Atezolizumab With Chemotherapy in Treating Patients With Anaplastic or Poorly Differentiated Thyroid Cancer
Atezolizumab With Chemotherapy in Treating Patients With Anaplastic or Poorly Differentiated Thyroid Cancer
This phase II trial studies how well atezolizumab in combination with chemotherapy works in
 treating patients with anaplastic or poorly differentiated thyroid cancer. 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. Vemurafenib and
 cobimetinib may stop the growth of cancer cells by blocking some of the enzymes needed for
 cell growth. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of
 cancer cells to grow and spread. Drugs such as nab-paclitaxel and paclitaxel work in
 different ways to stop the growth of cancer cells, either by killing the cells, by stopping
 them from dividing, or by stopping them from spreading. This trial is being done to see if
 atezolizumab in combination with chemotherapy works better in treating patients with
 anaplastic or poorly differentiated thyroid cancer compared to standard treatments.
PRIMARY OBJECTIVE:

 I. To determine if targeted therapy + atezolizumab (cohorts 1-3) will lead to improved
 overall survival (OS) in patients with anaplastic thyroid carcinoma (ATC).

 SECONDARY OBJECTIVES:

 I. To evaluate the safety and efficacy (Response Evaluation Criteria in Solid Tumors [RECIST]
 response rate, progression-free survival [PFS]) of targeted therapy + atezolizumab (cohorts
 1-3) in ATC and poorly differentiated thyroid cancer (PDTC).

 II. To determine the OS in patients with PDTC treated with targeted therapy + atezolizumab
 (cohorts 1-3).

 III. To determine the efficacy (RECIST/immune-related Response Criteria [irRC] response rate,
 progression-free survival [PFS]) and OS of ATC and PDTC patients treated with taxanes +
 atezolizumab (cohort 4).

 EXPLORATORY OBJECTIVES:

 I. To evaluate changes in the tumor-associated and systemic immune system biomarkers in ATC
 and PDTC patients treated with immunotherapy.

 II. To report radioactive iodine (RAI) uptake in patients who have a diagnostic whole body
 scan and therapeutic I-131 in cohort 2.

 OUTLINE: Patients are assigned to 1 of 4 cohorts.

 COHORT I (BRAF MUTATION): Patients receive vemurafenib orally (PO) twice daily (BID) on days
 1-21, cobimetinib PO once daily (QD) on days 1-21, and atezolizumab intravenously (IV) over
 30-60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease
 progression and unacceptable toxicity.

 COHORT II (RAS, NF1, OR NF2 MUTATION including patients with MAPK activating mutations at or
 above MEK): Patients receive cobimetinib PO QD on days 1-21 and atezolizumab IV over 30-60
 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression
 and unacceptable toxicity.

 COHORT III (NON-BRAF/NON-RAS MUTATION): Patients receive atezolizumab IV over 30-60 minutes
 and bevacizumab IV over 60-90 minutes on day 1. Cycles repeat every 21 days in the absence of
 disease progression and unacceptable toxicity.

 COHORT IV: Patients receive nab-paclitaxel IV over 30 minutes on days 1, 8, and 15 and
 atezolizumab IV over 30-60 minutes on day 1. Patients may receive paclitaxel IV over 30
 minutes on day 1 as a substitute for nab-paclitaxel. Cycles repeat every 21 days in the
 absence of disease progression and unacceptable toxicity.

 After completion of study treatment, patients are followed up every 3 months for years 1-2,
 every 6 months for years 3-4, then yearly thereafter.
Inclusion Criteria:

 -  Histologically confirmed anaplastic thyroid or poorly differentiated thyroid
 carcinomas.

 -  Patients deemed to have unresectable locoregional disease or metastatic disease.
 Patients who are unwilling to undergo surgery or external beam radiation are also
 eligible.

 -  Patients with poorly differentiated thyroid cancer must have at least one target
 lesion by RECIST version 1.1. This is not a requirement for ATC patients.

 -  Total bilirubin =< 1.5 x upper limit of normal (ULN). Total bilirubin: 3 x ULN for
 patients with Gilbert's syndrome.

 -  Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) /
 alanine aminotransferase (ALT) serum glutamate pyruvate transaminase (SGPT) =< 2.5 x
 ULN, (5 x ULN for patients with concurrent liver metastases).

 -  Serum creatinine =< within 1.5 x ULN.

 -  Absolute neutrophil count (ANC) >= 1.0 x 10^9 /L.

 -  Platelets (PLT) >= 100 x 10^9 /L.

 -  For patients receiving therapeutic anticoagulation: stable anticoagulant regimen and
 stable international normalized ratio (INR) during the 28 days immediately preceding
 initiation of study treatment.

 -  Subjects must be willing to undergo tumor biopsy prior to and after treatment with
 atezolizumab, unless in the opinion of the treating physician, a biopsy is not
 feasible or safe.

 -  Eastern Cooperative Oncology Group (ECOG) performance score (PS) =< 2.

 -  Age and reproductive status:

 -  Women of childbearing potential (WOCBP) must have a negative serum or urine
 pregnancy test within 14 days prior to the start of study drug and must use
 effective contraceptives throughout the duration of the study. Males who are
 sexually active with WOCBP must agree to use effective contraception throughout
 the duration of the study. Azoospermic males and WOCBP who are continuously not
 heterosexually active are exempt from contraceptive requirements.

 -  A Women of childbearing potential (WOCBP) is defined as any female who has
 experienced menarche and who has not undergone surgical sterilization
 (hysterectomy or bilateral oophorectomy) and is not postmenopausal.
 Menopause is defined as 12 months of amenorrhea in a woman over age 45 years
 in the absence of other biological or physiological causes.

 -  Ability to provide informed consent.

 -  ADDITIONAL INCLUSION CRITERIA FOR BRAF MUTATION (COHORT 1): Patients with a BRAFV600E
 mutation being considered for the triplet combination (vemurafenib + cobimetinib +
 atezolizumab) must meet the following end organ function criteria:

 -  COHORT 1: ANC >= 1.5 × 10^9 /L without granulocyte colony-stimulating factor support.

 -  COHORT 1: White blood cell (WBC) count >= 2.5 x 10^9 /L.

 -  COHORT 1: Lymphocyte count >= 0.5 x 10^9/L.

 -  COHORT 1: Platelet count >= 100 × 10^9 /L without transfusion.

 -  COHORT 1: Hemoglobin >= 9.0 g/L without transfusion.

 -  COHORT 1: Serum albumin > =2.5 g/L

 -  COHORT 1: Total bilirubin =< 1.5 x ULN

 -  COHORT 1: AST and ALT =< 2.0 x ULN

 -  COHORT 1: Alkaline phosphatase (ALP) =< 2.5 x ULN or, for patients with documented
 liver or bone metastases, ALP =< 5 x ULN

 -  COHORT 1: Serum creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 40 mL/min on
 the basis of measured CrCl from a 24-hour urine collection or Cockcroft-Gault
 glomerular filtration rate estimation.

 -  COHORT 1: Patients with BRAF mutation may be screened for eligibility in cohorts 2, 3,
 or 4 (in this order of preference) if they do not meet the entry criteria for cohort
 1.

 Exclusion Criteria:

 -  Subjects with an active, known or suspected autoimmune disease. Subjects with type I
 diabetes mellitus on stable insulin regimen, hypothyroidism only requiring hormone
 replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring
 systemic treatment, or conditions not expected to recur in the absence of an external
 trigger are permitted to enroll.

 -  For patients not receiving therapeutic anticoagulation: INR or partial thromboplastin
 time (aPTT) > 1.5 x ULN within 28 days prior to initiation of study treatment.

 -  Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway
 targeting agents. Patients who have received prior treatment with anti-CTLA-4 may be
 enrolled, provided the following requirements are met: Minimum of 12 weeks from the
 first dose of anti-CTLA-4 and > 6 weeks from the last dose, and no history of severe
 immune-related adverse effects from anti-CTLA 4 (National Cancer Institute [NCI]
 Common Terminology Criteria for Adverse Events [CTCAE] grade 3 and 4).

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

 -  History of human immunodeficiency virus (HIV) infection 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.
 However, patients with past or resolved hepatitis B virus (HBV) should be monitored
 for reactivation by a specialist. Patients positive for hepatitis C virus (HCV)
 antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV
 ribonucleic acid (RNA).

 -  Pregnant or lactating women. All pre-menopausal women being screened must have a
 negative serum pregnancy test within 14 days prior to commencement of dosing. Women of
 non-childbearing potential may be included if they are either surgically sterile or
 have been postmenopausal for >= 1 year. Fertile men and women must use an effective
 method of contraception during treatment and for at least 6 months after completion of
 treatment as directed by their physician.

 -  Untreated brain metastases.

 -  Chemotherapy within 21 days of enrollment with the exception of paclitaxel or
 nab-paclitaxel (Abraxane). Patients who have received one course of these agents prior
 to study entry are eligible. (One course of weekly paclitaxel or nab-paclitaxel is 3
 doses. One course of every 3 week dosing of paclitaxel or nab-paclitaxel is 1 dose).
 Patients who have received prior radiosensitizing chemotherapy are eligible.

 -  The use of corticosteroids is not allowed for 10 days prior to initiation of
 atezolizumab except patients who are taking steroids for physiological replacement.
 Inhaled or topical steroids, and adrenal replacement steroid doses are permitted in
 the absence of active autoimmune disease. This does not apply to patients receiving
 steroids as pre-medications for paclitaxel administration.

 -  Grade >= 2 uncontrolled hypertension (patients with a history of hypertension
 controlled with anti-hypertensive medication to Grade =< 1 are eligible).

 -  ADDITIONAL EXCLUSION CRITERIA FOR non-BRAF/non-RAS MUTATION (COHORT 3):

 -  Patients with clinically significant hemoptysis or tumor bleeding within two
 weeks prior to first dose of targeted therapy.

 -  Patients with suspected tracheal or esophageal invasion are excluded from cohort
 3 due to the high risk of trachealesophageal fistula. Patients excluded from
 cohort 3 may be enrolled on taxane + atezolizumab cohort (cohort 4).

 -  ADDITIONAL EXCLUSION CRITERIA FOR COHORTS 1 and 2: Ocular Exclusion Criteria for
 vemurafenib and cobimetinib containing cohorts-cohorts 1 and 2. (However, these
 patients may be assigned other cohorts if they do not meet the ocular exclusion
 criteria): History of or evidence of retinal pathology on ophthalmologic examination
 that is considered a risk factor for neurosensory retinal detachment, central serous
 chorioretinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration
 Patients will be excluded from participation in cohorts 1 and 2 if they currently are
 known to have any of the following risk factors for RVO unless a retinal specialist
 has determined that the risk of retinal detachment is low:

 -  History of serous retinopathy.

 -  History of retinal vein occlusion.

 -  History of ongoing serous retinopathy or RVO at baseline.

 -  ADDITIONAL EXCLUSION CRITERIA FOR PATIENTS IN COHORT 1
 (vemurafenib+cobimetinib+atezolizumab): History of clinically significant cardiac
 dysfunction, including the following:

 -  Mean (average of triplicate measurements) QTc interval corrected using
 Fridericia's method >= 480 ms at screening, or uncorrectable abnormalities in
 serum electrolytes (sodium, potassium, calcium, magnesium, and phosphorus).

 -  ADDITIONAL EXCLUSION CRITERIA FOR PATIENTS IN COHORTS 1 and 2 (cobimetinib-containing
 cohorts):

 -  Unstable angina, or new-onset angina within 3 months prior to initiation of study
 treatment.

 -  Symptomatic congestive heart failure, defined as New York Heart Association Class
 II or higher.

 -  Myocardial infarction within 3 months prior to initiation of study treatment.

 -  Left ventricular ejection fraction below the institutional lower limit of normal
 or below 50%, whichever is lower.