A Study of XTMAB-16 in Patients With Pulmonary Sarcoidosis

Study Overview
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Brief Summary
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A phase 1b/2 study of XTMAB-16 in patients with pulmonary sarcoidosis

Official Title
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A Seamless, Phase 1b/2 Multiple Ascending Dose/Proof of Concept Study of XTMAB-16 in Patients With Pulmonary Sarcoidosis With or Without Extrapulmonary Manifestations

Conditions
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Pulmonary Sarcoidosis

Intervention / Treatment
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* Drug: XTMAB-16 or Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant between 18 and 80 years (inclusive) of age. Weighs between 45 and 160 kg (99 to 353 lbs.) at Screening. Diagnosis of pulmonary sarcoidosis (at least 6 months before Screening) using the 2020 American Thoracic Society (ATS) Clinical Practice Guideline, the European Respiratory Society (ERS) or the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) criteria including a compatible clinical and radiologic presentation with other causes of granulomatous disease ruled out (cutaneous and ocular involvement permitted). Modified Medical Research Conference (mMRC) Dyspnea Scale of ≥1. Receiving treatment of 7.5 to 25 mg/day of oral prednisone (or equivalent), during the screening period and, at the determination of the investigator, is capable of undergoing the protocol specific corticosteroid taper regimen. Receiving treatment with methotrexate, azathioprine, mycophenolate, leflunomide, chloroquine or hydroxychloroquine for at least 3 months before Screening that has been at a stable dose for 4 weeks before Screening. All efforts should be made to maintain stable background therapy at the Screening dose through the intervention period at the Investigator's discretion. PART A only: Willing to refrain from consumption of grapefruit or grapefruit juice [pomelos, exotic citrus fruits, or grapefruit hybrids] from screening visit until after the final dose. Polymerase chain reaction (PCR) test or rapid antigen test negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at Screening. Able to provide written informed consent. In the opinion of the Investigator, the participant is capable of understanding and complying with protocol requirements. Exclusion Criteria: PART A ONLY: Known potentially significant fibrotic disease and/or active inflammation contained solely in the hilar region as shown by high-resolution computed tomography (HRCT), confirmed by a central reader. Participants with current active inflammation in the hilar region with concurrent inflammation outside the hilar region may be included. For participants with disease onset of <2 years, a historical computed tomography (CT) within 6 months prior to screening confirmed by a central read is acceptable. For participants with disease onset of >2 years and without a CT within 6 months prior to screening, a CT will be performed at Screening. PART A ONLY: Any prior Tumor Necrosis Factor α (TNFα) inhibitor therapy. Clinically significant extra-pulmonary sarcoidosis requiring systemic therapy as determined by the investigator. PART B ONLY: Any therapy with an anti-TNFα monoclonal antibody (e.g., infliximab, adalimumab, golimumab and their biosimilars) within 6 months. Baseline percent predicted Forced Vital Capacity (FVC) of <50%. Prior treatment with rituximab or repository corticotropin injection within the previous 12 months. Clinically significant Central Nervous System (CNS) sarcoidosis requiring therapy, except history of isolated seventh cranial nerve palsy or evidence of demyelinating neurologic disease. Advanced congestive heart failure (New York Heart Association [NYHA] 3 or 4). Current disease presentation consistent with Lofgren's syndrome (i.e., presence of the triad of erythema nodosum, bilateral hilar lymphadenopathy on chest X-ray, and joint pain). Clinically significant pulmonary hypertension requiring treatment Known hypersensitivity to any component of the formulation of XTMAB-16. Live or messenger ribonucleic acid (mRNA) vaccination within 2 weeks before Day 1 or inoculation with a live or mRNA vaccine is planned during study participation. Evidence of active or latent tuberculosis (TB) by interferon-gamma release assay (IGRA) or invasive fungal infections at Screening. Known positive history of malignancy other than non-melanomatous skin cancer in the last 2 years, including cervical carcinoma in-situ. Positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, coronavirus disease (COVID-19), TB, or a known history of human immunodeficiency virus (HIV) infection at Screening. Women of childbearing potential who are sexually active with a non sterilized male partner and are not willing to adhere to adequate birth control measures from the time of signing the informed consent, throughout the duration of the study, and for 90 days after 5 half-lives have elapsed since the last dose of study drug. Male participants who are non sterilized and sexually active with a female partner of childbearing potential and are not willing to use adequate contraception from the time of signing the informed consent throughout the duration of the study, and for 90 days after 5 half-lives have elapsed since last dose of study drug. Clinically significant hepatic or renal disease, including uncontrolled diabetes at the discretion of the investigator. Any severe prior reaction to any type of biologics or human blood product such as albumin, immunoglobulin G (IgG) etc. Concurrent emphysema. Known hypercalcemia due to non-sarcoidosis conditions such as untreated hyperparathyroidism, at the discretion of the investigator Abnormal electrocardiogram (ECG): ventricular arrhythmias (non-sustained ventricular tachycardia (VT), multifocal or frequent premature ventricular contractions, bundle branch block, axis deviation, or abnormal Q waves.). In the case of a QTcF (corrected QT interval by Fredericia) interval >450 ms (men) or >480 ms (women; participants with bundle branch block) or PR (P to QRS) interval outside the range of 120 to 220 ms, the assessment may be repeated once for eligibility determination at Screening or Baseline. Donation or loss of 450 mL or more of his or her blood volume (including plasmapheresis) or transfusion of any blood product within 90 days prior to dosing. Known uncontrolled hypertension. Clinical signs and symptoms consistent with COVID-19, e.g., fever, dry cough, dyspnea, sore throat, fatigue, new smell or taste disorder or confirmed infection by appropriate laboratory test within the last 4 weeks prior to Screening. In the opinion of the investigator, inability to tolerate corticosteroid taper. Concurrent systemic steroid use for non-sarcoidosis conditions. Concurrent known auto-immune disease requiring treatment. Participation in another clinical trial of an investigational agent within 3 months (small molecule) / 6 months (biologics) or 5 half-lives (if known) of the agent, whichever is longer. Any condition that required hospitalization within the 3 months prior to Day 1 or is likely to require so during the study. Clinically significant abnormalities in the Screening physical exam, medical history, vital signs, ECG, or clinical laboratory tests that are not known to be due to concurrent sarcoidosis, and in the opinion of the Investigator and Medical Monitor should preclude the patient's participation in the clinical study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A - XTMAB-16: 2 mg/kg every 4 weeks (Q4W) for 12 weeks or Placebo<br> | Drug: XTMAB-16 or Placebo<br>* Infusion<br>|
| Experimental: Part A - XTMAB-16: 4 mg/kg every 4 weeks (Q4W) for 12 weeks or Placebo<br> | Drug: XTMAB-16 or Placebo<br>* Infusion<br>|
| Experimental: Part A - XTMAB-16: 2 mg/kg every 2 weeks (Q2W) for 12 weeks or Placebo<br> | Drug: XTMAB-16 or Placebo<br>* Infusion<br>|
| Experimental: Part A - XTMAB-16: 4 mg/kg every 2 weeks (Q2W) for 12 weeks or Placebo<br> | Drug: XTMAB-16 or Placebo<br>* Infusion<br>|
| Experimental: Part B - XTMAB-16 (dose established in Part A) for 24 weeks or Placebo<br> | Drug: XTMAB-16 or Placebo<br>* Infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Adverse Events, including Serious Adverse Events, Dose Limiting Toxicities, and Adverse Events of Special Interest throughout the study duration | Safety and Tolerability | Throughout Study Duration, 12 weeks (Part A) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants who achieve the targeted tapered dose of corticosteroid | Efficacy | Baseline to Week 12 (Part A) | 
| Proportion of participants who achieve at least 50% reduction in dose of corticosteroid by Week 12 | Efficacy | Baseline to Week 12 (Part A) | 
| Proportion of patients able to maintain steroid reduction through Week 24 | Efficacy | Week 12 to Week 24 (Part B) |