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

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) and/or Maximum Administered Dose (MAD) [ Time Frame: 28 days during 1st cycle ]
   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.
2. Antitumor Activity of AG-01 by Overall Response Rate (ORR) [ Time Frame: Every 56 Days ]

   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.

Secondary Outcome Measures

1. Recommended phase 2 dose (RP2D) of AG-01-Phase 1A [ Time Frame: 28 days or 1cycle ]

   During 1A portion accelerated titration (1pt/dose) design will be utilized to guide dose progression and estimation of the maximum tolerated dose MTD and/or maximum administered dose (MAD) (1). Once treatment related DLT occurs, this cohort will be expanded to 3+3 design, and all subsequent cohorts will follow the 3+3 design.

   First dose/cohort level subjects will be monitored for 28 days from the D1 of the 1st infusion of AG01 (2 doses, D 1 and D15 of AG01) before the dose is escalated to the next dose level without expansion of cohort and assuming no DLTs during this time.

2. Safety and tolerability of AG-01 [ Time Frame: While receiving AG-01 for 56 days and for 30 days after the last dose of the study drug (day 86) ]
   Subjects will be monitored for emergence of any adverse events; with physical exams, laboratory assessments, ECOG PS, Vital signs, changes in weight, clinical symptoms. Adverse events will be assessed via CTACE V 5.0 on ongoing basis in Phase 1A and 1B:
3. Pharmacokinetic (PK) profile of AG-01-1A [ Time Frame: 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). ]
   Blood samples will be collected collected in cycles 1 and 2, End of Treatment and 30 days post-treatment, per study schedule to determine AG01 drug levels and PK profile.
4. Preliminary anti-tumor activity of the AG-01 in subjects with refractory/advanced solid tumor malignancies (1A and 1B). [ Time Frame: While receiving AG-01 treatment, at day 56 ]
   Response to treatment with AG-01 will be assessed with tumor imaging (CTs/MRIs/Bone scan-as applicable) every 56 days, response will be assessed via RECIST 1.1
5. Anti-drug antibodies (ADA) to AG-01 [ Time Frame: 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) ]
   ADA blood samples will be collected prior to AG-01 administration on Days 1, 15, 29, and 43 with blood sampling following the described time frame and tested via immunoassay for presence anti-AG01 antibodies

Other Outcome Measures

1. Serial Glycoprotein88 (GP-88) blood levels [ Time Frame: 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). ]
   Exploratory outcome-To determine the serial GP88 blood levels using the available ELISA blood test while on treatment with the Anti-GP88 monoclonal antibody (AG01).

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.