A Phase 2 Study of Bevacizumab, Erlotinib and Atezolizumab in Subjects With Advanced Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) Associated or Sporadic Papillary Renal Cell Cancer
A Phase 2 Study of Bevacizumab, Erlotinib and Atezolizumab in Subjects With Advanced Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) Associated or Sporadic Papillary Renal Cell Cancer
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.
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.
Inclusion Criteria:
Patients must have:
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)
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)
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 does not have a prior or concurrent invasive malignancy; patients are eligible if a prior or concurrent invasive malignancy exists, but the natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen
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 wounds must be healed prior to starting therapy
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/exclusion criteria) with the exception of alopecia or electrolyte abnormalities that can be corrected to =< grade 1 prior to treatment initiation
Treatment with any other investigational agent within 4 weeks prior to cycle 1, day 1
Treatment with systemic immunostimulatory agents (including, but not limited to, interferon [IFN]-alpha or interleukin [IL]-2) within 6 weeks prior to cycle 1, day 1
Treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to cycle 1, day 1
Hypercalcemia > grade 1 of the CTCAE v5 that is not corrected prior to treatment initiation
Patients taking bisphosphonate therapy for symptomatic hypercalcemia. Use of bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is allowed
History of autoimmune disease, including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis
Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible
Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible
Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:
History of idiopathic pulmonary fibrosis, pneumonitis (including drug-induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
Patients with untreated latent or active tuberculosis (TB) are excluded
Severe infections within 4 weeks prior to cycle 1, day 1, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
Administration of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 or anticipation that such a live, attenuated vaccine will be required during the study and up to 5 months after the last dose of atezolizumab
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring intravenous antibiotics, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Poorly controlled hypertension with at least 2 occasions of elevated blood pressure separated by a 24-hour periodd within a week before treatment initiation, despite optimal medical management. (Adults: resting systolic blood pressure greater than 140 mmHg or diastolic blood pressure greater than 90 mmHg. Pediatric [< 18 years old]: Blood pressure [BP] >= the 95th percentile for age, height, and sex). History of hypertensive crisis or hypertensive encephalopathy
Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
History of anaphylactic or severe allergic reactions attributed to compounds of similar chemical or biologic composition to the study agents
Patients with myocardial infarction, gastrointestinal (GI) perforation/fistula, intraabdominal abscess, or cerebrovascular accidents within 6 months before cycle 1, day 1
Documented baseline proteinuria > 1000 mg/day on 24-hour urine collection. Only patients with 1+ or greater proteinuria on urinalysis (UA) and a spot urine protein:creatinine ratio of > 0.5 will undergo a 24-hour urine collection for quantitation of proteinuria
Pregnant women are excluded from this study because study drugs may have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with study drugs, breastfeeding should be discontinued if the mother is treated with study drugs
Serious, non-healing wound or ulcer; bone fracture within 3 months prior to treatment initiation
Concomitant therapy with systemic medications or herbal supplements that are known strong inhibitors or inducers of CYP450 3A4, or strong CYP1A2 inducers. To determine the impact of a concomitant drug on CYP enzymes see the FDA-approved product labeling and/or tertiary compendia (e.g., Inhibitors and Inducers of Cytochrome P450 Enzymes)
Patients who use tobacco or nicotine products and cannot stop their use of these products for the duration of study treatment
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to cycle 1, day 1
History of or active hemoptysis within 1 month prior to cycle 1 day 1
History of grade >= 4 venous thromboembolism
History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e., in the absence of therapeutic anticoagulation)
Current or recent (< 10 days prior to initiation of study treatment) use of aspirin (> 325 mg/day), or clopidogrel (> 75 mg/day)
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