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

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).

PGRN/GP88 is an 88 kilodalton glycoprotein produced by cells of epithelial or mesenchymal origin. It is an autocrine growth factor, which is overexpressed in several human cancers including breast and ovarian cancer, multiple myeloma, prostate cancer, non small cell as well as other tumors. High GP88 expression is associated with the malignant phenotype, increased proliferation and survival associated with drug resistance to some currently used therapeutic agents. Pathological studies have shown that PGRN/GP88 is an independent prognostic factor in several cancers including breast, non-small cell lung carcinoma, prostate and digestive cancers. High GP88 expression in tumor tissues is associated with decreased disease-free survival and increased mortality. In addition, in stage 4 breast cancer patients, high circulating level of PGRN/GP88 is associated with decreased overall survival.

This study will enroll patients with relapsed/refractory solid tumor malignancies (1A) 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. In 1B portion of the study patients with triple negative breast cancer, hormone resistant breast cancer, non small cell lung cancer and mesothelioma will be accrued. The treatment period (cycle) will consist of 28-day cycles, the AGO1 will be infused every 14 days. The dosing schedule/frequency of treatments for subjects in the dose escalation portion (1A) will be the same as for subjects in the expansion portion (1B).

Eligibility Criteria:
Inclusion Criteria:

1. Signed informed consent/authorization is obtained prior to conducting any study-specific screening procedures.
2. 18 years of age or older.
3. Histologic or cytologic diagnosis of advanced cancer.
4. Radiographic evidence of at least 1 measurable metastatic lesion per RECIST 1.1 criteria.
5. 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.
6. 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.
7. At least 4 weeks after the last dose of chemotherapy or radiation therapy; 6 weeks for mitoxantrone or mitomycin therapy.
8. ECOG performance status must be ≤2 (Appendix A).
9. 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)
10. 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.
11. Men and women of all ethnic groups are eligible for this trial.
12. Females at reproductive age must have a negative urine pregnancy test prior to entry to this study.
13. 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.
14. Life expectancy is greater than 12 weeks.
15. Subjects with triple negative breast cancer (TNBC) cohort must have received 1 or more standard of care (SOC) or targeted therapies for metastatic TNBC. If PD(L)1-positive, must have received a combination of chemotherapy and a PD (L)-1 agent (Atezolizumab or 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. is FDA approved for treatment of advanced TNBC. Prior exposure to Sacituzumab Govitecan ADC therapy does not preclude eligibility in the current study.
16. Subjects with Cohort 2-Breast Cancer ER and/or PR positive, hormone-resistant breast cancer who received 1 or more hormonal (HT) therapies or HT/CD4/6 kinase inhibitor or HT/MTOR inhibitor for treatment of metastatic breast cancer are eligible. If the tumor has known PIK3CA mutation, HT/Alpelisib combination should be considered unless not a candidate for this therapy.
17. Subjects with metastatic/recurrent NSCLCA who failed 2 or more SOC therapies, including platinum-based chemotherapy and an anti-PD (L) -1 agent (sequentially or consecutively). Patients 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.
18. Mesothelioma patients who have received at least 1 SOC therapy for metastatic/recurrent mesothelioma per NCCN recommendations or not a candidate for SOC therapy.

Exclusion Criteria:

1. 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.
2. Uncontrolled or untreated CNS metastases and treated CNS metastases are allowed, as long as the patient is clinically stable.
3. Presence carcinomatous meningeal involvement.
4. 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.
5. Since the teratogenic potential of AG01 is currently unknown, females who are pregnant or lactating are excluded.
6. 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.
7. 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.