Brodalumab in the Treatment of Immune-Related Adverse Events

The proposed study will evaluate the safety and efficacy of brodalumab in improving and resolving Immune-Related Adverse Events (irAEs) in patients treated with brodalumab. Eligible subjects must have an immune-related adverse event with the intent to treat it with steroids. Subjects will receive subcutaneous brodalumab for 24 weeks. Peripheral blood will be collected at all in-person study visits for mechanistic studies. Participants will be evaluated at week 0, 1, 2, 4, and then every 4 weeks after that until week 24 as dictated by the standard of care using a combination of telemedicine and face-to-face evaluations. Additional safety follow-up visits will occur at weeks 28 and 36. All patients will have the Columbia Suicide Severity Rating Scale (C-SSRS), and Patient Health Questionnaire-9 (PHQ-9) administered at all visits. The treatment protocol consists of subcutaneous brodalumab 210 mg administered at baseline and then at weeks 0, 1, and 2, then bi-weekly for a total of 24 weeks (the current FDA-approved dosing for plaque psoriasis). Glucocorticoids may be used at baseline at the discretion of the investigators, with the goal of tapering off of steroids over 4-8 weeks if tolerated (see proposed taper in appendix). Continued treatment beyond the 24-week course can be evaluated by the treating investigator and the Sponsor-Investigator, weighing risks versus clinical benefit.

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 with immunotherapy. Patients being treated with curative intent are not eligible to enroll.
• 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 hours after test is placed) OR negative QuantiFERON test. Tuberculosis testing must be performed within 30 days prior to trial initiation.
• Subjects with a positive PPD and a history of Bacillus Calmette-Guérin vaccination are allowed with a negative QuantiFERON test.
• Subjects with a positive PPD test (without a history of Bacillus Calmette-Guérin vaccination) or subjects with a positive or indeterminate QuantiFERON test are allowed if they have all of the following: no symptoms of tuberculosis (defined as fever, shortness of breath, cough or night sweats), documented history of a completed course of adequate prophylaxis (per local standard of care), no known exposure to a case of active tuberculosis after most recent prophylaxis, no evidence of active tuberculosis on chest radiograph within 3 months prior to the first dose of brodalumab.

Exclusion criteria

• Estimated creatinine clearance < 40 mg/min
• Active suicidal ideation or severe depression (as defined by the Diagnostic and Statistical Manual of Mental Disorders Version IV criteria (DSM-IV)) at the time of enrollment or a PHQ-9 score > 20
• History of prior suicide attempts
• PHQ-9 score greater >5 and < 20 without an established mental health provider who verifies stability in their depression
• Current or prior drug or alcohol abuse within the past 6 months (as defined by the DSM IV)
• In the opinion of the investigator, the patient requires additional immunosuppressive treatment (other than corticosteroids and brodalumab)
• Known hypersensitivity or contraindication to brodalumab, corticosteroids or any components 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 highly effective methods of birth control during treatment and for at least 4 weeks after the last dose of brodalumab (except if surgically sterile or at least 2 years postmenopausal, with postmenopausal status confirmed by Follicle-Stimulating Hormone (FSH) in the postmenopausal range).
• Highly effective methods of birth control include: use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. Oral contraceptive pills must be supplemented by a barrier method.
• Patients planning to become pregnant while enrolled in the study and within 4 weeks 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 upon local 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 months prior to the first investigational product dose
• Any concurrent medical condition or electrocardiogram (ECG) abnormality that, in the opinion of the investigator, could cause this study to be detrimental to the subject.
• Any medical condition or treatment for a condition that, in the opinion of the investigator, might interfere with participation in the study or affect the reliability of clinician assessment or patient self-report
• Other known clinically significant active medical conditions, such as:

• Severe cardiovascular disease, including advanced heart failure (American Heart Association Stage D)
• Aspartate aminotransferase (AST) and or alanine aminotransferase (ALT) greater than 2 times the upper limit of normal or greater than 3 times the upper limit of normal in patients with liver metastases measured on at least two separate occasions
• Direct bilirubin greater than or equal to 1.5 mg/dL in patients with or without liver metastases
• Bone marrow insufficiency unrelated to the irAE (according to investigator judgment) with White Blood Cell (WBC) <2000/mm3, absolute neutrophil count <1500/ mm3, thrombocytopenia (platelet count) <50,000/mm3, hemoglobin < 8.0 g/dL
• Plan to proceed with further curative intent treatment for cancer at the time of enrollment despite the presence of irAE
• Participation in another therapeutic clinical trial and receipt of investigational drugs within 4 weeks before the screening visit
• Previous diagnosis of an autoimmune disease or administration of immunosuppressants in 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 of trial initiation
• Administration of live-virus vaccines within 4 weeks before the first dose of brodalumab