Alectinib in Treating Patients with RET-Rearranged Stage IIIB-IV Non-small Cell Lung Cancer or RET-Mutated Stage IV Thyroid Cancer

Inclusion Criteria

• Phase 1: Subjects must have a histologically or cytologically confirmed diagnosis of locally advanced (American Joint Committee on Cancer [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 Clinical Laboratory Improvement Act (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
• 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 version (v)1.1
• 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
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 9.0 g/dL
• Serum creatinine =< 1.5 x institutional upper limit of normal (ULN) OR
• Estimated glomerular filtration rate (eGFR) >= 45 mL/min/1.73 m^2 as calculated using the modification of diet renal disease equation
• 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
• 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: * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 x institutional ULN (>= 5 x 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 gastrointestinal (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
• National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (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 human immunodeficiency virus (HIV) positivity or acquired immunodeficiency syndrome (AIDS)-related illness