A Study of Alectinib in RET-rearranged Non-small Cell Lung Cancer or RET-mutated Thyroid Cancer

This is a Phase I/II research study, which means that researchers are testing different doses
of the drug alectinib in participants with cancer to evaluate its safety, determine a safe
dosage range, and identify side effects.

The FDA (the U.S. Food and Drug Administration) has approved alectinib as a treatment option
for NSCLC, but at a different dosage.

There are two parts to this study, Phase 1 and Phase 2. In Phase 1, patients with ALK or RET
rearranged NSCLC will receive different doses of alectinib to determine the highest dose that
can be administered without severe or unmanageable side effects. This is called the maximum
tolerated dose and will be the recommended dose for the next part of the study, Phase 2. A
Phase I clinical trial tests the safety of an investigational drug and also tries to define
the appropriate dose of the investigational drug to use for further studies.
"Investigational" means that the drug is being studied.

During Phase 2, participants with RET rearranged NSCLC or thyroid cancer will be given the
maximum tolerated dose. During both Phase 1 and Phase 2, the investigators will determine the
effect alectinib has on the body, and the effect alectinib has on cancer.

Alectinib belongs to a class of drugs known as tyrosine kinase inhibitors, which stop
tyrosine kinases from working. Tyrosine kinases are enzymes that are responsible for
activating many proteins in the body's cells. The ALK and RET kinases play an important role
in the survival and growth of tumor cells and in the ability of tumor cells to spread to
different parts of the body. In laboratory studies and in patients, alectinib has been shown
to block the ALK and RET kinases. By blocking these kinases and stopping them from working,
it is hoped that alectinib may prevent the survival of tumor cells in addition to stopping
their growth and ability to spread.

The purpose of this research study is to learn about the effects of the study drug alectinib,
and to find the best dose for treating ALK-positive or RET-positive cancers.

Inclusion Criteria:

- Tumor Types:

- Phase 1: Subjects must have a histologically or cytologically confirmed diagnosis
of locally advanced (AJCC Stage IIIB) not amenable to curative therapy or
metastatic (AJCC Stage IV) NSCLC that carries a RET rearrangement, as determined
by fluorescence in situ hybridization (FISH), reverse transcription polymerase
chain reaction (RT-PCR), or next generation sequencing (NGS) via a CLIA-certified
local diagnostic test (LDT).

--- OR-

- Phase 1: Subjects must have a histologically or cytologically confirmed diagnosis
of metastatic (AJCC Stage IV) NSCLC that carries an ALK rearrangement with CNS
metastases, as determined by FISH, RT-PCR, immunohistochemistry (IHC), or NGS via
a CLIA-certified LDT.

- Phase 2 Cohorts A&B: Subjects must have a histologically or cytologically
confirmed diagnosis of locally advanced (AJCC Stage IIIB) not amenable to
curative therapy or metastatic (AJCC Stage IV) NSCLC that carries a RET
rearrangement, as determined by FISH, RT-PCR, or NGS via a CLIA-certified LDT.

- Phase 2 Cohort C (thyroid cancer): Subjects must have a histologically or
cytologically confirmed diagnosis of metastatic thyroid cancer (Stage IV) that
carries either a RET rearrangement or activating RET mutation, as determined by
FISH, RT-PCR, or NGS via a CLIA-certified LDT.

- Disease Status Requirements:

- Phase 1: Subjects with a RET rearrangement must have had disease progression
after at least one prior line of systemic therapy. Subjects with an ALK
rearrangement may be either treatment naive or may have received prior treatment,
and must have CNS disease present at baseline. Subjects cannot have received more
than one prior RET TKI (such as, but not limited to, vandetanib, sorafenib,
sunitinib, ponatinib, or cabozantinib). Subjects enrolling to the Phase 1 portion
of the trial must not have received prior alectinib therapy.

- Phase 2:

- Cohort A: RET-positive NSCLC subjects must have received at least one prior
line of therapy, but must be RET TKI-naive.

- Cohort B: RET-positive NSCLC that has previously been treated with one RET
TKI. Subjects cannot have received more than one prior RET TKI and must not
have received prior alectinib.

- Cohort C: RET-positive thyroid cancer, must be radioactive iodine
refractory.

- Subjects must have at least one measurable target lesion according to RECIST v1.1.

- Subjects enrolling to the phase 1 portion of the trial who have received a prior RET
TKI must be able and willing to undergo a pre-treatment fresh tumor biopsy.

- Subjects enrolling to Cohort B or C of the phase 2 portion of the trial who have
received a prior RET TKI must be able and willing to undergo a pre-treatment fresh
tumor biopsy.

- All subjects must have archival tissue confirmed as available for enrollment. Subjects
who are TKI naive who do not have archival tissue may undergo a fresh tumor biopsy in
lieu of the archival tissue requirement. The archival tissue requirement may be waived
for subjects after discussion with the principal investigator.

- Age ≥ 18 years.

- ECOG performance status ≤2 (See APPENDIX A)

- Subjects must have normal organ and marrow function as defined below:

Adequate hematologic function

- Absolute neutrophil count ≥1,500/mcL

- Platelets ≥100,000/mcL

- Hemoglobin ≥ 9.0 g/dL -- Adequate renal function

- serum creatinine ≤1.5 x institutional ULN

---- OR-

- Estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2 as calculated using the
Modification of Diet Renal Disease Equation (See APPENDIX B)

- Subjects must have recovered from treatment toxicities to ≤ Grade 1 or to their
pretreatment levels. Subjects who have developed interstitial lung disease (ILD)
must have fully recovered.

- For all females of childbearing potential, a negative serum pregnancy test must
be obtained within 3 days prior to starting study treatment.

- For women who are not postmenopausal (≥12 months of non-therapy-induced
amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement
to remain abstinent or use single or combined contraceptive methods that result
in a failure rate of < 1% per year during the treatment period and for at least 3
months after the last dose of study drug. Abstinence is only acceptable if it is
in line with the preferred and usual lifestyle of the subject. Periodic
abstinence (e.g., calendar, ovulation, symptothermal or postovulation methods)
and withdrawal are not acceptable methods of contraception. Examples of
contraceptive methods with a failure rate of < 1% per year include tubal
ligation, male sterilization, hormonal implants, established, proper use of
combined oral or injected hormonal contraceptives, and certain intrauterine
devices.

- For men: agreement to remain abstinent or use a contraceptive method that results
in a failure rate of < 1% per year during the treatment period and for at least 3
months after the last dose of study drug. Abstinence is only acceptable if it is
in line with the preferred and usual lifestyle of the subject. Periodic
abstinence (e.g., calendar, ovulation, symptothermal or postovulation methods)
and withdrawal are not acceptable methods of contraception.

- Ability to understand and the willingness to sign a written informed consent
document.

Exclusion Criteria:

- Cytotoxic chemotherapy or immunotherapy within 3 weeks of study entry.

- Oral targeted therapy within 5 half-lives (if known) or 3 weeks (if half-life is
unknown) of study entry.

- Phase 1: subjects who have received prior alectinib therapy.

- For enrollment to the phase 1 portion of the trial: Administration of any cytochrome
P450 (CYP)3A inhibitors or inducers within 14 days prior to the first dose of
alectinib and from Cycle 1 Day 1 - Cycle 2 Day 8 of the phase 1 portion of the trial.
Following completion of this period, strong/potent cytochrome P450 (CYP)3A inhibitors
or inducers are prohibited while on study. Please see APPENDIX C.

- Radiation therapy (except palliative to relieve bone pain) within 2 weeks of study
entry. Palliative radiation (≤10 fractions) must have been completed at least 48 hours
prior to study entry. Stereotactic or small field brain irradiation must have
completed at least 2 weeks prior to study entry. Whole brain radiation must have
completed at least 4 weeks prior to study entry.

- Major surgery within 4 weeks of study entry. Minor surgical procedures (e.g., port
insertion) are not excluded, but sufficient time should have passed for wound healing
(as determined by the treating investigator).

- Subjects who are receiving any other investigational agents.

- Liver disease characterized by:

-- ALT or AST > 3 × institutional ULN (≥ 5 × ULN for subjects with concurrent liver
metastasis) confirmed on two consecutive measurements

--- OR-

- Absolute impaired excretory function (e.g., hyperbilirubinemia) or synthetic function
or other conditions of decompensated liver disease such as coagulopathy, hepatic
encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices

--- OR-

- Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or other
conditions of decompensated liver disease such as coagulopathy, hepatic
encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices

---OR-

- Acute viral or active autoimmune, alcoholic, or other types of acute hepatitis

- Subjects with symptomatic CNS metastases who are neurologically unstable and/or
require an increased dose of steroid to manage CNS symptoms within 1 week prior to the
first day of treatment are excluded.

- Subjects with brain or leptomeningeal metastases that do not meet the above
criteria are allowed.

- Symptomatic disease is allowed as long as symptoms are controlled and stable.

- History of hypersensitivity to any of the additives in the alectinib drug formulation.

- Subjects with symptomatic bradycardia.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant or breastfeeding women.

- Any GI disorder that may affect absorption of oral medications in the opinion of the
treating investigator, such as malabsorption syndrome or major bowel or stomach
resection.

- Subjects who are unable to swallow pills.

- Subjects with a history of a second primary malignancy. Exceptions include: subjects
with a history of malignancies that were treated curatively and have not recurred
within 3 years prior to study entry; resected basal and squamous cell carcinomas of
the skin, and completely resected carcinoma in situ of any type.

- NCI-CTCAE v4.03 Grade 3 or higher toxicities due to any prior therapy (excluding
alopecia), which have not shown improvement and are strictly considered to interfere
with current study medication.

- Known HIV positivity or AIDS-related illness.