Kidney Cancer, Renal Cell Carcinoma
Conditions
Keywords
RCC, avastin, temsirolimus
Brief summary
This is a single-arm phase II trial evaluating the combination of avastin and temsirolimus in patients with metastatic renal cell cancer (RCC) including both histologically confirmed clear cell (cc) or non-clear cell (ncc) subtypes. Patients must have experienced disease progression or intolerable toxicity with a vascular endothelial growth factor (VEGF)-targeted tyrosine kinase inhibitor (TKI) (e.g. sorafenib, sunitinib, pazopanib). Only 2 prior VEGF therapies are allowed. The purpose of this research study is to evaluate efficacy of the combination against an historical control. Temsirolimus has been approved by the Food and Drug Administration (FDA) in the treatment of renal cell carcinoma. Avastin has been approved by the FDA for other types of cancers but not renal cell carcinoma.
Detailed description
Avastin, a humanized IgG1 monoclonal antibody (MAb), inhibits vascular endothelial growth factor (VEGF). VEGF is one of the most potent and specific proangiogenic factors and has been identified as a crucial regulator of both normal and pathological angiogenesis. Temsirolimus specifically inhibits the mammalian target of rapamycin (mTOR), a highly conserved serine/threonine kinase which regulates cell growth and metabolism in response to environmental factors. The combination avastin and temsirolimus has already demonstrated efficacy in the phase I setting STATISTICAL CONSIDERATIONS: The primary endpoint is 4-month PFS. The null and alternative hypotheses are 50% vs. 70%. Assuming 2 ineligible patients, the target sample size is 41 patients (39 eligible patients). The probability of concluding that the treatment is effective was \>0.90 if the true rate is at least 70%. The probability of concluding that the treatment is effective was ≤ 0.10 if the true rate was 50% or less. If 24 or more patients are alive and progression-free at 4 months, then this regimen would be considered for further study.
Interventions
DRUGbevacizumab
DRUGtemsirolimus
Sponsors
Genentech, Inc.
Dana-Farber Cancer Institute
Brigham and Women's Hospital
Vanderbilt University Medical Center
Beth Israel Deaconess Medical Center
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
* Histologically confirmed renal cell carcinoma in either primary or metastatic lesions. Non-clear histology will be allowed. * Disease progression on a VEGF-targeted tyrosine kinase inhibitor as the most recent therapy or have experienced intolerable toxicity so as require discontinuation. Only one prior VEGF-targeted tyrosine kinase inhibitor. * Must be off of VEGF-targeted tyrosine kinase inhibitor for 2 weeks or greater. * One measurable lesion which is not curable by standard radiation therapy or surgery. * The enrolling site must agree to obtain paraffin-embedded tumor blocks or at least 10 unstained, paraffin-embedded slides for submission for correlative studies. * 18 years of age or older * ECOG Performance Status of 0 or 1 * Baseline laboratory values as outlined in the protocol * Life expectancy of greater than 3 months * No prior malignancy diagnosed within the past three years, other than superficial basal cell and superficial squamous cell, or carcinoma in situ of the cervix.
Exclusion criteria
* Known CNS disease, except for treated brain metastases * Previously treated with avastin or mTOR inhibitors * Other then VEFG-targeted TKI, patients may only have had prior immunotherapy or chemotherapy for stage IV disease * History of allergic reaction to Chinese hamster ovary cell products, other recombinant antibodies, or compounds of similar chemical or biologic composition to avastin or temsirolimus * History of bleeding diathesis or coagulopathy. Therapeutic anticoagulants are allowed * Patients with clinically significant cardiovascular disease * Patients receiving enzyme-inducing antiepileptic drugs or any other CYP3A4 inducer such as rifampin or St. John's wort * No serious non-healing wound, ulcer or bone fracture * No uncontrolled intercurrent illness including , but not limited to, ongoing active infection requiring parental antibiotics or psychiatric illness/social situations that would limit compliance with study requirements * HIV-positive receiving combination anti-retroviral therapy * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study * Core biopsy or other minor surgical procedure, excluding placement of vascular access device, within 7 days prior to enrollment on study * History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment * Known hypersensitivity to any component of avastin or temsirolimus * Life expectancy of less than 12 weeks * History of hemoptysis within 1 month prior to day 1
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 4-month Progression-Free Survival Rate | Disease evaluations occurred every 8 weeks (+/- 1 wk) on treatment. Relevant for this endpoint was disease status at 4 months. | 4-month progression-free survival rate was defined as the percentage of participants absent death or progression based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST) before 4 months. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | Disease evaluations occurred every 8 weeks (+/- 1 wk) on treatment; Treatment continued until disease progression or unacceptable toxicity. Median (range) of treatment duration for this study cohort was 5 cycles (1-39) [1 cycle=28days]. | Objective response (OR) rate is the percentage of participants achieving partial response (PR) or complete response (CR) based on RECIST 1.0 criteria on treatment. Per RECIST 1.0 for target lesions, CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. To be assigned a status of CR or PR, changes in tumor measurements must be confirmed by repeat assessments performed no fewer than 4 weeks after the response criteria are first met. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. |
| Overall Survival | Median follow-up for survival in this study cohort is 56 months. | Overall survival (OS) is defined from the date of registration to date of death, or censored at the date the participant was last known alive. OS is estimated based on the Kaplan-Meier method. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled between April 2009 and May 2013.
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab + Temsirolimus bevacizumab: given intravenously at a dose of 10mg/kg every 2 weeks (days 1 and 15)
temsirolimus: given intravenously at a dose of 25mg weekly on days 1, 8, 15, and 22
1 cycle=28 days
There were no dose reductions for bevacizumab allowed. If bevacizumab was held, the same dose would be used if treatment were resumed. If temsirolimus was held, the same or a reduced dose (15mg IV weekly) could be used upon resumption of therapy. Treatment was continued until the development of unacceptable toxicity or progression. | 40 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 11 |
| Overall Study | Not started treatment | 1 |
| Overall Study | Other | 3 |
| Overall Study | Physician Decision | 4 |
| Overall Study | Progressive Disease | 21 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Bevacizumab + Temsirolimus |
|---|---|
| Age, Continuous | 60 years |
| MSKCC Risk Category Favorable | 5 Participants |
| MSKCC Risk Category Intermediate | 31 Participants |
| MSKCC Risk Category Poor | 4 Participants |
| Primary VEGF Refractory Status Unevaluable | 1 Participants |
| Primary VEGF Refractory Status VEGF Refractory-No | 20 Participants |
| Primary VEGF Refractory Status VEGF Refractory-Yes | 19 Participants |
| Region of Enrollment United States | 40 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 38 / 40 |
| serious Total, serious adverse events | 28 / 40 |
Outcome results
Primary
4-month Progression-Free Survival Rate
4-month progression-free survival rate was defined as the percentage of participants absent death or progression based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST) before 4 months. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.
Time frame: Disease evaluations occurred every 8 weeks (+/- 1 wk) on treatment. Relevant for this endpoint was disease status at 4 months.
Population: The analysis dataset is comprised of all treated participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Temsirolimus | 4-month Progression-Free Survival Rate | 65 percentage of participants |
Comparison: The regimen was evaluated against an historical control with null and alternative 4-month PFS rates of 50% and 70%, respectively. With the final sample size of 40 eligible patients and using the same operating characteristics (alpha and beta 10%), the decision rule changes such that if 25 or more patients of 40 are alive and progression-free at 4 months then this regimen is considered promising.p-value: 0.081exact binomial test
Secondary
Objective Response Rate
Objective response (OR) rate is the percentage of participants achieving partial response (PR) or complete response (CR) based on RECIST 1.0 criteria on treatment. Per RECIST 1.0 for target lesions, CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. To be assigned a status of CR or PR, changes in tumor measurements must be confirmed by repeat assessments performed no fewer than 4 weeks after the response criteria are first met. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.
Time frame: Disease evaluations occurred every 8 weeks (+/- 1 wk) on treatment; Treatment continued until disease progression or unacceptable toxicity. Median (range) of treatment duration for this study cohort was 5 cycles (1-39) [1 cycle=28days].
Population: The analysis dataset is comprised of all treated participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Temsirolimus | Objective Response Rate | 17.5 percentage of participants |
Secondary
Overall Survival
Overall survival (OS) is defined from the date of registration to date of death, or censored at the date the participant was last known alive. OS is estimated based on the Kaplan-Meier method.
Time frame: Median follow-up for survival in this study cohort is 56 months.
Population: The analysis dataset is comprised of all treated participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + Temsirolimus | Overall Survival | 12.2 months |