To Determine Safe and Effective Dose of Sotatercept for the Treatment of Chemotherapy Induced Anemia in Participants With Advanced Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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The purpose of this study was to determine an effective and safe dose of sotatercept (ACE-011) for the treatment of chemotherapy-induced anemia (CIA) in participants with metastatic non-small cell lung cancer (NSCLC) who are being treated with first-line platinum based chemotherapy.

Detailed Description
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The ACE-011-NSCL-001 Phase 2a study was an open-label, randomized, dose-ranging study designed to assess the efficacy, safety, tolerability, pharmacokinetic and quality of life of sotatercept for treatment of CIA in participants with advanced or metastatic solid tumors treated with platinum-based chemotherapeutic regimens. Other objectives included the effect of sotatercept treatment on bone metabolism, the evaluation of the expression of Activin A and other proteins/biomarkers (including myostatin and follistatin) and the assessment of renal function biomarkers. The study consisted of a Screening Period, a Treatment Period of approximately 6 months (up to 4 doses of sotatercept at either 15 mg or 30 mg administered subcutaneously every 42 days) and a Post-treatment Follow-up Period or End of Treatment (42 days after the last dose of sotatercept). The study was terminated early due to a slower than expected rate of enrollment as a result of substantial changes in the standard of care for cancer participants with anemia which resulted in challenges to timely accrual and completion of the study. Therefore, 26 participants were randomized into the study and the planned Part 2 of the study consisting of a double-blind, randomized, placebo-controlled Phase 2b/3 study conducted at the optimal dose of sotatercept in up to 750 participants with metastatic NSCLC was not performed. Due to the small sample size and variability of the data, changes were made to modify the study endpoints and revise them to be exploratory only.

Official Title
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An Open-Label Randomized, Phase 2A, Dose-Ranging Study of Sotatercept (ACE-011) for Chemotherapy-Induced Anemia in Subjects With Advanced or Metastatic Solid Tumors Treated With Platinum-Based Chemotherapeutic Regimens

Conditions
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Carcinoma, Non-Small-Cell Lung, Carcinoma, Small-Cell Lung, Anemia, Bladder Cancer, Cancer of Head and Neck, Uterine Cervical Cancer

Intervention / Treatment
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* Drug: Sotatercept 15 mg
* Drug: Sotatercept 30 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women >18 years of age Part 1: Histologically confirmed (cytology or biopsy) solid tumor malignancy, excluding those solid tumors treated with curative intent. Part 2: Histologically confirmed non-small cell lung cancer Documented metastatic disease Measurable or non-measurable disease evaluable by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 All of the following laboratory values: Hemoglobin ≥6.5 to <11.0 g/dL (≥65 to <110 g/L), due to chemotherapy-induced anemia Absolute neutrophil count ≥500/mm^3 Platelet count ≥75,000/mm^3 (>2 hours since prior platelet transfusion Adequate renal function creatinine clearance ≥40mL/min or ≥50 mL/min if cisplatin is concomitantly administered and urine protein / creatinine ratio ≤1.0; or ≤2.0 if bevacizumab (Avastin®) is concomitantly administered Hepatic function (bilirubin <1.5 x upper limits of normal (ULN); AST and ALT <3.0 x ULN and ≤5.0 ULN for participants with liver metastases) Participants must have received: at least one cycle and up to 4 cycles (q3w schedule) of platinum-based chemotherapy and be randomized prior to receiving Cycle 5 OR at least one cycle and up to 3 months (depending upon regimen) of platinum-based chemotherapy >28 days since previous treatment with ESA >14 days since last red blood cell transfusions Eastern Oncology Cooperative Group (ECOG) Performance status 0-2 For females of childbearing potential, highly effective method of birth control for at least 28 days before starting study, during participation and at least 112 days following last dose of sotatercept Males must use latex condom or non-latex condom not made of (animal) membrane during any sexual contact with female of childbearing potential Life expectancy of >3 months Willing to adhere to study visit schedule Understand and voluntarily sign informed consent Exclusion Criteria: Part 2 only, history of prior regimen(s)of platinum-based chemotherapy for metastatic NSCLC and/or history of adjuvant platinum-based chemotherapy with last dose received less than six months prior to the start of current first-line platinum-based chemotherapy for metastatic NSCLC. National Cancer Institute Common Terminology for Adverse Events Grade >3 toxicity Prior radiation to >20% of whole skeleton Prior regimen(s) of platinum based chemotherapy for metastatic disease and/or history of adjuvant platinum-based chemotherapy with the last dose received less than six months prior to the start of current first-line platinum-based chemotherapy for metastatic disease Central nervous system metastases Clinically significant pulmonary, endocrine, neurologic, gastrointestinal, hepatic, or genitourinary disease unrelated to underlying malignancy Classification of 3 or higher heart failure (as classified by New York Heart Association) History of thrombosis, deep vein thrombosis, pulmonary emboli, or embolic stroke, if not stable on anticoagulants and/or one of these events occurring in past 6 months Diagnosis of a myeloid malignancy or known history of myelodysplasia Recent history (within 14 days of Day 1) of IV/oral antibiotics due to post septic episode Uncontrolled hypertension. Controlled hypertension is considered clinically stable, and systolic blood pressure (SBP) must be <150 mmHg and diastolic blood pressure (DBP) must be < 00 mmHg. Known human immunodeficiency virus (HIV) Known active hepatitis B or C antibody Iron deficiency History of anemia as a result of inherited hemoglobinopathy History of anemia due to autoimmune or hereditary hemolysis or gastrointestinal bleeding Received treatment with another investigational drug or device within 28 days prior to Day 1, or if the half life of the previous product is known, within 5 times the half life prior to dosing, whichever may be longer. Any prior use of sotatercept. Pregnant or lactating females or females planning to become pregnant History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product (Refer to the Investigator's Brochure for further information). Major surgery within 30 days prior to Day 1 (participants must have completely recovered from any previous surgery prior to Day 1).

Ages Eligible for Study
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Minimum Age: 18 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sotatercept 15 mg<br>Participants will receive sotatercept 15 mg by subcutaneous (SC) injection once every 42 days, up to four doses. | Drug: Sotatercept 15 mg<br>* Sotatercept 15 mg SC injection once every 42 days, up to four doses<br>* Other names: ACE-011;|
| Experimental: Sotatercept 30 mg<br>Participants will receive sotatercept 30 mg by SC injection once every 42 days, up to four doses. | Drug: Sotatercept 30 mg<br>* Sotatercept 30 mg SC injection once every 42 days, up to four doses<br>* Other names: ACE-011;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced a Hematopoietic Response | A hematopoietic response was defined as an increase in a participant's hemoglobin (Hgb) of ≥1.0 g/dL above the study baseline value for 4 consecutive weeks, in the absence of red blood cell transfusion and/or erythropoiesis-stimulating agents. | Up to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced One or More Adverse Events (AEs) | An AE is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. | Up to approximately 6 months | 
| Time to Progression (TTP) | TTP was defined as the time from date of randomization to date of diagnosis of progressive disease | Up to 6 months | 
| Progression Free Survival (PFS) | PFS was defined as the time from the start of study drug therapy to the first observation of disease progression or death due to any cause, whichever came first | Up to 12 months | 
| Overall Survival (OS) | OS was defined as the time between randomization and death | Up to 24 months | 
| Overall Response Rate (ORR) | Overall Response was defined as the percentage of participants who achieved an objective confirmed complete (CR) or partial response (PR). Response was determined according to Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 guidelines. CR: The disappearance of all known disease and no new sites or disease-related symptoms confirmed at least 4 weeks after initial documentation. All sites must be assessed, including non-measurable sites, such as effusions, or markers. PR: At least a 30% decrease in the sum of the longest diameters of target lesions, taking as a reference the baseline sum of the longest diameters confirmed at least 4 weeks after initial documentation and no new non-target lesions and/or unequivocal progression of existing non-target lesions. PR is also recorded when all measurable disease has completely disappeared, but a non-measurable component (i.e., ascites) is still present but not progressing. | Up to 12 months | 
| Number of Participants Who Experienced an Improvement in Quality of Life Scores | Participants were to be assessed on improvement of quality of life using the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale (Version 4.0) and the Lung Cancer Symptom Scale (LCSS). The FACIT Fatigue score ranges from 0 to 52, with 0 representing the best outcome and 52 representing the worst outcome. The LCSS is a 9-item patient-rated scale, 6 of which measure major symptoms (loss of appetite, fatigue, cough, dyspnoea, pain, and haemoptysis), and 3 of which are summation items related to total symptomatic distress, activity, and overall quality of life. Participants responses are measured using the mean score on the 9-item visual analogue scales, with 100-mm lines, with 0 representing the best outcome and 100 representing the worst outcome. | Up to 6 months | 
| Area Under the Concentration Versus Time Curve From Time 0 to 28 Days (AUC0-28d) of Sotatercept Following a Single Dose | AUC0-28d is a measure of the mean concentration levels of a drug in the plasma from time 0 to 28 days. | Pre-dose 1 Day 1, 4 hours post-dose Day 1, Day 5, Day 8, Day 11, Day 15, Day 22, Day 28 | 
| Area Under the Concentration Versus Time Curve From Time 0 to Infinity (AUC0-inf) of Sotatercept Following a Single Dose | AUC0-inf is the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time. | Pre-dose 1 Day 1, 4 hours post-dose Day 1, Day 5, Day 8, Day 11, Day 15, Day 22, Day 29, Day 36, pre-dose 2 Day 43 | 
| Maximum Plasma Concentration (Cmax) of Sotatercept Following a Single Dose | Cmax is a measure of the maximum amount of drug in the plasma after a dose is given. | Pre-dose 1 Day 1, 4 hours post-dose Day 1, Day 5, Day 8, Day 11, Day 15, Day 22, Day 29, Day 36, pre-dose 2 Day 43 | 
| Time to Maximum Concetration (Tmax) of Sotatercept Following a Single Dose | Tmax is a measure of the time it takes for a drug to reach maximum concentration in the plasma after the dose is given. | Pre-dose 1 Day 1, 4 hours post-dose Day 1, Day 5, Day 8, Day 11, Day 15, Day 22, Day 29, Day 36, pre-dose 2 Day 43 | 
| Apparent Terminal Half-life (t1/2) of Sotatercept Following a Single Dose | t1/2 is the elimination half-life of study drug: the time it takes for half of the study drug in the blood plasma to dissipate. | Pre-dose 1 Day 1, 4 hours post-dose Day 1, Day 5, Day 8, Day 11, Day 15, Day 22, Day 29, Day 36, pre-dose 2 Day 43 | 
| Apparent Serum Clearance (CL/F) of Sotatercept Following a Single Dose | Apparent serum CL is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. | Pre-dose 1 Day 1, 4 hours post-dose Day 1, Day 5, Day 8, Day 11, Day 15, Day 22, Day 29, Day 36, pre-dose 2 Day 43 | 
| Apparent Volume of Distribution (Vz/F) Following a Single Dose of Sotatercept | Vz/F is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. | Pre-dose 1 Day 1, 4 hours post-dose Day 1, Day 5, Day 8, Day 11, Day 15, Day 22, Day 29, Day 36, pre-dose 2 Day 43 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chemotherapy induced anemia, Non-small cell lung cancer