A Dose Escalation Study of AV-380 in Metastatic Cancer Patients With Cachexia

Study Overview
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Brief Summary
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This open label ascending dose study is designed to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of AV-380 in metastatic cancer patients with Cachexia. 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.

Official Title
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A Phase 1 Dose Escalation Study of AV-380 in Combination With Standard of Care Chemotherapy in Metastatic Cancer Patients With Cachexia and Elevated GDF-15 Levels

Conditions
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Cachexia

Intervention / Treatment
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* Biological: AV-380


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must be ≥ 18 years of age at the time of signing the informed consent. Patients with histologically confirmed metastatic CRC or pancreatic cancer, who are actively receiving SoC chemotherapy in the first line setting for metastatic disease; eligible patients must have completed at least 2 Cycles of chemotherapy to eligible: CRC patients who are receiving FOLFOX/FOLFOXIRI ± bevacizumab Pancreatic cancer patients who are receiving FOLFOX/FOLFIRINOX Patients with cachexia as defined by Fearon criteria: Weight loss > 5% over past 6 months (in absence of simple starvation), or BMI < 20 kg/m2 and any degree of weight loss > 2%, or Sarcopenia and any degree of weight loss > 2% Patients with life expectancy ≥ 3 months Exclusion Criteria: Significant clinical manifestation of any allergic, dermatological, hepatic, renal, hematological, pulmonary, metabolic, cardiovascular, gastrointestinal, neurological, or psychiatric disorders (e.g., anorexia nervosa). Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 2 weeks before first dose of study treatment. Significant cardiovascular disease, including myocardial infarction within 3 months prior to start of protocol therapy. Corrected QT interval calculated by the Fridericia formula (QTcF) > 460 ms within the Screening period prior to the first dose of study treatment.

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: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>IV infusion of AV-380. 7 doses will be given -- the 2nd dose will be 28 days after the first dose, the remaining 5 doses will be given every 2 weeks. | Biological: AV-380<br>* 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.<br>|
| Experimental: Cohort 2<br>IV infusion AV-380. This cohort will proceed at a new dose level with approval of the Dose Escalation Committee, after evaluation of data from the previous cohort. IV infusion AV-380. 7 doses will be given -- the 2nd dose will be 28 days after the first dose, the remaining 5 doses will be given every 2 weeks. | Biological: AV-380<br>* 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.<br>|
| Experimental: Cohort 3<br>IV infusion AV-380. This cohort will proceed at a new dose level with approval of the Dose Escalation Committee, after evaluation of data from the previous cohort. IV infusion AV-380. 7 doses will be given -- the 2nd dose will be 28 days after the first dose, the remaining 5 doses will be given every 2 weeks. | Biological: AV-380<br>* 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.<br>|
| Experimental: Cohort 4<br>IV infusion AV-380. This cohort will proceed at a new dose level with approval of the Dose Escalation Committee, after evaluation of data from the previous cohort. IV infusion AV-380. 7 doses will be given -- the 2nd dose will be 28 days after the first dose, the remaining 5 doses will be given every 2 weeks. | Biological: AV-380<br>* 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.<br>|
| Experimental: Cohort 5<br>IV infusion AV-380. This cohort will proceed at a new dose level with approval of the Dose Escalation Committee, after evaluation of data from the previous cohort. IV infusion AV-380. 7 doses will be given -- the 2nd dose will be 28 days after the first dose, the remaining 5 doses will be given every 2 weeks. | Biological: AV-380<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of adverse events (AEs) | AEs as characterized by incidence, type, frequency, and severity (graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v5.0) | Through 90 days post last dose | 
| Cmax | Maximum Observed Plasma Concentration for AV-380 | Up to 4 months | 
| Serum level of GDF-15 |  | Through 90 days post last dose | 
| Tmax | Time to Reach the Cmax for AV-380 | Up to 4 months | 
| AUC(0-t) | Area Under the Plasma Concentration-time Curve From Zero Time to the Last Measurable Point for AV-380 | Up to 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weight and body mass index (BMI) |  | Through 90 days post last dose | 
| Immunogenicity | Serum levels of Anti-Drug Antibody (ADA) against AV-380 | Up to 4 months | 
| 6-minute walk test | Assess aerobic capacity and endurance by measuring the distance covered over a time of 6 minutes | Through 60 days post last dose | 
| Metabolic Vulnerability Index (MVX) | The MVX is a blood test that combines results from analytes that represent metabolic malnutrition (MMX; valine, leucine, isoleucine, citrate) and inflammation (IFX; GlycA and S-HDLP) to provide a single prognostic score (1-100) for risk of death. | Through 60 days post last dose | 
| Handgrip test | Handgrip strength test to measure the maximum isometric strength of the hand and forearm muscles | Through 60 days post last dose | 
| L3 Skeletal Muscle Index (L3SMI) | Measurement of a cross-sectional area of muscle at the level of the third lumbar vertebra (L3) using computed tomography (CT) scan | Through 60 days post last dose | 
| Lean body mass (LBM) | The difference between total body mass and fat mass | Through 60 days post last dose |