First in Human Phase 1 Study of AG01 Anti-Progranulin/GP88 Antibody in Advanced Solid Tumor Malignancies

NCT05627960 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: GCC1950
• Study Type: interventional
• Target: 77
• Locations: 1 country
• Sites: 1

Brief Summary

This is a first in human phase 1 study of AG01 an anti-Progranulin/Glycoprotein88 (PGRN/GP88) antibody in patients with advanced solid tumors. 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. This study will have a dose escalation portion (1A) to evaluate maximum tolerated dose (MTD) and/or maximum administered dose (MAD), the safety and tolerability of AG01treatment before the dose expansion portion (1B) of the study is initiated. The dose escalation portion of this study (1A) will also be used to determine the recommended phase 2 dose (RP2D) of AG01 antibody to be evaluated in the cohort expansion portion (1B).

Conditions

Triple Negative Breast Cancer; Hormone-Resistant Breast Cancer; Non Small Cell Lung Cancer; Mesothelioma

Keywords

Progranulin; Advanced solid malignancies; Phase 1; Anti-Progranulin antibody; Advanced solid tumors; Breast Cancer; Lung Cancer; Mesothelioma

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose (MTD) and/or Maximum Administered Dose (MAD)

  Determine the MTD and/or MAD of anti GP88 monoclonal antibody (AG-01) in subjects with advanced/refractory solid tumor malignancies for which no effective therapies exist.

  28 days during 1st cycle

• Antitumor Activity of AG-01 by Overall Response Rate (ORR)

  To evaluate the antitumor activity of AG-01 monoclonal antibody as assessed by ORR defined as complete response (CR), partial response (PR), stable disease \>24 weeks (SD) (CR+PR+ SD) based on RECIST v1.1 in subjects with TNBC, ER+ hormone resistant Breast Cancer, NSCLCA and mesothelioma. Each cohort will be assessed separately for response.

  Every 56 Days

Secondary Outcomes (5)

• Recommended phase 2 dose (RP2D) of AG-01-Phase 1A

  28 days or 1cycle

• Safety and tolerability of AG-01

  While receiving AG-01 for 56 days and for 30 days after the last dose of the study drug (day 86)

• Pharmacokinetic (PK) profile of AG-01-1A

  Day 1 (cycle1 first dose), Day 4, Day 8, Day 15 (cycle 1 second dose), day 29 (Cycle 2 first dose), day 43 (cycle 2 second dose), Day 46, Day 50, Day 57 (end of treatment) and Day 87 (30 days post end of treatment).

• Preliminary anti-tumor activity of the AG-01 in subjects with refractory/advanced solid tumor malignancies (1A and 1B).

  While receiving AG-01 treatment, at day 56

• Anti-drug antibodies (ADA) to AG-01

  Day 1 (cycle1 first dose) Day 15 (cycle 1 second dose), day 29 (Cycle 2 first dose), day 43 (cycle 2 second dose), Day 57 (end of treatment),and Day 87 (30 days post end of treatment)

Other Outcomes (1)

• Serial Glycoprotein88 (GP-88) blood levels

  Day 1 (cycle1 first dose) Day 15 (cycle 1 second dose), day 29 (Cycle 2 first dose), day 43 (cycle 2 second dose), Day 57 (end of treatment),and Day 87 (30 days post end of treatment).

Study Arms (5)

AG-01 treated group phase 1A

EXPERIMENTAL

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.

Drug: AG-01 Compound

AG-01 1B triple negative breast cancer treated group

EXPERIMENTAL

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.

Drug: AG-01 Compound

AG-01 1B Hormone-resistant breast cancer

EXPERIMENTAL

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.

Drug: AG-01 Compound

AG-01 1B NSCLC

EXPERIMENTAL

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.

Drug: AG-01 Compound

AG-01-1B mesothelioma

EXPERIMENTAL

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

Drug: AG-01 Compound

Interventions

AG-01 Compound DRUG

Phase 1A dose escalation study: enrolled subjects with advanced solid tumors will receive AG-01 compound at various doses. Phase 1B patients will be treated with AG-01 at the RP2D.

AG-01 1B Hormone-resistant breast cancer; AG-01 1B NSCLC; AG-01 1B triple negative breast cancer treated group; AG-01 treated group phase 1A; AG-01-1B mesothelioma

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed informed consent/authorization is obtained prior to conducting any study-specific screening procedures.
• years of age or older.
• Histologic or cytologic diagnosis of advanced cancer.
• Radiographic evidence of at least 1 measurable metastatic lesion per RECIST 1.1 criteria.
• Patients with relapsed/refractory solid tumor malignancies who failed one or more standard chemotherapy or targeted therapy regimens per SOC guidelines such as NCCN guidelines and for whom no standard therapy exists (Phase 1A). No GP88 expression pre-required for phase 1A.
• For phase 1B, patients must have GP88 tissue tumor tissue expression of 1+, 2+ or 3+ by IHC, archival tumor tissue will be used whenever possible. If no archival tissue is available, subject will be asked to consent to a study specific tumor biopsy for GP88 testing (phase1B). Patients who do not have archival tissue available for the dose expansion cohort (1B) will not be exposed to significant risk procedure to obtain tissue and may still be eligible for the study, after discussion with the Sponsor and Medical Monitor.
• At least 4 weeks after the last dose of chemotherapy or radiation therapy; 6 weeks for mitoxantrone or mitomycin therapy.
• ECOG performance status must be ≤2 (Appendix A).
• Adequate hepatic, renal, and bone marrow function:
• Absolute neutrophil count ≥ 1,000/uL Platelets ≥ 100,000/µL Total bilirubin WNL per Institution ULN AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional ULN Creatinine ≤1.2 mg/dL Clearance ≥50ml/min (Cockcroft-Gault)
• All study participants (male and female) with reproductive potential must practice highly effective methods of contraception (failure rate \<1% annually) while on this study and for 90 days after completion of study therapy.
• Men and women of all ethnic groups are eligible for this trial.
• Females at reproductive age must have a negative urine pregnancy test prior to entry to this study.
• Males with partners at reproductive age must use highly effective birth control methods to prevent partners' pregnancy while on study and for 90 days after completion of study treatments.
• Life expectancy is greater than 12 weeks.

You may not qualify if:

• Uncontrolled inter-current illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmias not well controlled with medication, myocardial infarction within the previous 6 months, or psychiatric illness/social situations that would limit compliance with study requirements.
• Uncontrolled or untreated CNS metastases and treated CNS metastases are allowed, as long as the patient is clinically stable.
• Presence carcinomatous meningeal involvement.
• Patients may not be receiving any other investigational agents, or have participated in any investigational drug study \< 28 days prior to starting on the current study.
• Since the teratogenic potential of AG01 is currently unknown, females who are pregnant or lactating are excluded.
• Males and females unable to adhere to abstinence or use highly effective methods of contraception (annual failure rate \< 1%) to prevent study subjects' pregnancy or study subjects' partner pregnancy.
• History of any other malignancies in the last 2 years except for in-situ cancer, basal or squamous cell skin cancer treated with curative intent.

Sponsors & Collaborators

• A&G Pharmaceutical Inc.: lead
• University of Maryland Greenebaum Cancer Center: collaborator

Study Sites (1)

University of Maryland Greenebaum Comprehensive Cancer Center

Baltimore, Maryland, 21201, United States

RECRUITING

Related Publications (11)

• Serrero G. Potential of Theranostic Target Mining in the Development of Novel Diagnostic and Therapeutic Products in Oncology: Progranulin/GP88 as a Therapeutic and Diagnostic Target for Breast and Lung Cancers. Rinsho Byori. 2016 Nov;64(11):1296-1309.

  PMID: 30695312 BACKGROUND

• Tkaczuk KHR, Hawkins D, Yue B, Hicks D, Tait N, Serrero G. Association of Serum Progranulin Levels With Disease Progression, Therapy Response and Survival in Patients With Metastatic Breast Cancer. Clin Breast Cancer. 2020 Jun;20(3):220-227. doi: 10.1016/j.clbc.2019.11.010. Epub 2019 Dec 5.

  PMID: 31928925 BACKGROUND

• Koo DH, Do IG, Oh S, Lee YG, Kim K, Sohn JH, Park SK, Yang HJ, Jung YS, Park DI, Jeong KU, Kim HO, Kim H, Serrero G, Chun HK; KBSMC Colorectal Cancer Team. Prognostic Value of Progranulin in Patients with Colorectal Cancer Treated with Curative Resection. Pathol Oncol Res. 2020 Jan;26(1):397-404. doi: 10.1007/s12253-018-0520-7. Epub 2018 Oct 30.

  PMID: 30378010 BACKGROUND

• Greither T, Steiner T, Bache M, Serrero G, Otto S, Taubert H, Eckert AW, Kappler M. GP88/PGRN Serum Levels Are Associated with Prognosis for Oral Squamous Cell Carcinoma Patients. Biology (Basel). 2021 May 4;10(5):400. doi: 10.3390/biology10050400.

  PMID: 34064411 BACKGROUND

• Guha R, Yue B, Dong J, Banerjee A, Serrero G. Anti-progranulin/GP88 antibody AG01 inhibits triple negative breast cancer cell proliferation and migration. Breast Cancer Res Treat. 2021 Apr;186(3):637-653. doi: 10.1007/s10549-021-06120-y. Epub 2021 Feb 22.

  PMID: 33616772 BACKGROUND

• Serrero G, Hawkins DM, Bejarano PA, Ioffe O, Tkaczuk KR, Elliott RE, Head JF, Phillips J, Godwin AK, Weaver J, Hicks D, Yue B. Determination of GP88 (progranulin) expression in breast tumor biopsies improves the risk predictive value of the Nottingham Prognostic Index. Diagn Pathol. 2016 Aug 8;11(1):71. doi: 10.1186/s13000-016-0520-4.

  PMID: 27501955 BACKGROUND

• Edelman MJ, Feliciano J, Yue B, Bejarano P, Ioffe O, Reisman D, Hawkins D, Gai Q, Hicks D, Serrero G. GP88 (progranulin): a novel tissue and circulating biomarker for non-small cell lung carcinoma. Hum Pathol. 2014 Sep;45(9):1893-9. doi: 10.1016/j.humpath.2014.05.011. Epub 2014 Jun 5.

  PMID: 25033727 BACKGROUND

• Serrero G, Hawkins DM, Yue B, Ioffe O, Bejarano P, Phillips JT, Head JF, Elliott RL, Tkaczuk KR, Godwin AK, Weaver J, Kim WE. Progranulin (GP88) tumor tissue expression is associated with increased risk of recurrence in breast cancer patients diagnosed with estrogen receptor positive invasive ductal carcinoma. Breast Cancer Res. 2012 Feb 8;14(1):R26. doi: 10.1186/bcr3111.

  PMID: 22316048 BACKGROUND

• Arechavaleta-Velasco F, Perez-Juarez CE, Gerton GL, Diaz-Cueto L. Progranulin and its biological effects in cancer. Med Oncol. 2017 Nov 7;34(12):194. doi: 10.1007/s12032-017-1054-7.

  PMID: 29116422 BACKGROUND

• Abrhale T, Brodie A, Sabnis G, Macedo L, Tian C, Yue B, Serrero G. GP88 (PC-Cell Derived Growth Factor, progranulin) stimulates proliferation and confers letrozole resistance to aromatase overexpressing breast cancer cells. BMC Cancer. 2011 Jun 9;11:231. doi: 10.1186/1471-2407-11-231.

  PMID: 21658239 BACKGROUND

• Wong NC, Cheung PF, Yip CW, Chan KF, Ng IO, Fan ST, Cheung ST. Antibody against granulin-epithelin precursor sensitizes hepatocellular carcinoma to chemotherapeutic agents. Mol Cancer Ther. 2014 Dec;13(12):3001-12. doi: 10.1158/1535-7163.MCT-14-0012. Epub 2014 Sep 24.

  PMID: 25253787 BACKGROUND

MeSH Terms

Conditions

Triple Negative Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Mesothelioma; Breast Neoplasms; Lung Neoplasms

Interventions

AG-01 compound

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms, Mesothelial

Study Officials

• Katherine Tkaczuk, MD

  University of Maryland, Baltimore

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ginette Serrero, PhD/DSC.

CONTACT

(410)884-4100; gserrero@agpharma.com

Katherine Tkaczuk, MD

CONTACT

(410) 328-7394; ktkaczuk@umm.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: For dose escalation, model is an accelerated titration design-1-(3+3)

Study Record Dates

• First Submitted: March 16, 2022
• First Posted: November 28, 2022
• Study Start: February 14, 2022
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): November 1, 2026
• Last Updated: November 28, 2022

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)