AG-01 Antibody Therapy for Advanced Cancers

Overseen By Katherine Tkaczuk, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: A&G Pharmaceutical Inc.

Must not be taking: Investigational agents

Disqualifiers: Uncontrolled illness, CNS metastases, others

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

Compensation: Varies

Number of Visits: 5

77 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called AG01 for individuals with advanced cancers that have not responded to standard therapies. AG01 is an antibody therapy designed to target specific proteins on cancer cells. The trial will first determine the safest dose and then assess its effectiveness across various cancer types, such as lung cancer, hormone-resistant breast cancer, and mesothelioma. Individuals with these cancers who have seen limited success with standard treatments might be suitable candidates for this trial. As a Phase 1 trial, this research focuses on understanding how AG01 works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you must stop taking your current medications. However, you must be at least 4 weeks after your last dose of chemotherapy or radiation therapy (6 weeks for mitoxantrone or mitomycin therapy) and cannot be on any other investigational agents or have participated in an investigational drug study within 28 days prior to starting this trial.

Is there any evidence suggesting that AG01 Antibody Therapy is likely to be safe for humans?

Research has shown that AG01 is a new treatment currently being tested for safety. This study marks the first use of AG01, which targets a protein on cancer cells, in humans. As it is in the early testing stages, the primary goal is to assess how well people tolerate the treatment and to determine the correct dose.

Currently, little information exists on AG01's safety. This phase of the study aims to uncover that information. Early lab studies, conducted before human testing, demonstrated that AG01 can target specific cancer cells, but human testing is necessary to understand its safety.

In these trials, researchers carefully increase the dose to identify the highest amount people can take without serious side effects. This process helps ensure the treatment's safety before further testing. Although AG01 is not yet approved for any condition, this trial is a crucial step in understanding its safety for people with advanced cancers. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about AG-01 antibody therapy because it offers a novel approach to treating advanced cancers, specifically in patients who have exhausted standard options. Unlike traditional chemotherapy and targeted therapies that often focus on specific cancer markers, AG-01 is an antibody-based treatment that may provide a more targeted attack on cancer cells while sparing healthy ones. This could mean fewer side effects and improved outcomes for patients. The potential of AG-01 to be effective in various hard-to-treat cancers, such as non-small cell lung cancer, hormone-resistant breast cancer, mesothelioma, and triple-negative breast cancer, highlights its versatility and promise in the fight against these challenging conditions.

What evidence suggests that AG01 could be an effective treatment for advanced cancers?

Research has shown that the AG01 compound targets a protein called Progranulin/Glycoprotein 88 (PGRN/GP88) found on cancer cells. This protein aids tumor growth and treatment resistance in cancers such as breast and lung cancer. Studies indicate that PGRN/GP88 can predict cancer progression. By attaching to PGRN/GP88, AG01 may prevent cancer cells from growing and becoming drug-resistant. Early results suggest this method could be promising for treating difficult cancers that have not responded to other treatments. In this trial, participants will be assigned to different treatment arms to evaluate AG01's effectiveness in various advanced cancers, including non-small cell lung cancer, hormone-resistant breast cancer, mesothelioma, and triple-negative breast cancer. ^{1 2 4 5 6}

Who Is on the Research Team?

Katherine Tkaczuk, MD

Principal Investigator

University of Maryland, Baltimore

Are You a Good Fit for This Trial?

This trial is for adults with advanced solid tumors who have failed standard treatments. It includes those with specific types of lung, breast, and mesothelioma cancers. Participants must have measurable metastatic lesions, be in a stable condition, and use effective contraception. Those with certain recent malignancies or uncontrolled illnesses are excluded.

Inclusion Criteria

I am eligible regardless of my gender or ethnicity.

I am able to care for myself and perform daily activities.

You have at least one visible and measurable spread of cancer according to specific medical guidelines.

Exclusion Criteria

I am not currently on any experimental drugs and haven't been in the last 28 days.

I am not pregnant or breastfeeding.

I haven't had any cancer except skin cancer or in-situ cancer in the last 2 years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation (1A)

Participants receive increasing doses of AG01 to evaluate maximum tolerated dose and safety

28 days per cycle

2 infusions per cycle (Day 1 and Day 15)

Dose Expansion (1B)

Participants receive AG01 at the recommended phase 2 dose to further evaluate safety and efficacy

28 days per cycle

2 infusions per cycle (Day 1 and Day 15)

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days post-treatment

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• AG01 Compound

Trial Overview AG01, an anti-Progranulin/Glycoprotein88 antibody designed to target cancer cells, is being tested for safety and the maximum tolerated dose in phase 1A. Phase 1B will expand on this to find the optimal dose for future studies based on participants' responses.

How Is the Trial Designed?

Group I: AG-01-1B mesothelioma Experimental Treatment 1 Intervention

Subjects with mesothelioma who received at least 1 SOC therapy for metastatic/recurrent mesothelioma per NCCN guidelines or not a candidate for SOC therapy.

Group II: AG-01 treated group phase 1A Experimental Treatment 1 Intervention

For dose escalation, subjects will be treated with increasing doses of AG01 from 1 mg/kg to 8 mg/kg. The duration of each treatment cycle is 28 days with two infusions of AG01 every 14 days.

Group III: AG-01 1B triple negative breast cancer treated group Experimental Treatment 1 Intervention

TNBC is defined as ER and/or PR \< 1% by IHC, HER2 \<3+ by IHC and/or FISH negative, subjects must have received 1 or more standard of care (SOC) therapies for metastatic TNBC. If PD(L)1-positive, must have received a combination of chemotherapy and a PD (L)-1 agent (Pembrolizumab), unless not a candidate for these therapies If gBRCA 1 or 2 mutation is present, must have received SOC therapies including a PARPi, unless not a candidate for these therapies. Sacituzumab Govitecan ADC is FDA approved for treatment of advanced TNBC, prior exposure to this therapy does not preclude eligibility in the current study.

Group IV: AG-01 1B NSCLC Experimental Treatment 1 Intervention

Subjects with metastatic/recurrent NSCLCA failed 2 or more SOC therapies, including platinum-based chemotherapy and an anti-PD (L) -1 agent (sequentially or consecutively), Subjects with sensitizing mutations/alterations/rearrangements are eligible if received 1 or more SOC agent/s targeting these mutations unless not a candidate for these therapies.

Group V: AG-01 1B Hormone-resistant breast cancer Experimental Treatment 1 Intervention

Hormone-resistant breast cancer is defined as, ER and/or PR \>1%, HER2 \<3+ by IHC and/or FISH negative, received 1 or more hormonal (HT) therapies or HT/CD4/6 kinase inhibitor or HT/MTOR inhibitor for treatment of metastatic breast cancer. If the tumor has known PIK3CA mutation, HT/Alpelisib combination should be considered unless not a candidate for this therapy.

Who Is Running the Clinical Trial?

A&G Pharmaceutical Inc.

Lead Sponsor

Trials

1

Recruited

80+

University of Maryland Greenebaum Cancer Center

Collaborator

Trials

15

Recruited

430+

Published Research Related to This Trial

The study demonstrated that the single-chain antibody fragment (131)I-anti-ProGRP(31-98) scFv has a rapid clearance from the bloodstream and low accumulation in normal tissues, making it a promising candidate for targeted radioimmunoimaging in small cell lung cancer (SCLC).

Imaging of SCLC xenografts was successful as early as 1 hour post-injection, with optimal imaging at 24 hours, indicating that this antibody fragment can effectively highlight tumors while minimizing exposure to healthy tissues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preliminary radioimmunoimaging and biodistribution of ¹³¹iodine-labeled single-chain antibody fragment against progastrin-releasing peptide(₃₁₋₉₈) in small cell lung cancer xenografts. Hong, Z., Shi, Y., Liu, Z., et al.[2016]

In a study of 101 patients with metastatic breast cancer, lower serum levels of GP88 (< 55 ng/mL) were associated with a four-fold increase in overall survival compared to higher levels, indicating its potential as a prognostic marker.

Serum GP88 levels correlated significantly with disease status, showing promise for monitoring treatment response and disease progression, suggesting it could be a cost-effective tool alongside traditional imaging methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Serum Progranulin Levels With Disease Progression, Therapy Response and Survival in Patients With Metastatic Breast Cancer. Tkaczuk, KHR., Hawkins, D., Yue, B., et al.[2023]

Researchers successfully developed monoclonal antibodies (mAbs) against the F domain of human progranulin (GrnF) using a yeast expression system, which involved immunizing BALB/c mice with a purified fusion protein.

Two specific hybridoma cell lines (1G6 and 4E8) were created, both producing IgG1 subclass antibodies that can specifically recognize GrnF, indicating potential for further research and therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Preparation and characterization of monoclonal antibodies against F domain of human progranulin]. Li, Y., Ren, D., Xia, H.[2018]

TAK-264, an investigational antibody-drug conjugate, demonstrated a manageable safety profile in adult patients with advanced gastrointestinal cancers, with the maximum tolerated dose established at 1.8 mg/kg and common side effects including nausea and neutropenia.

Preliminary results indicated potential antitumor activity, with one patient showing a partial response and three others achieving stable disease, suggesting that TAK-264 may be a promising treatment option for certain gastrointestinal malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of the Investigational Anti-Guanylyl Cyclase Antibody-Drug Conjugate TAK-264 (MLN0264) in Adult Patients with Advanced Gastrointestinal Malignancies. Almhanna, K., Kalebic, T., Cruz, C., et al.[2022]

Progranulin (PGRN) is found to be highly expressed in osteosarcoma (OS) tissues, and its elevated levels are linked to poor patient prognosis, indicating its potential role as a biomarker for cancer severity.

Knocking down PGRN in OS cells significantly reduced their proliferation and migration while increasing cell death, suggesting that targeting PGRN could be a therapeutic strategy; this effect is mediated through the activation of the MAPK signaling pathway influenced by hypoxic conditions and mesenchymal stem cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activation of PGRN/MAPK axis stimulated by the hypoxia-conditioned mesenchymal stem cell-derived HIF-1α facilitates osteosarcoma progression. Shang, C., Ou, X., Zhang, H., et al.[2022]

Progranulin/GP88 plays a significant role in cancer by acting as a growth and survival factor, influencing processes like drug resistance, migration, and inflammation within the tumor microenvironment.

The review highlights that progranulin levels in tumor tissues and circulation can serve as important prognostic factors for various cancers, indicating its potential as a biomarker for disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progranulin/GP88, A Complex and Multifaceted Player of Tumor Growth by Direct Action and via the Tumor Microenvironment. Serrero, G.[2022]

The novel anti-AGR2 monoclonal antibody mAb18A4 effectively inhibited lung cancer progression and metastasis in mice without causing adverse side effects on major organs or blood, highlighting its safety as a potential cancer treatment.

mAb18A4 works by activating the p53 pathway and inhibiting the ERK1/2-MAPK pathway, leading to reduced cancer cell proliferation, increased apoptosis, and significant tumor size reduction in xenograft models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anterior Gradient-2 monoclonal antibody inhibits lung cancer growth and metastasis by upregulating p53 pathway and without exerting any toxicological effects: A preclinical study. Negi, H., Merugu, SB., Mangukiya, HB., et al.[2020]

The novel monoclonal antibody ST2485 shows promising potential for therapeutic applications, demonstrating comparable efficacy to the previously studied antibody ST2146 and outperforming the clinical trial antibody BC2 in various tests.

Combining ST2485 with ST2146 enhances tumor targeting, achieving a tumor-to-blood ratio greater than 24 in a xenograft model, indicating that this antibody mixture could significantly improve the effectiveness of pretargeted antibody-guided radioimmunotherapy (PAGRIT).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved tumor targeting by combined use of two antitenascin antibodies. Petronzelli, F., Pelliccia, A., Anastasi, AM., et al.[2007]

In a study involving 29 patients with viral hepatitis C, those who developed hepatocellular carcinoma after treatment had significantly higher serum GP88 concentrations compared to those who did not, indicating GP88 as a potential predictive biomarker.

Patients with sustained high serum GP88 levels post-treatment or minimal changes in GP88 concentrations were at a greater risk for developing hepatocellular carcinoma, suggesting that monitoring GP88 could help identify individuals at higher risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serum GP88 as a predictive biomarker for hepatocellular carcinoma in patients with viral hepatitis C after direct-acting antiviral agents. Ishida, H., Takemura, M., Suetsugu, A., et al.[2022]

Progranulin directly influences the growth, migration, and invasion of human colon cancer cells, with reduced tumor activity observed in cells where progranulin was knocked down and increased activity in cells overexpressing progranulin.

The study suggests that targeting progranulin could be a promising therapeutic strategy for treating human colon cancer, as its effects on cancer cell behavior can be modulated by specific inhibitors like neamine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Progranulin on Migration and Invasion of Human Colon Cancer Cells. Zhao, J., Li, X., Liu, J., et al.[2018]

The study developed a novel antibody-drug conjugate (ADC) targeting LRG1, which is abundant in tumor microenvironments and contributes to vascular dysfunction, potentially improving therapeutic delivery.

In vivo tests showed that this ADC increased survival compared to the antibody alone and had similar anti-tumor effects as standard chemotherapy, but without the associated side effects, indicating its potential as a safer cancer treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leucine-rich alpha-2-glycoprotein 1 (LRG1) as a novel ADC target. Javaid, F., Pilotti, C., Camilli, C., et al.[2023]

TAK-264, an investigational antibody-drug conjugate targeting guanylyl cyclase C (GCC), effectively binds and kills GCC-expressing cancer cells in vitro, demonstrating its potential as a targeted therapy for metastatic colorectal cancer and other GCC-expressing tumors.

In xenograft models, TAK-264 induced significant tumor regressions and long-term growth inhibition, although some tumors showed resistance, indicating that while the treatment is promising, further evaluation is needed to understand its limitations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A monomethyl auristatin E-conjugated antibody to guanylyl cyclase C is cytotoxic to target-expressing cells in vitro and in vivo. Gallery, M., Zhang, J., Bradley, DP., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05627960

First in Human Phase 1 Study of AG01 Anti-Progranulin ... Pathological studies have shown that PGRN/GP88 is an independent prognostic factor in several cancers including breast, non-small cell lung carcinoma, prostate ...

2. cdek.pharmacy.purdue.edu cdek.pharmacy.purdue.edu/trial/NCT05627960/

Trial | NCT05627960 AG01 is a recombinant monoclonal antibody expressed in a CHO production cell line. The antibody AG01 binds to human PGRN/GP88, expressed on cancer cells.

3. withpower.com withpower.com/trial/phase-1-breast-cancer-triple-negative-breast-cancer-tnbc-1-2022-13843

AG-01 Antibody Therapy for Advanced Cancers This trial tests AG01, a protein that targets PGRN/GP88 on cancer cells, in patients with advanced cancers who haven't responded to other treatments.

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33616772/

Anti-progranulin/GP88 antibody AG01 inhibits triple negative ... Progranulin (PGRN/GP88) is a biological driver of tumorigenesis, survival, and drug resistance in several cancers including breast cancer (BC).

5. delta.larvol.com delta.larvol.com/Products/?ProductId=63741124-775e-4bce-81f5-617352bab449

AG01 / A&G Pharma On-going phase 1A clinical trial of A01, a chimerized monoclonal antibody to Progranulin/Glycoprotein 88 (GP88) in patients with advanced malignancy.

6. aacrjournals.org aacrjournals.org/cancerres/article/78/13_Supplement/1934/626269/Abstract-1934-Anti-Progranulin-GP88-antibody-AG01

Abstract 1934: Anti-Progranulin (GP88) antibody AG01 ... Progranulin (PGRN, GP88) is a secreted glycoprotein autocrine growth/survival factor functions as a biological driver of tumor cell ...