Clinical trial NCT04815551: A Phase 1 Study of AV-380 in Healthy Subjects
Official title: A Phase 1, First-in-human, Randomized, Placebo Controlled, Double Blind, Single Ascending Dose (SAD) Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Immunogenicity of AV-380 in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cachexia
Lead sponsor: AVEO Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2021-03-25
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This double-blinded, placebo-controlled, single ascending dose (SAD) study is designed to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity in healthy subjects of a single dose of AV-380. AV-380 is an immunoglobulin (Ig) G1 monoclonal antibody (mAb) intended to bind circulating human growth differentiation factor 15 (GDF-15), a cytokine involved in cancer-induced cachexia.


Eligibility criteria: Inclusion Criteria:

1. Healthy male and female volunteers, 18 to 50 years of age, inclusive.
2. A body mass index (BMI) between 18 and 30 kg/m2 and weight between 60 and 90 kg.
3. Healthy as indicated by a comprehensive clinical assessment (detailed medical history and complete physical examination). Supine blood pressure (BP), heart rate (HR), electrocardiogram (ECG) intervals and routine laboratory tests within the normal range of the study center (see Appendix 4) or considered not clinically significant by the Investigator. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin must be \< 1.5 times the upper limit of the normal range (ULN). Total bilirubin, if above 1.5 x ULN, is only acceptable with a history of Gilbert's Syndrome.
4. Non-smoker or ex-smoker for longer than 6 months.
5. Sexually active pre-menopausal female subjects and female partners of male subjects must use adequate contraceptive measures, while on study and for at least 100 days after the IMP administration. Sexually active male subjects must use adequate contraceptive measures, while on study and for at least 160 days after the last dose of IMP. All fertile male and female subjects and their partners must agree to use a highly effective method of contraception. Effective birth control includes hormonal contraception (oral, intravaginal, transdermal, injectable or implantable), intrauterine device (IUD) plus one barrier method; or 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm). Vasectomy (at least 3 months before IMP administration) and vasectomized partner (provided that the partner is the sole sexual partner of the trial participant and that the absence of sperm in the ejaculate has been confirmed) are acceptable methods of contraception, as well as post-menopausal female for at least 1 year (confirmed with serum follicle stimulating hormone \[FSH\] \> 25.8 IU/L at screening), or surgically sterilized female subjects. Abstinence is not an acceptable contraception method. Female subjects who are of non-childbearing potential due to a surgical procedure or medical condition must provide documentation, and vasectomized male subjects must bring in the surgical report of the procedure.
6. Able to sign and understand an ICF and able to comply with study restrictions prior to selection.

Exclusion Criteria:

1. Presence or history of any disorder that may prevent the successful completion of the study.
2. Clinically significant abnormalities in laboratory test results (including hepatic and renal panels, complete blood count, chemistry panel and urinalysis), such as:

   * White blood cell count \< 3.0x109/L.
   * Neutrophils \< 1.5x109/L or clinically abnormal according to the subject's ethnic group (must be \> 1.0x109/L for subjects of African descent).
   * Hemoglobin \< 10 g/dL.
   * Platelet count \< 125x109/L or \> 450x109/L.
   * ALT \> 1.5 ULN.
   * AST \> 1.5 ULN.
   * Total bilirubin \> 1.5 ULN (except in the presence of Gilbert's syndrome).
   * Creatinine \> 1.2 ULN.
   * Sodium \< 132 mmol/L or \> 147 mmol/L.
   * Potassium \< 3.2 mmol/L or \> 5.5 mmol/L.
   * Chloride \< 93 mmol/L or \> 111 mmol/L.
   * Calcium \< 8.3 mmol/L or \> 10.7 mmol/L. Clinically significant abnormal values for all other laboratory parameters are at the investigator's discretion.
3. Any surgical or medical condition that may interfere with the absorption, distribution, metabolism, or excretion of the investigational medicine product.
4. Any history of drug related hypersensitivity reaction.
5. Prior treatment with a monoclonal antibody.
6. Intercurrent illness as evidenced by, e.g., nausea, vomiting, fever, or diarrhea) within 7 days before D1.
7. History of drug abuse (habitual taking of addictive or illegal drugs) within 1 year before D1.
8. Consumption of any caffeine-containing products (e.g., coffee, tea, chocolate, or soda) or grapefruit-containing products or alcoholic beverages within 48 hours before D1 and until D7.
9. Any condition or disease detected during the medical interview / physical examination that would render the subject unsuitable for the study, place the subject at undue risk or interfere with the ability of the subject to complete the study in the opinion of the Investigator or his designee.
10. Frequent headaches and/or migraine, recurrent nausea and / or vomiting.
11. Female subjects who are pregnant, or breastfeeding.
12. Positive screen for drugs of abuse (amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, phencyclidine \[PCP\]) and breath alcohol test at screening or D-2.
13. Positive serology for hepatitis B or hepatitis C or human immunodeficiency viruses (HIV).
14. Positive SARS-CoV-2 RT-PCR.
15. Any condition detected at screening that may interfere with or bias the physical examinations to be performed during the study.
16. Any prescribed or over-the-counter medication or herbal products taken within 1 week prior to start of administration of IMP (D1) or within 6 times the elimination half-life of the medication prior to start of IMP intake (whichever is longer), except birth control as described in inclusion criterion number 5 in Section 6.1. Vitamin/mineral supplements and occasional use of acetaminophen is allowed up until 24 hours before dosing.
17. Participation in a clinical trial or use of an investigational drug within 30 days before randomization.
18. Any vaccination within 30 days before signature of informed consent.

Primary outcomes:
measure: Assessment of adverse events (AEs) and treatment emergent adverse events (TEAEs)
timeFrame: Through study completion, an average of 60 days
measure: Injection site safety and tolerability assessment
timeFrame: Visit Day 1
measure: Clinical laboratory measurements - Hematology - hemoglobin
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Hematology - hematocrit
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Hematology - erythrocytes
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Hematology - white blood cell count
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Blood chemistry - sodium
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Blood chemistry - potassium
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Blood chemistry - calcium
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Blood chemistry - chloride
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Blood chemistry - CO2
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Blood chemistry - blood urea nitrogen
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Blood chemistry - creatinine
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Blood chemistry - glucose
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Blood chemistry - total proteins
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Blood chemistry - triglycerides
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Blood chemistry - total cholesterol
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Blood chemistry - AST
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Blood chemistry - ALT
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Blood chemistry - Gamma-glutamyltransferase
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Blood chemistry - Creatinine phosphokinase
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Blood chemistry - albumin
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Blood chemistry - alkaline phosphatase
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Blood chemistry - total bilirubin
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Coagulation - partial thromboplastin time
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Coagulation - prothrombin time
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Coagulation - International normalized ratio
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Hormonology
timeFrame: Visits Day 1 through Day 90
measure: Clinical laboratory measurements - Hormonology - TSH
timeFrame: Visits Day 1 through Day 90
measure: Clinical laboratory measurements - Hormonology - FSH
timeFrame: Visits Day 1 through Day 90
measure: Clinical laboratory measurements - Urinalysis - pH
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Urinalysis - protein
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Urinalysis - glucose
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Urinalysis - leukocytes
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Urinalysis - nitrites
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Urinalysis - ketones
timeFrame: Visits Day 1 through Day 60
measure: Clinical laboratory measurements - Urinalysis - blood
timeFrame: Visits Day 1 through Day 60
measure: Vital signs measurements - Blood pressure
timeFrame: Visits Day 1 through Day 90
measure: Vital signs measurements - Heart rate
timeFrame: Visits Day 1 through Day 90
measure: Vital signs measurements - Body temperature
timeFrame: Visits Day 1 through Day 90
measure: Vital signs measurements - Respiratory rate
timeFrame: Visits Day 1 through Day 90
measure: Electrocardiogram (ECG) measurements - Mean heart rate
timeFrame: Visits Day 1 through Day 90
measure: Electrocardiogram (ECG) measurements - PR interval
timeFrame: Visits Day 1 through Day 90
measure: Electrocardiogram (ECG) measurements - QRS axis
timeFrame: Visits Day 1 through Day 90
measure: Electrocardiogram (ECG) measurements - QTcF interval
timeFrame: Visits Day 1 through Day 90
Secondary outcomes:
measure: Serum PK of single dose AV-380 via intravenous infusion and subcutaneous injection
timeFrame: Visits Day 1 through D90
measure: Serum PK of single dose AV-380 via intravenous infusion and subcutaneous injection
timeFrame: Visits Day 1 through Day 90
measure: To correlate the serum level of GDF-15 with the dose and serum level of AV-380
timeFrame: Visits Day 1 through Day 90
measure: To correlate the serum level of GDF-15 with the dose and serum level of AV-380
timeFrame: Visits Day 1 through Day 90
measure: To correlate the serum level of GDF-15 with the dose and serum level of AV-380
timeFrame: Visits Day 1 through Day 90
measure: AV-380 immunogenicity in healthy subjects - anti-AV-380 antibodies (human anti-human antibodies [HAHA]) levels in serum.
timeFrame: Visits Day 1 through Day 180
measure: AV-380 immunogenicity in healthy subjects - Monocyte chemoattractant protein 1 (MCP-1) levels in serum.
timeFrame: Visits Day 1 and Day 2
Other outcomes:
Locations:
city: Newark
country: United States
facility: Biotrial Inc.
state: New Jersey
Study officials:
References: