Clinical Trials /

Safety, Tolerability and Pharmacokinetics of an Anti-PD-1 Monoclonal Antibody in Subjects With Advanced Malignancies

NCT03474640

Description:

The primary objective is to assess the safety and tolerability of Toripalimab in subjects with various advanced malignancies and to evaluate the recommended Phase 2 dose. The secondary objectives are to: 1) describe the pharmacokinetic (PK) profile of Toripalimab, 2) evaluate antitumor activity of Toripalimab; 3) determine the immunogenicity of Toripalimab; 4) evaluate overall survival. The exploratory objectives are to: 1) evaluate biomarkers that may correlate with activity of Toripalimab, 2) evaluate pharmacodynamic effects of Toripalimab on its target receptor, programmed cell death 1 (PD-1), as well as effects on the immune system. 3) evaluate the utility of PD-L1 & additional exploratory markers as biomarkers that could aid in selection of appropriate subjects for TAB001 therapy, and 4) identification of additional biomarkers correlating with response to treatment with TAB001.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Safety, Tolerability and Pharmacokinetics of an Anti-PD-1 Monoclonal Antibody in Subjects With Advanced Malignancies
  • Official Title: A Phase 1, Multicenter, Open-label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TAB001 in Subjects With Advanced Malignancies

Clinical Trial IDs

  • ORG STUDY ID: TAB001-01
  • NCT ID: NCT03474640

Conditions

  • Advanced Malignancies

Interventions

DrugSynonymsArms
TAB001, Recombinant Humanized anti-PD-1 Monoclonal AntibodyJS001TAB001 80 mg repeat dose every 14 days

Purpose

The primary objective is to assess the safety and tolerability of TAB001 in subjects with various advanced malignancies and to evaluate the recommended Phase 2 dose. The secondary objectives are to: 1) describe the pharmacokinetic (PK) profile of TAB001, 2) evaluate antitumor activity of TAB001; 3) determine the immunogenicity of TAB001 , and 4) evaluate pharmacodynamic effects of TAB001 on its target receptor, programmed cell death 1 (PD-1), as well as effects on the immune system. The exploratory objectives are to: 1) evaluate biomarkers that may correlate with activity of TAB001, 2) evaluate the utility of PD-L1 & additional exploratory markers as biomarkers that could aid in selection of appropriate subjects for TAB001 therapy, and 3) identification of additional biomarkers correlating with response to treatment with TAB001.

Detailed Description

      OVERVIEW: This is a Phase 1, multi-center, open-label, dose-escalation study of TAB001, a
      humanized monoclonal IgG4 antibody targeting the Programmed Death -1 (PD-1). It is estimated
      that up to 78 subjects with advanced malignancies will be enrolled in the study. Subjects
      must have an advanced solid malignancy that is refractory to standard therapy or for which no
      standard therapy exists.

      The study has 2 parts. In Part A, up to 18 subjects will be enrolled who have not received
      prior immunotherapy for their cancer. Three dose levels are planned and include: 80, 240 and
      480 mg/dose. Part A will be the traditional 3 + 3 design with 3 or 6 subjects per dose level
      (cohort) and will receive their assigned dose every 14 days in the absence of a dose limiting
      toxicity (DLT) that would prevent further dosing. Subjects will be assigned to a dose level
      in the order of study entry.

      If no DLTs occur in a cohort of 3 subjects, a new cohort of 3 subjects will be treated at the
      next higher dose level. If 1 of 3 subjects in a dose level experiences a DLT, that dose level
      will be expanded to 6 subjects. If only 1 of the 6 subjects has a DLT, then the next cohort
      of 3 subjects will be treated at the next higher dose level. If 2 or more DLTs occur within a
      cohort, then that dose level will be above the maximum tolerated dose (MTD), and the previous
      lower tolerated dose level will be considered the MTD.

      In Part B, up to 60 subjects will be enrolled. Solid tumors may include, but will not be
      limited to, esophageal and gastric carcinoma, nasopharyngeal carcinoma, endometrial cancer,
      soft tissue sarcoma, or other orphan tumors who have received at least one line of therapy in
      the metastatic setting. Subjects must not have received more than 3 prior lines of cytotoxic
      chemotherapy.

      Tumor response will be evaluated using the Response Evaluation Criteria in Solid Tumors
      (RECIST v1.1) and the immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).

      In the absence of confirmed disease progression and intolerable toxicities, subjects will be
      allowed to continue TAB001 administration every 14 days .

      DOSAGE AND ADMINISTRATION TAB001 doses are 80, 240 and 480 mg. TAB001 will be administered as
      a 60-minute i.v. infusion for the first 2 doses and may be decreased at the investigators
      discretion to 30 minutes in subsequent infusions.

      SAFETY EVALUATIONS Assessment of safety will be determined by vital sign measurements,
      clinical laboratory tests, Eastern Cooperative Oncology Group (ECOG) performance status
      evaluations, diagnostic imaging, physical examinations, electrocardiograms, and the incidence
      and severity of adverse events.

      Safety will also include evaluations of immune safety and immunogenicity. Particular
      attention will be given to adverse events that may follow enhanced T-cell activation such as
      dermatitis and colitis, uveitis, or other immune-related adverse events (irAEs).

      An irAE is a clinically significant adverse event of any organ that is associated with drug
      exposure, of unknown etiology, and is consistent with an immune-mediated mechanism.

      EFFICACY EVALUATIONS will include overall response, disease control, duration of response,
      and progression free survival .

      PHARMACOKINETIC EVALUATIONS Pharmacokinetic parameters include AUC, Cmax, CL, Vd and t½z.

      STATISTICAL METHODS The sample size for this study is not determined from power analysis. In
      Part A, it is based on the 3+3 design for dose escalation and safety evaluation requirements.

      Descriptive statistics will include: mean, standard deviation, median, and minimum and
      maximum values for continuous variables; frequencies and percentages for categorical
      variables.

      The efficacy parameters will be summarized using descriptive statistics. All safety and
      pharmacokinetic parameters will be summarized using descriptive statistics.
    

Trial Arms

NameTypeDescriptionInterventions
TAB001 80 mg repeat dose every 14 daysExperimental3-6 subjects
  • TAB001, Recombinant Humanized anti-PD-1 Monoclonal Antibody
TAB001 240 mg repeat dose every 14 daysExperimental3-6 subjects
  • TAB001, Recombinant Humanized anti-PD-1 Monoclonal Antibody
TAB001 480 mg repeat dose every 14 daysExperimental3-6 subjects
  • TAB001, Recombinant Humanized anti-PD-1 Monoclonal Antibody

Eligibility Criteria

        Inclusion Criteria:

          -  1. Willing to sign Informed Consent;

          -  2. Part A, must have a histologically or cytologically documented, incurable, or
             metastatic solid tumor that has progressed on, or been intolerant to, all standard
             systemic therapy options for the tumor type in the metastatic setting, or must have a
             tumor type for which no such standard systemic option exists;

          -  3. Part B, must have a histologically or cytologically documented diagnosis of
             esophageal or gastric carcinoma, nasopharyngeal carcinoma (NPC), endometrial cancer,
             soft tissue sarcoma, or other orphan tumor who have received at least one line of
             standard systemic therapy for their respective tumor type in the metastatic setting
             with progressive locally advanced or metastatic disease that is not amenable to
             definitive local therapy with curative intent;

               1. Subjects with NPC must have received, or been intolerant to, a platinum-based
                  combination as part of their prior therapy for advanced/metastatic disease;

               2. Subjects with soft tissue sarcoma must have radiographic evidence of progression
                  within the previous 3-4 months and must have received, or been intolerant to,
                  prior treatment with an anthracycline +/- olaratumab or ifosfamide;

               3. Patients with esophageal cancer must have received, or been intolerant to, a
                  platinum-based combination as part of their prior therapy for advanced/metastatic
                  disease;

               4. Patients with gastric cancer must have received, or been intolerant to, a
                  fluoropyrimidine-platinum combination as part of their prior therapy for
                  advanced/metastatic disease; Subjects in Part B must not have had more than 3
                  prior lines of cytotoxic chemotherapy;

          -  4. Measurable disease per RECIST v1.1 and irRECIST;

          -  5. ECOG performance status of 0 or 1;

          -  6. Adequate organ and marrow function;

          -  7. Willingness to provide consent for biopsy samples;

          -  8. For females of childbearing potential, use effective contraception from time of
             screening though 90 days post last dose of TAB001.

        Exclusion Criteria:

          -  1. Concurrent enrollment in another clinical study, unless it is an observational
             (non-interventional) clinical study or the follow-up period of an interventional
             study;

          -  2. Any concurrent chemotherapy, radiotherapy, immunotherapy, or biologic therapy for
             cancer treatment. Concurrent use of hormones for non-cancer related conditions is
             acceptable (e.g., insulin for diabetes & hormone replacement therapy). Local treatment
             of isolated lesions for palliative intent is acceptable;

          -  3. Receipt of any investigational anti-cancer therapy within 4 weeks prior to first
             dose of TAB001;

          -  4. Receipt of G-CSF, GM-CSF or erythropoietin within 28 days prior to study entry or
             receiving TAB001;

          -  5. Current use or prior use of immunosuppressive medication within 4 weeks prior to
             first dose of TAB001, with the exception of intranasal and inhaled corticosteroids or
             systemic corticosteroids not to exceed 10mg/day of prednisone or equivalent;

          -  6. Part A: Prior exposure to immunotherapy such as but not limited to other
             anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibodies excluding vaccines. Part B: Exclusion
             of prior immunotherapy exposure will be limited to anti-PD-1, anti-PD-L1, or
             anti-PD-L2;

          -  7. Prior allogeneic bone marrow transplantation or prior solid organ transplantation;

          -  8. Major surgery within 4 weeks prior to first dose of TAB001 or still recovering from
             prior surgery;

          -  9. Unresolved toxicities from prior anticancer therapy defined as having not resolved
             to baseline or to Grade 0 or 1, or to levels dictated in the inclusion/exclusion
             criteria with the exception of alopecia;

          -  10. Active or prior documented autoimmune disease within the past 2 years. Subjects
             with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment within
             the past 2 years are not excluded;

          -  11. Known history of tuberculosis;

          -  12. Known to be human immunodeficiency virus (HIV) positive, hepatitis B, or hepatitis
             C positive;

          -  13. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
             ulcerative colitis);

          -  14. History of primary immunodeficiency;

          -  15. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure according to NYHA Functional
             Classification ≥3, uncontrolled hypertension, unstable angina pectoris, cardiac
             arrhythmia, active peptic ulcer disease or gastritis, or psychiatric illness/social
             situations that would limit compliance with study requirements, substantially increase
             risk of incurring adverse events from TAB001, or compromise the ability of the subject
             to give written informed consent;

          -  16. Symptomatic or untreated central nervous system metastases requiring concurrent
             treatment, inclusive of but not limited to surgery, radiation, and/or corticosteroids.
             Subjects with previously treated brain metastases may participate provided they are
             clinically stable for at least 8 weeks prior to study entry, have no evidence of new
             or enlarging metastases, and are off steroids;

          -  17. Receipt of live attenuated vaccination within 30 days prior to study entry or
             within 30 days of receiving TAB001;

          -  18. Pregnancy or breastfeeding women.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame:Through Day 90 of last dose
Safety Issue:
Description:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Secondary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:Every 8 weeks through study completion, an average of 1 year
Safety Issue:
Description:The treatment effect of TAB001 will be assessed using RECIST 1.1 to determine objective response rate.
Measure:Disease Control Rate (DCR)
Time Frame:Every 8 weeks through study completion, an average of 1 year
Safety Issue:
Description:The treatment effect of TAB001 will be assessed using RECIST 1.1 to determine disease control rate.
Measure:Progression-Free survival (PFS)
Time Frame:Every 8 weeks through study completion, an average of 1 year
Safety Issue:
Description:The treatment effect of TAB001 will be assessed using RECIST 1.1 to determine progression-free survival time.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Shanghai Junshi Bioscience Co.,Ltd.

Trial Keywords

  • immunotherapy
  • check point inhibitor
  • PD-1 antibody
  • solid tumor
  • esophageal carcinoma
  • gastric carcinoma
  • nasopharyngeal carcinoma
  • endometrial cancer
  • soft tissue sarcoma
  • orphan tumors
  • phase 1 trial

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