Metastatic Renal Cell Carcinoma
Conditions
Brief summary
The purpose of this study is to determine whether ramucirumab is effective treatment in participants with metastatic renal cell carcinoma who have developed progressive disease or become intolerant to tyrosine kinase inhibitor therapy.
Detailed description
The Primary objective is to determine the best objective response rate (ORR) of ramucirumab when administered to participants with metastatic renal cell carcinoma (RCC) whose disease has progressed during therapy with a tyrosine kinase inhibitor (TKI, sunitinib and/or sorafenib) or who have developed intolerance to these agents.
Interventions
BIOLOGICALRamucirumab
Ramucirumab is an injectable solution administered as an intravenous infusion over 1 hour at a dose of 8 mg/kg day 1 of every 14-day cycle.
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The participant has histologically or cytologically confirmed clear cell RCC * The participant is ≥ 18 years of age * The participant has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 or Karnofsky Performance Status (KPS) ≥ 80% * The participant has had a prior nephrectomy (as therapy for RCC) * The participant has metastatic RCC * The participant has a life expectancy of \> 3 months * The participant has measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) * The participant has received prior therapy with a TKI (sunitinib and/or sorafenib) with either disease progression on TKI therapy (progression within 60 days of the last dose of TKI) or intolerance to TKI (unable to continue therapy because of side-effects). A participant with progression during a protracted treatment break is not eligible unless the participant has had progression or intolerance as defined above * The participant has resolution of all clinically significant toxic effects of prior cancer therapy to grade ≤ 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 (NCI-CTCAE) * The participant has adequate hematological functions \[absolute neutrophil count (ANC) ≥ 1500 cells per milliliter (cells/mL), hemoglobin ≥ 9 grams per deciliter (g/dL) and platelets ≥ 100,000 cells/mL\] * The participant has adequate hepatic function \[bilirubin within normal limits (WNL), aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤ 2.5 times the upper limit of normal (ULN), or ≤ 5.0 times the ULN if the transaminase elevation is due to liver metastases\] * The participant has normal renal function or mild renal dysfunction \[creatinine ≤ 2.2 milligrams per deciliter (mg/dL)\] * The participant's urinary protein ≤ 1+ on dipstick or routine urinalysis \[(UA); if urine dipstick or routine analysis is ≥ 2+, a 24-hour urine for protein must demonstrate \< 1000 (milligrams) mg of protein in 24 hours to allow participation in the study\] * The participant must have adequate coagulation function as defined by International Normalized Ratio (INR) ≤ 1.8 and a partial thromboplastin time (PTT) ≤ 1.5 X ULN. Participants on full-dose anticoagulation must be on a stable dose of oral anticoagulant or low molecular weight (LMW) heparin and if on warfarin must have a INR between 2 and 3 and have no active bleeding or pathological condition that carries a high risk of bleeding (for example, tumor involving major vessels or known varices) * The participant is able to provide informed written consent * The participant , if sexually active, is postmenopausal (last menstrual period \> 2 years prior to study), surgically sterile, or is using effective method of contraception in the opinion of the investigator * The participant , if female, must have a negative serum pregnancy test upon entry into this study * The participant has a normal thyroid stimulating hormone (TSH) value. Participants with an abnormal TSH may be eligible provided they meet all other eligibility criteria and have ECOG performance status 0-1. Participants with an abnormal TSH value require a full thyroid evaluation prior to enrollment. Endocrinology consultation may be performed at the discretion of the investigator * The participant has serum calcium within normal limits
Exclusion criteria
* The participant has received prior treatment with bevacizumab * The participant has known brain or leptomeningeal metastases * The participant has received \>2 prior cytotoxic chemotherapy regimens for RCC * The participant has received antitumor therapy (biologic agents, major surgery, or investigational agent) within 28 days prior to enrollment on study. The participant has received radiation therapy within 14 days prior to enrollment on study. Participants with metastasis in weight bearing bones at high risk for pathologic fracture may participate provided that appropriate surgical intervention and/or radiation therapy is undertaken and completed at least 28 days prior to enrollment * The participant has received \> 1 prior bio-immunotherapy regimens (defined as either interleukin-2 or interferon alpha given as monotherapy, concurrently, or sequentially as planned) * The participant has a concurrent active malignancy other than adequately treated non-melanomatous skin cancer or other non-invasive carcinoma or in situ neoplasm. A participant with previous history of malignancy is eligible, provided that he/she has been disease free for \> 3 years * The participant has a nonhealing wound or ulcer * The participant has a known alcohol or drug dependency * The participant is pregnant or breastfeeding * The participant has a coexisting medical or psychiatric problem of sufficient severity to limit compliance with the study and/or increase the risks associated with study participation or study drug administration or interfere with the interpretation of study results * The participant has an ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia, psychiatric illness/social situations, or any other serious uncontrolled medical disorders in the opinion of the investigator * The participant has known human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Objective Response (Objective Response Rate) | First dose to date of objective progressive disease or death due to any cause (up to 34 months) | The percentage of participants with a best overall response of confirmed complete response (CR) or partial response (PR) as classified according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0) criteria. CR is the disappearance of all target and non-target lesions and normalization of tumor marker levels. PR is having at least a 30% decrease in the sum of the longest diameter of target lesions without new lesions and progression of non-target lesions. The percentage of participants with objective response=(number of participants whose best overall response during therapy is CR or PR/number of participants treated)\*100. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Showing Disease Control at Week 12 | Week 12 [Cycle 6 (1 cycle=14 days)] | Participants who were alive and did not experience disease progression were considered to have disease control at 12 weeks. Disease control was based on lack of disease progression using Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0) criteria. According to RECIST criteria, disease progression was having at least a 20% increase in the sum of the longest diameter of target lesions and/or unequivocal progression of non-target lesion and/or detection of new lesion. Participants whose disease progression was symptomatic were not considered to have disease control. The percentage of participants showing disease control=(number of participants who did not have disease or symptomatic progression at Week 12/number of participants treated)\*100. |
| Percentage of Participants With Objective Response (Objective Response Rate) at 12 Weeks | Week 12 [Cycle 6 (1 cycle=14 days)] | The percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR) at Week 12, as classified according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0) criteria. CR is the disappearance of all target and non-target lesions and the normalization of tumor marker levels. PR is having at least a 30% decrease in the sum of the longest diameter of target lesions without new lesions and progression of non-target lesions. The percentage of participants with objective response=(number of participants whose best overall response achieved at 12 weeks was CR or PR/number of participants treated)\*100. |
| Median Duration of Overall Response | Time of first response (CR or PR) to disease progression, initiation of other (or additional) antitumor therapy, or death due to any cause (up to 34 months) | Duration of response is the interval from the date of initial documented response \[confirmed complete response (CR) or partial response (PR)\] to the first documented date of disease progression as classified according to Response Evaluation Criteria In Solid Tumors (RECIST version 1.0) criteria, or initiation of other (or additional) antitumor therapy is first reported, or death due to any cause. CR is the disappearance of all target and non-target lesions and the normalization of tumor marker levels. PR is having at least a 30% decrease in the sum of the longest diameter of target lesions without new lesions and progression of non-target lesions. Disease progression is having at least a 20% increase in the sum of the longest diameter of target lesions and/or unequivocal progression of a non-target lesion and/or detection of a new lesion. Data from participants who did not relapse were censored on the day of their last tumor assessment. |
| Progression-Free Survival | First dose to measured progressive disease or death due to any cause (up to 34 months) | Progression-free survival (PFS) is measured from the date of the first dose to the first documented date of disease progression as classified according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0) criteria or death from any cause. Disease progression is having at least a 20% increase in the sum of the longest diameter of target lesions and/or unequivocal progression of a non-target lesion and/or detection of a new lesion. Data for participants whose disease does not progress or for whom no post-baseline assessment is made are censored at the day of their last tumor assessment. Data for participants whose disease does not progress who are subsequently lost to follow-up are also censored at the day of their last tumor assessment. |
| Maximum Concentration (Cmax) of Ramucirumab | 1 hour after the end of the Week 32 infusion treatment [Cycle 16 (1 cycle=14 days)] | — |
| Summary Listing of Participants Reporting Drug-Related Treatment-Emergent Adverse Events | First dose to study completion (up to 34 months) plus 30-day safety follow-up | Data presented are the number of participants who experienced treatment-emergent adverse events (TEAE), serious adverse events (SAE), Grade 3 or 4 TEAE, or adverse events (AE) leading to discontinuation of treatment that were considered to be related to ramucirumab. A summary of SAEs and other nonserious AEs, regardless of causality, is located in the Reported Adverse Events section. |
| Minimum Concentration (Cmin) of Ramucirumab | Immediately prior to the Week 32 infusion treatment [Cycle 16 (1 cycle=14 days)] | — |
Countries
United States
Participant flow
Pre-assignment details
This study comprised 3 study periods: pretreatment, treatment, and (posttreatment) follow-up. 40 participants signed the informed consent.
Participants by arm
| Arm | Count |
|---|---|
| Ramucirumab Ramucirumab at 8 milligrams per kilogram (mg/kg) infused intravenously over 1 hour, on Day 1 of every 14-day cycle. Treatment continued until there was evidence of disease progression or intolerable toxicity. | 39 |
| Total | 39 |
Baseline characteristics
| Characteristic | Ramucirumab |
|---|---|
| Age, Customized >=65 years | 12 participants |
| Age, Customized Between 18 and 65 years | 27 participants |
| Ethnicity Hispanic or Latino | 1 participants |
| Ethnicity Not Hispanic or Latino | 38 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants |
| Race/Ethnicity, Customized Asian | 1 participants |
| Race/Ethnicity, Customized Black or African American | 3 participants |
| Race/Ethnicity, Customized More than one race | 0 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants |
| Race/Ethnicity, Customized White | 35 participants |
| Region of Enrollment United States | 39 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 39 / 39 |
| serious Total, serious adverse events | 12 / 39 |
Outcome results
Primary
Percentage of Participants With Objective Response (Objective Response Rate)
The percentage of participants with a best overall response of confirmed complete response (CR) or partial response (PR) as classified according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0) criteria. CR is the disappearance of all target and non-target lesions and normalization of tumor marker levels. PR is having at least a 30% decrease in the sum of the longest diameter of target lesions without new lesions and progression of non-target lesions. The percentage of participants with objective response=(number of participants whose best overall response during therapy is CR or PR/number of participants treated)\*100.
Time frame: First dose to date of objective progressive disease or death due to any cause (up to 34 months)
Population: Intent-to-treat population: participants who received any quantity of ramucirumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramucirumab | Percentage of Participants With Objective Response (Objective Response Rate) | 5.1 percentage of participants |
Secondary
Maximum Concentration (Cmax) of Ramucirumab
Time frame: 1 hour after the end of the Week 32 infusion treatment [Cycle 16 (1 cycle=14 days)]
Population: Participants who received any quantity of ramucirumab and had evaluable pharmacokinetic data at the specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ramucirumab | Maximum Concentration (Cmax) of Ramucirumab | 595 micrograms per milliliter (mcg/mL) | Standard Deviation 239 |
Secondary
Median Duration of Overall Response
Duration of response is the interval from the date of initial documented response \[confirmed complete response (CR) or partial response (PR)\] to the first documented date of disease progression as classified according to Response Evaluation Criteria In Solid Tumors (RECIST version 1.0) criteria, or initiation of other (or additional) antitumor therapy is first reported, or death due to any cause. CR is the disappearance of all target and non-target lesions and the normalization of tumor marker levels. PR is having at least a 30% decrease in the sum of the longest diameter of target lesions without new lesions and progression of non-target lesions. Disease progression is having at least a 20% increase in the sum of the longest diameter of target lesions and/or unequivocal progression of a non-target lesion and/or detection of a new lesion. Data from participants who did not relapse were censored on the day of their last tumor assessment.
Time frame: Time of first response (CR or PR) to disease progression, initiation of other (or additional) antitumor therapy, or death due to any cause (up to 34 months)
Population: Participants who received any quantity of ramucirumab and had confirmed complete response or partial response. The number of participants censored was 1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ramucirumab | Median Duration of Overall Response | NA months |
Secondary
Minimum Concentration (Cmin) of Ramucirumab
Time frame: Immediately prior to the Week 32 infusion treatment [Cycle 16 (1 cycle=14 days)]
Population: Participants who received any quantity of ramucirumab and had evaluable pharmacokinetic data at the specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ramucirumab | Minimum Concentration (Cmin) of Ramucirumab | 147 micrograms per milliliter (mcg/mL) | Standard Deviation 76.2 |
Secondary
Percentage of Participants Showing Disease Control at Week 12
Participants who were alive and did not experience disease progression were considered to have disease control at 12 weeks. Disease control was based on lack of disease progression using Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0) criteria. According to RECIST criteria, disease progression was having at least a 20% increase in the sum of the longest diameter of target lesions and/or unequivocal progression of non-target lesion and/or detection of new lesion. Participants whose disease progression was symptomatic were not considered to have disease control. The percentage of participants showing disease control=(number of participants who did not have disease or symptomatic progression at Week 12/number of participants treated)\*100.
Time frame: Week 12 [Cycle 6 (1 cycle=14 days)]
Population: Intent-to-treat population: participants who received any quantity of ramucirumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramucirumab | Percentage of Participants Showing Disease Control at Week 12 | 64.1 percentage of participants |
Secondary
Percentage of Participants With Objective Response (Objective Response Rate) at 12 Weeks
The percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR) at Week 12, as classified according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0) criteria. CR is the disappearance of all target and non-target lesions and the normalization of tumor marker levels. PR is having at least a 30% decrease in the sum of the longest diameter of target lesions without new lesions and progression of non-target lesions. The percentage of participants with objective response=(number of participants whose best overall response achieved at 12 weeks was CR or PR/number of participants treated)\*100.
Time frame: Week 12 [Cycle 6 (1 cycle=14 days)]
Population: Intent-to-treat population: participants who received any quantity of ramucirumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramucirumab | Percentage of Participants With Objective Response (Objective Response Rate) at 12 Weeks | 0.0 percentage of participants |
Secondary
Progression-Free Survival
Progression-free survival (PFS) is measured from the date of the first dose to the first documented date of disease progression as classified according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0) criteria or death from any cause. Disease progression is having at least a 20% increase in the sum of the longest diameter of target lesions and/or unequivocal progression of a non-target lesion and/or detection of a new lesion. Data for participants whose disease does not progress or for whom no post-baseline assessment is made are censored at the day of their last tumor assessment. Data for participants whose disease does not progress who are subsequently lost to follow-up are also censored at the day of their last tumor assessment.
Time frame: First dose to measured progressive disease or death due to any cause (up to 34 months)
Population: Intent-to-treat population: participants who received any quantity of ramucirumab. The number of participants censored was 4.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ramucirumab | Progression-Free Survival | 7.1 months |
Secondary
Summary Listing of Participants Reporting Drug-Related Treatment-Emergent Adverse Events
Data presented are the number of participants who experienced treatment-emergent adverse events (TEAE), serious adverse events (SAE), Grade 3 or 4 TEAE, or adverse events (AE) leading to discontinuation of treatment that were considered to be related to ramucirumab. A summary of SAEs and other nonserious AEs, regardless of causality, is located in the Reported Adverse Events section.
Time frame: First dose to study completion (up to 34 months) plus 30-day safety follow-up
Population: Intent-to-treat population: participants who received any quantity of ramucirumab.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ramucirumab | Summary Listing of Participants Reporting Drug-Related Treatment-Emergent Adverse Events | Related TEAE | 37 participants |
| Ramucirumab | Summary Listing of Participants Reporting Drug-Related Treatment-Emergent Adverse Events | Related SAE | 6 participants |
| Ramucirumab | Summary Listing of Participants Reporting Drug-Related Treatment-Emergent Adverse Events | Related Grade 3 or 4 TEAE | 10 participants |
| Ramucirumab | Summary Listing of Participants Reporting Drug-Related Treatment-Emergent Adverse Events | Related AE leading to discontinuation | 7 participants |