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).
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
77
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.
University of Maryland Greenebaum Comprehensive Cancer Center
Baltimore, Maryland, United States
RECRUITINGMaximum 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.
Time frame: 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.
Time frame: Every 56 Days
Recommended phase 2 dose (RP2D) of AG-01-Phase 1A
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.
Time frame: 28 days or 1cycle
Safety and tolerability of AG-01
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:
Time frame: 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
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.
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).
Preliminary anti-tumor activity of the AG-01 in subjects with refractory/advanced solid tumor malignancies (1A and 1B).
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
Time frame: While receiving AG-01 treatment, at day 56
Anti-drug antibodies (ADA) to AG-01
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
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)
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