Atezolizumab Combinations With Chemotherapy for Anaplastic and Poorly Differentiated Thyroid Carcinomas

Inclusion Criteria:

1. Histologically confirmed anaplastic thyroid or poorly differentiated thyroid
carcinomas.

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

3. Patients with poorly differentiated thyroid cancer must have at least one target
lesion by RECIST v1.1. This is not a requirement for ATC patients.

4. Total bilirubin patients with Gilbert's syndrome. AST (SGOT)/ALT (SGPT) patients with concurrent liver metastases). Serum creatinine >/= 1.0 x 10^9/L; PLT >/= 100 x 10^9/L.

5. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen and
stable INR during the 28 days immediately preceding initiation of study treatment

6. 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.

7. ECOG PS
8. Age >/= 18 years.

9. Age and Reproductive Status a) Males and Females, >/=18 years. 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.

10. Ability to provide informed consent.

11. 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: ANC >/= 1.5 ×
10^9/L without granulocyte colony-stimulating factor support, WBC count >/= 2.5 ×
10^9/L, Lymphocyte count >/= 0.5 × 10^9/L, Platelet count >/= 100 × 10^9/L without
transfusion, Hemoglobin >/= 9.0 g/L without transfusion.

12. ADDITIONAL INCLUSION CRITERIA FOR BRAF MUTATION (COHORT 1): Serum albumin >/=2.5 g/L,
Total bilirubin ULN, Serum creatinine /= 40 mL/min on
the basis of measured CrCl from a 24-hour urine collection or Cockcroft-Gault
glomerular filtration rate estimation: CrCl = ((140 － age) / (serum creatinine in
mg/dL)) × (weight in kg) (× 0.85 if female)/ 72). 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:

1. 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.

2. For patients not receiving therapeutic anticoagulation: INR or aPTT >1.5 x ULN within
28 days prior to initiation of study treatment

3. 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 (NCI CTCAE Grade 3 and 4)

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

5. History of 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 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 RNA.

6. 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.

7. Untreated brain metastases.

8. 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.

9. 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.

10. Grade >/= 2 uncontrolled hypertension (patients with a history of hypertension
controlled with anti-hypertensive medication to Grade
11. ADDITIONAL EXCLUSION CRITERIA FOR non-BRAF/non-RAS MUTATION (COHORT 3): a. Patients
with clinically significant hemoptysis or tumor bleeding within two weeks prior to
first dose of targeted therapy. b. Patients with suspected tracheal or esophageal
invasion are excluded from cohort 3 due to the high risk of tracheoesophageal fistula.
Patients excluded from cohort 3 may be enrolled on taxane + atezolizumab cohort
(cohort 4).

12. 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: a. History of serous
retinopathy b. History of retinal vein occlusion c. History of ongoing serous
retinopathy or RVO

13. ADDITIONAL EXCLUSION CRITERIA FOR PATIENTS IN COHORT 1
(vemurafenib+cobimetinib+atezolizumab): Cardiac Exclusion Criteria: History of
clinically significant cardiac dysfunction, including the following: a.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)

14. ADDITIONAL EXCLUSION CRITERIA FOR PATIENTS IN COHORTS 1 and 2 (cobimetinib-containing
cohorts): Cardiac Exclusion Criteria: a. Unstable angina, or new-onset angina within 3
months prior to initiation of study treatment b. Symptomatic congestive heart failure,
defined as New York Heart Association Class II or higher c. Myocardial infarction
within 3 months prior to initiation of study treatment d. Left ventricular ejection
fraction below the institutional lower limit of normal or below 50%, whichever is
lower