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

  • STATUS
    Recruiting
  • End date
    Dec 31, 2024
  • participants needed
    65
  • sponsor
    National Cancer Institute (NCI)
Updated on 17 October 2022

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 has spread to other places in 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.

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 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 30-90 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 contrast or CT without contrast and magnetic resonance imaging (MRI) throughout the trial. Patients may also undergo a biopsy during screening, collection of blood throughout the trial, and a brain MRI/CT scan with contrast 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.

Details
Condition Advanced Papillary Renal Cell Carcinoma, Advanced Renal Cell Carcinoma, Hereditary Leiomyomatosis and Renal Cell Carcinoma, Recurrent Renal Cell Carcinoma, Sporadic Papillary Renal Cell Carcinoma, Stage III Renal Cell Cancer AJCC v8, Stage IV Renal Cell Cancer AJCC v8
Treatment biopsy, computed tomography, magnetic resonance imaging, positron emission tomography, bevacizumab, Erlotinib, biospecimen collection, Atezolizumab, Computed Tomography with Contrast, Sodium Fluoride F-18
Clinical Study IdentifierNCT04981509
SponsorNational Cancer Institute (NCI)
Last Modified on17 October 2022

Eligibility

Yes No Not Sure

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 (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
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
diameter to be recorded for non-nodal lesions and short axis for nodal
Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
lesions) as >= 20 mm (>= 2 cm) by chest x-ray or as >= 10 mm (>= 1 cm) with
Absolute neutrophil count >= 1,000/mcL
computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers
Platelets >= 100,000/mcL
by clinical exam. To be considered pathologically enlarged and measurable, a
lymph node must be >= 15 mm (>= 1.5 cm) in short axis
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)
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
Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
Subjects must provide archival tissue block or unstained tumor tissue or be willing to undergo biopsy to collect samples for retrospective central pathology review
therapy with an undetectable viral load within 6 months are eligible for this
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)
trial

Exclusion Criteria

Patients who have had chemotherapy, radiotherapy, or major surgery within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to cycle 1, day 1. 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
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
Patients 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
The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed
Patients taking bisphosphonate therapy for symptomatic hypercalcemia. Use of bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is allowed
Patients who have not recovered from adverse events due to prior anti-cancer therapy
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
(i.e., have residual toxicities > grade 1 of the Common Terminology Criteria
Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible
for Adverse Events [CTCAE] version [v]5 or to a level permitted under other
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
sections of inclusion/exclusion criteria) with the exception of alopecia or
electrolyte abnormalities that can be corrected to =< grade 1 prior to
Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations
treatment initiation
Rash must cover less than 10% of body surface area (BSA)
The 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%)
No 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)
Patients with 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
Hypercalcemia > grade 1 of the CTCAE v5 that is not corrected prior to treatment
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
initiation
NOTE: 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)
Poorly 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 gender on at least two occasions separated by a 24-hour period despite optimal medical management)
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
Patients who use tobacco or nicotine products and cannot stop their use of these products for the duration of study treatment
History of idiopathic pulmonary fibrosis, pneumonitis (including drug-induced)
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
pneumonia, etc.), or evidence of active pneumonitis on screening chest
computed tomography (CT) scan. History of radiation pneumonitis in the
radiation field (fibrosis) is permitted
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
Concomitant 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
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