AV-380 for Cachexia

Recruiting at 27 trial locations

Overseen By AVEO Clinical Trials Office

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: AVEO Pharmaceuticals, Inc.

Must be taking: Chemotherapy

Disqualifiers: Allergic, Cardiovascular, Brain metastases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called AV-380, an anti-GDF15 IgG1 monoclonal antibody, for people with cancer who have cachexia, a condition causing severe weight loss and muscle wasting. The goal is to determine AV-380's safety and its movement and function in the body. Participants must have cancer, experience cachexia-related weight loss, and currently receive standard cancer treatment. As a Phase 1 trial, participants will be among the first to receive this treatment, aiding researchers in understanding its effects in people.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify whether you need to stop taking your current medications. However, since participants must be actively receiving standard chemotherapy, it seems you may continue with your current cancer treatment.

Is there any evidence suggesting that AV-380 is likely to be safe for humans?

Research shows that AV-380, a monoclonal antibody treatment, is being tested for safety in individuals with cancer-related weight loss and muscle wasting, known as cachexia. This treatment targets a protein called GDF-15, linked to these symptoms in cancer patients.

In previous studies, treatments like AV-380 have generally been well-tolerated. For instance, a similar treatment targeting GDF-15 was tested in individuals with advanced cancer and was well-received. This suggests that AV-380 might also be safe.

Since this trial is in an early stage, the main goal is to identify any side effects and understand how the body processes the drug. Safety information is still being gathered. However, testing AV-380 in humans indicates that it has shown promise in earlier research. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for cachexia, which typically focus on nutritional support and appetite stimulants, AV-380 targets the underlying biological mechanisms of the condition. AV-380 is unique because it works by inhibiting myostatin, a protein that plays a key role in muscle wasting. Researchers are excited about this treatment because it offers a novel approach that could directly address the muscle loss associated with cachexia, potentially improving patient outcomes more effectively than current options. Additionally, AV-380 is administered through an IV infusion, which may enhance its ability to deliver results efficiently.

What evidence suggests that AV-380 might be an effective treatment for Cachexia?

Research shows that AV-380, administered to participants in this trial, targets a protein called GDF-15, linked to cancer cachexia. Cachexia causes severe weight and muscle loss. Studies have found that blocking GDF-15 with AV-380 may help reduce these effects. Early results suggest that patients treated with AV-380 experienced improvements in muscle mass and appetite. This treatment aims to enhance the quality of life for those experiencing weight loss due to cancer. ^{1 2 3 4 5}

Are You a Good Fit for This Trial?

This trial is for metastatic cancer patients with cachexia, which means significant weight loss due to illness. They must have a life expectancy of at least 3 months and be undergoing first-line chemotherapy for colorectal or pancreatic cancer. Participants need to be adults who've completed at least two chemo cycles and can't join if they have untreated brain tumors, recent heart issues, severe allergies or organ problems.

Inclusion Criteria

I am undergoing first-line chemotherapy for metastatic CRC or pancreatic cancer and have completed at least 2 cycles.

I have lost more than 5% of my weight in the last 6 months, or my BMI is below 20 with any weight loss, or I have muscle loss with any weight loss.

Patients with life expectancy ≥ 3 months

Exclusion Criteria

Your heart's electrical activity (QT interval) is longer than normal.

I do not have severe allergies or major health issues affecting my organs or mental health.

My brain metastases have been treated and stable for at least 2 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive an 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.

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of adverse events and various secondary outcome measures.

Up to 4 months

What Are the Treatments Tested in This Trial?

Interventions

• AV-380

Trial Overview AV-380, an antibody designed to target a specific protein (GDF-15) related to cachexia in cancer patients, is being tested. The study will gradually increase the dose given to participants while monitoring safety, how the body processes the drug (PK), its effects on the body (PD), and any immune response against it.

How Is the Trial Designed?

Group I: Dose Escalation Cohorts Experimental Treatment 1 Intervention

Experimental: Dose escalation cohorts of AV-380 administered by IV infusion

Who Is Running the Clinical Trial?

AVEO Pharmaceuticals, Inc.

Lead Sponsor

Trials

46

Recruited

4,000+

Published Research Related to This Trial

The monoclonal antibody 3P10 effectively targets the GFRAL-RET signaling pathway, which is activated by the growth differentiation factor 15 (GDF15) and is responsible for weight loss in cancer cachexia, showing promise as a therapeutic intervention.

Treatment with 3P10 not only prevents cancer cachexia in tumor-bearing mice but also reverses excessive lipid oxidation, indicating its potential to improve metabolic health and preserve muscle and fat mass even in calorie-restricted conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibody-mediated inhibition of GDF15-GFRAL activity reverses cancer cachexia in mice. Suriben, R., Chen, M., Higbee, J., et al.[2021]

MIC-1/GDF15 has been shown to consistently induce anorexia and cachexia in animal models by acting on brainstem feeding centers, leading to significant weight loss and undernutrition.

Elevated serum levels of MIC-1/GDF15 are linked to anorexia/cachexia syndromes in various diseases, suggesting that targeting the MIC-1/GDF15-GFRAL pathway could be a promising therapeutic approach for treating these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the divergent TGFβ superfamily cytokine MIC-1/GDF15 for therapy of anorexia/cachexia syndromes. Tsai, VW., Brown, DA., Breit, SN.[2019]

Researchers have developed an antagonistic antibody that targets the GDF15-GFRAL axis, which is involved in the muscle and fat wasting seen in cancer cachexia.

This antibody has been shown to effectively block tumor-induced body wasting in experimental animal models, offering a potential new approach to prevent cachexia in cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Antibody Attack against Body Wasting in Cancer. Rohm, M., Herzig, S.[2021]

A 21-year-old woman with subacute cerebellar degeneration was diagnosed with Hodgkin lymphoma, indicating a potential link between the two conditions.

Radiation therapy for the lymphoma not only treated the cancer but also successfully halted the progression of her neurological disease, suggesting a possible therapeutic effect on the underlying autoimmune response, as evidenced by the presence of antibodies to cerebellar Purkinje cells in her serum.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cerebellar degeneration with Hodgkin disease. An immunological study. Trotter, JL., Hendin, BA., Osterland, CK.[2019]

Two patients with paraneoplastic cerebellar degeneration (PCD) associated with lung adenocarcinoma were found to have high concentrations of autoantibodies against TRIM9 and TRIM67, indicating these antibodies may serve as specific biomarkers for PCD.

Despite receiving immunomodulatory and cancer treatments, the patients did not show improvement in cerebellar ataxia, suggesting that the presence of these autoantibodies may be linked to persistent neurological symptoms even after cancer remission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TRIM9 and TRIM67 Are New Targets in Paraneoplastic Cerebellar Degeneration. Do, LD., Gupton, SL., Tanji, K., et al.[2021]

In a phase Ib study involving 10 patients with advanced cancer and cachexia, ponsegromab was well tolerated with no significant adverse effects, indicating its safety for use in this population.

Ponsegromab effectively reduced serum GDF-15 levels and led to an average weight increase of 4.63 kg (about 6.6% from baseline) over 12 weeks, along with improvements in physical activity and quality of life, suggesting its potential efficacy in treating cachexia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 1b First-In-Patient Study Assessing the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Ponsegromab in Participants with Cancer and Cachexia. Crawford, J., Calle, RA., Collins, SM., et al.[2023]

The GFRAL antagonist antibody A11 effectively inhibits the GDF15/GFRAL/RET signaling pathway, leading to significant reductions in chemotherapy-induced cachexia symptoms in tumor-bearing mice, including improved food intake and reduced body weight loss.

In a melanoma mouse model, A11 demonstrated a 21% recovery in anorexia and significantly improved the loss of skeletal muscle and adipose tissue, suggesting it could be a promising treatment for patients suffering from cachexia due to chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GDNF family receptor alpha-like antagonist antibody alleviates chemotherapy-induced cachexia in melanoma-bearing mice. Lee, BY., Jeong, J., Jung, I., et al.[2023]

A 68-year-old woman diagnosed with low-titre antiglutamic acid decarboxylase antibody-associated cerebellar ataxia (GAD-Abs CA) showed significant improvement after receiving intravenous immunoglobulin (IVIg) therapy, highlighting its potential efficacy in treating this rare autoimmune disorder.

The patient's condition was assessed using multiple scales, including the modified Rankin Scale, International Cooperative Ataxia Rating Scale, and Scale for Assessment and Rating of Ataxia, confirming the severity of her cerebellar ataxia and the effectiveness of the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-Titre GAD Antibody-Associated Late-Onset Cerebellar Ataxia with a Significant Clinical Response to Intravenous Immunoglobulin Treatment. Petrijan, T., Menih, M.[2018]

A 75-year-old woman with progressive cerebellar ataxia was found to have high levels of anti-CARP VIII autoantibodies, linking these antibodies to paraneoplastic cerebellar degeneration associated with her breast cancer.

Despite treatment with intravenous immunoglobulin, the patient's condition showed poor improvement, highlighting the challenges in managing this syndrome and confirming the role of CARP VIII antibodies in cerebellar degeneration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paraneoplastic cerebellar degeneration in a patient with breast cancer associated with carbonic anhydrase-related protein VIII autoantibodies. Prevezianou, A., Tzartos, JS., Dagklis, IE., et al.[2022]

In a mouse model of cancer cachexia, treatment with the anti-GDF15 antibody mAB2 led to significant body weight gain and nearly complete restoration of muscle mass, improving physical performance.

The benefits of GDF15 neutralization were mainly due to increased caloric intake and restoration of gene expression in muscles, suggesting it could be a promising therapy for enhancing physical performance in cachexia patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GDF15 neutralization restores muscle function and physical performance in a mouse model of cancer cachexia. Kim-Muller, JY., Song, L., LaCarubba Paulhus, B., et al.[2023]

In a study of 35 patients with paraneoplastic cerebellar degeneration (PCD), only 3 showed weak reactivity to non-N-methyl-D-aspartate glutamate receptors (GluRs), suggesting that GluR antibodies are not commonly present in these patients.

The findings indicate that GluR antibodies cannot be reliably used as markers for paraneoplastic neurologic disorders, as most patients did not exhibit any significant antibody presence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Absence of antibodies to non-NMDA glutamate-receptor subunits in paraneoplastic cerebellar degeneration. Degenhardt, A., Duvoisin, RM., Frennier, J., et al.[2019]

Growth differentiation factor-15 (GDF15) is identified as a key biomarker for cachexia in cancer, linking inflammation and metabolism to reduced life expectancy in chronic conditions.

The discovery of GDF15's receptor, GFRAL, provides insights into its role in energy regulation and suggests potential therapeutic targets to improve outcomes for cancer patients experiencing cachexia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GDF15/GFRAL Pathway as a Metabolic Signature for Cachexia in Patients with Cancer. Ahmed, DS., Isnard, S., Lin, J., et al.[2021]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.TPS12142

A phase 1b dose escalation study of AV-380 (anti-GDF15 ... This is an open-label, dose-escalation, multicenter phase 1b study to assess the safety, tolerability, PK, and PD of AV-380.

2. nature.com nature.com/articles/d41573-025-00168-x

Cancer cachexia contender enters first pivotal trial Cachexia results in decreased appetite and the loss of skeletal muscle and fat, as well as fatigue, weakness and declining quality of life. It ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05865535

NCT05865535 | A Dose Escalation Study of AV-380 in ... This open label ascending dose study is designed to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of AV-380 in cancer ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11341059/

Neutralizing antibody against GDF15 for treatment of cancer ... Abstract 1153: Effective treatment of cancer associated cachexia by AV-380, a GDF15 inhibitory antibody. Cancer Research. 2015;75(15 ...

5. aacrjournals.org aacrjournals.org/cancerrescommun/article/5/6/896/762820/First-in-Human-Study-to-Evaluate-the-Safety-and

First-in-Human Study to Evaluate the Safety and Efficacy of ... Here, we report results from the first-in-human phase I/IIa study of AZD8853 monotherapy in patients with previously treated advanced/metastatic solid tumors.