Clinical Trials /

Atezolizumab in Combination With Entinostat and Bevacizumab in Patients With Advanced Renal Cell Carcinoma

NCT03024437

Description:

This study will assess the immunomodulatory activity of entinostat in patients with advanced renal cell carcinoma receiving the PD-L1 inhibitor atezolizumab. The overall hypothesis is that entinostat will increase the immune response and anti-tumor effect induced by the PD-L1 inhibition by suppressing Treg function. We have chosen renal cell carcinoma that has been reported to respond to PD1/PD-L 1 inhibition. The schedule of entinostat is based on our previous experience with this agent. Based on our working hypothesis that low dose HDAC inhibitors will have a suppressive function on Tregs but not on T effector cells, the starting dose of entinostat will be 1 mg and will be escalated up to 5 mg rather than the 10 mg dose. The combination also with bevacizumab will provide an effective VEGF inhibition that may potentiate the immune response and anti-tumor effect induced by atezolizumab. The proposed dose and schedule for atezolizumab and bevacizumab has been shown to be well tolerated in prior Phase/I/II studies and is currently tested in a Phase III randomized study in patients with renal cell carcinoma with sunitinib as a control arm. The highest proposed dose level for entinostat (5 mg) represents 50% of the recommended Phase II dose for this compound as a single agent.

Related Conditions:
  • Renal Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Atezolizumab in Combination With Entinostat and Bevacizumab in Patients With Advanced Renal Cell Carcinoma
  • Official Title: A Phase I/II Study to Evaluate the Safety, Pharmacodynamics and Efficacy of Atezolizumab in Combination With Entinostat and Bevacizumab in Patients With Advanced Renal Cell Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: IUSCC-0574
  • NCT ID: NCT03024437

Conditions

  • Metastatic Cancer
  • Renal Cancer

Interventions

DrugSynonymsArms
AtezolizumabMDPL3280APhase I - Dose Escalation
BevacizumabAvastinPhase I - Dose Escalation
EntinostatSNDX-275Phase I - Dose Escalation

Purpose

This study will assess the immunomodulatory activity of entinostat in patients with advanced renal cell carcinoma receiving the PD-L1 inhibitor atezolizumab. The overall hypothesis is that entinostat will increase the immune response and anti-tumor effect induced by the PD-L1 inhibition by suppressing Treg function. We have chosen renal cell carcinoma that has been reported to respond to PD1/PD-L 1 inhibition. The schedule of entinostat is based on our previous experience with this agent. Based on our working hypothesis that low dose HDAC inhibitors will have a suppressive function on Tregs but not on T effector cells, the starting dose of entinostat will be 1 mg and will be escalated up to 5 mg rather than the 10 mg dose. The combination also with bevacizumab will provide an effective VEGF inhibition that may potentiate the immune response and anti-tumor effect induced by atezolizumab. The proposed dose and schedule for atezolizumab and bevacizumab has been shown to be well tolerated in prior Phase/I/II studies and is currently tested in a Phase III randomized study in patients with renal cell carcinoma with sunitinib as a control arm. The highest proposed dose level for entinostat (5 mg) represents 50% of the recommended Phase II dose for this compound as a single agent.

Detailed Description

      This is a Phase l/II, open-label, safety, pharmacodynamics and efficacy study of atezolizumab
      in combination with entinostat and bevacizumab in patients with advanced renal cell
      carcinoma. This clinical study will be composed of a Dose Finding Phase (Phase I) and a
      two-stage Dose Expansion Phase (Phase II) portion.

      In Phase 1, patients will be treated with oral entinostat every 7 days, with bevacizumab at
      the fixed dose of 15 mg/kg IV every 3 weeks and with atezolizumab at the fixed dose of 1200
      mg IV every 3 weeks. Each cycle length is 21 days. Three dose levels of entinostat will be
      tested in 3-patient cohorts according to the 3 + 3 standard design (level 1 = 1 mg, level 2 =
      3 mg and level 3 = 5 mg). For the Dose Finding Phase, the starting dose level of entinostat
      will be 1 mg PO every 7 days. The first dose level will have a minimum of 3 patients treated
      (unless the first 2 patients experience DLT(s) before the 3rd patient is enrolled. DLTs
      attributable to entinostat and/or bevacizumab and/or atezolizumab will be evaluated during
      the first 21 days of the combination treatment.

      If DLTs occur in 1 patient treated at the starting dose level, a minimum of 3 additional
      patients will be treated at this dose level. If DLTs occur in more than 1 patient in the
      first 6 patients, the study will be terminated. If a DLT occurs in 1/6 patient, dose level 1
      will be considered the Recommended Phase II Dose (RP2D). If no DLTs occur at the starting
      dose level 1, 3 additional patients will be treated at the next dose level (level 2). If no
      DLTs occur at the dose level 2, 3 additional patients will be treated at the next dose level
      (level 3). If no DLTs occur at dose level 3, this dose level will be recommended for the
      Phase II portion of the study. Patients who experience grade ≥ 3 toxicity and recover to ≤
      grade 1 (or to pretreatment baseline level toxicity) may continue treatment at the next lower
      level. The Phase II dose will be RP2D of entinostat (i.e., the highest tested dose that is
      declared safe and tolerable by the Investigators and Sponsor).

      Once the RP2D is identified, the Phase II portion (Simon's two stage design) will be opened.
      During Phase II, Cohort A will have a Run-In period with entinostat for one cycle followed by
      atezolizumab and bevacizumab for the second cycle, and then the Combination Phase. The reason
      for the Run-In period during Cohort A is to obtain data on the immunomodulatory effects of
      entinostat separately from bevacizumab and atezolizumab. The run-in period will be optional
      for patients who are rapidly progressing or if it is in the patient's best interest
      clinically as determined by the treating physician's discretion. In Stage I, 32 patients with
      prior treatments will be enrolled in two Phase II cohorts: 18 treatment naïve (anti-PD1
      naïve) patients (Cohort A), and 14 anti-PD1 resistant (defined as patients who have been on
      PD1 inhibitors for at least 3 months and have progressed by either clinical or radiographic
      assessment) patients (Cohort B). If ≥ 5 responses are observed in Cohort A, Stage II will be
      conducted with 15 additional patients.

      Cohort B is a pilot arm which aims to test atezolizumab in anti-PD1 resistant patients. If
      there is no response to atezolizumab, then the RP2D dose of entinostat will be added to the
      standard dose of atezolizumab. If there is a response to atezolizumab, patients will continue
      to be treated with atezolizumab alone.

      The RP2D is the dose of entinostat, atezolizumab, and bevacizumab in combination chosen for
      further clinical development. Further experience in Phase II may result in a RP2D dose lower
      than the maximum tolerated dose.

      Objectives:

        1. Primary Phase I: To assess the safety and tolerability of atezolizumab in combination
           with entinostat and bevacizumab in patients with advanced renal cell carcinoma.

        2. Primary Phase II: To assess the objective response rate of atezolizumab in combination
           with entinostat and bevacizumab in anti-PD 1 naïve patients and atezolizumab in
           combination with entinostat in anti-PD 1 resistant patients with advanced renal cell
           carcinoma.

        3. Secondary: To assess the objective response rate (Phase I only), progression-free
           survival and overall survival.

        4. Correlative: To characterize PD-L1/2, immune cell subsets, and miRs in tumor and/or
           blood in correlation with response.
    

Trial Arms

NameTypeDescriptionInterventions
Phase I - Dose EscalationExperimentalOpen to patients meeting eligibility criteria with advanced renal cell carcinoma and ANY or NO prior treatments. Three dose levels of entinostat will be tested in 3-patient cohorts according to the 3 + 3 standard design (1 mg, 3 mg and 5 mg). The starting dose level of entinostat will be 1 mg orally every 7 days. The Phase II dose will be recommended phase II dose of entinostat (i.e., the highest tested dose that is declared safe and tolerable by the Investigators and Sponsor).
  • Atezolizumab
  • Bevacizumab
  • Entinostat
Phase II - Cohort AExperimentalOpen to patients meeting eligibility criteria with advanced renal cell carcinoma and NO prior treatments. Patients in Cohort A will be treated with atezolizumab, bevaciuzmab, and the recommended phase II dose of entinostat. During Phase II, the study will have a run-in period with entinostat for one cycle followed by atezolizumab and bevacizumab for the second cycle, and then the combination phase (i.e., atezolizumab + bevacizumab + entinostat for all cycles thereafter).
  • Atezolizumab
  • Bevacizumab
  • Entinostat
Phase II - Cohort BExperimentalOpen to patients meeting eligibility criteria with advanced renal cell carcinoma and at least one prior treatment with a PD1 inhibitor. Patients in Cohort B will be treated with atezolizumab alone. If there is no response to atezolizumab, then the recommended phase II dose of entinostat will be added to the standard dose of atezolizumab. If there is a response to atezolizumab, patients will continue to be treated with atezolizumab alone.
  • Atezolizumab
  • Entinostat

Eligibility Criteria

        Inclusion Criteria:

        Patients must meet the following criteria for study entry:

          -  Signed Informed Consent Form (ICF)

          -  Ability and willingness to comply with the requirements of the study protocol

          -  Age ≥ 18 years

          -  Metastatic renal cell carcinoma

               -  During Phase I - All prior treatments or none are allowed

               -  During Phase II/Cohort A - No prior treatments are allowed

               -  During Phase II/Cohort B - Must have at least one prior treatment with a PD1
                  inhibitor

          -  Life expectancy of at least 6 months

          -  Adequate hematologic and end organ function, defined by the following laboratory
             results obtained within 14 days prior to the first study treatment (Cycle 1, Day 1):

               -  Absolute neutrophil count (ANC) ≥ 1500 cells/microL

               -  White blood cell (WBC) counts > 2500/microL

               -  Lymphocyte count ≥ 300/microL

               -  Platelet count ≥ 100,000/microL; for patients with hematologic malignancies,
                  platelet count ≥ 75,000/microL

               -  Hemoglobin ≥ 9.0 g/dL

               -  Total bilirubin ≤ 1.5 x upper limit of normal (ULN) with the following exception:

        Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be
        enrolled.

        Direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 x ULN

        - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN with the
        following exception: Patients with liver involvement: AST and/or ALT ≤ 5 x ULN

        - Alkaline phosphatase (ALP) ≤ 2.0 x ULN with the following exception: Patients with
        documented liver involvement or bone metastases: ALP ≤ 5 x ULN

          -  Serum creatinine ≤ 1.25 x ULN or creatinine clearance ≥ 60 mL/min on the basis of the
             Cockcroft-Gault glomerular filtration rate estimation:

             (140 - age) x (weight in kg) x (0.85 if female) / 72 x (serum creatinine in mg/dL)

          -  Urine dipstick for proteinuria < 2+ or 24-hour urine protein < 1 g of protein is
             demonstrated

          -  International Normalized Ratio (INR) and activated Partial Thromboplastin Time (aPTT)
             ≤ 1.5 x ULN This applies only to patients who do not receive therapeutic
             anticoagulation; patients receiving therapeutic anticoagulation (such as
             low-molecular-weight heparin or warfarin) should be on a stable dose.

               -  Measurable disease per RECIST v1.1 for patients with solid malignancies and
                  evaluable disease as assessed by bone scan and/or PET scan

               -  If a female of childbearing potential, negative serum blood pregnancy test during
                  screening and a negative urine pregnancy test ≤ 3 days prior to receiving the
                  first dose of study drug. If the screening serum test is done ≤ 3 days prior to
                  receiving the first dose of study drug, a urine test is not required.

          -  Non-childbearing potential is defined as (by other than medical reasons):

               -  45 years of age and has not had menses for > 2 years Amenorrheic for < 2 years
                  without a hysterectomy and/or oophorectomy and a follicle-stimulating hormone
                  value in the postmenopausal range upon pre-study (screening) evaluation Post
                  hysterectomy, oophorectomy or tubal ligation. Documented hysterectomy or
                  oophorectomy must be confirmed with medical records of the actual procedure or
                  confirmed by an ultrasound. Tubal ligation must be confirmed with medical records
                  of the actual procedure.

                    -  For female patients of childbearing potential and male patients with
                       partners of childbearing potential, agreement (by patient and/or partner) to
                       use two forms of highly effective contraception (i.e., one that results in a
                       low failure rate [< 1% per year] when used consistently and correctly) and
                       to continue its use for 150 days after the last dose of all study drugs
                       (atezolizumab, entinostat, and bevacizumab).

                    -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

        Exclusion Criteria Patients who meet any of the following criteria will be excluded from
        study entry.

        General Exclusion Criteria:

          -  Any approved anti-cancer therapy, including chemotherapy, hormonal therapy, or
             radiotherapy, ≤ 3 weeks prior to first dose of study drug; however, the following are
             allowed:

             - Hormone-replacement therapy or oral contraceptives

             - Herbal therapy > 1 week prior to Cycle 1, Day 1 (herbal therapy intended as
             anti-cancer 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

          -  Currently participating and receiving study therapy or has participated in a study of
             an investigational agent and received study therapy or used an investigational device
             ≤ 4 weeks of the first dose of study drug.

          -  AEs from prior anti-cancer therapy that have not resolved to Grade ≤ 1 except for
             alopecia and neuropathy

          -  Any contraindication to oral agents or significant nausea and vomiting, malabsorption,
             or significant small bowel resection that, in the opinion of the investigator, would
             preclude adequate absorption.

          -  Bisphosphonate therapy for symptomatic hypercalcemia

             - Use of bisphosphonate therapy for other reasons (e.g., bone metastasis or
             osteoporosis) is allowed.

          -  Known clinically significant liver disease, including active viral, alcoholic, or
             other hepatitis; cirrhosis; fatty liver; and inherited liver disease

          -  Patients with acute leukemias, accelerated/blast phase chronic myelogenous leukemia,
             chronic lymphocytic leukemia, Burkitt lymphoma, plasma cell leukemia, or non-secretory
             myeloma

          -  Known primary central nervous system (CNS) malignancy or symptomatic CNS metastases -
             Patients with asymptomatic untreated CNS disease may be enrolled, provided all of the
             following criteria are met: Evaluable or measurable disease outside the CNS No
             metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm of the
             optic apparatus (optic nerves and chiasm) No history of intracranial hemorrhage or
             spinal cord hemorrhage No ongoing requirement for dexamethasone for CNS disease;
             patients on a stable dose of anticonvulsants are permitted.

        No neurosurgical resection or brain biopsy ≤ 28 days prior to Cycle 1, Day 1

        - Patients with asymptomatic treated CNS metastases may be enrolled, provided all the
        criteria listed above are met as well as the following: Radiographic demonstration of
        improvement upon the completion of CNS directed therapy and no evidence of interim
        progression between the completion of CNS-directed therapy and the screening radiographic
        study No stereotactic radiation or whole-brain radiation ≤ 28 days prior to Cycle 1, Day 1
        Screening CNS radiographic study ≥ 4 weeks from completion of radiotherapy and ≥ 2 weeks
        from discontinuation of corticosteroids

          -  Pregnancy, lactation, or breastfeeding

          -  Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
             human antibodies

          -  Known hypersensitivity to an component of bevacizumab

          -  Allergy to benzamide or inactive components of entinostat

          -  Inability to comply with study and follow-up procedures

          -  Known psychiatric or substance abuse disorders that would interfere with cooperation
             with the requirements of the study.

          -  Uncontrolled hypertension (defined as systolic blood pressure >150 mmHg and/or
             diastolic blood pressure > 100 mmHg)

          -  Prior history of hypertensive crisis or hypertensive encephalopathy

          -  Uncontrolled diabetes mellitus

          -  History or risk 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, Sjögren's
             syndrome, Bell's palsy, Guillain-Barré 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 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:

        Rash must cover less than 10% of body surface area (BSA) Disease is well controlled at
        baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%,
        hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate
        0.05%) No acute exacerbations of 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.

          -  Any other diseases, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding giving reasonable suspicion of a disease or condition that
             contraindicates the use of an investigational drug or that may affect the
             interpretation of the results or render the patient at high risk from treatment
             complications

          -  History of HIV infection (HIV 1/2 antibodies) or active hepatitis B (chronic or acute)
             or hepatitis C infection

               -  Patients with past or resolved hepatitis B infection (defined as having a
                  negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc
                  [antibody to hepatitis B core antigen] antibody test) are eligible. HBV DNA test
                  must be performed in these patients prior to study treatment.

               -  Patients positive for hepatitis C virus (HCV) antibody are eligible only if
                  polymerase chain reaction (PCR) is negative for HCV RNA.

          -  Active tuberculosis

          -  Clinically significant (i.e. active) cardiovascular disease (e.g., myocardial
             infarction or arterial thromboembolic events ≤ 6 months prior to screening or severe
             or unstable angina, New York Heart Association (NYHA) Class III or IV disease, Grade
             II or greater congestive heart failure, or serious cardiac arrhythmia (see Appendix
             5), or a QTc interval > 470 msec.)

          -  Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
             recent peripheral arterial thrombosis ≤ 6 months of study enrollment

          -  Any previous venous thromboembolism > NCI CTCAE Grade 3

          -  History of hemoptysis (≥ ½ teaspoon of bright red blood per episode) ≤ 28 days of
             study enrollment

          -  Evidence of bleeding diathesis or significant coagulopathy (in the absence of
             therapeutic anticoagulation)

          -  Current or recent (≤ 10 days of study enrollment) use of aspirin (> 325 mg/day),
             clopidogrel (>75 mg/day), or therapeutic oral or parenteral anticoagulants or
             thrombolytic agents for therapeutic purposes The use of full-dose oral or parenteral
             anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits
             (according to medical standard of the institution) and the patient has been on a
             stable dose of anticoagulants for at least 2 week at the time of study enrollment.
             Prophylactic use of anticoagulants is allowed.

          -  Severe infections ≤ 4 weeks prior to Cycle 1, Day 1, including but not limited to
             hospitalization for complications of infection, bacteremia, or severe pneumonia

          -  Signs or symptoms of infection ≤ 2 weeks prior to Cycle 1, Day 1

          -  Received oral or IV antibiotics ≤ 2 weeks prior to Cycle 1, Day 1

             - Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract
             infection or chronic obstructive pulmonary disease) are eligible.

          -  Major surgical procedure ≤ 28 days prior to Cycle 1, Day 1 or anticipation of need for
             a major surgical procedure during the course of the study

          -  Administration of a live, attenuated vaccine ≤ 4 weeks before Cycle 1, Day 1 or
             anticipation that such a live, attenuated vaccine will be required during the study

             - Influenza vaccination should be given during influenza season only (approximately
             October to March). Patients must not receive live, attenuated influenza vaccine (e.g.,
             FluMist) ≤ 4 weeks prior to Cycle 1, Day 1 or at any time during the study.

          -  History of abdominal fistula or gastrointestinal perforation ≤ 6 months before Cycle
             1, Day 1. Serious non-healing wound, active ulcer, or untreated bone fracture
             (adjuvant trials: bone fractures must be healed)

          -  Proteinuria as demonstrated by a UPC ratio ≥ 1.0 at screening

          -  Malignancies other than the disease under study ≤ 5 years prior to Cycle 1, Day 1,
             with the exception of those with a negligible risk of metastasis or death and with
             expected curative outcome (such as adequately treated carcinoma in situ of the cervix,
             basal or squamous cell skin cancer, localized prostate cancer treated surgically with
             curative intent, or ductal carcinoma in situ treated surgically with curative intent)
             or undergoing active surveillance per standard-of-care management (e.g., chronic
             lymphocytic leukemia Rai Stage 0, prostate cancer with Gleason score ≤ 6, and
             prostate-specific antigen [PSA] ≤ 10 mg/mL, etc.)

        Medication-Related Exclusion Criteria:

          -  Treatment with systemic immunostimulatory agents (including but not limited to
             interferon or interleukin) ≤ 6 weeks or five half-lives of the drug (whichever is
             shorter) prior to Cycle 1, Day 1

          -  Treatment with investigational agent ≤ 4 weeks prior to Cycle 1, Day 1 (or within five
             half lives of the investigational product, whichever is longer)

          -  Treatment with systemic immunosuppressive medications (including but not limited to
             prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
             necrosis factor [anti-TNF] agents) ≤ 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) may be enrolled.

               -  The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone)
                  for patients with orthostatic hypotension or adrenocortical insufficiency is
                  allowed.

          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins

          -  Patients with prior allogeneic bone marrow transplantation or prior solid organ
             transplantation
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I: Recommended phase II dose of entinostat when combined with atezolizumab and bevacizumab
Time Frame:21 days
Safety Issue:
Description:Dose determined using 3 + 3 design

Secondary Outcome Measures

Measure:Phase I: Objective response rate
Time Frame:Up to 1 year
Safety Issue:
Description:Proportion of subjects who achieve a complete response or partial response to treatment as measured per RECIST 1.1
Measure:Phase II: Progression-free survial
Time Frame:Up to 1 year
Safety Issue:
Description:Proportion of subjects who do not get worse from the start of treatment as measured per RECIST 1.1
Measure:Phase II: Overall survival
Time Frame:Up to 2 years
Safety Issue:
Description:Length of time that subject is still alive from the start of treatment

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Roberto Pili

Trial Keywords

  • PD-L1 inhibitor

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