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

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.