Hereditary Leiomyomatosis and Renal Cell Carcinoma, Papillary Renal Cell Carcinoma, Renal Cell Carcinoma, Sporadic Papillary Renal Cell Carcinoma, Stage III Renal Cell Cancer AJCC v8, Stage IV Renal Cell Cancer AJCC v8
Conditions
Brief summary
This phase II trial studies the effects of combination therapy with bevacizumab, erlotinib, and atezolizumab in treating patients with hereditary leiomyomatosis and kidney cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Bevacizumab is in a class of medications called antiangiogenic agents. They work by stopping the formation of blood vessels that bring oxygen and nutrients to tumors. This may slow the growth and spread of tumors. Erlotinib is in a class of medications called kinase inhibitors. It works by blocking the action of a protein called EGFR that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Combination therapy with bevacizumab, erlotinib, and atezolizumab may stabilize or shrink advanced hereditary leiomyomatosis and kidney cancer.
Detailed description
PRIMARY OBJECTIVE: I. To assess the complete response (CR) rate according to standard Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) in patients with 1) advanced renal cell cancer (RCC) associated with hereditary leiomyomatosis and renal cell cancer (HLRCC) and 2) advanced sporadic/non-HLRCC papillary renal cell cancer treated with a combination of bevacizumab, erlotinib, and atezolizumab. SECONDARY OBJECTIVES: I. To determine the safety and tolerability of the combination of bevacizumab, erlotinib, and atezolizumab. II. To determine the objective response rate (ORR) as complete response (CR) + partial response (PR). III. To determine disease control rate (DCR) - confirmed response, or stable disease (SD) lasting for at least 6 months. IV. To assess progression-free survival time (PFS) according to RECIST 1.1. V. To assess overall survival (OS). VI. To assess the duration of response. VII. To assess response to treatment using immune-modified Response Evaluation Criteria in Solid Tumors (iRECIST). EXPLORATORY OBJECTIVES: I. To evaluate immunologic modulation associated with the administered treatment regimen, including: Ia. Peripheral immune subset analysis before and on treatment; Ib. Evaluation of relevant soluble factors before and on treatment. (e.g., cytokine profiles); Ic. Tumor tissue immune infiltration cells before and after treatment (immune microenvironment, CD8/CD4/CD3 cells, T-cell receptor clonality); Id. Evaluation of tissue PDL1/PD1 expression and their correlation with outcome. II. To assess specific genomic alterations (including fumarate hydratase \[FH\], NRF2 pathway) and determine if there is a correlation with clinical outcomes. OUTLINE: Patients receive bevacizumab intravenously (IV) over 30-90 minutes and atezolizumab IV over 30-60 minutes on day 1 of each cycle. Patients also receive erlotinib orally (PO) once daily (QD) on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) with or without contrast and magnetic resonance imaging (MRI) throughout the trial. Patients undergo collection of blood throughout the trial, and may undergo a biopsy during screening, as well as a brain MRI/CT scan with contrast, bone scan, and/or F-18 sodium fluoride positron emission tomography (PET) scan as clinically indicated. After completion of study treatment, patients are followed up every 6 months.
Interventions
BIOLOGICALAtezolizumab
Given PO
BIOLOGICALBevacizumab
Given IV
PROCEDUREBiopsy Procedure
Undergo biopsy
PROCEDUREBiospecimen Collection
Undergo blood collection
PROCEDUREBone Scan
Undergo bone scan
PROCEDUREComputed Tomography
Undergo CT without contrast
PROCEDUREComputed Tomography with Contrast
Undergo CT with contrast
DRUGErlotinib
Given PO
PROCEDUREMagnetic Resonance Imaging
Undergo MRI
PROCEDUREPositron Emission Tomography
Undergo PET
Given F-18 sodium fluoride
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have: * A diagnosis of HLRCC with a histologic or cytologic confirmation of RCC consistent with this diagnosis (Cohort 1) OR * Cytologically or histologically confirmed sporadic/non-HLRCC papillary renal cell carcinoma (presence of papillary component) (Cohort 2) * Patients must have advanced RCC with measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as \>= 20 mm (\>= 2 cm) by chest x-ray or as \>= 10 mm (\>= 1 cm) with CT scan, MRI, or calipers by clinical exam. To be considered pathologically enlarged and measurable, a lymph node must be \>= 15 mm (\>= 1.5 cm) in short axis * Patients must have received no more than two prior regimens targeting the VEGF pathway and no prior bevacizumab therapy in the metastatic/advanced setting. No prior treatment with PD-1 or PD-L1 inhibitors in the metastatic/advanced setting. No prior therapy is required for eligibility * Age \>= 12 years * Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%) * Absolute neutrophil count \>= 1,000/mcL * Platelets \>= 100,000/mcL * Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) (\< 3 x upper limit of reference range in patients with known/suspected Gilbert's disease) * Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional ULN (or =\< 5 x upper limit of reference range if considered to be related to liver or bone metastases by the principal investigator \[PI\]) * Alkaline phosphatase =\< 2.5 x institutional ULN (or =\< 5 x upper limit of reference range if considered to be related to liver or bone metastases by the PI) * Note: For pediatric patients (\< 18 years of age), ULN for alkaline phosphatase will be defined as 390 IU/L for males and 320 IU/L for females * Glomerular filtration rate (GFR) \>= 30 mL/min/1.73 m\^2 * Note: For pediatric patients (\< 18 years of age) the following creatinine thresholds will be utilized. Patients with a creatinine that exceeds this threshold will require further testing with a confirmation of GFR \>= 40 as determined by either 24-hour urine collection or with radioisotope based nuclear medicine evaluation * Age: 12 to \< 13 years; Maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female) * Age: 13 to \< 16 years; Maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female) * Age: 16 to \< 18 years; Maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female) * The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR, utilizing child length and stature data published by the Centers for Disease Control and Prevention (CDC) * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with an undetectable viral load within 6 months are eligible for this trial * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load * Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression/recurrence for \>= 3 months and the patient no longer requires more than a physiologic dose of steroids * Patients with a prior or concurrent invasive malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial * Patients with a known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better * The effects of study drugs on the developing human fetus are unknown. For this reason, all women and men of childbearing potential must agree to use adequate contraception (including but not limited to abstinence, barrier methods, hormonal contraceptives \[birth control pills, injections, or implants\], intrauterine device \[IUD\], tubal ligation, vasectomy) prior to study entry and for 6 months after completion of study therapy. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, and 6 months after completion of study drugs administration * Subjects must provide archival tissue block or unstained tumor tissue or be willing to undergo biopsy to collect samples for retrospective central pathology review * The ability of subject or parent/guardian to understand and the willingness to sign a written informed consent document or subjects with impaired decision making capacity (IDMC) if they are represented by a legally authorized representative (LAR)
Exclusion criteria
* Any prior systemic therapy to treat the patient's kidney cancer within 4 weeks or, if known, 5 half-lives of the prior agent (whichever is shorter) prior to cycle 1 day 1 * Other prior therapies for kidney cancer: Radiotherapy \< 2 weeks prior to cycle 1, day 1 * Major surgical procedure \< 28 days before cycle 1, day 1. Surgical procedure change (including open biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity) or significant traumatic injury within 28 days prior to initiation of study treatment, or anticipation of need for major surgical procedure during the course of the study. Surgical wounds must be healed prior to starting therapy. However, the following therapies are allowed: * Hormone-replacement therapy or oral contraceptives * Herbal therapy \> 1 week prior to cycle 1, day 1. All herbal therapy must be discontinued at least 1 week prior to cycle 1, day 1 * Palliative radiotherapy for bone metastases \> 2 weeks prior to cycle 1, day 1 * Patients who have not recovered from adverse events due to prior systemic anti-cancer therapy (i.e., have residual toxicities \> grade 1 of the Common Terminology Criteria for Adverse Events \[CTCAE\] version \[v\]5, pre-treatment baseline or to a level permitted under other sections of inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of adverse events | Up to 28 days after treatment | To determine the safety and tolerability of the combination of bevacizumab, erlotinib, and atezolizumab, the fraction of patients with a dose-limiting toxicity will be reported, along with the maximum grade and type of toxicity for each type noted. Note: In addition to adverse events in the entire study population, pediatric toxicities will also be reported and analyzed separately. |
| Objective response rate | Up to 2 years from study enrollment | Defined as complete response (CR) + partial response (PR), the fraction with a response (CR+PR) will be reported separately by cohort, along with a 95% confidence interval. |
| Disease control rate | Up to 2 years from study enrollment | Will be reported for patients with confirmed response, or stable disease (SD) lasting for at least 6 months. Will be reported separately by cohort, along with a 95% confidence interval. |
| Progression-free survival time (PFS) | Time from study treatment initiation until disease progression or death, assessed up to 2 years from study enrollment | Assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, PFS will be determined using the Kaplan-Meier method, and the curves presented along with a 95% confidence interval on the median PFS, separately by cohort. |
| Overall survival (OS) | From study treatment initiation until death from any cause, assessed up to 2 years from study enrollment | The Kaplan-Meier method will be used and the curves presented along with a 95% confidence interval on the median OS, separately by cohort. |
| Duration of response (DOR) | Length of time without disease progression or recurrence, up to 2 years from study enrollment | The Kaplan-Meier method will be used and the curves presented along with a 95% confidence interval on the median DOR, separately by cohort. |
| Response to treatment | Assessed up to 2 years from study enrollment | Response to treatment using immune-modified Response Evaluation Criteria in Solid Tumors (iRECIST), the fraction with a response (CR+PR) according to iRECIST will be reported separately by cohort, along with a 95% confidence interval. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORRamaprasad Srinivasan
National Cancer Institute LAO
Outcome results
None listed