Adjuvant Axitinib Therapy of Renal Cell Cancer in High Risk Patients

Adjuvant Axitinib Treatment of Renal Cancer: A Randomized Double-blind Phase 3 Study of Adjuvant Axitinib vs. Placebo in Subjects at High Risk of Recurrent RCC

Status

Terminated

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01599754

Acronym

ATLAS

Enrollment

724

Registered

2012-05-16

Start date

2012-04-30

Completion date

2018-05-31

Last updated

2019-09-20

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Clear Cell Renal Carcinoma

Keywords

renal cell carcinoma, axitinib, tyrosine kinase inhibitor

Brief summary

The purpose of this trial is to determine if adjuvant therapy with axitinib will prevent or delay the recurrence of renal cell cancer after surgery to remove the primary tumor in high risk patients.

Detailed description

This is a prospective, randomized, double blind placebo controlled Phase 3 trial of oral axitinib starting at 5 mg twice daily given 3 years vs. placebo. Approximately 700 patients will be randomized in a 1:1 ratio between axitinib vs placebo.

Interventions

DRUGAxitinib

Axitinib 5 mg twice daily

DRUGPlacebo

Placebo twice daily

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

Patients must be treated by nephrectomy and patients must meet all of the following inclusion criteria to be eligible for enrollment into the trial: 1. Patients must have no evidence of macroscopic residual disease or metastatic disease. 2. Male or female, age \>=18 years (age \>=20 years in Japan, Korea and Taiwan). 3. Patients must be diagnosed with one of the following based on American Joint Committee on Cancer (AJCC) TNM staging version 2010, Eastern Collaborative Oncology Group (ECOG) performance status (PS): * pT2, pN0 or pNx, M0 and ECOG PS 0-1 * pT3, pN0 or pNx, M0 and ECOG PS 0-1 * pT4, pN0 or pNx, M0 and ECOG PS 0-1 * Any pT, pN1, M0 and ECOG PS 0-1 4. Patients must have histologically confirmed preponderant, defined as \>50%, clear cell RCC. 5. Patients must not have received any previous systemic (includes chemotherapeutic, hormonal, or immunotherapeutic) treatment for RCC. 6. Patients must not have received any previous anti angiogenic treatment. 7. Patients must have adequate organ function.

Exclusion criteria

1. Histologically undifferentiated carcinomas, sarcomas, collecting duct carcinoma, lymphoma, or patients with any metastatic renal sites. 2. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 hemorrhage \<4 weeks of date of randomization. 3. Diagnosis of any non-RCC malignancy within the 5 years from date of randomization, except basal cell carcinoma, squamous cell skin cancer, or in situ carcinoma of the cervix uteri that has been adequately treated with no evidence of recurrent disease for 12 months. 4. Any of the following within the 12 months prior to study drug administration: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack and 6 months for deep vein thrombosis or pulmonary embolism. 5. Gastrointestinal abnormalities

Design outcomes

Primary

Measure	Time frame	Description
Disease Free Survival (DFS) as Assessed by Blinded Independent Review Committee (IRC)	From randomization date up to first date of recurrence or the occurrence of a secondary malignancy or death (up to 5 years)	DFS is defined as time interval from the date of randomization to first date of recurrence/relapse (distant or local recurrence of \[RCC\] or occurrence of a secondary malignancy {occurrence of a second primary cancer other than RCC} or death). For participants with no DFS event, DFS was censored at date of last scan prior to time of analyses. Participants alive who did not have post-baseline disease assessments, DFS was censored at randomization. Participants who received further anti-tumor therapy prior to recurrence or occurrence of a secondary malignancy or death, DFS was censored on date of last scan prior to taking anti-tumor medication. Participants who missed 2 or more consecutive tumor scans immediately followed by an event were censored at date of last objective tumor assessment prior to missing/not readable scan.

Secondary

Measure	Time frame	Description
Number of Participants With Treatment-Emergent Adverse Events (AE) and Serious Adverse Events (SAEs)	From Day 1 up to 28 days after last dose (maximum duration of 3 years)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. AEs included both serious and non-serious adverse events.
Number of Participants With Treatment-Emergent Treatment Related Adverse Events and Serious Adverse Events (SAEs)	From Day 1 up to 28 days after last dose (maximum duration of 3 years)	A treatment related AE is any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event had a causal relationship with the treatment or usage. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Relatedness was judged by investigator. AEs included both serious and non-serious adverse events.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) By Severity	From Day 1 up to 28 days after last dose (maximum duration of 3 years)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. AE was assessed according to severity as: Grade 1 (mild AE), Grade 2 (moderate AE), Grade 3 (severe AE), Grade 4 (life-threatening consequences) and Grade 5 (death related to AE).
Overall Survival (OS)	From randomization date until death due to any cause (up to 5 years)	OS defined as the time from the date of randomization to the date of death due to any cause. In the absence of confirmation of death, survival time was censored at the last date the participant was known to be alive. Participants lacking data beyond randomization had their survival times censored at randomization.
Number of Participants With Laboratory Abnormalities By Maximum CTCAE Grade: Chemistry	From Day 1 up to 28 days after last dose (maximum duration of 3 years)	Chemistry parameters included: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatine phosphokinase increased, creatinine increased, hypoalbuminemia, hypercalcemia, hypocalcemia, hyperglycemia, hypoglycemia, hyperkalemia, hypokalemia, hypernatremia, hyponatremia. CTCAE grades: Grade 1 (mild AE), Grade 2 (moderate AE), Grade 3 (severe AE), Grade 4 (life-threatening consequences) and Grade 5 (death related to AE).
Number of Participants With Laboratory Abnormalities: Thyroid Function	From Day 1 up to 28 days after last dose (maximum duration of 3 years)	Number of participants with thyrotropin levels: \<5 milli-international units per litre (mIU/L), \>=5 to \<10 mIU/L, \>=10 mIU/L are reported.
Number of Participants With Laboratory Abnormalities: Urinalysis	From Day 1 up to 28 days after last dose (maximum duration of 3 years)	Number of participants with urine protein dipstick grading: negative/trace (5 to 20 milligram per deciliter \[mg/dL\]), 1+ (30 mg/dL\]), 2+ (100 mg/dL), 3+ (300 mg/dL) and 4+ (more than 1000 mg/dL) are reported.
Number of Participants With Laboratory Abnormalities By Maximum CTCAE Grade: Hematology	From Day 1 up to 28 days after last dose (maximum duration of 3 years)	Hematology parameters included anemia, hemoglobin increased, lymphocyte count increased, lymphocyte count decreased, neutrophil count decreased, platelet count decreased, and white blood cell count decreased. CTCAE grades: Grade 1 (mild AE), Grade 2 (moderate AE), Grade 3 (severe AE), Grade 4 (life-threatening consequences) and Grade 5 (death related to AE).

Countries

China, France, Hong Kong, India, Japan, South Korea, Spain, Taiwan, United States

Participant flow

Recruitment details

A total of 128 study sites in 9 countries randomized 724 participants into this study.

Participants by arm

Arm	Count
Axitinib Participants at high risk of recurrent RCC received Axitinib 5 mg twice a day, in cycles of 4 weeks, up to 3 years with a minimum treatment duration of 1 year unless relapse, the occurrence of secondary malignancy or death occurred prior to 1 year. Participants were followed up after every 6 months after end of treatment. .	363
Placebo Participants at high risk of RCC received placebo matched to Axitinib twice a day in cycles of 4 weeks, up to 3 years with a minimum treatment duration of 1 year unless relapse, the occurrence of secondary malignancy or death occurred prior to 1 year. Participants were followed up after every 6 months after end of treatment.	361
Total	724

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	3	2
Overall Study	Anticancer therapy need not in protocol	5	2
Overall Study	Death	31	33
Overall Study	Investigator decision	1	3
Overall Study	Lost to Follow-up	13	6
Overall Study	Participant noncompliance	4	4
Overall Study	Study terminated by sponsor	282	285
Overall Study	Withdrawal by Subject	24	25

Baseline characteristics

Characteristic	Axitinib	Placebo	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	108 Participants	114 Participants	222 Participants
Age, Categorical Between 18 and 65 years	255 Participants	247 Participants	502 Participants
Age, Continuous	57.9 Years STANDARD_DEVIATION 10.8	58.1 Years STANDARD_DEVIATION 11.33	58.0 Years STANDARD_DEVIATION 11.06
BMI Missing	4 Participants	1 Participants	5 Participants
BMI Normal Weight	187 Participants	173 Participants	360 Participants
BMI Obese	50 Participants	51 Participants	101 Participants
BMI Overweight	115 Participants	124 Participants	239 Participants
BMI Overweight + Obese	165 Participants	175 Participants	340 Participants
BMI Underweight	7 Participants	12 Participants	19 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	264 Participants	267 Participants	531 Participants
Race (NIH/OMB) Black or African American	3 Participants	1 Participants	4 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	5 Participants	3 Participants	8 Participants
Race (NIH/OMB) White	91 Participants	90 Participants	181 Participants
Region of Enrollment China	63 participants	65 participants	128 participants
Region of Enrollment France	23 participants	23 participants	46 participants
Region of Enrollment Hong Kong	6 participants	5 participants	11 participants
Region of Enrollment India	7 participants	8 participants	15 participants
Region of Enrollment Japan	81 participants	79 participants	160 participants
Region of Enrollment South Korea	87 participants	88 participants	175 participants
Region of Enrollment Spain	28 participants	27 participants	55 participants
Region of Enrollment Taiwan	18 participants	19 participants	37 participants
Region of Enrollment United States	50 participants	47 participants	97 participants
Sex: Female, Male Female	83 Participants	111 Participants	194 Participants
Sex: Female, Male Male	280 Participants	250 Participants	530 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	31 / 360	33 / 360
other Total, other adverse events	353 / 360	332 / 360
serious Total, serious adverse events	75 / 360	54 / 360

Outcome results

Primary

Disease Free Survival (DFS) as Assessed by Blinded Independent Review Committee (IRC)

DFS is defined as time interval from the date of randomization to first date of recurrence/relapse (distant or local recurrence of \[RCC\] or occurrence of a secondary malignancy {occurrence of a second primary cancer other than RCC} or death). For participants with no DFS event, DFS was censored at date of last scan prior to time of analyses. Participants alive who did not have post-baseline disease assessments, DFS was censored at randomization. Participants who received further anti-tumor therapy prior to recurrence or occurrence of a secondary malignancy or death, DFS was censored on date of last scan prior to taking anti-tumor medication. Participants who missed 2 or more consecutive tumor scans immediately followed by an event were censored at date of last objective tumor assessment prior to missing/not readable scan.

Time frame: From randomization date up to first date of recurrence or the occurrence of a secondary malignancy or death (up to 5 years)

Population: ITT population included all randomized participants regardless of whether or not treatment was administered and based on randomized treatment assignment.

Arm	Measure	Value (MEDIAN)
Axitinib	Disease Free Survival (DFS) as Assessed by Blinded Independent Review Committee (IRC)	NA years
Placebo	Disease Free Survival (DFS) as Assessed by Blinded Independent Review Committee (IRC)	NA years

p-value: 0.321195% CI: [0.66, 1.147]Log Rank

Secondary

Number of Participants With Laboratory Abnormalities By Maximum CTCAE Grade: Chemistry

Chemistry parameters included: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatine phosphokinase increased, creatinine increased, hypoalbuminemia, hypercalcemia, hypocalcemia, hyperglycemia, hypoglycemia, hyperkalemia, hypokalemia, hypernatremia, hyponatremia. CTCAE grades: Grade 1 (mild AE), Grade 2 (moderate AE), Grade 3 (severe AE), Grade 4 (life-threatening consequences) and Grade 5 (death related to AE).