Study of GNX102 in Patients With Advanced Solid Tumors

• ClinicalTrials.gov Identifier: NCT04250597
• Recruitment Status: Recruiting
• First Posted: January 31, 2020
• Last Update Posted: October 26, 2020
• Sponsor: GlycoNex, Inc.
• Collaborator: Linical Co., Ltd.
• Information provided by (Responsible Party): GlycoNex, Inc.

Tracking Information

• First Submitted Date: January 27, 2020
• First Posted Date: January 31, 2020
• Last Update Posted Date: October 26, 2020
• Actual Study Start Date: July 29, 2020
• Estimated Primary Completion Date: December 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 30, 2020)

maximum tolerated dose (MTD) [ Time Frame: Through study completion, an average of 2 years ]

If ≤ 1 of 6 patients has a dose limiting toxicity (DLT) after all previous dose testing the dose will be declared the Maximum Tolerable Dose (MTD).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: January 30, 2020)

• Antitumor activity of GNX102 [ Time Frame: Through study completion, an average of 2 years ]
  To evaluate antitumor activity of GNX102 by objective radiographic assessment
• AUC: Area under the concentration curve of GNX102 (μg × h/mL) [ Time Frame: Through study completion, an average of 2 years ]
  To determine the AUC Area under the concentration curve of GNX102
• Cmax: Maximum plasma concentration of GNX102 (μg) [ Time Frame: Through study completion, an average of 2 years ]
  To determine the pharmacokinetics (PK) of GNX102
• Tmax: Time to maximum plasma concentration of GNX102 (minutes) [ Time Frame: Through study completion, an average of 2 years ]
  To determine the pharmacokinetics (PK) of GNX102
• t1/2: Terminal phase half-life of GNX102 (minutes) [ Time Frame: Through study completion, an average of 2 years ]
  To determine the pharmacokinetics (PK) of GNX102
• CL: Clearance of GNX102 (L/hr) [ Time Frame: Through study completion, an average of 2 years ]
  To determine the pharmacokinetics (PK) of GNX102
• Vz: Apparent volume of distribution in the terminal phase of GNX102 (L) [ Time Frame: Through study completion, an average of 2 years ]
  To determine the pharmacokinetics (PK) of GNX102
• Number of adverse events (AEs) and number of toxicities [ Time Frame: Through study completion, an average of 2 years ]
  Dose-limiting AEs and toxicities will be used to establish the MTD and the recommended dose for phase 2 studies (RP2D)

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: July 30, 2020)

• Exploratory Outcome: GNX102 targeted antigens (counts) [ Time Frame: Through study completion, an average of 2 years ]
  To explore tumor expression of GNX102 targeted antigens as a biomarker to predict toxicity or response to GNX102
• Exploratory Outcome: Serum LeB / LeY antigen levels (counts) [ Time Frame: Through study completion, an average of 2 years ]
  To explore serum LeB / LeY antigen levels as a potential biomarker to predict toxicity or response to GNX102
• Exploratory Outcome: Serum tumor-specific antigen levels (counts) [ Time Frame: Through study completion, an average of 2 years ]
  To explore biomarkers related to cancer type to predict toxicity or response to GNX102
• Exploratory Outcome: Anti-drug antibody (ADA) to GNX102 (counts) [ Time Frame: Through study completion, an average of 2 years ]
  To evaluate the development of anti-drug antibody (ADA) to GNX102

Original Other Pre-specified Outcome Measures (submitted: January 30, 2020)

• Exploratory Outcome: GNX102 targeted antigens (counts) [ Time Frame: Through study completion, an average of 2 years ]
  To explore tumor expression of GNX102 targeted antigens as a biomarker to predict toxicity or response to GNX102
• Exploratory Outcome: Serum LeB / LeY antigen levels (counts) [ Time Frame: Through study completion, an average of 2 years ]
  To explore serum LeB / LeY antigen levels as a potential biomarker to predict toxicity or response to GNX102
• Exploratory Outcome:Serum CA 19-9 antigen levels (counts) [ Time Frame: Through study completion, an average of 2 years ]
  To explore biomarkers related to cancer type (e.g. pancreas) to predict toxicity or response to GNX102
• Exploratory Outcome: Serum CA 125 antigen levels (counts) [ Time Frame: Through study completion, an average of 2 years ]
  To explore biomarkers related to cancer type (e.g. ovarian) to predict toxicity or response to GNX102
• Exploratory Outcome: Serum CEA antigen levels (counts) [ Time Frame: Through study completion, an average of 2 years ]
  To explore biomarkers related to cancer type (e.g. colon) to predict toxicity or response to GNX102
• Exploratory Outcome: Anti-drug antibody (ADA) to GNX102 (counts) [ Time Frame: Through study completion, an average of 2 years ]
  To evaluate the development of anti-drug antibody (ADA) to GNX102

Descriptive Information

• Brief Title: Study of GNX102 in Patients With Advanced Solid Tumors
• Official Title: A Phase I Study of GNX102 in Patients With Advanced Solid Tumors

Brief Summary

GNX-001 is an open-label, phase 1, multicenter, dose-escalation and expansion study of GNX102 infused every 21 days. Approximately 30 patients may be enrolled in the dose escalation portion of this study. Once the MTD or recommended phase 2 dose (RP2D) has been identified, up to 15 additional patients may be enrolled in one or two expansion cohort(s) at one or two dose levels recommended by the Safety Review Committee) to confirm the safety profile of the RP2D and provide additional information on anti-tumor activity.

Patients with adeno- or epithelial-cancers that have a likelihood of GNX102 targeted antigen expression based on previous studies, including colorectal, hepatocellular, non-small cell lung, gastric, breast, pancreatic, cutaneous, acral, or mucosal melanoma, esophageal, prostate, and epithelial uterine cancers, can be screened for enrollment in the study.

Detailed Description

GNX102 is a humanized monoclonal antibody (mAb) developed by GlycoNex. GNX102 binds with high affinity to branched Lewis B/Lewis Y (LeB/LeY) glycans, which are novel glycans caused by glycosylation changes in tumors. The monomeric LeB and LeY are blood group related antigens, commonly present in healthy adult tissues at low to moderate levels, but are overexpressed in multiple carcinomas and their presence correlates with tumor development and progression.

Higher affinity for branched LeB/LeY glycans is intended to allow GNX102 to discriminate between the monomeric LeB and LeY glycans presented on normal tissues from the branched LeB and LeY glycans present on cancer tissues. This preferential binding to branched LeB/LeY versus monomeric LeB and LeY could improve the therapeutic index by both improving selectivity for tumor cells and reducing toxicity to normal tissues.

The investigational product GNX102 will be administered as an intravenous infusion over one hour every 21 days as a single agent. One cycle is 21 days in duration. Patients may continue to receive study drug every 21 days without interruption between cycles unless there is unacceptable toxicity or experiences progressive disease. A dose delay of up to 14 days is permitted between cycles to address toxicities.

The GNX102 starting dose will be 1 mg/kg and escalating to 3 mg/kg, 10 mg/kg, 30 mg/kg and 60 mg/kg. This dosing schedule is designed to start with a dose that is anticipated to produce an exposure level in patients that has some potential to provide clinical benefit yet is many-fold below an exposure level that was associated with an acceptable safety profile in toxicology studies. The half-log dose escalation strategy is designed to ensure that there are clinically meaningful differences in GNX102 exposure between successive cohorts.

Up to five (5) dose levels are planned during dose escalation. Dose escalation will depend on the number and intensity of observed toxicities as well as review of available pharmacokinetic (PK data). A Safety Review Committee (SRC) will review available safety and PK data as relevant to make recommendations related to selection of dose and schedule (dosing interval), as well as modifications to PK time points. At the recommendation of the SRC, a cohort may be repeated or intermediate dose levels between scheduled dose levels may be explored during the escalation phase.

Dose escalation will follow a standard oncology 3+3 design with a dose-escalation schema.

Up to 30 patients may be enrolled in the dose expansion cohorts. Once the MTD has been determined in the dose escalation phase of the study, approximately 15 additional patients may be enrolled in one or two dose expansion cohort(s) (at the MTD and one lower dose level) to further assess safety and the RP2D as well as anti-tumor activity.

In accordance with FDA COVID-19 Guidance on the Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic (dated March 18, 2020; updated March 27, 2020; updated April 16, 2020), GlycoNex and the Contract Research Organization (CRO), Linical Americas, supporting this study are modifying their processes and procedures in alignment with FDA Guidance to ensure the safety of study participants, while streamlining study conduct and decreasing the burden on patients and sites. The intent is to reduce visits, procedures and/or tests that are considered non-essential in order to assure patient safety and address the most important trial objectives. The SRC may determine that procedures or visits need to be rescheduled or omitted. The IRB will be notified promptly of such change(s) and a subsequent amendment will be provided in a timely manner.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Solid Tumor
• Metastatic Cancer
• Advanced Cancer
• Unresectable Solid Neoplasm

Intervention

Drug: GNX102

Dose Escalation

Study Arms

• Experimental: 1.0 mg/kg
  Intervention: Drug: GNX102
• Experimental: 3.0 mg/kg
  Intervention: Drug: GNX102
• Experimental: 10 mg/kg
  Intervention: Drug: GNX102
• Experimental: 30 mg/kg
  Intervention: Drug: GNX102
• Experimental: 60 mg/kg
  Intervention: Drug: GNX102

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 30, 2020): 30
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: February 2022
• Estimated Primary Completion Date: December 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria

The study population consists of adult patients with advanced solid tumors that meet all of the following criteria to be enrolled into this study:

1. Age ≥ 18 years.

2. Patients with histologically confirmed solid tumors with a likelihood of expression of GNX102 targeted antigens, which are limited to:

   • colorectal
   • hepatocellular
   • non-small cell lung
   • gastric
   • breast
   • bladder
   • pancreatic
   • melanoma (cutaneous, acral, or mucosal)
   • esophageal
   • prostate
   • ovarian
   • cervical
   • epithelial uterine cancers.
3. Patient has a paraffin block of non-necrotic tumor tissue available for immunohistochemistry (IHC) analyses, to be shipped prior to initiation of treatment. Processing includes an option to send formalin-fixed paraffin embedded slides [FFPE] slides if a tumor block is not available.
4. Advanced, unresectable (local, regionally, recurrent not amenable to curative therapy) or metastatic disease that has no standard therapeutic option with a proven clinical benefit, are intolerant to or have refused all standard of care options with demonstrated clinical benefit.
5. Expansion Phase only: patient has measurable disease per RECIST v 1.1 criteria.
6. ECOG performance status of 0 or 1.
7. Baseline QTC interval of ≤ 480 msec using Frederica's formula.

8. Acceptable liver function:

   • Bilirubin ≤ 1.5 times upper limit of normal
   • AST (SGOT) and ALT (SGPT) ≤ 3 times upper limit of normal. If liver metastases are present, then ≤ 5 x ULN is allowed, and
   • Serum albumin ≥ 2.5 g/dL.
9. Acceptable renal function, defined as calculated creatinine clearance > 30 mL/min per institution laboratory values.

10. Acceptable hematologic status:

    • Hemoglobin ≥ 8 g/dL (no packed red blood cell [PRBC] transfusions allowed within 2 weeks)
    • Absolute neutrophil count (ANC) ≥ 1500 cells/mm^3 or ≥ 1.5 x 10^9/L
    • Platelet count ≥ 100,000 platelets/mm^3 or ≥ 100 x 10^9/L, and
    • Absolute reticulocyte count (x10^9/L) < ULN.
11. Serum haptoglobin (mg/dL) > LLN.
12. Acceptable coagulation status with fibrinogen, above LLN; PT/INR and PTT ≤ 1.5 times upper limit of normal (may be on a stable dose of coumadin with stable INR in the therapeutic range).
13. Life expectancy of at least 3 months.
14. Signed IRB-approved informed consent.
15. Able and willing to comply with the protocol for the duration of the study, including undergoing treatment and scheduled visits and examinations.
16. A negative serum pregnancy test, if female of child-bearing potential.
17. For men and women of child-bearing potential, agreement to the use of at least 1 highly effective contraceptive method(s) during the study and in the 3 months following the last dose of GNX102.

Exclusion Criteria

Patients who meet any of the following criteria will be excluded from participation in this study:

1. Has any other malignancy not listed in Inclusion Criteria # 2.
2. Has a positive PCR test for active COVID-19 infection or has signs or symptoms consistent with COVID-19 in the absence of a negative PCR test.
3. Has New York Heart Association Class III or IV heart disease.
4. History of myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, within the past 6 months.
5. History of cerebral vascular accident or transient ischemic attack within the past 6 months.
6. History of primary CNS tumor.
7. History of CNS metastases, unless previously treated and stable for at least 4 weeks in the absence of steroids. Patients with meningeal carcinomatosis are excluded regardless of treatment.
8. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy within 72 hours of start of therapy.
9. Active, nonmalignant GI disease requiring treatment (such as inflammatory bowel disease, Crohn's disease, colitis) that would impart, in the judgment of the investigator and/or sponsor, excess risk associated with study participation or study drug administration, which would make the patient inappropriate for entry into this study.
10. Clinical symptoms of pancreatitis within the past 28 days.

11. Known active infection with HIV, hepatitis B (HBV), or hepatitis C (HCV).

    • Patients with a history of HBV or HCV are allowed if HBV DNA or HCV RNA are undetectable. Patients with hepatocellular cancer on anti-viral therapy must have DNA levels ≤ 500 IU/ml.
    • Patients with a history of HBV or HCV will be monitored for reactivation while on study.
12. Pregnant or nursing women.
13. Treatment with radiation therapy within 14 days prior to dosing with GNX102.
14. Major surgery within 14 days prior to dosing with GNX102.
15. History of autoimmune hemolytic anemia or autoimmune thrombocytopenia.
16. No second malignancy which is considered active or requires concurrent treatment.

17. For patients with hepatocellular carcinoma

    • Ascites requiring more than 1 paracentesis per month
    • History of hepatic encephalopathy within 12 months of study entry.
18. History of bleeding esophageal or gastric varices within 6 months of study entry.
19. Prior or ongoing cancer treatment, including investigational treatment within 5 half-lives or 21 days whichever is less, prior to dosing with GNX102 and 6 weeks for nitrosoureas or mitomycin C.
20. Allergies to any excipients in GNX102 (i.e., L-histidine, sucrose, Polysorbate 80).
21. Severe acute or chronic medical or psychiatric conditions or other laboratory abnormalities that would impart, in the judgment of the investigator and/or sponsor, excess risk associated with study participation or study drug administration, which would make the patient inappropriate for entry into this study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Yun-Ting Liao; 886-2-26974168; ytliao@glyconex.com.tw

• Listed Location Countries: Taiwan, United States

Administrative Information

• NCT Number: NCT04250597
• Other Study ID Numbers: GNX-001
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: GlycoNex, Inc.
• Study Sponsor: GlycoNex, Inc.
• Collaborators: Linical Co., Ltd.

Investigators

• Study Director: Mei-Chun Yang, PhD; GlycoNex, Inc.

• PRS Account: GlycoNex, Inc.
• Verification Date: July 2020