AV-380 for Cachexia

Recruiting at20 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: AVEO Pharmaceuticals, Inc.

Must be taking: Chemotherapy

Disqualifiers: Allergic, Cardiovascular, Brain metastases, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This open label ascending dose study is designed to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of AV-380 in 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.

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.

What data supports the effectiveness of the drug AV-380 for treating cachexia?

Research shows that neutralizing GDF15, a protein linked to cachexia, can help restore muscle function and improve physical performance in mice with cancer-induced cachexia. This suggests that targeting GDF15 with treatments like AV-380 could potentially be effective in improving symptoms of cachexia in humans. ^{1 2 3 4 5}

Is AV-380 safe for humans?

There is limited safety data available for AV-380 in humans. A Phase 1b study assessed the safety of ponsegromab, a similar antibody against GDF-15, in adults with cancer and cachexia, but specific safety outcomes were not detailed in the provided information. ^{1 2 3 6 7}

What makes the drug AV-380 unique for treating cachexia?

AV-380 is unique because it targets GDF15, a protein involved in the development of cachexia, using a specific antibody (a protein that can bind to and neutralize other proteins) called Anti-GDF15 IgG1 mAb. This approach is different from other treatments that may not specifically target the underlying biological pathways of cachexia. ^{8 9 10 11 12}

Research Team

Eligibility Criteria

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 am 18 years old or older.

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.

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.

Trial Timeline

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

Treatment Details

Interventions

• AV-380 (Monoclonal Antibodies)

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

GDF15 neutralization restores muscle function and physical performance in a mouse model of cancer cachexia. [2023]

2. United States 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. [2023]

3. Germany pubmed.ncbi.nlm.nih.gov

GDNF family receptor alpha-like antagonist antibody alleviates chemotherapy-induced cachexia in melanoma-bearing mice. [2023]

4. Australia pubmed.ncbi.nlm.nih.gov

GDF15/GFRAL Pathway as a Metabolic Signature for Cachexia in Patients with Cancer. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Targeting the divergent TGFβ superfamily cytokine MIC-1/GDF15 for therapy of anorexia/cachexia syndromes. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

An Antibody Attack against Body Wasting in Cancer. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Antibody-mediated inhibition of GDF15-GFRAL activity reverses cancer cachexia in mice. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

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

9. Netherlands pubmed.ncbi.nlm.nih.gov

Paraneoplastic cerebellar degeneration in a patient with breast cancer associated with carbonic anhydrase-related protein VIII autoantibodies. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Absence of antibodies to non-NMDA glutamate-receptor subunits in paraneoplastic cerebellar degeneration. [2019]

11. United States pubmed.ncbi.nlm.nih.gov

Cerebellar degeneration with Hodgkin disease. An immunological study. [2019]

12. United States pubmed.ncbi.nlm.nih.gov

TRIM9 and TRIM67 Are New Targets in Paraneoplastic Cerebellar Degeneration. [2021]