CR or PR) to date of first documentation of objective tumor progression (PD) assessed by investigator or death due to any cause whichever occurred first. As per RECIST v1.1. CR: complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis\<10 mm). All target lesions must be assessed. PR: \>=30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed. PD: at least a 20% increase in the sum of all the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to relative increase of 20%, sum must have also demonstrated an absolute \> of at least 5 mm. The appearance of one or more new lesions was also considered progression.
PFS as Assessed by Investigator in Participants Irrespective of PD-L1 Expression From date of randomization until PD, whichever occurred first (maximum up to approximately 89 months) Investigator assessed PFS: time from the date of randomization to the date of the first documentation of PD according to RECIST v1.1 or death due to any cause, whichever occurred first. PFS data was censored on date of last adequate tumor assessment for participants who did not have an event (PD or death), who started new anti-cancer therapy prior to an event or for participants with an event after 2 or more missing tumor assessments. PD was defined as at least a 20% increase in the sum of all the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to relative increase of 20 %, sum must have also demonstrated an absolute \> of at least 5 mm. The appearance of one or more new lesions was also considered progression.
Progression-Free Survival on Next-line Therapy (PFS2) in Participants Irrespective of PD-L1 Expression From date of randomization until PD or death, whichever occurred first (maximum up to approximately 89 months) PFS2 is defined as the time (in months) from randomization to discontinuation of next-line treatment after first objective disease progression by investigator assessment, second objective disease progression by investigator assessment after initiation of next-line treatment, or death from any cause, whichever occurred first. PD was defined as at least a 20% increase in the sum of all the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to relative increase of 20 %, sum must have also demonstrated an absolute \> of at least 5 mm. The appearance of one or more new lesions was also considered progression.
Number of Participants With Treatment-Emergent Adverse Events (AEs) Graded Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Version (V) 4.03 From first dose of study drug to 90 days after last administration of study drug An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were those events with onset dates occurring during the on-treatment period for the first time, or if the worsening of an event is during the on-treatment period (time from the first dose of study treatment through minimum \[30 days+last dose of study treatment, start day of new anti-cancer drug therapy-1 day\]). As per NCI-CTCAE v4.03, Grade(G)1:asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; G2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life \\(ADL); G3: severe or medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; G4: life-threatening consequence, urgent intervention indicated; G5: death related to AE.
Number of Participants With Vital Signs Abnormalities From first dose of study drug to 90 days after last administration of study drug Time to Treatment Discontinuation/Failure Due to Toxicity From first dose of study treatment until discontinuation of study treatment Time to treatment discontinuation/ failure due to toxicity is defined as the time from first dose of study treatment to discontinuation of study treatment due to an adverse event or death due to study treatment toxicity.
Trough Plasma Concentration (Ctrough) of Avelumab Pre dose (0 hour) on Day 1, 15 and 29 of Cycle 1, Day 1 and 29 of Cycles 2, 3, 4 and Day 1 of Cycle 6 Predose concentration during multiple dosing.
Ctrough of Axitinib Pre dose (0 hour) on day 15 and 29 of cycle 1 (each cycle= 6 weeks) Predose concentration during multiple dosing.
Maximum Plasma Concentration (Cmax) of Axitinib 2 hours post-dose on Day 1, pre-dose and 2 hours post dose on Days 15 and 29 of Cycle 1 Number of Participants With Positive PD-L1 Biomarker Expression in Pre-treatment Tumor Tissue At screening Tumor biospecimens from pre-treatment tissue samples were analyzed by immunohistochemistry for PD-L1 biomarker expression. Number of participants with positive PD-L1 biomarker expression are reported in this outcome measure.
PFS in PD-L1 Biomarker-Positive and PD-L1 Biomarker-Negative Subgroups From date of randomization to the first documentation of PD or death due to any cause or censoring date, whichever occurred first (maximum up to approximately 26 months) PFS: time from the date of randomization to the date of the first documentation of PD according to RECIST v1.1 or death due to any cause, whichever occurred first. PFS data was censored on date of last adequate tumor assessment for participants who did not have an event (PD or death), who started new anti-cancer therapy prior to an event or for participants with an event after 2 or more missing tumor assessments. PD was defined as at least a 20% increase in the sum of all the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to relative increase of 20 %, sum must have also demonstrated an absolute \> of at least 5 mm. The appearance of one or more new lesions was also considered progression.
Percentage of Participants With OR in PD-L1 Biomarker-Positive and PD-L1 Biomarker-Negative Subgroups From date of randomization until PD (maximum up to approximately 26 months) OR was defined as best overall response of CR or PR according to RECIST v1.1 as assessed by BICR recorded from date of randomization until disease progression. CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis\<10 mm). All target lesions must be assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed.
Percentage of Participants With DC in Biomarker-Positive Subgroup From date of randomization until PD or death, whichever occurred first (maximum up to approximately 26 months) DC was defined as a best overall response of CR, PR, or stable disease (SD) according to the RECIST v.1.1 recorded from randomization until disease progression or death due to any cause, whichever occurred first. CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis\<10 mm). All target lesions must be assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed. SD was defined as PR that the sum increases by less than 20% from the nadir, (smallest sum of diameters consider baseline and all assessments prior to the time point under evaluation), but enough that a previously documented 30% decrease no longer holds.
TTR in Biomarker-Positive Subgroup From the date of randomization to the first documentation of objective response (CR or PR) (maximum up to approximately 26 months) TTR was defined as the time from randomization to the first documentation of objective tumor response (CR or PR) according to RECIST v1.1 which is subsequently confirmed. CR was defined as complete disappearance of all target and non-target lesions with the exception of nodal disease. All lymph nodes must decrease to normal size (short axis\<10 mm). All target lesions must be assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. All target lesions must be assessed.
DR in PD-L1 Biomarker-Positive and PD-L1 Biomarker-Negative Subgroups From documentation of OR until date of first documentation of PD or death due to any cause, whichever occurred first (maximum up to approximately 26 months) DR: time from first documentation of OR (confirmed CR or PR) to date of first documentation of PD or death due to any cause, whichever occurred first. As per RECIST version 1.1, CR: disappearance of all target and non-target lesions, and sustained for at least 4 weeks. Any pathological lymph nodes (target or non-target) must have reduction in short axis to \<10 mm. PR: at least 30%\< in sum of longest dimensions of target lesions taking as reference baseline sum longest dimensions. PD: defined as at least a 20% \> in sum of diameters of target lesions, taking as reference the smallest sum on study (this included baseline sum if that is smallest on study). In addition to relative increase of 20%, sum must have also demonstrated an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered progression.
Number of Participants With Positive Anti-Drug Antibodies (ADA) and Neutralizing Antibodies (nAb) of Avelumab When Used in Combination With Axitinib From start of treatment until 30 days after the end of avelumab treatment (maximum up to approximately 89 months) Time to Symptom Deterioration (TTD) for Functional Assessment of Cancer Therapy (FACT)-Kidney Symptom Index - Disease Related Symptoms (FKSI-DRS) Date of randomization to the first time the participant's score showed a 3-point or greater decrease in FKSI-DRS (maximum up to approximately 26 months) TTD was defined as the time from date of randomization to the first time the participant's score showed a 3-point or greater decrease in FKSI-DRS. FKSI was used to assess symptoms and quality of life (QoL) for those diagnosed with advanced kidney cancer and it consisted of 19 questions. A 9-item subscale of the FKSI known as FKSI-Disease Related Symptoms subscale (FKSI-DRS). This subscale included 9 items: lack of energy, pain, losing weight, bone pain, fatigue, shortness of breath, coughing, bothered by fevers, and hematuria. Each of the 9 items was answered on a 5-point Likert-type scale ranging from 0 to 4 (0= not at all, 1= a little bit, 2= somewhat, 3= quite a bit, 4= very much). Total FKSI-DRS score = sum of the 9 item scores; total range: 0 - 36; 0 (no symptoms) to 36 (very much); higher score indicated greater presence of symptoms.
Change From Baseline in European Quality of Life (EuroQol) 5-Dimension 5 Levels (EQ-5D-5L) Utility Score Baseline, Day 1 of Cycle 2 to Cycle 60, End of treatment (any Day from Day 1 of dosing; maximum up to approximately 89 months) EQ-5D-5L is a 5-item participant-completed questionnaire designed to assess health status in terms of a single utility score. EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. Overall scores ranged from 0 to 1, with low scores representing a higher level of dysfunction. Published UK weights were used to create a single summary utility score. Utility scores range from -0.594 to 1, with higher scores representing better health status.
Change From Baseline in EQ-5D Visual Analogue Scale (VAS) Score Baseline, Day 1 of Cycle 2 to Cycle 60, End of treatment (any Day from Day 1 of dosing; maximum up to approximately 89 months) EQ-VAS records the participant's self-rated health status from 0 (worst imaginable health status) to 100 (best imaginable health status), where higher scores indicated better health status.
Number of Participants With Laboratory Abnormalities Based on NCI-CTCAE V4.03 From first dose of study drug to 90 days after last administration of study drug Number of Participants Who Discontinued Treatment Due to Toxicity From first dose of study treatment until discontinuation of study treatment
Trial Locations
- Locations (271)
Los Angeles General Medical Center
🇺🇸Los Angeles, California, United States
Southern Cancer Center
🇺🇸Mobile, Alabama, United States
Tower Hematology Oncology Medical Group
🇺🇸Beverly Hills, California, United States
City of Hope National Medical Center
🇺🇸Duarte, California, United States
City of Hope
🇺🇸Duarte, California, United States
Keck Hospital of USC
🇺🇸Los Angeles, California, United States
LAC + USC Medical Center
🇺🇸Los Angeles, California, United States
USC IDS Pharmacy
🇺🇸Los Angeles, California, United States
USC/Norris Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
Cedars-Sinai Advanced Health Sciences Pavilion
🇺🇸Los Angeles, California, United States
Scroll for more (261 remaining)Los Angeles General Medical Center🇺🇸Los Angeles, California, United States