Clinical trial NCT01284348: To Determine Safe and Effective Dose of Sotatercept for the Treatment of Chemotherapy Induced Anemia in Participants With Advanced Non-small Cell Lung Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Anemia
Carcinoma, Non-Small-Cell Lung
Carcinoma, Small-Cell Lung
Bladder Cancer
Cancer of Head and Neck
Uterine Cervical Cancer
Keywords: Chemotherapy induced anemia
Non-small cell lung cancer
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2011-01-27
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Men and women \>18 years of age
2. 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
3. Documented metastatic disease
4. Measurable or non-measurable disease evaluable by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
5. 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)
6. 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
7. \>28 days since previous treatment with ESA
8. \>14 days since last red blood cell transfusions
9. Eastern Oncology Cooperative Group (ECOG) Performance status 0-2
10. 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
11. Males must use latex condom or non-latex condom not made of (animal) membrane during any sexual contact with female of childbearing potential
12. Life expectancy of \>3 months
13. Willing to adhere to study visit schedule
14. 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.

1. National Cancer Institute Common Terminology for Adverse Events Grade \>3 toxicity
2. Prior radiation to \>20% of whole skeleton
3. 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
4. Central nervous system metastases
5. Clinically significant pulmonary, endocrine, neurologic, gastrointestinal, hepatic, or genitourinary disease unrelated to underlying malignancy
6. Classification of 3 or higher heart failure (as classified by New York Heart Association)
7. 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
8. Diagnosis of a myeloid malignancy or known history of myelodysplasia
9. Recent history (within 14 days of Day 1) of IV/oral antibiotics due to post septic episode
10. 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.
11. Known human immunodeficiency virus (HIV)
12. Known active hepatitis B or C antibody
13. Iron deficiency
14. History of anemia as a result of inherited hemoglobinopathy
15. History of anemia due to autoimmune or hereditary hemolysis or gastrointestinal bleeding
16. 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.
17. Any prior use of sotatercept.
18. Pregnant or lactating females or females planning to become pregnant
19. 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).
20. Major surgery within 30 days prior to Day 1 (participants must have completely recovered from any previous surgery prior to Day 1).

Primary outcomes:
measure: Number of Participants Who Experienced a Hematopoietic Response
timeFrame: Up to Day 28
Secondary outcomes:
measure: Number of Participants Who Experienced One or More Adverse Events (AEs)
timeFrame: Up to approximately 6 months
measure: Time to Progression (TTP)
timeFrame: Up to 6 months
measure: Progression Free Survival (PFS)
timeFrame: Up to 12 months
measure: Overall Survival (OS)
timeFrame: Up to 24 months
measure: Overall Response Rate (ORR)
timeFrame: Up to 12 months
measure: Number of Participants Who Experienced an Improvement in Quality of Life Scores
timeFrame: Up to 6 months
measure: Area Under the Concentration Versus Time Curve From Time 0 to 28 Days (AUC0-28d) of Sotatercept Following a Single Dose
timeFrame: Pre-dose 1 Day 1, 4 hours post-dose Day 1, Day 5, Day 8, Day 11, Day 15, Day 22, Day 28
measure: Area Under the Concentration Versus Time Curve From Time 0 to Infinity (AUC0-inf) of Sotatercept Following a Single Dose
timeFrame: 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
measure: Maximum Plasma Concentration (Cmax) of Sotatercept Following a Single Dose
timeFrame: 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
measure: Time to Maximum Concetration (Tmax) of Sotatercept Following a Single Dose
timeFrame: 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
measure: Apparent Terminal Half-life (t1/2) of Sotatercept Following a Single Dose
timeFrame: 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
measure: Apparent Serum Clearance (CL/F) of Sotatercept Following a Single Dose
timeFrame: 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
measure: Apparent Volume of Distribution (Vz/F) Following a Single Dose of Sotatercept
timeFrame: 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
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Raftopoulos H, Laadem A, Hesketh PJ, Goldschmidt J, Gabrail N, Osborne C, Ali M, Sherman ML, Wang D, Glaspy JA, Puccio-Pick M, Zou J, Crawford J. Sotatercept (ACE-011) for the treatment of chemotherapy-induced anemia in patients with metastatic breast cancer or advanced or metastatic solid tumors treated with platinum-based chemotherapeutic regimens: results from two phase 2 studies. Support Care Cancer. 2016 Apr;24(4):1517-25. doi: 10.1007/s00520-015-2929-9. Epub 2015 Sep 14.