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Official Title

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

Phase
Phase 2
Sponsor
National Cancer Institute (NCI)
Enrollment
65
Timeline
Jun 2022 → Dec 2027
About This Study

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.

Eligibility Criteria

Inclusion Criteria

  • 1Patients must have:
  • 2A diagnosis of HLRCC with a histologic or cytologic confirmation of RCC consistent with this diagnosis (Cohort 1) OR
  • 3Cytologically or histologically confirmed sporadic/non-HLRCC papillary renal cell carcinoma (presence of papillary component) (Cohort 2)
  • 4Patients 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
  • 5Patients 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
  • 6Age \>= 12 years
  • 7Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
  • 8Absolute neutrophil count \>= 1,000/mcL
  • 9Platelets \>= 100,000/mcL
  • 10Total 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)
  • 11Aspartate 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 \[PI\])
  • 12Alkaline 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)
  • 13Note: 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
  • 14Glomerular filtration rate (GFR) \>= 30 mL/min/1.73 m\^2
  • 15Note: 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
  • 16Age: 12 to \< 13 years; Maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female)
  • 17Age: 13 to \< 16 years; Maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female)
  • 18Age: 16 to \< 18 years; Maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female)
  • 19The 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)
  • 20Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with an undetectable viral load within 6 months are eligible for this trial
  • 21For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
  • 22Patients 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
  • 23Patients 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
  • 24Patients 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
  • 25Patients 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
  • 26The 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
  • 27Subjects must provide archival tissue block or unstained tumor tissue or be willing to undergo biopsy to collect samples for retrospective central pathology review
  • 28The 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

  • 1Any 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
  • 2Other prior therapies for kidney cancer: Radiotherapy \< 2 weeks prior to cycle 1, day 1
  • 3Major 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:
  • 4Hormone-replacement therapy or oral contraceptives
  • 5Herbal 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
  • 6Palliative radiotherapy for bone metastases \> 2 weeks prior to cycle 1, day 1
  • 7Treatment with any other investigational agent within 4 weeks prior to cycle 1, day 1
  • 8Treatment 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
  • 9Treatment 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
  • 10Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea or for purposes of pre-medication prior to radiology studies) may be enrolled
  • 11The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed
  • 12Hypercalcemia \> grade 1 of the CTCAE v5 that is not corrected prior to treatment initiation
  • 13Patients taking bisphosphonate therapy for symptomatic hypercalcemia. Use of bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is allowed
  • 14History 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
  • 15Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible
  • 16Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible
  • 17Patients 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:
  • 18Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations
  • 19Rash must cover less than 10% of body surface area (BSA)
  • 20The disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)
  • 21No acute exacerbations of the underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation \[PUVA\], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids)
  • 22History 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
  • 23Patients with active tuberculosis (TB) are excluded
  • 24Severe infections within 4 weeks prior to cycle 1, day 1, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
  • 25Administration 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
  • 26NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines and are not allowed. Influenza vaccination should be given during influenza season only (approximately October to March)
  • 27Uncontrolled 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
  • 28Poorly controlled hypertension with at least 2 occasions of elevated blood pressure within a week before treatment initiation (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 on at least two occasions separated by a 24-hour period despite optimal medical management). History of hypertensive crisis or hypertensive encephalopathy
  • 29Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
  • 30History of anaphylactic or severe allergic reactions attributed to compounds of similar chemical or biologic composition to the study agents
  • 31Patients with myocardial infarction, gastrointestinal (GI) perforation/fistula, intraabdominal abscess, or cerebrovascular accidents within 6 months before cycle 1, day 1
  • 32Documented 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
  • 33Pregnant 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
  • 34Serious, non-healing wound or ulcer; bone fracture within 3 months prior to treatment initiation
  • 35Concomitant therapy with potent inhibitors of CYP450 3A4 (e.g. ketoconazole, verapamil, etc.) or potent CYP3A4 inducers or with potent CYP450 1A2 inhibitors (fluoroquinolone antibiotics including ciprofloxacin, levofloxacin, and norfloxacin; ticlopidine, cimetidine, amiodarone, etc.) who cannot discontinue or change these medications prior to the start of study treatment
  • 36Patients who use tobacco or nicotine products and cannot stop their use of these products for the duration of study treatment
  • 37Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to cycle 1, day 1
  • 38History of or active hemoptysis within 1 month prior to cycle 1 day 1
  • 39History of grade \>= 4 venous thromboembolism
  • 40History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e., in the absence of therapeutic anticoagulation)
  • 41Current or recent (\< 10 days prior to initiation of study treatment) use of aspirin (\> 325 mg/day), or clopidogrel (\> 75 mg/day)
  • 42Note: The use of full-dose oral or parenteral anticoagulants for therapeutic purpose is permitted as long as the International Normalized Ratio (INR) and/or a partial thromboplastin time (PTT) is within therapeutic limits (according to institution standards) within 7 days prior to initiation of study treatment and the patient has been on a stable dose of anticoagulants for \>= 2 weeks prior to initiation of study treatment. Prophylactic use of anticoagulants is allowed. However, the use of direct oral anticoagulant therapies such as dabigatran (Pradaxa \[registered trademark\]) and rivaroxaban (Xarelto \[registered trademark\]) may be used per PI discretion

Locations

13 sites participating in this study

Emory University Hospital Midtown

Atlanta, Georgia 30308

Recruiting

Mehmet A. Bilen

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia 30322

Recruiting

Mehmet A. Bilen

Emory Saint Joseph's Hospital

Atlanta, Georgia 30342

Recruiting

Mehmet A. Bilen

Data sourced from ClinicalTrials.govView on ClinicalTrials.gov →