Brodalumab in the Treatment of Immune-Related Adverse Events

Inclusion Criteria:

• Ability to provide written informed consent by subject or guardian

• Individuals >18 years of age

• Diagnosis of an irAE clinically suspected to be IL-17 mediated

• Intent-to-treat or prior treatment with systemic steroids for irAE management

• Histology-proven primary advanced or metastatic solid organ malignancy treated withimmunotherapy. Patients being treated with curative intent are not eligible toenroll.

• Subject has a negative test for tuberculosis during screening defined as either:negative purified protein derivative (PPD) (< 5 mm of induration at 48 to 72 hoursafter test is placed) OR negative QuantiFERON test. Tuberculosis testing must beperformed within 30 days prior to trial initiation.

• Subjects with a positive PPD and a history of Bacillus Calmette-Guérin vaccinationare allowed with a negative QuantiFERON test.

• Subjects with a positive PPD test (without a history of Bacillus Calmette-Guérinvaccination) or subjects with a positive or indeterminate QuantiFERON test areallowed if they have all of the following: no symptoms of tuberculosis (defined asfever, shortness of breath, cough or night sweats), documented history of acompleted course of adequate prophylaxis (per local standard of care), no knownexposure to a case of active tuberculosis after most recent prophylaxis, no evidenceof active tuberculosis on chest radiograph within 3 months prior to the first doseof brodalumab.

Exclusion Criteria:

• Estimated creatinine clearance < 40 mg/min

• Active suicidal ideation or severe depression (as defined by the Diagnostic andStatistical Manual of Mental Disorders Version IV criteria (DSM-IV)) at the time ofenrollment or a PHQ-9 score > 20

• History of prior suicide attempts

• PHQ-9 score greater >5 and < 20 without an established mental health provider whoverifies stability in their depression

• Current or prior drug or alcohol abuse within the past 6 months (as defined by theDSM IV)

• In the opinion of the investigator, the patient requires additionalimmunosuppressive treatment (other than corticosteroids and brodalumab)

• Known hypersensitivity or contraindication to brodalumab, corticosteroids or anycomponents of brodalumab

• Prior treatment with brodalumab

• Pregnancy, breastfeeding, or use of a nonreliable method of contraception

• For patients assigned female at birth: lack of willingness to use highlyeffective methods of birth control during treatment and for at least 4 weeksafter the last dose of brodalumab (except if surgically sterile or at least 2years postmenopausal, with postmenopausal status confirmed byFollicle-Stimulating Hormone (FSH) in the postmenopausal range).

• Highly effective methods of birth control include: use of hormonalcontraceptives that inhibit ovulation, hormone-releasing intrauterine devices,and copper intrauterine devices. Oral contraceptive pills must be supplementedby a barrier method.

• Patients planning to become pregnant while enrolled in the study and within 4weeks after the last dose of brodalumab will not be permitted to enroll

• Chronic or current severe infection requiring IV therapy

• Evidence of active hepatitis B, C, or tuberculosis.

• History of latent tuberculosis infection which is incompletely treated based uponlocal standard of care or which was never treated

• History of or active Crohn's disease.

• Myocardial infarction, unstable angina pectoris or stroke within the past 12 monthsprior to the first investigational product dose

• Any concurrent medical condition or electrocardiogram (ECG) abnormality that, in theopinion of the investigator, could cause this study to be detrimental to thesubject.

• Any medical condition or treatment for a condition that, in the opinion of theinvestigator, might interfere with participation in the study or affect thereliability of clinician assessment or patient self-report

• Other known clinically significant active medical conditions, such as:

• Severe cardiovascular disease, including advanced heart failure (American HeartAssociation Stage D)

• Aspartate aminotransferase (AST) and or alanine aminotransferase (ALT) greaterthan 2 times the upper limit of normal or greater than 3 times the upper limitof normal in patients with liver metastases measured on at least two separateoccasions

• Direct bilirubin greater than or equal to 1.5 mg/dL in patients with or withoutliver metastases

• Bone marrow insufficiency unrelated to the irAE (according to investigatorjudgment) with White Blood Cell (WBC) <2000/mm3, absolute neutrophil count <1500/ mm3, thrombocytopenia (platelet count) <50,000/mm3, hemoglobin < 8.0g/dL

• Plan to proceed with further curative intent treatment for cancer at the time ofenrollment despite the presence of irAE

• Participation in another therapeutic clinical trial and receipt of investigationaldrugs within 4 weeks before the screening visit

• Previous diagnosis of an autoimmune disease or administration of immunosuppressantsin a time frame that would impede interpretation of brodalumab administration

• Planned use of immunosuppressive agents other than steroids (including infliximab,vedolizumab, tocilizumab etc.) or administration of such agents within 28 days oftrial initiation

• Administration of live-virus vaccines within 4 weeks before the first dose ofbrodalumab