Clinical Trials /

A Study to Evaluate the Safety, Tolerability of DN1508052-01 in Advanced Solid Tumors

NCT03934359

Description:

This is a phase I, open-label, multicenter study in adult patients with advanced solid tumors that have progressed despite standard therapy or for which no standard therapy exists. DN1508052-01 will be administered subcutaneously on Day 1, Day 8 and Day 15 in 28-day cycles. Other dose regimens may be explored based on the analysis of emerging PK, pharmacodynamics (PD) and safety data. This study is designed to determine the MTD, RP2D and investigate the safety, tolerability, PK, biomarkers, HPV status and ISR in DN1508052-01-treated patients.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study to Evaluate the Safety, Tolerability of DN1508052-01 to Advanced Solid Tumors
  • Official Title: A Phase Ⅰ, Multi-Center, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antitumor Activity of DN1508052-01 as a Single Agent When Administered Subcutaneously to Adult Patients With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: DN1508052-01-101
  • NCT ID: NCT03934359

Conditions

  • Advanced Solid Tumors

Interventions

DrugSynonymsArms
DN1508052-01

Purpose

This is a phase I, open-label, multicenter study in adult patients with advanced solid tumors that have progressed despite standard therapy or for which no standard therapy exists. DN1508052-01 will be administered subcutaneously on Day 1, Day 8 and Day 15 in 28-day cycles. Other dose regimens may be explored based on the analysis of emerging PK, pharmacodynamics (PD) and safety data. This study is designed to determine the MTD, RP2D and investigate the safety, tolerability, PK, biomarkers, HPV status and ISR in DN1508052-01-treated patients.

Detailed Description

      Study Population is adult patients (≥18 years) with histologically or cytologically
      confirmed, unresectable advanced solid tumors that have progressed despite standard therapy
      or for which no standard therapy exists.The selected starting dose, 0.01 mg/m2 of
      DN1508052-01, SC, on Day 1, Day 8 and Day 15 of each cycle.The starting dose will proceed
      with one patient. The next dose 0.1 mg/m2 will be explored if safety data permit in that
      there is no instance of a ≥ Common Terminology Criteria for Adverse Event (CTCAE v5.0) Grade
      2 AE that is at least possibly related to the study intervention.then Dose escalation will
      then proceed following the 3+3 cohorts design.Dose escalation will continue until MTD or RP2D
      is reached, or the dose escalation will be terminated at the discretion of Investigators and
      Sponsor (or its designee) based on the analyses of emerging PK, PD, safety and efficacy
      data.The Primary objective is to determine the maximum tolerated dose (MTD) and recommended
      phase Ⅱ dose (RP2D) and assess dose-limiting toxicity (DLT) of DN1508052-01 as a single agent
      when administered subcutaneously to adult patients with advanced solid tumors.
    

Trial Arms

NameTypeDescriptionInterventions

Eligibility Criteria

        Inclusion Criteria:

          1. Age 18 years or older;

          2. Patients with histologically or cytologically confirmed, unresectable advanced solid
             tumors that have progressed despite standard therapy or for which no standard therapy
             exists;

          3. Patients must have at least one measurable lesion as defined by RECIST v1.1;

          4. ECOG performance score 0 or 1;

          5. Life expectancy ≥ 3 months;

          6. Patients who have sufficient Baseline organ function and whose laboratory data meet
             the following criteria at enrollment:

               1. Absolute neutrophil count (ANC)≥1.5 × 109/L;

               2. Platelets ≥100 × 109/L;

               3. Hemoglobin ≥90g/dL;

               4. Liver function:

                  Serum bilirubin ≤1.5 × upper limit of normal (ULN) or ≤ 3×ULN in any subject with
                  Gilbert's Syndrome; Aspartate aminotransferase(AST) and alanine
                  aminotransferase(ALT) ≤2.5 × ULN without liver metastases, or ≤5 × ULN if the
                  patient has documented liver metastases;

               5. International normalization ratio ≤1.2 if the patient is not on anticoagulants,
                  or ≤3 if the patient is on anticoagulants;

               6. Serum creatinine ≤1.5 mg/dL, or estimated glomerular filtration rate (eGFR)≥60
                  mL/min/1.73 m2;

          7. Women of childbearing potential must have a negative serum pregnancy test prior to
             study entry, and agree to use adequate contraception from study entry through at least
             1 month after the last dose of study drug. A female patient of nonchildbearing
             potential will have had at least 12 continuous months of natural (spontaneous)
             amenorrhea, follicle stimulating hormone level ≥40 mIU/mL at Screening, and an
             appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms),
             or have had surgical bilateral oophorectomy, hysterectomy, or tubal ligation ≥6 weeks
             prior to Screening; in the case of oophorectomy alone, reproductive status will be
             confirmed by hormone level assessment;

          8. A male patient must agree to use adequate contraception (male condom with spermicide
             or provide evidence of successful vasectomy; sterile sexual partner; or female sexual
             partner who uses an intrauterine device with spermicide, a female condom with
             spermicide, a contraceptive sponge with spermicide, an intravaginal system, a double
             diaphragm with spermicide, a cervical cap with spermicide) from study entry through at
             least 1 month after the last dose of study drug;

          9. Patients must provide written informed consent prior to any study procedures.

        Exclusion Criteria:

          -  Disease

               1. Patients with symptomatic central nervous system (CNS) metastases or
                  carcinomatous meningitis; Note: Patients with treated CNS metastases may
                  participate in this trial if the patient has completed radiotherapy or surgery
                  for CNS metastases >2 weeks prior to study entry and if the patient is
                  neurologically stable ≥ 2 weeks (no new neurologic deficits from brain metastasis
                  on Screening clinical examination, no new findings on CNS imaging, and no
                  corticosteroids being used).

                  Medical Conditions

               2. Patients who have a history of another primary malignancy, with the exception of
                  locally excised non-melanoma skin cancer and carcinoma in situ of uterine cervix.
                  A patient who has had no evidence of disease from another primary cancer for 3 or
                  more years is allowed to participate in the study;

               3. Patients who have a known history of active hepatitis C or chronic hepatitis B
                  ("active hepatitis" defined as HCV RNA level ≥ 103 copies/mL for hepatitis C or
                  HBV DNA level ≥ 104 copies/mL for hepatitis B at Screening);

               4. Patients who have a known diagnosis of human immunodeficiency virus (HIV);

               5. Patients who have any severe and/or uncontrolled medical conditions or other
                  conditions that, in the opinion of the Investigator and Sponsor, could affect the
                  patient's participation in the study such as:

                    1. Uncontrolled diabetes mellitus, HbA1c≥8%;

                    2. Malignant illnesses that are uncontrolled or whose control may be
                       jeopardized by treatment with this study treatment;

                    3. Moderate or severe hepatic impairment, i.e., Child-Pugh class B or C (see
                       appendix 8.6);

                    4. Autoimmune disorders with systemic therapy;

               6. Patients who with an allo-transplant of any kind (including those with a
                  xenograft heart valve);

               7. Any significant ophthalmologic abnormality, including but not limited to the
                  following:

                    1. Grade 2 or greater severity syndrome of dry eye;

                    2. Keratoconjunctivitis sicca;

                    3. Sjogren's syndrome;

                    4. Iritis;

               8. Patients who have a history of definite neurological disorders that affected
                  brain function activity, including epilepsy or dementia;

               9. Active infections requiring antibiotic intravenous therapy at Screening;

              10. Pregnancy or lactation;

              11. Patients with any comorbid medical disorder that, in the opinion of the
                  Investigator or Sponsor, may increase the risk of toxicity; Organ Function and
                  Laboratory Values

              12. Patients who have impaired cardiac function or clinically significant cardiac
                  diseases, including any of the following:

                    1. Baseline QT interval corrected for heart rate using Fridericia's formula
                       >480 msec or congenital long QT syndrome;

                    2. Concomitant diseases that could prolong the QT interval, as assessed by the
                       Investigator, such as autonomic neuropathy (caused by diabetes or
                       Parkinson's disease), cirrhosis, uncontrolled hypothyroidism, or grade 3 or
                       greater severity electrolyte abnormality (CTCAE v5.0);

                    3. Concomitant medications known to prolong the QT interval;

                    4. History or presence of serious uncontrolled ventricular arrhythmias;

                    5. Left ventricular ejection fraction <50% assessed by echocardiogram;

                    6. Any of the following within 3 months prior to the first dose of study
                       medication: myocardial infarction, severe/unstable angina, coronary artery
                       bypass graft, congestive heart failure, cerebrovascular accident, or
                       transient ischemic attack;

                    7. Other clinically significant heart disease such as congestive heart failure
                       NYHA Class Ⅱ or greater severity and requiring heart transplant or
                       uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic
                       blood pressure > 100 mmHg, in spite of antihypertensive medication); Prior
                       Therapy

              13. Chemotherapy, biologic therapy, herbal therapy, radiotherapy or investigational
                  agents within 5 half lives or within 4 weeks (whichever is longer) prior to
                  administration of the first dose of study drug on Day 1 or have not recovered to
                  grade 1 or below from the side effects of such therapy (excluding cases of
                  alopecia);

              14. Patients received potent CYP3A4 inducer or inhibitor within 2 weeks prior to
                  administration of the first dose of study drug on Day 1.

              15. Patients received systemic corticosteroids within 2 weeks prior to administration
                  of the first dose of study drug on Day 1.

              16. Major surgery for any cause within 4 weeks of first dosing;

              17. Treated with immunomodulator (e.g., motolimod, GS9688, IMO4200, E-6742, E-6887,
                  etc).

              18. Patients who have a history of allergic reactions (significant urticaria,
                  angioedema, anaphylaxis) attributed to compounds of similar chemical or biologic
                  composition to DN1508052-01; Patients with scheduled surgeries or who are, in the
                  Investigator's opinion, likely to require surgery.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:the maximum tolerated dose (MTD)
Time Frame:28 days
Safety Issue:
Description:MTD is the highest dose of DN1508052-01 in subjects with DLT less than 33.3% during the DLT observation in the dose escalation

Secondary Outcome Measures

Measure:Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Time Frame:Up to 24 months
Safety Issue:
Description:Assessment of the cidence and severity of treatment-related AEs in who received at least 1 dose of in DN1508052-01
Measure:Time to peak (Tmax) of plasma concentration
Time Frame:Up to 2 months
Safety Issue:
Description:Pharmacokinetics profile of DN1508052-01 :Time to peak (Tmax) of plasma concentration
Measure:Maximum plasma concentration (Cmax)
Time Frame:Up to 2 months
Safety Issue:
Description:Pharmacokinetics profile of DN1508052-01 : Maximum plasma concentration (Cmax)
Measure:Halflife (T1/2)
Time Frame:Up to 2 months
Safety Issue:
Description:Pharmacokinetics profile of DN1508052-01 : Halflife (T1/2)
Measure:Clearance/ bioavailability (CL/F)
Time Frame:Up to 2 months
Safety Issue:
Description:Pharmacokinetics profile of DN1508052-01 : Clearance/ bioavailability (CL/F)
Measure:Area under curve (AUC)
Time Frame:Up to 2 months
Safety Issue:
Description:Pharmacokinetics profile of DN1508052-01 : Area under curve (AUC)
Measure:Efficacy Assessments
Time Frame:Up to 24 months
Safety Issue:
Description:Subjects will be assessed using RECIST v1.1. The primary aim is to demonstrate clinically meaning in ORR

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Shanghai De Novo Pharmatech Co., Ltd.

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