Metastatic Renal Cell Carcinoma
Conditions
Keywords
Metastatic Renal Cell Carcinoma, sunitinib, alternating, temsirolimus
Brief summary
In the past 5 years, treatment for metastatic Renal Cell Carcinoma (mRCC) has focused on agents directed at blocking tumor and vascular growth pathways. Sunitinib blocks the vascular endothelial growth factor receptor (VEGFr) and temsirolimus is an inhibitor of mammalian target of rapamycin (mTOR). Both sunitinib and temsirolimus are FDA approved agents for mRCC. When agents like these are given together, the toxicity increases but they can be given safely, at full doses, sequentially. We hypothesize that alternating these agents will double the progression free survival (PFS) of the agents when given sequentially.
Detailed description
SUMMARY: Alternating Targeted Therapy in Patients with Metastatic Renal Cell Carcinoma: A Phase II Study of Alternating Sunitinib and Temsirolimus Patients with measurable metastatic renal cell carcinoma (any histology) are eligible. All patients will be treated as outlined below with sunitinib alternating with temsirolimus. Patients will be treated continuously, until evidence of progression of disease, or for up to two cycles following disappearance of all disease. A cycle is defined as: Sunitinib 50mg by mouth daily for 4 weeks followed by a two week rest Temsirolimus 25mg IV weekly for 4 weeks followed by a two week rest
Interventions
DRUGSunitinib
Sunitinib 50mg by mouth daily for 4 weeks followed by a two week rest
DRUGTemsirolimus
Temsirolimus 25mg IV weekly for 4 weeks followed by a two week rest
Sponsors
Dartmouth-Hitchcock 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 metastatic renal cell cancer with evaluable disease. * Patients must be at least 2 weeks from their last immunotherapy, surgery or chemotherapy (6 weeks for nitrosureas) and recovered from all ill effects. * Karnofsky Performance Status ≥60% * Life expectancy ≥ twelve weeks * Adequate end organ function: Cardiac Left ventricular ejection fraction (LVEF) ≥lower limit of institutional normal (LLN) as assessed by echocardiography (ECHO) . The same modality used at baseline must be applied for subsequent evaluations. * Women should not be lactating and, if of childbearing age, have a negative pregnancy test within two weeks of entry to the study and practicing acceptable forms of birth control * Appropriate Contraception in both sexes * The patient must be competent and signed informed consent.
Exclusion criteria
* Concomitant second malignancy except for non-melanoma skin cancer, and non-invasive cancer such as cervical CIS, superficial bladder cancer without local recurrence, breast CIS. * In patients with a prior history of invasive malignancy, less than five years in complete remission. * Have evidence of significant co-morbid illness such as uncontrolled diabetes, hypertension or active infection that would preclude treatment on this regimen. * Prior treatment with either sunitinib or temsirolimus * Clinically significant gastrointestinal abnormalities * Presence of uncontrolled infection. * Prolongation of corrected QT interval (QTc) \> 480 milliseconds - History of any one or more of the following cardiovascular conditions within the past 12 months: 1. Cardiac angioplasty or stenting 2. Myocardial infarction 3. Unstable angina 4. Coronary artery by-pass graft surgery 5. Symptomatic peripheral vascular disease 6. Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA) * History of cerebrovascular accident (CVA) including transient ischemic attack (TIA) within the past 12 months. * History of pulmonary embolism or untreated deep venous thrombosis (DVT)within the past 6 months. Note: Subjects with recent DVT who have been treated with therapeutic anticoagulating agents for at least 6 weeks are eligible. * Poorly controlled hypertension \[defined as systolic blood pressure (SBP) of ≥150 or diastolic blood pressure (DBP) of ≥ 90. Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. * Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer. * Evidence of active bleeding or bleeding diathesis * Hemoptysis within 6 weeks of first dose of study drug. * Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels * Any serious and/or unstable pre-existing medical, psychiatric, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study. * Is now undergoing and/or has undergone in the 14 days immediately prior to first dose of study drug any minor surgeries (i.e. skin biopsy, tooth extraction, etc.) and recovered from all ill effects. * Any ongoing toxicity from prior anti-cancer therapy that is \>Grade 1 and/or that is progressing in severity. * Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to sunitinib or temsirolimus. * Untreated brain metastasis. (Brain metastases that are stable based on radiographic evidence 4 weeks after radiation and/or surgery are permitted).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | From the date of randomization until the first documented disease progression or date of death from any cause, evaluated every 12 weeks throughout duration of study treatment | To determine the time to disease progression in metastatic renal cell carcinoma patients treated with alternating targeted therapy. This time interval constitutes the metric progression free survival time. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response Rate as Measured by Best Response Achieved | Every 12 weeks from randomization until progression, estimated time frame is 18 months | To be assigned a status of partial response or complete response, changes in tumor measurements must be confirmed by repeat assessments that should be performed no less than 4 weeks after the criteria for response are first met. In the case of stable disease, follow-up measurements must have met the stable disease criteria at least once after study entry at a minimum interval (in general, not less than 6-8 weeks) that is defined in the study protocol. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR |
| To Characterize the Toxicity Profile | Throughout the duration of the patient remaining on study treatment which was a median time of 8 months | The toxicity profile will be characterized by observations of AEs and SAEs graded by the CTCAE criteria v4.0. |
Countries
United States
Participant flow
Recruitment details
37 participants signed consent, of those, 3 withdrew consent and 15 were screen failures
Participants by arm
| Arm | Count |
|---|---|
| Number of Participants Classified by Tumor Histology/Cytology A cycle is defined as:
Sunitinib 50mg by mouth daily for 4 weeks followed by a two week rest Temsirolimus 25mg IV weekly for 4 weeks followed by a two week rest
Sunitinib: Sunitinib 50mg by mouth daily for 4 weeks followed by a two week rest
Temsirolimus: Temsirolimus 25mg IV weekly for 4 weeks followed by a two week rest | 19 |
| Total | 19 |
Baseline characteristics
| Characteristic | Number of Participants Classified by Tumor Histology/Cytology |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 9 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Age, Continuous | 63.0 Years STANDARD_DEVIATION 10.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Region of Enrollment United States | 19 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 16 Participants |
| Tumor Histology/Cytology Clear Cell | 16 participants |
| Tumor Histology/Cytology Papillary | 1 participants |
| Tumor Histology/Cytology Unclassified | 2 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 19 |
| other Total, other adverse events | 19 / 19 |
| serious Total, serious adverse events | 4 / 19 |
Outcome results
Primary
Progression Free Survival
To determine the time to disease progression in metastatic renal cell carcinoma patients treated with alternating targeted therapy. This time interval constitutes the metric progression free survival time.
Time frame: From the date of randomization until the first documented disease progression or date of death from any cause, evaluated every 12 weeks throughout duration of study treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alternating Sunitinib and Temsirolimus | Progression Free Survival | 8.8 Months |
Secondary
Clinical Response Rate as Measured by Best Response Achieved
To be assigned a status of partial response or complete response, changes in tumor measurements must be confirmed by repeat assessments that should be performed no less than 4 weeks after the criteria for response are first met. In the case of stable disease, follow-up measurements must have met the stable disease criteria at least once after study entry at a minimum interval (in general, not less than 6-8 weeks) that is defined in the study protocol. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time frame: Every 12 weeks from randomization until progression, estimated time frame is 18 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alternating Sunitinib and Temsirolimus | Clinical Response Rate as Measured by Best Response Achieved | Partial Response | 5 Participants |
| Alternating Sunitinib and Temsirolimus | Clinical Response Rate as Measured by Best Response Achieved | Stable Disease | 9 Participants |
| Alternating Sunitinib and Temsirolimus | Clinical Response Rate as Measured by Best Response Achieved | Progression of Disease | 3 Participants |
| Alternating Sunitinib and Temsirolimus | Clinical Response Rate as Measured by Best Response Achieved | Not Evaluable | 2 Participants |
Secondary
To Characterize the Toxicity Profile
The toxicity profile will be characterized by observations of AEs and SAEs graded by the CTCAE criteria v4.0.
Time frame: Throughout the duration of the patient remaining on study treatment which was a median time of 8 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alternating Sunitinib and Temsirolimus | To Characterize the Toxicity Profile | 19 participants |