Cobimetinib and Atezolizumab in Advanced Rare Tumors

Study Drug Administration:

Each cycle is 28 days.

You will take cobimetinib tablets by mouth 1 time a day on Days 1-21 of each cycle. Each dose
should be taken at about the same time each day, with or without a meal. Do not crush, cut,
or chew the tablets.

On Days 1 and 15 of each cycle, you will receive atezolizumab by vein over about 60 minutes.

Length of Treatment:

You may receive the study drugs for as long as the doctor thinks it is in your best interest.
You will no longer be able to take the study drugs if the disease gets worse, if intolerable
side effects occur, or if you are unable to follow study directions.

It is expected that your participation in this study may last about 12 months.

Your participation in this study will be over after follow-up.

Study Visits:

On Day 1 of Cycle 1, if not done within the previous 7 days:

- You will have a physical exam.

- Blood (about 3 tablespoons) will be drawn for genetic research to learn how your DNA
(genetic information) relates to your response to the study drugs, the disease, and your
immune system.

On Day 15 of all cycles, blood (about 3-4 teaspoons) will be drawn for routine tests and
genetic research.

On Day 1 of Cycles 2 and beyond:

- You will have a physical exam.

- Blood (about 3-4 teaspoons) will be drawn for routine tests and genetic research.

- During Cycles 2 and 3 only, urine will be collected for routine testing.

On Day 1 of Cycles 2, 5, 8, 11, and 15 and every 4 cycles after that (Cycles 19, 23, 27, and
so on), you will have an ECHO or MUGA to check your heart function.

On Day 1 of Cycle 2 and every 3 cycles after that (Cycles 5, 8, 11, and so on), you will have
an eye exam.

Between Days 22-28 of Cycle 2, you will have a tumor biopsy for biomarker testing and to
check the status of the disease.

Every 8 weeks, you will have an MRI or CT scan.

End-of-Treatment Visit:

Within 2 weeks after your last dose of study drugs:

- You will have a physical exam.

- Blood (about 3 tablespoons) will be drawn for routine tests and genetic research.

- Urine will be collected for routine tests

- You will have an ECHO or MUGA.

- You will have an MRI, CT, or PET/CT scan.

- If the disease appears to have gotten worse and the doctor thinks it is safe to do so,
you will have a tumor biopsy for biomarker testing.

Follow-Up:

You will be contacted every 3 months to ask how you are doing. This may be done by phone or
at a routine clinic visit. If you are called, it should last about 5-10 minutes. These calls
will continue until the study closes, you withdraw from the study, or you can no longer be
contacted.

Inclusion Criteria:

1. Must have histologically or cytologically documented rare tumor as defined per
protocol that is metastatic or locally advanced and unresectable. Patients with
locally advanced cutaneous squamous cell carcinoma that are technically resectable but
in whom surgery is expected to lead to substantial function impairment or
disfigurement are eligible.

2. Must be refractory or intolerant to standard lines of therapy.

3. Presence of radiographically evaluable disease.

4. Must have completed prior chemotherapy, immunotherapy, or radiation therapy at least
14 days prior to start of treatment and all toxicity must be resolved to CTCAE v4.0
Grade 1 (with the exception of CTCAE v4.0 Grade 2 neuropathy) prior to start of
treatment.

5. ECOG Performance Status of 0-2.

6. Age >/= 18 years.

7. Tissue Parameters: a. Representative formalin-fixed paraffin-embedded (FFPE) tumor
specimens in paraffin blocks (blocks are preferred) or at least 4 unstained slides,
with an associated pathology report, for testing of tumor PD-L1 expression (Tumor
tissue from bone metastases is not evaluable for PD-L1 expression and is therefore not
acceptable). b. Tumor tissue should be of good quality based on total and viable tumor
content. Fine needle aspiration, brushing, cell pellet from pleural effusion, bone
metastases, and lavage samples are not acceptable. For core-needle biopsy specimens,
at least three cores should be submitted for evaluation. c. Patients who do not have
tissue specimens meeting eligibility requirements must be willing to undergo a biopsy
during the screening period.

8. Must have adequate hematologic function as evidenced by all of the following within 14
days prior to enrollment: ANC >/= 1,000/mcL; platelets >/= 75,000/mcL; and hemoglobin
>/= 9 g/dL.

9. Must have adequate hepatic function as evidenced by all of the following within 14
days prior to enrollment: AST, ALT, and ALP normal (IULN) without liver mets or
10. Must have adequate kidney function as evidenced by calculated creatinine clearance >
30 ml/min within 14 days prior to enrollment.

11. Patients must be informed of investigational nature of this study and must be willing
to give written informed consent in accordance with institutional and federal
guidelines. Patients must be able to comply with the requirements and assessments of
the study protocol

12. 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. Effective methods of contraception are defined as those that result in a
low failure rate (i.e., less than 1% per year) when used consistently and correctly
(e.g., implants, injectables, combined oral contraception or intra-uterine devices).
At the discretion of the Investigator, acceptable methods of contraception may include
total abstinence in cases where the lifestyle of the patient ensures compliance.
(Periodic abstinence [e.g., calendar, ovulation, symptothermal, post ovulation
methods] and withdrawal are not acceptable methods of contraception.)

Exclusion Criteria:

1. For individual baskets: Appendiceal Adenocarcinoma: Must not have clinically
symptomatic malignant bowel obstruction; Cutaneous squamous cell carcinoma: None;
Small bowel adenocarcinoma: Must not have clinically symptomatic malignant small bowel
obstruction.

2. Presence of Brain metastases (unless they have been adequately treated with
radiotherapy or surgery and stable for at least 30 days prior to enrollment provided
patient is neurologically asymptomatic and without corticosteroid treatment for at
least 7 days prior to enrollment).

3. Uncontrolled intercurrent illness including, but not limited to diabetes,
hypertension, severe infection, severe malnutrition, unstable angina, Class III-IV New
York Heart Association (NYHA) congestive heart failure, ventricular arrhythmias,
active ischemic heart disease, or myocardial infarction within 6 months prior to
enrollment.

4. 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.

5. Patients will be excluded from study participation if they currently are known to have
any of the following risk factors for RVO: a. Glaucoma with intraocular pressure >/=
21 mmHg b. Grade>/= 2 serum cholesterol c. Grade >/= 2 hypertriglyceridemia d. Grade
>/= 2 or symptomatic hyperglycemia (fasting) e. Grade >/= 2 uncontrolled hypertension
(patients with a history of hypertension controlled with anti-hypertensive medication
to Grade
6. Active malignancy (other than CRC) or a history of prior malignancy within the past 3
years. Adequately treated basal cell or squamous cell skin cancer, in situ cervical
cancer, ductal carcinoma in situ, other low grade lesions such as incidental appendix
carcinoid, or any other cancer from which the patient has been disease and treatment
free for two years are allowed. Prostate cancer patients on active surveillance are
eligible.

7. Pregnant or nursing patients due to risk of fetal or nursing infant harm. Women/men of
reproductive potential who do not agree to use an effective contraceptive method while
on study and for at least 6 months after study treatment.

8. Exclusion criteria related to study medication (any cancer immunotherapy including
CD137 agonists, anti－PD-1, anti－PD-L1, or anti-CTLA4 or any MEK or ERK inhibitor).

9. Left ventricular ejection fraction (LVEF) < institutional lower limit of normal or <
50%.

10. 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 a. Patients with a history of
autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be
eligible. b. Patients with controlled Type 1 diabetes mellitus on a stable insulin
regimen may be eligible. c. 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:

11. Inclusion #10 cont'd) i. Patients with psoriasis must have a baseline ophthalmologic
exam to rule out ocular manifestations ii. Rash must cover less than 10% of body
surface area (BSA) iii. Disease is well controlled at baseline and only requiring low
potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,
fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%) iv. 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)

12. 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 a. History of radiation pneumonitis in the radiation field
(fibrosis) is permitted.

13. History of HIV infection or active hepatitis B (chronic or acute) or hepatitis C
infection. a. 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. b. Patients positive for
hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR)
is negative for HCV RNA.

14. Active tuberculosis or severe infections within 4 weeks prior to Cycle 1, Day 1,
including but not limited to hospitalization for complications of infection,
bacteremia, or severe pneumonia

15. Treatment with systemic immunostimulatory agents (including but not limited to
interferon [IFN] or interleukin [IL]-2) within 6 weeks or five half-lives of the drug
(whichever is shorter) prior to Cycle 1, Day 1.

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

17. Prior allogeneic bone marrow transplantation or prior solid organ transplantation.