Carboplatin Plus Pemetrexed Plus Atezolizumab Plus Bevacizumab in Chemotherapy and Immunotherapy-naïve Patients With Stage IV Non-squamous Non-small Cell Lung Cancer
Condition: NSCLC Stage IV; NSCLC, Recurrent
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: Carboplatin; Pemetrexed; Atezolizumab; Bevacizumab
Intervention description: Carboplatin, AUC 5; Pemetrexed 500mg/m2; Atezolizumab 1200mg; Bevacizumab 15mg/kg
Intervention MeSH terms: Bevacizumab; Atezolizumab; Carboplatin; Pemetrexed
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention model description: Single Arm Therapeutic study using historical controls
Masking: None (Open Label)
Enrollment: 30.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a multicenter single arm phase II clinical trial. All eligible patients will receive:

      Carboplatin (AUC 5) i.v. day 1 plus pemetrexed (500 mg/m2) i.v. day 1 plus atezolizumab 1200
      mg i.v. day 1 plus bevacizumab 15 mg/kg i.v. day 1 every 3 weeks for up to 4 cycles.

      Patients with non-PD after 4 cycles will be permitted to continue with maintenance therapy
      with pemetrexed plus atezolizumab plus bevacizumab every 3 weeks until the time of disease
      progression or intolerable toxicities.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Written informed consent and HIPAA authorization for release of personal health
             information. NOTE: HIPAA authorization may be included in the informed consent or
             obtained separately.

          -  Age ≥ 18 years at the time of consent.

          -  ECOG Performance Status of 0-1 within 28 days prior to registration.

          -  Must have life expectancy of > 3 months at time of consent

          -  Histological or cytological confirmation of non-squamous NSCLC.

          -  Must have known PD-L1 status using the Dako 22C3 antibody (+ vs. -) OR must have at
             least 5 unstained slides to perform PD-L1 testing (results not required for
             eligibility). PD-L1 positive is defined as a tumor proportion score (TPS) ≥ 1%. PD-L1
             negative is defined as a TPS <1%.

          -  Patients with known targetable mutations in EGFR or BRAF or known translocations in
             ALK or ROS1 are eligible if they have received FDA approved targeted therapy first. A
             1-week washout prior to enrollment is strongly encouraged (3 weeks preferred).

          -  Stage IV disease or recurrent disease

          -  Measurable disease according to RECIST v1.1 criteria within 28 days prior to
             registration with either PET/CT scan, CT scan of chest and abdomen, or CT chest
             including upper abdomen and adrenal glands which define stage IV disease.

          -  Patients who had disease progression greater than 1 year after completing prior
             adjuvant therapy for stage I - III are eligible as long as no systemic therapy was
             given for recurrence.

          -  No prior immunotherapy or antiangiogenic therapy.

          -  Prior platinum therapy or pemetrexed are permissible if previously given in the
             adjuvant setting for stage I-III disease and disease recurrence is > 1 year from
             completion of therapy.

          -  If subject received major surgery or radiation therapy of > 30 Gy, they must have
             recovered from the toxicity and/or complications from the intervention.

          -  Demonstrate adequate organ function as defined below, with all screening labs to be
             obtained within 28 days prior to registration

               -  Absolute Neutrophil Count (ANC) ≥ 1.5 K/mm3

               -  Hemoglobin (Hgb) ≥ 9 g/dL

               -  Platelets ≥ 100 K/mm3

               -  Serum creatinine: ≤1.5 X upper limit of normal (ULN) OR Calculated Creatinine
                  Clearance: ≥ 40 cc/min using the Cockcroft-Gault formula

               -  Bilirubin ≤ 1.5 × upper limit of normal (ULN)

               -  Aspartate aminotransferase (AST) ≤ 1.5 × ULN or < 5x ULN if the transferase
                  elevation was due to liver metastases

               -  Alanine aminotransferase (ALT) ≤ 1.5 × ULN or <5x ULN if the transferase
                  elevation was due to liver metastases

               -  International Normalized Ratio (INR) or Prothrombin Time (PT) & aPTT ≤ 1.5 × ULN
                  (unless subjects is receiving anticoagulant therapy, as long as PT or PTT is
                  within therapeutic range of intended use of anticoagulants)

          -  Females of childbearing potential must have a negative serum pregnancy test within 7
             days prior to registration. NOTE: A woman is considered to be of childbearing
             potential if she is postmenarcheal, has not reached a postmenopausal state (> 12
             continuous months of amenorrhea with no identified cause other than menopause), and
             has not undergone surgical sterilization (removal of ovaries and/or uterus).

          -  For women of childbearing potential: agreement to remain abstinent (refrain from
             heterosexual intercourse) or use two non-hormonal methods of contraception, including
             at least one method with a failure rate of < 1% per year, during the treatment period
             and for 5 months after the last dose of atezolizumab or 120 days after the last dose
             of any study drug, whichever is later;

               -  examples of non-hormonal contraceptive methods with a failure rate of < 1% per
                  year include bilateral tubal ligation, male sterilization, hormonal
                  contraceptives that inhibit ovulation, hormone-releasing intrauterine devices,
                  and copper intrauterine devices. Must use "estrogen-free" hormonal method if this
                  is chosen contraception method.

               -  A barrier method may be used as the second contraceptive method. The reliability
                  of sexual abstinence should be evaluated in relation to the duration of the
                  clinical trial and the preferred and usual lifestyle of the patient. Periodic
                  abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods)
                  and withdrawal are not acceptable methods of contraception.

          -  Contraception method must begin starting from the time of informed consent until 120
             days after treatment discontinuation.

          -  For men: Agreement to remain abstinent (refrain from heterosexual intercourse) or use
             a condom, and agreement to refrain from donating sperm, as defined below:

          -  With female partners of childbearing potential or pregnant female partners, men must
             remain abstinent or use a condom during the treatment period and for 120 days after
             the last dose of study treatment to avoid exposing the embryo. Men must refrain from
             donating sperm during this same period.

          -  The reliability of sexual abstinence should be evaluated in relation to the duration
             of the clinical trial and the preferred and usual lifestyle of the patient. Periodic
             abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and
             withdrawal are not acceptable methods of contraception.

          -  As determined by the enrolling physician or protocol designee, ability of the subject
             to understand and comply with study procedures for the entire length of the study

        Exclusion Criteria:

          -  Active infection requiring systemic therapy

          -  Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
             mother is being treated on study).

          -  Active secondary cancers.

          -  Symptomatic, untreated, or actively progressing central nervous system (CNS)
             metastases. Brain imaging with either MRI or CT with contrast must be performed on all
             subjects at screening to evaluate for the presence of brain metastases. Patients with
             a history of treated CNS lesions are eligible, provided that all of the following
             criteria are met:

               -  Measurable disease, per RECIST v1.1, must be present outside the CNS.

               -  The patient has no history of intracranial hemorrhage or spinal cord hemorrhage.

               -  Metastases are limited to the cerebellum or the supratentorial region (i.e., no
                  metastases to the midbrain, pons, medulla, or spinal cord).

               -  The patient has not received stereotactic radiotherapy within 14 days prior to
                  initiation of study treatment or whole-brain radiotherapy within 21 days prior to
                  initiation of study treatment

               -  The patient has no ongoing requirement for corticosteroids as therapy for CNS
                  disease and off steroid therapy for at least 14 days. Anticonvulsant therapy at a
                  stable dose is permitted.

               -  Asymptomatic patients with CNS metastases newly detected at screening are
                  eligible for the study after receiving radiotherapy or surgery, with no need to
                  repeat the screening brain scan.

          -  Major surgery within 3 weeks of the first dose of trial treatment.

          -  Completed palliative radiotherapy within 7 days of the first dose of trial treatment.

          -  The patient had a history of uncontrolled hereditary or acquired thrombotic disorder.

          -  Patients with a history of gross hemoptysis (defined as bright red blood or ≥1/2
             teaspoon) within 2 months prior to enrollment.

          -  The patient had clinically relevant congestive heart failure (CHF; NYHA II-IV) or
             symptomatic or poorly controlled cardiac arrhythmia.

          -  The patient had experienced any arterial thrombotic event, including myocardial
             infarction, unstable angina, cerebrovascular accident, or transient ischemic attack,
             within 6 months prior to enrollment.

          -  The patient had uncontrolled arterial hypertension ≥150 / ≥90 mm Hg despite standard
             medical management.

          -  The patient has had a serious or non-healing wound, ulcer, or bone fracture within 28
             days prior to enrollment.

          -  Patients with ≥ 2 + protein on dipstick urinalysis. All patients with ≥ 2 + protein on
             dipstick urinalysis at baseline must undergo a 24-hour urine collection and must
             demonstrate ≤ 1 g of protein in 24 hours to be eligible.

          -  Clear cavitation of pulmonary lesions seen on imaging.

          -  The patient had significant bleeding disorders, vasculitis, or experienced Grade 3-4
             gastrointestinal (GI) bleeding within 3 months prior to enrollment.

          -  History of GI perforation and/or fistulae within 6 months prior to enrollment.

          -  Evidence of tumor invading or abutting major blood vessels.

          -  The patient had a bowel obstruction, history or presence of inflammatory enteropathy
             or extensive intestinal resection (hemicolectomy or extensive small intestine
             resection with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic
             diarrhea.

          -  Has received a live-virus vaccination within 30 days of planned treatment start.
             Seasonal flu vaccines that do not contain live virus are permitted.

          -  Previously had a severe hypersensitivity reaction to treatment with another monoclonal
             antibody (mAb).

          -  Has active autoimmune disease that has required systemic treatments in the past 2
             years, including but not limited to cyclophosphamide, azathioprine, methotrexate,
             thalidomide, and anti-TNF-α agents; chronic or occasional use of low-dose steroid
             therapy can be still be considered eligible as long as no greater than the daily
             equivalent of 5mg oral prednisone.

          -  Exceptions to excluding patients with active autoimmune disease include the following:

               -  Patients with a history of autoimmune-related hypothyroidism who are on thyroid
                  replacement hormone are eligible for the study.

               -  Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen
                  are eligible for the study.

               -  Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
                  dermatologic manifestations are eligible for the study provided all of following
                  conditions are met:

                    -  Rash must cover < 10% of body surface area

                    -  Disease is well controlled at baseline and requires only low-potency topical
                       corticosteroids

                    -  No occurrence of acute exacerbations of the underlying condition requiring
                       psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic
                       agents, oral calcineurin inhibitors, or high potency or oral corticosteroids
                       within the previous 12 months

          -  Subjects with asthma that require intermittent use of bronchodilators, inhaled
             steroids, or local steroid injections would not be excluded from the study. Subjects
             on chronic systemic steroids would be excluded from the study.

          -  Had prior treatment with CD137 agonists or immune checkpoint blockade therapies,
             including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies

          -  Treatment with systemic immunostimulatory agents (including, but not limited to,
             interferon and interleukin 2 [IL-2]) within 4 weeks or five half-lives of the drug
             (whichever is longer) prior to initiation of study treatment

          -  Treatment with systemic immunosuppressive medication (including, but not limited to
             corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
             anti-TNF-α agents) within 2 weeks prior to initiation of study treatment, or
             anticipation of need for systemic immunosuppressive medication during the course of
             the study, with the following exceptions:

               -  Patients who received acute, low-dose systemic immunosuppressant medication or a
                  one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of
                  corticosteroids for a contrast allergy) are eligible for the study.

               -  Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids
                  for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose
                  corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible
                  for the study.

          -  Treatment with denosumab (a RANKL inhibitor) within 4 weeks prior to initiation of
             study treatment. Patients receiving denosumab prior to enrollment must be willing and
             eligible to receive a bisphosphonate during atezolizumab treatment.

          -  History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
             or fusion proteins

          -  Known hypersensitivity to Chinese hamster ovary cell products or to any component of
             the atezolizumab formulation

          -  Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

          -  Has known active Hepatitis B or C. Active Hepatitis B is defined as a known positive
             HBsAg result. Active Hepatitis C is defined by a known positive Hep C Ab result and
             known quantitative HCV RNA results greater than the lower limits of detection of the
             assay. For patients with past HBV infection or resolved HBV infection (defined as the
             presence of hepatitis B core antibody [HBcAb] and absence of HBsAg), the patient is
             only eligible if they are negative for HBV DNA.

          -  Active tuberculosis

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the study, interfere with the subject's
             participation for the full duration of the study, or is not in the best interest of
             the subject to participate, in the opinion of the treating Investigator.

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

          -  Has known interstitial lung disease or history of idiopathic pulmonary fibrosis,
             organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or
             idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed
             tomography (CT) scan; history of radiation pneumonitis in the radiation field
             (fibrosis) is permitted. Lymphangitic spread of the NSCLC is not exclusionary.