Enfortumab Vedotin for the Treatment of Unresectable or Metastatic Radioiodine Refractory Differentiated Thyroid Cancer, Anaplastic Thyroid Cancer, Medullary Thyroid Cancer, or NUT Carcinoma

Patients must have histologically or cytologically confirmed:

* radioiodine refractory (RAIR) differentiated thyroid cancer (DTC)\^A (including RAIR poorly differentiated thyroid cancer \[PDTC\])\^A

* radioiodine refractory (RAIR) differentiated thyroid cancer (DTC\^1), (including RAIR poorly differentiated thyroid cancer (\[PDTC\^2\]), that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective

* ≥ 1 line of systemic therapy allowed including radioactive iodine (RAI) therapy, tyrosine kinase inhibitors (TKIs), targeted therapies, radiation therapy, chemotherapy and immunotherapy. NOTE: prior treatment with enfortumab vedotin or other monomethyl auristatin E (MMAE) based antibody-drug conjugates (anti-drug congigates \[ADCs\] is not allowed.)

* Washout of 2 weeks from prior anti-cancer treatments before start of study treatment (C1D1) required OR

* anaplastic thyroid cancer (ATC)\^B

* anaplastic thyroid cancer (ATC)\^4 that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective

* For BRAF V600E mutated: 2 lines as TKIs and ≥ 1 line of immunotherapy allowed; all other systemic therapies, ≥ 1 line, including radiation therapy and chemotherapy;

* wild type (WT) for BRAF: ≥ 1 line of systemic therapy allowed including TKIs, targeted therapies, radiation therapy, chemotherapy and immunotherapy

* For both: Washout of 2 weeks from prior anti-cancer treatments before start of study treatment (C1D1) required. NOTE: prior treatment with enfortumab vedotin or other monomethyl auristatin E (MMAE) based antibody-drug conjugates (ADCs is not allowed.

OR

medullary thyroid cancer (MTC)\^C

* medullary thyroid cancer (MTC) that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective

* ≥ 1 line of systemic therapy allowed including TKIs, targeted therapies, radiation therapy, chemotherapy and immunotherapy. NOTE: prior treatment with enfortumab vedotin or other monomethyl auristatin E (MMAE) based antibody-drug conjugates (ADCs is not allowed.

* Washout of 2 weeks from prior anti-cancer treatment before start of study treatment (cycle 1 day 1 \[C1D1\]) required OR

NUT carcinoma\^D

* NUT carcinoma\^3 that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective

* Any number of lines allowed. NOTE: prior treatment with enfortumab vedotin or other monomethyl auristatin E (MMAE) based antibody-drug conjugates (ADCs is not allowed).

* Washout of 2 weeks from prior anti-cancer treatments before start of study treatment (C1D1) required

Footnote 1: Main histological types of differentiated thyroid carcinoma (DTC) include: papillary, follicular and oncocytic thyroid carcinoma. Differentiated cancers are classified as such as they tend to grow and spread slowly compared to undifferentiated cancers, which are faster growing and spread rapidly. This study is for RAIR-DTC (or RAIR PDTC) patients that have failed Radioactive iodine therapy (radioactive iodine \[RAI\], and those that have failed are called RAI refractory or RAIR), have metastatic or unresectable disease; original histology/cytology/pathology reports for diagnosis of DTC (or PDTC) and most recent imaging (ultrasound/CT/MRI/radioiodine imaging and recent Tg lab results) for review of disease progression and RAI uptake for RAIR determination. Also, pathology report of most recent biopsy if available.

Footnote 2: Poorly differentiated thyroid cancer (PDTC) is typically classified as a type of differentiated thyroid cancer (unlike an undifferentiated thyroid cancer such as anaplastic thyroid cancer4); see footnote 1.

Footnote 3: Patients must have histologically or cytologically confirmed NUT carcinoma based on the ectopic expression of NUT protein per World Health Organization (WHO) criteria as determined by immunohistochemistry (IHC) and/or detection of NUT gene translocation as determined by fluorescence in situ hybridization (FISH) at a Clinical Laboratory Improvement Act (CLIA) certified laboratory and/or by detection of the NUT gene translocation as determined by sequencing (e.g., dioxyribonucleic acid \[DNA\] next generation sequencing (NGS) or ribonucleic acid \[RNA\] sequencing) at a CLIA certified laboratory.

Footnote 4: Anaplastic Thyroid Carcinoma (ATC) is an aggressive undifferentiated tumor, the least common type of thyroid carcinoma, and develops from more differentiated tumors as a result of one or more dedifferentiating (transforming) steps leading to its fast growth and capacity to spread rapidly; in particular, via loss of the p53 tumor suppressor protein. ATC is an undifferentiated cancer that is refractory to iodine-131 (radioiodine) imaging and radioiodine therapy (RAI) and is considered RAIR and is generally incurable. The original histology/cytology/pathology reports for diagnosis of the original thyroid malignancy and for confirmation of ATC by surgical biopsy (pathology report for biopsy results) and most recent imaging (ultrasound/CT/MRI/radioiodine imaging) and recent lab results (including complete blood count \[CBC\], complete metabolic panel \[CMP\], thyroid stimulating hormone \[TSH\] and molecular testing) for review of disease progression.

* Patients must have measurable disease by RECIST v 1.1

* Patients must be age ≥ 18 years

* Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

* Leukocytes (white blood cell \[WBC\]) ≥ 3,000/mcL

* Absolute neutrophil count (ANC) ≥ 1,500/mcL

* Hemoglobin (Hgb) ≥ 9 g/dL

* Platelets (PLT) ≥ 100,000/mcL

* Total bilirubin ≤ 1.5 x Institutional upper limit of normal (ULN)

* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) ≤ 3 x institutional ULN

* Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 x institutional ULN

* Creatinine ≤ 1.5 x Institutional ULN

* Glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 m\^2

estimated glomerular filtration rate (eGFR) is estimated GFR calculated by the abbreviated Modification of Diet in Renal Disease (MDRD) equation

* The effects of enfortumab vedotin (EV) on the developing human fetus are unknown. For this reason and because ADC agents as well as other therapeutic agents used in this trial are known to be teratogenic. For this reason, patients of child-bearing potential (POCBP) and their partners with sperm-producing reproductive capacity must agree to use adequate contraception from time of start of study therapy (C1D1), for the duration of study participation, and for 60 days following completion of study drug therapy. Should a person of child bearing potential (POCBP) become pregnant or suspect they are pregnant while they or their partner are participating in this study, they should inform their treating physician immediately. Patients with sperm-producing reproductive capacity (PWSPRC) treated or enrolled on this protocol must also agree to use adequate contraception with partners of childbearing potential from time of start of study therapy (C1D1), for the duration of study participation, and 120 days after completion of administration

Note: A POCBP is any patient (regardless of gender, sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) with an egg-producing reproductive tract who meets the following criteria:

* Has not undergone a hysterectomy or bilateral oophorectomy

* Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for \> 12 months)

* POCBP must have a negative pregnancy test prior to registration on study

* Patients must have the ability to understand and the willingness to sign a written informed consent document and comply with the study requirements

* NOTE: Patients with an HCV infection must have been treated and cured in order to participate.

* NOTE: CD4+ T cell counts, and viral load are monitored per standard of care

Patients who have an uncontrolled intercurrent illness including, but not limited to any of the following:

* Hypertension that is not controlled on medication

* Ongoing or active infection requiring systemic treatment

* Routine microbial prophylaxis is allowed (e.g., uncomplicated urinary tract infections, sinus infections and are on antibiotics).

* Symptomatic congestive heart failure

* Unstable angina pectoris

* Cardiac arrhythmia

* Psychiatric illness/social situations that would limit compliance with study requirements

* Any other illness, laboratory finding or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints

Patients with a concurrent malignancy or prior malignancy diagnosed within 3 years before first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy.

* NOTE: Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, localized prostate cancer treated with curative intent with no evidence of progression, low-risk or very low-risk (per standard guidelines) localized prostate cancer under active surveillance/watchful waiting without intent to treat, or in situ cervical cancer that has undergone potentially curative therapy are allowed

Patients with documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction or cardiac symptoms (including congestive heart failure) consistent with New York Heart Association Class III-IV within 6 months prior to the first dose of study drug

Patients who are pregnant or nursing. Pregnant patients are excluded from this study because is enfortumab vedotin has the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with enfortumab vedotin breastfeeding should be discontinued if the mother is treated with enfortumab vedotin

What this study is about