ADG126, ADG126 in Combination With Anti PD1 Antibody, and ADG126 in Combination With ADG106 in Advanced/Metastatic Solid Tumors

• ClinicalTrials.gov Identifier: NCT04645069
• Recruitment Status: Recruiting
• First Posted: November 27, 2020
• Last Update Posted: May 25, 2022
• Sponsor: Adagene Inc
• Information provided by (Responsible Party): Adagene Inc

Tracking Information

• First Submitted Date: November 20, 2020
• First Posted Date: November 27, 2020
• Last Update Posted Date: May 25, 2022
• Actual Study Start Date: March 15, 2021
• Estimated Primary Completion Date: March 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 24, 2022)

• Number of participants experiencing dose-limiting toxicities escalating dose levels in adults with advanced / metastatic solid tumors [ Time Frame: From first dose of ADG126 (Week 1 Day 1) until 21 days ]
• Number of participants with adverse events as assessed by CTCAE v5.0 ADG126-ADG106 combination regimens [ Time Frame: From first dose of ADG126 (Week 1 Day 1) to 90 days post last dose ]

Original Primary Outcome Measures (submitted: November 20, 2020)

• Number of participants experiencing dose-limiting toxicities escalating dose levels in adults with advanced / metastatic tumors [ Time Frame: From first dose of ADG126 (Week 1 Day 1) until 21 days ]
• Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 [ Time Frame: From first dose of ADG126 (Week 1 Day 1) to 28 days post last dose ]

Current Secondary Outcome Measures (submitted: April 24, 2022)

• Antidrug antibodies (ADAs) [ Time Frame: From first dose (Cycle 1 Day 1, ) until the last dose (up to 2 years) ]
• Area under the time concentration curve (AUC) from time zero to infinity (AUC0-inf) [ Time Frame: From first dose (Cycle 1 Day 1, ) until the last dose (up to 2 years) ]
• Maximum (peak) plasma concentration (Cmax) [ Time Frame: From first dose (Cycle 1 Day 1, ) until the last dose (up to 2 years) ]
• Time to maximum (peak) plasma concentration (Tmax) [ Time Frame: From first dose (Cycle 1 Day 1, ) until the last dose (up to 2 years) ]
• Trough plasma concentration (Ctrough) [ Time Frame: From first dose (Cycle 1 Day 1, ) until the last dose (up to 2 years) ]

Original Secondary Outcome Measures (submitted: November 20, 2020)

• Area under the time concentration curve (AUC) from time zero to infinity (AUC0-inf) [ Time Frame: From first dose (Cycle 1 Day 1, each cycle is 21 days) until the last dose (up to 2 years) ]
• Maximum (peak) plasma concentration (Cmax) [ Time Frame: From first dose (Cycle 1 Day 1, each cycle is 21 days) until the last dose (up to 2 years) ]
• Time to maximum (peak) plasma concentration (Tmax) [ Time Frame: From first dose (Cycle 1 Day 1, each cycle is 21 days) until the last dose (up to 2 years) ]
• Trough plasma concentration (Ctrough) [ Time Frame: From first dose (Cycle 1 Day 1, each cycle is 21 days) until the last dose (up to 2 years) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: ADG126, ADG126 in Combination With Anti PD1 Antibody, and ADG126 in Combination With ADG106 in Advanced/Metastatic Solid Tumors
• Official Title: A First-in-Human (FIH), Open-Label, Phase I Dose Escalation and Expansion Study of ADG126, ADG126 in Combination With Anti PD1 Antibody, and ADG126 in Combination With ADG106 in Patients With Advanced/Metastatic Solid Tumors
• Brief Summary: ADG126, ADG126 in Combination with anti-PD1 antibody, and ADG126 in Combination with ADG106 in Patients with Advanced/Metastatic Solid Tumors .
• Detailed Description: ADG126 is a novel anti-CTLA-4 fully human IgG1 antibody prodrug that is modified with Adagene Safebody technology to control the activation of anti-CTLA4 activity.ADG106 is a fully human ligand-blocking, agonistic anti-CD137 IgG4 mAb which is expected to enhance the activity of activated T cells. The enhanced antitumor efficacy results observed from the preclinical studies of ADG126 in combination with ADG106 or anti-PD-1 provided further support to explore such combinations in clinical settings for better patient responses.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Advanced/Metastatic Solid Tumors

Intervention

• Biological: ADG126 Mono
  ADG126 will be administered as an IV infusion over 60-90 minutes ± 15 minutes.
• Biological: ADG126-anti PD1
  Anti PD1 drug will be IV administered over 60-90 minutes beginning 15 to 30 minutes after the end of the ADG126 infusion.
• Biological: ADG126-ADG106
  ADG106 will be IV administered over 60-90 minutes beginning 15 to 30 minutes after the end of the ADG126 infusion.

Study Arms

• Experimental: ADG126 mono dose escalation
  ADG126 monotherapy dose escalation will be traditional 3+3 cohort design.
  Intervention: Biological: ADG126 Mono
• Experimental: ADG126 mono dose expansion
  Monotherapy dose expansion is designed to evaluate the preliminary antitumor activity of ADG126 at RP2D or the doses approved by the SRC.
  Intervention: Biological: ADG126 Mono
• Experimental: ADG126-anti PD1 drug dose escalation
  Combination therapy will commence at a dose level lower than the cleared dose from the monotherapy dose escalation arms and approved by the SRC.
  Intervention: Biological: ADG126-anti PD1
• Experimental: ADG126-anti PD1 drug dose expansion
  Combination therapy expansion will commence at RP2D or the dose approved by the SRC.
  Intervention: Biological: ADG126-anti PD1
• Experimental: ADG126-ADG106 dose escalation
  Combination therapy will commence at a dose level lower than the cleared dose from the monotherapy dose escalation arms and approved by the SRC.
  Intervention: Biological: ADG126-ADG106
• Experimental: ADG126-ADG106 dose expansion
  Combination therapy expansion will commence at RP2D or the dose approved by the SRC.
  Intervention: Biological: ADG126-ADG106

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 24, 2022): 146
• Original Estimated Enrollment (submitted: November 20, 2020): 100
• Estimated Study Completion Date: December 31, 2024
• Estimated Primary Completion Date: March 31, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Adults ≥18 years of age
2. ECOG performance status ≤1
3. Estimated life expectancy of more than 12 weeks
4. Patients with advanced or metastatic solid tumors, confirmed by histologically or pathologically documented (except patients with HCC, please see below for HCC requirement), who have progressed after all standard therapies, or for whom no further standard therapy exists. Patients who have declined standard therapy or have no access to standard therapy may be enrolled and the reasons for lack of access need to be documented
5. At least one measurable lesion at baseline per RECIST version 1.1

6. Adequate organ function as defined by the following criteria:

   1. ANC ≥1000 cells/μL
   2. Platelet count ≥100,000/μL
   3. Hemoglobin ≥9.0 g/dL
   4. Serum AST and serum ALT, ≤3.0 x ULN (≤5 x ULN for patients with liver metastases).
   5. Total serum bilirubin ≤1.5 x ULN (the following may be an exception - patients with unconjugated hyperbilirubinemia due to underlying Gilbert's Syndrome or familial benign unconjugated hyperbilirubinemia)
   6. Serum creatinine ≤2 x ULN or creatinine clearance of ≥45 mL/min.
7. INR and activated partial thromboplastin time (aPTT) ≤1.5 x ULN; patients on full-dose oral anticoagulation must be on a stable dose (minimum duration 14 days); if receiving warfarin, the patient must have an INR ≤3.0 and no active bleeding (i.e., no bleeding within 14 days prior to first dose of study drug); patients on low molecular weight heparin will be allowed.
8. Willing to complete all scheduled visits and assessments at the institution administering therapy
9. Able to read, understand and provide written informed consent

Exclusion Criteria:

1. Treatment with any local or systemic antineoplastic therapy (including chemotherapy, hormonal therapy, radiation, or immunotherapy, etc.) within 4 weeks prior to first dose of study drug(s), with the following exceptions:

   1. Hormonal therapy with gonadotropin-releasing hormone (GnRH) agonists or antagonists for prostate cancer
   2. Hormone replacement therapy or oral contraceptives
   3. Palliative radiotherapy for bone metastases or other non-target lesions ≥2 weeks prior to first dose of study drug(s)
2. Major trauma or major surgery within 4 weeks prior to first dose of study drug(s)
3. AEs from prior anticancer therapy that have not resolved to Grade ≤1 (except for alopecia) or irAE of immunotherapy resulting in permanent discontinuation, prior Grade 2 pneumonitis or any life-threatening Grade 4 irAE from prior anticancer therapy
4. Central nervous system disease involvement (but allow patients with prior brain metastases treated at least 4 weeks prior to the first dose of study drug(s)that are clinically stable and do not require chronic corticosteroid treatment to be enrolled in the study), or prior history of NCI CTCAE Grade ≥3 drug-related CNS toxicity .
5. Any evidence of underlying liver decompensation due to other causes, such as history of significant alcohol abuse, alcoholic or drug-induced hepatitis, or documented F4 non alcoholic steatohepatitis.
6. Prior organ allograft transplantations or allogeneic peripheral blood stem cell (PBSC)/bone marrow (BM) transplantation

7. Clinically significant cardiac disease, such as:

   1. New York Heart Association Class III IV cardiac disease, including pre-existing clinically significant ventricular arrhythmia, congestive heart failure or cardiomyopathy
   2. Unstable angina pectoris ≤6 months prior to Cycle 1 Day 1
   3. Acute myocardial infarction ≤6 months prior to Cycle 1 Day 1
   4. Other clinically significant heart disease (eg, Grade ≥3 uncontrolled hypertension or history of poor compliance with an antihypertensive regimen)
   5. Clinically significant valvular disease, cardiomegaly, ventricular hypertrophy, or cardiomyopathy
   6. Significant ECG abnormalities including QTc interval >470 msec, 2nd degree (type II) or 3rd degree atrioventricular (AV) block
8. Evidence of active uncontrolled viral, bacterial, or systemic fungal infection defined as requiring use of systemic antimicrobials within 2 weeks of Cycle 1 Day 1; prophylactic therapy according to institutional protocols is acceptable

9. Patients who received:

   1. A COVID-19 vaccine within 7 days of Cycle 1 Day 1.
   2. Live vaccines or live-attenuated vaccines within 28 days prior Cycle 1 Day 1.
10. Known positive test result for human immunodeficiency virus (HIV) (unless the disease is clinically controlled) or acquired immune deficiency syndrome (AIDS)
11. Patients who have immunosuppressive medications or immunosuppressive doses of systemic corticosteroids (>10 mg/day prednisone or equivalent) within 28 days prior to Cycle 1 Day 1.However, patients who received a short course of corticosteroids (eg, premedication prior to a contrast computed tomography [CT]) will be eligible for study entry

12. Infection of hepatitis B virus (HBV), or hepatitis C virus (HCV), except for the following:

    1. The diseases are clinically controlled
    2. Patients with anti-hepatitis B core antibody but with undetectable HBV DNA and negative for surface antigen of HBV
    3. Patients with resolved or treated HCV (i.e., HCV antibody positive but undetectable HCV RNA) in the study
13. Second primary malignancy not in remission for greater than 3 years; exceptions that do not require a 3-year remission include: non-melanoma skin cancer, cervical carcinoma in situ on biopsy or squamous intraepithelial lesion on Papanicolaou (PAP) smear, localized prostate cancer (Gleason score <6), or resected melanoma in situ; other localized, solid tumors in situ or other low risk cancers may also be exempt after discussion with the Sponsor medical monitor
14. History (within the last 5 years) or risk of autoimmune disease (eg, autoimmune thyroid disease, Bell's palsy, glomerulonephritis, Guillain-Barré syndrome, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, Sjögren's syndrome, systemic lupus erythematosus, vascular thrombosis associated with antiphospholipid syndrome, vasculitis, or Wegener's granulomatosis)
15. Any serious underlying medical (eg, pulmonary, renal, hepatic, gastrointestinal, or neurological) or psychiatric condition (eg, alcohol or drug abuse, dementia or altered mental status) or any issue that would limit compliance with study requirements, impair the ability of the patient to understand informed consent, or that in the opinion of the investigator would contraindicate the patient's participation in the study or confound the results of the study
16. Known hypersensitivity, allergies, or intolerance to immunoglobulins or to any excipient contained in ADG126, ADG106 and toripalimab (see Investigator's Brochure and Toripalimab Product Insert)
17. Pregnant, lactating, or breastfeeding females
18. Females of childbearing potential who either have a positive pregnancy test before enrollment or who do not agree to use 2 highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom; intrauterine device and condom; diaphragm with spermicidal gel and condom) during the trial and for 90 days after the last dose of the study drug
19. Male patients (with female pregnant or lactating partners or of childbearing potential) who do not agree to using one form of highly effective contraception [condom plus spermicide] during the trial and for 90 days after the last dose of the study drug
20. Participation or plans to participate in another interventional clinical study while taking part in this protocol.
21. Has received a positive COVID-19 test result within 14 days of Cycle 1 Day 1

Sex/Gender

• Sexes Eligible for Study: All

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

Contacts

Contact: Xiaohong She; 4088389296; kristine_she@adagene.com

• Listed Location Countries: Australia, United States

Administrative Information

• NCT Number: NCT04645069
• Other Study ID Numbers: ADG126-1001
• 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
• Current Responsible Party: Adagene Inc
• Original Responsible Party: Same as current
• Current Study Sponsor: Adagene Inc
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Paul De Souza, Professor; Southside Hospital
• Principal Investigator: Gary Richardson, Professor; Cabrini Private Hospital
• Principal Investigator: Michelle Morris, Professor; Sunshine Coast University Private Hospital
• Principal Investigator: Anthony Tolcher, Professor; Next oncology

• PRS Account: Adagene Inc
• Verification Date: May 2022