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.