A Study to Evaluate YH003 in Combination With Toripalimab (Anti-PD-1 mAb) in Subjects With Advanced Solid Tumors

• ClinicalTrials.gov Identifier: NCT04481009
• Recruitment Status: Completed
• First Posted: July 22, 2020
• Last Update Posted: December 12, 2022
• Sponsor: Eucure (Beijing) Biopharma Co., Ltd
• Information provided by (Responsible Party): Eucure (Beijing) Biopharma Co., Ltd

Tracking Information

• First Submitted Date: July 17, 2020
• First Posted Date: July 22, 2020
• Last Update Posted Date: December 12, 2022
• Actual Study Start Date: August 4, 2020
• Actual Primary Completion Date: May 16, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 17, 2020)

• Overall safety and tolerability profile of YH003 in combination with Toripalimab. [ Time Frame: From screening up to 1 year ]
  The safety profile of YH003 in combination with Toripalimab will be assessed by monitoring the adverse events (AE) per NCI CTCAE v5.0
• Maximum tolerated dose (MTD) and Recommended phase 2 dose (RP2D) [ Time Frame: Cycle 1 of each cohort. Duration of one cycle is 3 weeks ]
  The MTD and RP2D will be determined based on the data of safety and tolerability

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 17, 2020)

• Area under the serum concentration versus time curve (AUC) [ Time Frame: Up to 1 year ]
  To determine the PK profile of YH003 alone and in combination with Toripalimab
• Maximum serum concentration (Cmax) [ Time Frame: Up to 1 year ]
  To determine the PK profile of YH003 alone and in combination with Toripalimab
• Trough concentration before the next dose is administered (Ctrough) [ Time Frame: Up to 1 year ]
  To determine the PK profile of YH003 alone and in combination with Toripalimab
• Time to reach maximum serum concentration (Tmax) [ Time Frame: Up to 1 year ]
  To determine the PK profile of YH003 alone and in combination with Toripalimab
• Clearance (CL) [ Time Frame: Up to 1 year ]
  To determine the PK profile of YH003 alone and in combination with Toripalimab
• Volume of distribution (Vd) [ Time Frame: Up to 1 year ]
  To determine the PK profile of YH003 alone and in combination with Toripalimab
• Volume of distribution at steady state (Vss) [ Time Frame: Up to 1 year ]
  To determine the PK profile of YH003 alone and in combination with Toripalimab
• Terminal half-life (T1/2) [ Time Frame: Up to 1 year ]
  To determine the PK profile of YH003 alone and in combination with Toripalimab
• Dose proportionality [ Time Frame: Up to 1 year ]
  To determine the PK profile of YH003 alone and in combination with Toripalimab
• Incidence of anti-drug antibodies (ADAs) [ Time Frame: Up to 1 year ]
  To assess the immunogenicity of YH003 in combination with Toripalimab
• Incidence of neutralizing antibodies (NAbs) [ Time Frame: Up to 1 year ]
  To assess the immunogenicity of YH003 in combination with Toripalimab
• Objective response rate (ORR) [ Time Frame: Up to 1 year ]
  To assess the preliminary antitumor activity of YH003 in combination with Toripalimab
• Duration of response (DOR) [ Time Frame: Up to 1 year ]
  To assess the preliminary antitumor activity of YH003 in combination with Toripalimab
• Time to response (TTR) [ Time Frame: Up to 1 year ]
  To assess the preliminary antitumor activity of YH003 in combination with Toripalimab
• Progression free survival (PFS) [ Time Frame: Up to 1 year ]
  To assess the preliminary antitumor activity of YH003 in combination with Toripalimab
• Overall survival (OS) [ Time Frame: Up to 1 year ]
  To assess the preliminary antitumor activity of YH003 in combination with Toripalimab
• Disease control rate (DCR) [ Time Frame: Up to 1 year ]
  To assess the preliminary antitumor activity of YH003 in combination with Toripalimab
• Duration of disease control (DDC) [ Time Frame: Up to 1 year ]
  To assess the preliminary antitumor activity of YH003 in combination with Toripalimab

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Evaluate YH003 in Combination With Toripalimab (Anti-PD-1 mAb) in Subjects With Advanced Solid Tumors
• Official Title: A Multicenter, Open-Label, Phase I/II Dose Escalation and Expansion Study to Evaluate the Safety, Tolerability, Efficacy and Pharmacokinetics of YH003 in Combination With Toripalimab (Anti-PD-1 mAb) in Subjects With Advanced Solid Tumors
• Brief Summary: This is a phase I/II, multi-center, open-label study of YH003 in combination with Toripalimab (anti-PD-1 mAb). The study is comprised of a dose escalation part (Part I) exploring escalating doses of YH003 in combination with fixed dose toripalimab in subjects with advanced solid tumors (Part I), followed by an expansion part (Part II) with three expansion cohorts.

Detailed Description

The study is comprised of a dose escalation part (Part I) exploring escalating doses of YH003 in combination with fixed dose toripalimab in subjects with advanced solid tumors (Part I), followed by an expansion part (Part II) with three expansion cohorts.

During Part I, dose escalation part of the study, a traditional 3+3 dose algorithm will be utilized to identify MTD(maximum tolerated dose) and/or RP2D (recommended phase 2 dose).

This dose escalation part will consist two phases, the run-in phase to explore safety and tolerability of YH003 as single agent and the combination phase to explore safety and tolerability of escalating doses of YH003 in combination with fixed dose Toripalimab.

The Phase II expansion part of this clinical trial will include three parallel cohorts(cohort 2A, 2B and 2C) of 20 subjects each treated with a dose around the RP2D of YH003 in combination with Toripalimab to assess the antitumor activity and safety/tolerability. One expansion cohort (2A) is YH003 and toripalimab in subjects with unresectable/metastatic melanoma, the other two expansion cohorts (2B and 2C) are YH003 and toripalimab with or without nab-paclitaxel + gemcitabine in unresectable/ metastatic pancreatic ductal adenocarcinoma.

Subjects will be monitored for safety, tolerability and efficacy throughout the study.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Advanced Solid Tumors

Intervention

• Drug: YH003
  YH003 will be administered intravenously over 60 minutes every 21-day cycle.
• Drug: Toripalimab
  Toripalimab with fixed dose of 240 mg administered intravenously followed by YH003 administered intravenously every 21-day cycle.
• Drug: Nab-paclitaxel
  Nab-paclitaxel will be administered each 21-day cycle.
• Drug: Gemcitabine
  Gemcitabine will be administrated each 21-day cycle.

Study Arms

• Experimental: YH003 with Toripalimab after PD-1/L1 +/- CTLA-4 treatment
  YH003 in combination with Toripalimab in subjects with unresectable /metastatic melanoma after having failed PD-1/L1 +/- CTLA-4 treatment.
  Interventions:

  • Drug: YH003
  • Drug: Toripalimab
• Experimental: YH003 with Toripalimab in subjects with PDAC
  YH003 in combination with Toripalimab in subjects with unresectable/ metastatic pancreatic ductal adenocarcinoma (PDAC) as 2nd line treatment.
  Interventions:

  • Drug: YH003
  • Drug: Toripalimab
• Experimental: YH003 with Toripalimab plus standard chemotherapy
  YH003 in combination with Toripalimab plus standard chemotherapy (Nab-paclitaxel + Gemcitabine) in subjects with unresectable/metastatic PDAC as 1st line treatment
  Interventions:

  • Drug: YH003
  • Drug: Toripalimab
  • Drug: Nab-paclitaxel
  • Drug: Gemcitabine

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 9, 2022): 26
• Original Estimated Enrollment (submitted: July 17, 2020): 60
• Actual Study Completion Date: May 26, 2022
• Actual Primary Completion Date: May 16, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Subjects must have the ability to understand and willingness to sign a written informed consent document.

2. Part I dose escalation:

   Have histologically advanced or cytologically confirmed solid tumor. Have progressed on after treatment with at least one standard therapy or intolerant of the standard therapy.

   Part II dose expansion:

   Cohort 2A: Histologically or cytologically confirmed unresectable or metastatic melanoma that had confirmed progressive disease during treatment with an anti-PD-1/PD-L1 therapy with or without additional CTLA-4 therapy. Subjects with BRAF activating mutation could have also received a BRAF inhibitor and/or MEK inhibitor regimen prior to anti-PD-1/PD-L1 therapy.

   Cohort 2B, 2C: Subject has histologically or cytologically documented diagnosis of pancreatic ductal adenocarcinoma with unresectable locally advanced/metastatic disease Cohort 2B: had confirmed progressive disease during treatment with first line standard of care of chemotherapy per local standard.

   Cohort 2C: treatment-naïve for unresectable locally advanced/metastatic disease.

3. Subject must have measurable disease by RECIST 1.1. At least 1 unidimensional measurable target lesion per RECIST v1.1 for study Part II expansion cohorts.
4. Subjects must be age 18 years or older.
5. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Life expectancy ≥3 months.
6. Subjects must have adequate organ function.
7. Women of reproductive potential must have negative serum beta human chorionic gonadotropin (β -HCG) pregnancy test.

Exclusion Criteria:

1. Part II Cohort 2A: History of life-threatening toxicity or treatment discontinuation due to related to prior anti-PD-1/PD-L1 and with or without CTLA-4 combination treatment for subjects with unresectable/metastatic melanoma.
2. Subjects must not have another active invasive malignancy.
3. Previous exposure to TNFR such as anti-CD137, OX40, CD27 and CD357 antibodies.
4. Subjects must not have received any anticancer therapy or another investigational agent within the shorter of 4 weeks or 5 half-lives before the first dose of the study treatment.
5. Subjects with a history of ≥ Grade 3 immune-related adverse events resulted from previous immunotherapy.
6. History of clinically significant sensitivity or allergy to monoclonal antibodies and their excipients or known allergies to antibodies produced from Chinese hamster ovary cells, which in the opinion of the Investigator suggests an increased potential for an adverse hypersensitivity to YH003 or Toripalimab. Also history of severe hypersensitivity reaction to Nap-paclitaxel and/or gemcitabine.
7. Primary central nervous system (CNS) malignancies or symptomatic CNS metastases.
8. History of (non-infectious) pneumonitis that required corticosteroids or current pneumonitis, or history of interstitial lung disease.
9. Subjects must not have a known or suspected history of an autoimmune disorder, including but not limited to inflammatory bowel disease, celiac disease, Wegner syndrome, Hashimoto syndrome, systemic lupus erythematosus, scleroderma, sarcoidosis, or autoimmune hepatitis, within 3 years of the first dose of study treatment.
10. Clinically uncontrolled intercurrent illness, including an ongoing or active infection, active coagulopathy, uncontrolled diabetes, psychiatric illness that would limit compliance with the study requirements and other serious medical illnesses requiring systemic therapies.
11. Severe cardiovascular disease including symptomatic congestive heart failure (New York Heart Association class III or IV), unstable angina, uncontrolled hypertension, cardiac arrhythmia, a history of myocardial infarction within 6 months or a history of arterial thromboembolic event and pulmonary embolism within 3 months of the first dose of investigational agent.
12. QTc > 450 ms at baseline; no concomitant medications that would prolong the QT interval; no family history of long QT syndrome.
13. Subjects must not have active infection of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C.
14. Subjects must not have a history of primary immunodeficiency.
15. Subjects from endemic area will be specifically screened for tuberculosis. Subjects with active tuberculosis are excluded.
16. Subjects must not receive concurrent or prior use of an immunosuppressive agent within 4 weeks of the first dose of YH003.
17. Major surgery within 4 weeks prior to study entry and Minor surgery within 2 weeks prior to the first dose of YH003.
18. Subjects must not have received a live attenuated vaccine within 28 days before the first dose of YH003, and subjects, if enrolled, should not receive live vaccines during the study or for 180 days after the last dose of YH003.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia

Administrative Information

• NCT Number: NCT04481009
• Other Study ID Numbers: YH003002
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Eucure (Beijing) Biopharma Co., Ltd
• Original Responsible Party: Same as current
• Current Study Sponsor: Eucure (Beijing) Biopharma Co., Ltd
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Eucure (Beijing) Biopharma Co., Ltd
• Verification Date: October 2022