Durvalumab, Tremelimumab, and Selumetinib in Treating Participants With Recurrent or Stage IV Non-small Cell Lung Cancer

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a dose
level of selumetinib based on when you join this study. Up to 3 dose levels of selumetinib
will be tested. Up to 3 participants will be enrolled at each dose level. The first group of
participants will receive the lowest dose level. Each new group will receive a higher dose
than the group before it, if no intolerable side effects were seen. This will continue until
the highest tolerable dose of selumetinib is found.

All participants will receive the same dose of tremelimumab and durvalumab.

If you were enrolled to receive the first 2 dose levels of selumetinib and the third dose
level is found to be safe and tolerable, your dose may be increased to the third dose level.
This will be discussed with you.

Study Drug Administration:

Each study cycle is 28 days.

You will be randomly assigned (as in the flip of a coin) to 1 of 2 study cohorts (groups).
This is done because no one knows if one study group is better, the same, or worse than the
other group.

- If you are in Cohort 1, you will take selumetinib on an intermittent schedule
(alternating 7 days on, 7 days off). This means you will take selumetinib on Days 1-7
and Days 15-21 of each cycle. You will not take the study drug on Days 8-14 and 22-28.

- If you are in Cohort 2, you will take selumetinib every day.

You will take selumetinib 2 times every day. Each dose should be taken about 12 hours apart.
You must fast (having nothing to eat or drink except water) for 1 hour before and 2 hours
after taking selumetinib.

You should record each selumetinib dose in the dosing diary that will be given to you. You
should bring the diary to your study visits at the end of every cycle.

You will also receive tremelimumab and durvalumab by vein over about 60 minutes on Day 1 of
each cycle. After Cycle 4, you will only receive durvalumab. You will be given standard drugs
to help decrease the risk of side effects. You may ask the study staff for information about
how the drugs are given and their risks.

Length of Study:

You may receive selumetinib and durvalumab for as long as the doctor thinks is in your best
interest. You may receive tremelimumab for up to 4 cycles. 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.

If you complete the 4 cycles of treatment with selumetinib, durvalumab, and tremelimumab and
the disease later gets worse while you are receiving selumetinib and durvalumab, you may be
able to restart treatment with all 3 drugs for an additional 4 cycles. This may only be done
1 time and this possibility will be discussed with you.

Study Visits:

About 14 days before the first dose of the study drugs:

- You will have a physical exam.

- Blood (about 3 teaspoons) will be drawn for routine tests.

- If the doctor thinks it is needed, you will have an EKG.

On Day 1 of each cycle:

- You will have a physical exam.

- Blood (about 3 teaspoons) and urine will be collected for routine tests.

- During Cycle 2, blood (about 5 teaspoons) will be drawn for biomarker testing, including
genetic biomarkers.

- If the doctor thinks it is needed, you will have an eye exam.

- If you can become pregnant and the doctor thinks it is needed, blood (about ½ teaspoon)
will be drawn for a pregnancy test.

On Day 1 of Cycles 1 and 4 (about Week 16), you will have an EKG. During Cycle 1, you will
have an EKG before and up to 3 hours after your dose of study drugs.

During even-numbered cycles (Cycles 2, 4, 6, and so on), you will have a CT scan or MRI to
check the status of the disease.

Every 3 cycles starting with Cycle 3 (Cycles 6, 9, and so on), you will have an ECHO or MUGA
scan.

At any time while on study, if the doctor thinks it is needed, the above tests/procedures
(routine blood and urine collections and EKGs, for example) may be repeated.

Follow-Up Visits:

At about 30 days and 90 days after your last dose of the study drugs:

- You will have a physical exam.

- Blood (about 3 teaspoons) will be drawn for routine tests.

- You will have an EKG.

- At the 90-day follow-up visit, blood (about 5 teaspoons) will be drawn for biomarker
testing, including genetic biomarkers.

- If you can become pregnant and the doctor thinks it is needed, blood (about ½ teaspoon)
will be drawn for a pregnancy test.

About 60 days after your last dose of study drugs, blood (about 3 teaspoons) will be drawn
for routine tests.

If you stop taking the study drugs for any reason other than the disease getting worse, you
will continue to have an MRI or CT scan to check the status of the disease about every 8
weeks. If the disease worsens, these scans will stop.

Long-Term Follow-Up:

Every 6 months for up to 2 years, the study staff will call you to ask how you are doing.
These calls should last about 5-10 minutes.

Inclusion Criteria:

1. Written informed consent and any locally-required authorization will be obtained from
the patient prior to performing any protocol-related procedures, including screening
evaluations

2. Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up.

3. Histologically or cytologically confirmed recurrent non-small cell lung cancer not
amenable to curative intent therapy or stage IV NSCLC

4. Known KRAS mutation status by CLIA certified test.

5. Documented progression following at least one line of chemotherapy or immunotherapy
for metastatic or recurrent disease, or progression within 6 months of receiving
adjuvant chemotherapy or concurrent chemotherapy for early stage or locally advanced
disease

6. Biopsy accessible disease and willingness to undergo tumor biopsy.

7. Measurable disease by RECIST 1.1.

8. Age >/=18 years at time of study entry

9. Total body weight > 30 kg

10. ECOG performance status 0 or 1

11. Ability to take pills by mouth

12. Patients must have normal organ and marrow function as defined below: 1) leukocytes
>/= 3,000/mcL, 2) absolute neutrophil count >/= 1,500/mcL, 3) platelets >/=
100,000/mcL, 4) hemoglobin >/= 9.0 g/dL, 5) total bilirubin total bilirubin upper limit of normal (ULN) (higher is allowed if in the setting of known Gilbert's
disease), 6) AST(SGOT)/ALT(SGPT) x ULN if liver metastases are present,7) Alkaline phosphatase upper limit of normal or <6 x ULN if liver metastases are present, 7) creatinine
clearance >/=50 mL/min/1.73 m2 by Cockcroft-Gault equation (creatinine clearance=
([140-age]× body mass)/(plasma creatinine × 72) × gender correction factor) or by
24-hour urine collection.

13. Brain metastases are allowed, as long as they are stable and do not require treatment
with anticonvulsants or escalating doses of steroids.

14. Females of Childbearing potential must have a negative serum pregnancy test and must
agree to use adequate contraception for the duration of the study and six months
after.

15. Have adequate renal function, with a GFR of >/= 50ml/min by the Cockcroft-Gault
formula or by 24 hour urine collection.

Exclusion Criteria:

1. Have received or are receiving an investigational medicinal product (IMP) or other
systemic anticancer treatment within 4 weeks prior to the first dose of study
treatment, or within a period during which the IMP or systemic anticancer treatment
has not been cleared from the body (e.g. a period of 5 'half-lives'), whichever is the
most appropriate and as judged by the Investigator.

2. Concurrent enrolment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an
interventional study.

3. Current or prior use of immunosuppressive medication within 14 days of the 1st dose of
durvalumab, with the exception of intranasal and inhaled corticosteroids or oral
corticosteroids at physiological doses, which are not to exceed 10 mg/day of
prednisone, or an equivalent corticosteroid.

4. Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer
treatment.

5. Receipt of radiation therapy within 4 weeks prior to starting study treatment. Limited
field of radiation for palliation at any time prior to the start of study treatment is
acceptable if: a) The lung is not in the radiation field, b) The irradiated lesions
are not used as target lesions.

6. Receipt of live attenuated vaccination within 30 days prior to study entry or within
30 days of receiving durvalumab.

7. Prior treatment with a MEK, Ras, or Raf inhibitor.

8. Patients who have received prior anti PD-1, anti PD-L1 or anti CTLA-4 a) must not have
experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
b) All AEs while receiving prior immunotherapy must have completely resolved or
resolved to baseline prior to screening for this study c) Must not have experienced a
>/= Grade 3 immune related AE or an immune related neurologic or ocular AE of any
grade while receiving prior immunotherapy. NOTE: Patients with endocrine AE of Grade 2 are permitted to enroll if they are stably maintained on appropriate
replacement therapy and are asymptomatic.

9. Must not have required the use of additional immunosuppression other than
corticosteroids for the management of an AE, not have experienced recurrence of an AE
if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or
equivalent per day

10. Patients who are receiving any other investigational agents.

11. Any unresolved chronic toxicity with CTC AE grade >/=2, from previous anticancer
therapy, except for alopecia. Any unresolved toxicity NCI CTCAE Grade >/=2 from
previous anticancer therapy with the exception of alopecia, vitiligo, and the
laboratory values defined in the inclusion criteria. 1) Patients with Grade >/=2
neuropathy will be evaluated on a case-by-case basis after consultation with the Study
Physician. 2) Patients with irreversible toxicity not reasonably expected to be
exacerbated by treatment with durvalumab or tremelimumab may be included only after
consultation with the Study Physician

12. Known hypersensitivity to selumetinib, durvalumab, tremelimumab or any excipient or
history of allergic reactions attributed to compounds of similar chemical or biologic
composition to selumetinib, tremelimumab or durvalumab

13. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease (e.g., colitis or Crohn's disease), diverticulitis (with
the exception of diverticulosis), systemic lupus erythematosus, Sarcoidosis syndrome,
or Wegener syndrome (granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc). The following are exceptions to this
criterion: a) Patients with vitiligo or alopecia, b) Patients with hypothyroidism
(e.g., following Hashimoto syndrome) stable on hormone replacement, c) Any chronic
skin condition that does not require systemic therapy, d) Patients without active
disease in the last 5 years may be included but only after consultation with the study
physician, e) Patients with celiac disease controlled by diet alone

14. Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and TB testing in line with
local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),
hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients
with a past or resolved HBV infection (defined as the presence of hepatitis B core
antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative
for HCV RNA.

15. History of leptomeningeal carcinomatosis.

16. Have known or suspected brain metastases or spinal cord compression, unless the
condition has been asymptomatic, has been treated with surgery and / or radiation, and
has been stable without requiring corticosteroids nor anti-convulsant medications for
at least 4 weeks prior to the first dose of study medication.

17. Known history of previous clinical diagnosis of tuberculosis.

18. History of primary immunodeficiency

19. History of organ transplant requiring therapeutic immunosuppression.

20. Cardiac conditions as follows: a) Mean QT interval corrected for heart rate (QTc) ≥
450 ms calculated from 3 ECGs using Fredericia's formula [QTcF] or other factors that
increase the risk of QT prolongation, b) Uncontrolled hypertension (BP ≥ 150/95
despite optimal medical therapy), c) Acute coronary syndrome within 6 months prior to
starting treatment d) Uncontrolled Angina - Canadian Cardiovascular Society grade
II-IV despite medical therapy, e) Symptomatic heart failure NYHA Class II-IV, prior or
current cardiomyopathy, or severe valvular heart disease.

21. Continue from #20 f) Prior or current cardiomyopathy including but not limited to the
following: i) known hypertrophic cardiomyopathy, ii) known arrhythmogenic right
ventricular cardiomyopathy, iii) previous moderate or severe impairment of left
ventricular systolic function (LVEF < 45% on echocardiography or equivalent on MuGA)
even if full recovery has occurred, g) Baseline Left ventricular ejection fraction
(LVEF) below the LLN or <55% measured by echocardiography or institution's LLN for
MUGA, h) Severe valvular heart disease, i) Atrial fibrillation with a ventricular rate
> 100 bpm on ECG at rest

22. Ophthalmologic conditions as follows: a) Current or past history of retinal pigment
epithelial detachment (RPED)/central serous retinopathy (CSR) or retinal vein
occlusion, b) Intraocular pressure (IOP) > 21 mmHg or uncontrolled glaucoma
(irrespective of IOP)

23. Any gastrointestinal disorder expected to limit absorption of selumetinib

24. History of another primary malignancy within 5 years prior to starting study
treatment, except for adequately treated basal or squamous cell carcinoma of the skin
or cancer of the cervix in situ

25. Recent major surgery within 4 weeks prior to starting study treatment, with the
exception of surgical placement for vascular access

26. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
situations that would limit compliance with study requirement, substantially increase
risk of incurring AEs or compromise the ability of the patient to give written
informed consent.

27. Pregnant or breastfeeding women

28. Receiving or have received systemic anti-cancer therapy within 4 weeks prior to
starting study treatment (6 weeks for nitrosoureas, mitomycin, and suramin), or any
anticancer therapy which has not been cleared from the body by the time of starting
study treatment.

29. Have evidence of any other significant clinical disorder or laboratory finding that,
as judged by the investigator, makes it undesirable for the patient to participate in
the study.

30. Have refractory nausea and vomiting, chronic gastrointestinal diseases (e.g.,
inflammatory bowel disease), or significant bowel resection that would adversely
affect the absorption / bioavailability of the orally administered study medication.

31. Are male or female patients of reproductive potential and, as judged by the
investigator, are not employing an effective method of birth control from screening to
180 days after the last dose of durvalumab and tremelimumab combination therapy.

32. Patient weight