Atezolizumab With Chemotherapy in Treating Patients With Anaplastic or Poorly Differentiated Thyroid Cancer

Inclusion Criteria:

• Histologically confirmed anaplastic thyroid or poorly differentiated thyroidcarcinomas.

• Patients deemed to have unresectable locoregional disease or metastatic disease.Patients who are unwilling to undergo surgery or external beam radiation are alsoeligible.

• Patients with poorly differentiated thyroid cancer must have at least one targetlesion 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 forpatients with Gilbert's syndrome.

• Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) /alanine aminotransferase (ALT) serum glutamate pyruvate transaminase (SGPT) =< 2.5 xULN, (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 andstable international normalized ratio (INR) during the 28 days immediately precedinginitiation of study treatment.

• Subjects must be willing to undergo tumor biopsy prior to and after treatment withatezolizumab, unless in the opinion of the treating physician, a biopsy is notfeasible 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 urinepregnancy test within 14 days prior to the start of study drug and must useeffective contraceptives throughout the duration of the study. Males who aresexually active with WOCBP must agree to use effective contraception throughoutthe duration of the study. Azoospermic males and WOCBP who are continuously notheterosexually active are exempt from contraceptive requirements.

• A Women of childbearing potential (WOCBP) is defined as any female who hasexperienced 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 45years in the absence of other biological or physiological causes.

• Ability to provide informed consent.

• ADDITIONAL INCLUSION CRITERIA FOR BRAF MUTATION (COHORT 1): Patients with aBRAFV600E 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 factorsupport.

• 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 documentedliver or bone metastases, ALP =< 5 x ULN

• COHORT 1: Serum creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 40 mL/minon the basis of measured CrCl from a 24-hour urine collection or Cockcroft-Gaultglomerular 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 forcohort 1.

Exclusion Criteria:

• Subjects with an active, known or suspected autoimmune disease. Subjects with type Idiabetes mellitus on stable insulin regimen, hypothyroidism only requiring hormonereplacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiringsystemic treatment, or conditions not expected to recur in the absence of anexternal trigger are permitted to enroll.

• For patients not receiving therapeutic anticoagulation: INR or partialthromboplastin time (aPTT) > 1.5 x ULN within 28 days prior to initiation of studytreatment.

• Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathwaytargeting agents. Patients who have received prior treatment with anti-CTLA-4 may beenrolled, provided the following requirements are met: Minimum of 12 weeks from thefirst dose of anti-CTLA-4 and > 6 weeks from the last dose, and no history of severeimmune-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, orother 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 hepatitisB infection (defined as having a negative hepatitis B surface antigen [HBsAg] testand a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) areeligible. However, patients with past or resolved hepatitis B virus (HBV) should bemonitored for reactivation by a specialist. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative forHCV ribonucleic acid (RNA).

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

• Untreated brain metastases.

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

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

• Grade >= 2 uncontrolled hypertension (patients with a history of hypertensioncontrolled 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 twoweeks prior to first dose of targeted therapy.

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

• ADDITIONAL EXCLUSION CRITERIA FOR COHORTS 1 and 2: Ocular Exclusion Criteria forvemurafenib and cobimetinib containing cohorts-cohorts 1 and 2. (However, thesepatients may be assigned other cohorts if they do not meet the ocular exclusioncriteria): History of or evidence of retinal pathology on ophthalmologic examinationthat is considered a risk factor for neurosensory retinal detachment, central serouschorioretinopathy, retinal vein occlusion (RVO), or neovascular macular degenerationPatients will be excluded from participation in cohorts 1 and 2 if they currentlyare known to have any of the following risk factors for RVO unless a retinalspecialist 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 cardiacdysfunction, including the following:

• Mean (average of triplicate measurements) QTc interval corrected usingFridericia's method >= 480 ms at screening, or uncorrectable abnormalities inserum 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 ofstudy treatment.

• Symptomatic congestive heart failure, defined as New York Heart AssociationClass II or higher.

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

• Left ventricular ejection fraction below the institutional lower limit ofnormal or below 50%, whichever is lower.