AV-380 for Cachexia
Recruiting in Palo Alto (17 mi)
+16 other 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 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.
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.12345
Is AV-380 safe for humans?
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.89101112
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.
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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.
See 1 more
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 OverviewAV-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
5Treatment groups
Experimental Treatment
Group I: Cohort 5Experimental Treatment1 Intervention
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.
Group II: Cohort 4Experimental Treatment1 Intervention
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.
Group III: Cohort 3Experimental Treatment1 Intervention
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.
Group IV: Cohort 2Experimental Treatment1 Intervention
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.
Group V: Cohort 1Experimental Treatment1 Intervention
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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Piedmont Cancer InstituteStockbridge, GA
New York Cancer And Blood SpecialistsBabylon, NY
Piedmont Cancer InstituteAtlanta, GA
North Shore Hematology Oncology Associates P.C. dba NY Cancer and Blood SpecialistsBronx, NY
More Trial Locations
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Who Is Running the Clinical Trial?
AVEO Pharmaceuticals, Inc.Lead Sponsor
References
GDF15 neutralization restores muscle function and physical performance in a mouse model of cancer cachexia. [2023]Cancer cachexia is a disorder characterized by involuntary weight loss and impaired physical performance. Decline in physical performance of patients with cachexia is associated with poor quality of life, and currently there are no effective pharmacological interventions that restore physical performance. Here we examine the effect of GDF15 neutralization in a mouse model of cancer-induced cachexia (TOV21G) that manifests weight loss and muscle function impairments. With comprehensive assessments, our results demonstrate that cachectic mice treated with the anti-GDF15 antibody mAB2 exhibit body weight gain with near-complete restoration of muscle mass and markedly improved muscle function and physical performance. Mechanistically, the improvements induced by GDF15 neutralization are primarily attributed to increased caloric intake, while altered gene expression in cachectic muscles is restored in caloric-intake-dependent and -independent manners. The findings indicate potential of GDF15 neutralization as an effective therapy to enhance physical performance of patients with cachexia.
A Phase 1b First-In-Patient Study Assessing the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Ponsegromab in Participants with Cancer and Cachexia. [2023]Cachexia is common in patients with advanced cancer and is associated with elevated serum growth differentiation factor 15 (GDF-15) concentrations. This first-in-patient (phase Ib), 24-week study assessed use of ponsegromab, a monoclonal antibody against GDF-15, in adults with advanced cancer, cachexia, and elevated GDF-15 serum concentration.
GDNF family receptor alpha-like antagonist antibody alleviates chemotherapy-induced cachexia in melanoma-bearing mice. [2023]Patients with cancer undergoing chemotherapy experience cachexia with anorexia, body weight loss, and the depletion of skeletal muscles and adipose tissues. Effective treatment strategies for chemotherapy-induced cachexia are scarce. The growth differentiation factor 15 (GDF15)/GDNF family receptor alpha-like (GFRAL)/rearranged during transfection (RET) axis is a critical signalling pathway in chemotherapy-induced cachexia. In this study, we developed a fully human GFRAL antagonist antibody and investigated whether it inhibits the GDF15/GFRAL/RET axis, thereby alleviating chemotherapy-induced cachexia in tumour-bearing mice.
GDF15/GFRAL Pathway as a Metabolic Signature for Cachexia in Patients with Cancer. [2021]Cachexia is a metabolic mutiny that directly reduces life expectancy in chronic conditions such as cancer. The underlying mechanisms associated with cachexia involve inflammation, metabolism, and anorexia. Therefore, the need to identify cachexia biomarkers is warranted to better understand catabolism change and assess various therapeutic interventions. Among inflammatory proteins, growth differentiation factor-15 (GDF15), an atypical transforming growth factor-beta (TGF-β) superfamily member, emerges as a stress-related hormone. In inflammatory conditions, cardiovascular diseases, and cancer, GDF15 is a biomarker for disease outcome. GDF15 is also implicated in energy homeostasis, body weight regulation, and plays a distinct role in cachexia. The recent discovery of its receptor, glial cell line-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL), sheds light on its metabolic function. Herein, we critically review the mechanisms involving GDF15 in cancer cachexia and discuss therapeutic interventions to improve outcomes in people living with cancer.
Targeting the divergent TGFβ superfamily cytokine MIC-1/GDF15 for therapy of anorexia/cachexia syndromes. [2019]To review recent finding on MIC-1/GDF15 and re-evaluate it as a potential target for the therapy of anorexia/cachexia syndromes.
An Antibody Attack against Body Wasting in Cancer. [2021]Cachexia is a devastating, non-curable condition in many cancer patients that is marked by severe wasting of the muscle and fat tissue. Its prevention has been hampered by an insufficient knowledge of the underlying molecular mechanism(s) that lead to its pathogenesis. Suriben et al. (2020) now report the development and characterization of an antagonistic antibody for the previously identified GDF15-GFRAL axis that efficiently blocks tumor-induced body wasting in experimental animals.
Antibody-mediated inhibition of GDF15-GFRAL activity reverses cancer cachexia in mice. [2021]Cancer cachexia is a highly prevalent condition associated with poor quality of life and reduced survival1. Tumor-induced perturbations in the endocrine, immune and nervous systems drive anorexia and catabolic changes in adipose tissue and skeletal muscle, hallmarks of cancer cachexia2-4. However, the molecular mechanisms driving cachexia remain poorly defined, and there are currently no approved drugs for the condition. Elevation in circulating growth differentiation factor 15 (GDF15) correlates with cachexia and reduced survival in patients with cancer5-8, and a GDNF family receptor alpha like (GFRAL)-Ret proto-oncogene (RET) signaling complex in brainstem neurons that mediates GDF15-induced weight loss in mice has recently been described9-12. Here we report a therapeutic antagonistic monoclonal antibody, 3P10, that targets GFRAL and inhibits RET signaling by preventing the GDF15-driven interaction of RET with GFRAL on the cell surface. Treatment with 3P10 reverses excessive lipid oxidation in tumor-bearing mice and prevents cancer cachexia, even under calorie-restricted conditions. Mechanistically, activation of the GFRAL-RET pathway induces expression of genes involved in lipid metabolism in adipose tissues, and both peripheral chemical sympathectomy and loss of adipose triglyceride lipase protect mice from GDF15-induced weight loss. These data uncover a peripheral sympathetic axis by which GDF15 elicits a lipolytic response in adipose tissue independently of anorexia, leading to reduced adipose and muscle mass and function in tumor-bearing mice.
Low-Titre GAD Antibody-Associated Late-Onset Cerebellar Ataxia with a Significant Clinical Response to Intravenous Immunoglobulin Treatment. [2018]Antiglutamic acid decarboxylase antibody-associated cerebellar ataxia (GAD-Abs CA) is a rare, but increasingly detected, autoimmune neurological disorder characterized by the clinical presence of a cerebellar syndrome concomitant with positive GAD-Abs levels in serum and cerebrospinal fluid (CSF). It represents 3% of all immune-mediated sporadic CAs. Low-titre GAD-Abs CA is an even rarer subtype of GAD-Abs CA. We report on a 68-year-old woman with a 3-year history of progressive gait ataxia. In addition to the modified Rankin Scale (mRS), we used two other objective scales to evaluate CA severity, i.e. the International Cooperative Ataxia Rating Scale (ICARS) and the Scale for Assessment and Rating of Ataxia (SARA). Series of CT and MRI showed atrophy of the cerebellum. Except for the glycated haemoglobin (HbA1c) levels, all other routine laboratory examinations were within normal limits. Autoimmune laboratory examinations showed positive (25.8 U/mL) serum GAD-Abs levels. The GAD antibody index was <1.0. The CSF analysis showed no oligoclonal immunoglobulin bands. Intravenous immunoglobulin (IVIg) therapy was started and significant improvement was observed. The diagnosis of low-titre GAD-Abs CA was established.
Paraneoplastic cerebellar degeneration in a patient with breast cancer associated with carbonic anhydrase-related protein VIII autoantibodies. [2022]Paraneoplastic cerebellar degeneration is a neurological syndrome resulting from immune-mediated dysfunction of Purkinje cells and commonly is associated with a tumor. In most cases, well-characterized onconeural antibodies are detected, such as anti-Yo and anti-Ri antibodies. Carbonic anhydrase-related protein VIII (CARP VIII) antibodies associated with paraneoplastic cerebellar degeneration have been previously described in only two cases. Herein, we present a 75-year-old female who developed progressive cerebellar ataxia. Anti-CARP VIII autoantibodies were found at high titres and screening for underlying malignancies revealed a breast cancer. Intravenous immunoglobulin was administered with poor results. Our report further confirms the role of CARP VIII antibodies in cerebellar degeneration.
Absence of antibodies to non-NMDA glutamate-receptor subunits in paraneoplastic cerebellar degeneration. [2019]To determine whether patients with antineuronal antibody-associated paraneoplastic cerebellar degeneration (PCD) harbor antibodies to non-N-methyl-D-aspartate glutamate receptors (GluRs) in their serum.
Cerebellar degeneration with Hodgkin disease. An immunological study. [2019]A 21-year-old woman with subacute cerebellar degeneration was found to have Hodgkin lymphoma. Radiation therapy for the lymphoma halted the progression of her neurological disease. Using an immunofluorescent technique, we found the patient's serum to have antibodies to cerebellar Purkinje cells.
TRIM9 and TRIM67 Are New Targets in Paraneoplastic Cerebellar Degeneration. [2021]To describe autoantibodies (Abs) against tripartite motif-containing (TRIM) protein 9 and 67 in two patients with paraneoplastic cerebellar degeneration (PCD) associated with lung adenocarcinoma. Abs were characterized using immunohistochemistry, Western blotting, cultures of murine cortical, and hippocampal neurons, immunoprecipitation, mass spectrometry, knockout mice for Trim9 and 67, and cell-based assay. Control samples included sera from 63 patients with small cell lung cancer without any paraneoplastic neurological syndrome, 36 patients with lung adenocarcinoma and PNS, CSF from 100 patients with autoimmune encephalitis, and CSF from 165 patients with neurodegenerative diseases. We found Abs targeting TRIM9 and TRIM67 at high concentration in the serum and the cerebrospinal fluid (CSF) of a 78-year-old woman and a 65-year-old man. Both developed subacute severe cerebellar ataxia. Brain magnetic resonance imaging found no abnormality and no cerebellar atrophy. Both had CSF inflammation with mild pleiocytosis and a few oligoclonal bands. We identified a pulmonary adenocarcinoma, confirming the paraneoplastic neurological syndrome in both patients. They received immunomodulatory and cancer treatments without improvement of cerebellar ataxia, even though both were in remission of their cancer (for more than 10 years in one patient). Anti-TRIM9 and anti-TRIM67 Abs were specific to these two patients. All control serum and CSF samples tested were negative for anti-TRIM9 and 67. Anti-TRIM9 and anti-TRIM67 Abs appeared to be specific biomarkers of PCD and should be added to the panel of antigens tested when this is suspected.