Testing of Bevacizumab, Erlotinib, and Atezolizumab for Advanced-Stage Kidney Cancer

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Brief Title

Testing of Bevacizumab, Erlotinib, and Atezolizumab for Advanced-Stage Kidney Cancer

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

Brief Summary

      This phase II trial studies the effects of 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 a monoclonal antibody that may interfere with
      the ability of tumor cells to grow and spread. Erlotinib may stop the growth of tumor cells
      by blocking some of the enzymes needed for cell growth. 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. Giving bevacizumab,
      erlotinib, and atezolizumab may help reduce symptoms and stop the tumor from growing.
    

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 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. Patients also receive erlotinib orally (PO) once daily (QD) on days
      1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, patients are followed up every 6 months.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Incidence of adverse events


Condition

Advanced Papillary Renal Cell Carcinoma

Intervention

Atezolizumab

Study Arms / Comparison Groups

 Treatment (bevacizumab, atezolizumab, erlotinib)
Description:  Patients receive bevacizumab IV over 30-90 minutes and atezolizumab IV over 30-90 minutes on day 1. Patients also receive erlotinib PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

42

Start Date

September 17, 2021

Completion Date

December 31, 2024

Primary Completion Date

December 31, 2024

Eligibility Criteria

        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 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 computed tomography (CT) scan,
             magnetic resonance imaging (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 Center 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

        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

          -  Patients who have not recovered from adverse events due to prior anti-cancer therapy
             (i.e., have residual toxicities > grade 1 of the Common Terminology Criteria for
             Adverse Events [CTCAE] version [v]5 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

               -  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

          -  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:

                    -  Patients with psoriasis must have a baseline ophthalmologic exam to rule out
                       ocular manifestations

                    -  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)

          -  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

          -  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

          -  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

               -  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)

          -  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
             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

          -  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;
             ticlodipine, cimetidine, amiodarone, etc.) who cannot discontinue or change these
             medications prior to the start of study treatment

          -  Patients who use tobacco or nicotine products and cannot stop their use of these
             products for the duration of study treatment
      

Gender

All

Ages

12 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Ramaprasad Srinivasan, , 



Administrative Informations


NCT ID

NCT04981509

Organization ID

NCI-2021-07744

Secondary IDs

NCI-2021-07744

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Ramaprasad Srinivasan, Principal Investigator, National Cancer Institute LAO


Verification Date

August 2021