Clinical Trials /

A Phase I Open-label Study for Subjects With Advanced Malignancies

NCT04136834

Description:

This is a first-in-human (FIH) Phase 1 dose escalation study to evaluate the safety, tolerability, PK, PD, and preliminary activity of PT01 administered IV in subjects with advanced malignancies.`

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Phase I Open-label Study for Subjects With Advanced Malignancies
  • Official Title: A Phase I Open-label Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Activity o f Ascending Doses of PT0I (Pegtomarginase) in Subjects With Advanced Malignancies

Clinical Trial IDs

  • ORG STUDY ID: ATX-PT01-001
  • NCT ID: NCT04136834

Conditions

  • Advanced Solid Malignancies

Interventions

DrugSynonymsArms
PT01 (Pegtomarginase)Pegtomarginase (PT01)

Purpose

This is a first-in-human (FIH) Phase 1 dose escalation study to evaluate the safety, tolerability, PK, PD, and preliminary activity of PT01 administered IV in subjects with advanced malignancies.`

Detailed Description

      The study consists of a Dose Escalation Phase and a Dose Expansion Phase, both of which
      include a 28-day Screening Period, Baseline, a Treatment Period (comprised of 28-day cycles
      with weekly dosing on Days 1, 8, 15, and 22), and a Follow-up Period. Unique to the Dose
      Escalation Phase is the inclusion of Cycle 0 during which a single dose of PT01 will be
      administered before Cycle 1 for detailed exploration of the PK/PD relationship.

      All PT01 IV doses will be administered at the clinical site.
    

Trial Arms

NameTypeDescriptionInterventions
Pegtomarginase (PT01)ExperimentalTo determine the MTD of PT01 based on the toxicity observed during Cycle 1 of the Dose Escalation Phase and to investigate the safety and tolerability of PT01 when administered intravenously(IV) to subjects with advanced malignancies
  • PT01 (Pegtomarginase)

Eligibility Criteria

        Inclusion Criteria:

        Eligible subjects must have/be:

          1. Able to understand and voluntarily sign an informed consent form (ICF)

          2. Male and female adults ≥18 years of age at the time of informed consent

          3. Advanced solid malignancies for which no standard therapy is available. Subjects in
             whom available standard therapy is contraindicated may be eligible.

          4. For Dose Expansion Phase:

             • Expansion Group A: Histologically confirmed unresectable locally advanced or
             metastatic (AJCC stage IIIB, IIIC, or IV) cutaneous malignant melanoma for which no
             standard therapy is suitable.

          5. At least 1 measurable site of disease as defined per RECIST v1.1 criteria (Dose
             Expansion Phase) or evaluable disease (Dose Escalation Phase only)

          6. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1

          7. Life expectancy of >12 weeks

          8. Adequate hematologic status within 28 days prior to dosing as demonstrated by not
             requiring transfusion support or granulocyte-colony stimulating factor (G-CSF) to
             maintain:

               -  Absolute neutrophil count (ANC) ≥1.5 × 109/L

               -  Platelet count ≥100 × 109/L

               -  Hemoglobin ≥90 g/L

          9. Adequate liver function as demonstrated by:

               -  Serum bilirubin <2 × the upper limit of normal (ULN)

               -  Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤3 × ULN or ≤5 ×
                  ULN in subjects with liver metastases

               -  Gamma-glutamyl transferase ≤5 × ULN Athenex, Inc. Confidential Page 9 Final
                  v2.0_17 Jun 2019 Clinical Study Protocol_Amendment 01 ATX-PT01-001

               -  Alkaline phosphatase ≤3 × ULN or ≤5 × ULN if bone or liver metastasis is present

         10. Serum creatinine ≤1.5 × ULN or estimated creatinine clearance ≥50 mL/min according to
             the Cockcroft-Gault formula

         11. Prothrombin time(PT) (or International Normalized Ratio[INR]) and activated partial
             thromboplastin time (aPTT) ≤1.5 × ULN or within the intended therapeutic range within
             72 hours before the first dose of study drug in subjects receiving anticoagulant
             therapy

         12. Willing and able to comply with scheduled visits, treatment plan, and laboratory tests

         13. Absence of any other malignancy which has been active or treated within the past 3
             years, except for cervical intraepithelial neoplasia, and nonmelanoma skin cancers
             (basal cell and squamous cell carcinomas)

         14. Men who are sterile (including vasectomy confirmed by post vasectomy semen analysis)
             OR agree to use a condom with spermicide and to not donate sperm during the study and
             for at least 90 days following last dose of PT01

         15. Female subjects must be postmenopausal (>12 months without menses) or surgically
             sterile (ie,by hysterectomy and/or bilateral oophorectomy) or must be using highly
             effective contraception (ie, oral contraceptives, intrauterine device, double barrier
             method of condom and spermicide) and agree to continue use of contraception for 90
             days after their last dose of PT01

         16. Subjects who are of childbearing potential must have a negative serum pregnancy test
             at Screening and within 72 hours prior to the first dose

         17. Peripheral forearm veins suitable for venous access including cannulation for infusion
             of PT01 and multiple blood sampling

        Exclusion Criteria:

        Eligible subjects must not have/be:

          1. Received prior arginase or arginine deiminase therapy

          2. Received recent anticancer therapy defined by:

               -  Chemotherapy, immunotherapy, hormonal therapy, and monoclonal antibodies (but
                  excluding nitrosourea, mitomycin-C, targeted therapy) ≤28 days prior to starting
                  study drug or who have not recovered from side effects of such therapy to Grade≤1
                  (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events
                  [CTCAE] v4.03) except for subjects with alopecia; subjects receiving luteinizing
                  hormone-releasing hormone agonists may be considered for enrollment after
                  discussion with the Sponsor

               -  Last administration of nitrosourea or mitomycin-C ≤42 days prior to starting
                  study drug or who have not recovered from the side effects of such therapy to
                  Grade ≤1

               -  Targeted therapy (eg, sunitinib, sorafenib, pazopanib) ≤14 days prior to starting
                  study drug, or who have not recovered from the side effects of such therapy to
                  Grade ≤1

               -  Radiotherapy ≤28 days prior to starting study drug or ≤14 days prior to starting
                  study drug in the case of localized radiotherapy (eg, for analgesic purpose or
                  for lytic lesions at risk of fracture) or who have not recovered from
                  radiotherapy toxicities to Grade ≤1

          3. Undergone major surgery (eg, intrathoracic, intraabdominal, or intrapelvic), open
             biopsy, or significant traumatic injury ≤28 days prior to starting study treatment;
             subjects who have had minor procedures, percutaneous biopsies, or placement of
             vascular access device ≤7 days prior to starting study drug; or subjects who have not
             recovered from side effects of such procedure or injury

          4. Uncontrolled concurrent illness including, but not limited to, ongoing or active
             serious infection Athenex, Inc. Confidential Page 10 Final v2.0_17 Jun 2019 Clinical
             Study Protocol_Amendment 01 ATX-PT01-001 requiring systemic antimicrobials (within 14
             days prior to first dose), uncontrolled arterial hypertension (>160/100 mm Hg on
             antihypertensive medications), chronic pulmonary disease requiring oxygen, known
             bleeding disorders, uncontrolled endocrine diseases, altered mental status, or
             psychiatric illness/social situations that would limit compliance with protocol
             requirements

          5. Significant cardiac or pulmonary disease defined by New York Heart Association Class
             III or IV, history of myocardial infarction within 6 months prior starting study drug,
             significant unstable arrhythmia, or evidence of ischemia on ECG

          6. Symptomatic or uncontrolled brain metastases requiring current treatment (fewer than
             28 days from last cranial radiation or from last steroids use)

          7. Healing or open wound(s)

          8. Lack of recovery of prior AEs to Grade ≤1 severity (except alopecia or lymphopenia)
             due to medications administered prior to the first dose of study drug

          9. Any other condition or finding (including social situation) that, in the opinion of
             the Investigator, may render the subject to be either at excessive risk for treatment
             complications or not able to provide evaluable outcome information

         10. Pregnantorbreast-feedingwomen

         11. Known allergy to any of the formulation components of PT01
      
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), and/or recommended Phase 2 dose (RP2D) together with the biologically effective dose (BED) of PT01.
Time Frame:4 weeks
Safety Issue:
Description:Dose-limiting toxicity (DLT) for determination of MTD and/or RP2D. The grading of toxicity is based on the NCI CTCAE v4.03 criteria. Reduction and duration of arginine for determination of BED

Secondary Outcome Measures

Measure:Area Under Plasma Concentration-Time Curve (AUC)
Time Frame:Cycle 0 Day 1: predose PT01 (Hour 0) and at 0.5 (end of infusion), 2, 4, 8, 24, 48, 72, 168, and 240 hours after the start of the PT01 IV infusion. Cycle 1 and Beyond, prepose and .5 hour post dose.
Safety Issue:
Description:
Measure:Maximum Observed Plasma Concentration (Cmax) of PT01
Time Frame:Cycle 0 Day 1: predose PT01 (Hour 0) and at 0.5 (end of infusion), 2, 4, 8, 24, 48, 72, 168, and 240 hours after the start of the PT01 IV infusion. Cycle 1 and Beyond, prepose and .5 hour post infusion.
Safety Issue:
Description:
Measure:The preliminary activity of PT01 by evaluating tumor response.
Time Frame:8 weeks
Safety Issue:
Description:Tumor response according to RECIST v1.1 (best ORR for complete response [CR] and partial response [PR], stable disease, progressive disease), duration of response, PFS Tumor biomarkers in appropriate tumor types
Measure:The elimination half-life (t1/2) of PT01
Time Frame:Cycle 0 Day 1: predose PT01 (Hour 0) and at 0.5 (end of infusion), 2, 4, 8, 24, 48, 72, 168, and 240 hours after the start of the PT01 IV infusion. Cycle 1 and Beyond, prepose and .5 hour post infusion.
Safety Issue:
Description:
Measure:The amount of PT01present at the maximum concentration in plasma (Tmax)
Time Frame:Cycle 0 Day 1: predose PT01 (Hour 0) and at 0.5 (end of infusion), 2, 4, 8, 24, 48, 72, 168, and 240 hours after the start of the PT01 IV infusion. Cycle 1 and Beyond, prepose and .5 hour post infusion.
Safety Issue:
Description:
Measure:The time of last quantifiable presence of PT01 in plasma(Tlast)
Time Frame:Cycle 0 Day 1: predose PT01 (Hour 0) and at 0.5 (end of infusion), 2, 4, 8, 24, 48, 72, 168, and 240 hours after the start of the PT01 IV infusion. Cycle 1 and Beyond, prepose and .5 hour post infusion.
Safety Issue:
Description:
Measure:PT01 concentration at the end of a dosing interval, immediately before next administration (Ctrough), the lowest observed concentration.
Time Frame:Cycle 0 Day 1: predose PT01 (Hour 0) and at 0.5 (end of infusion), 2, 4, 8, 24, 48, 72, 168, and 240 hours after the start of the PT01 IV infusion. Cycle 1 and Beyond, prepose and .5 hour post infusion.
Safety Issue:
Description:
Measure:The volume of PT01 distribution (Vd) in plasma.
Time Frame:Cycle 0 Day 1: predose PT01 (Hour 0) and at 0.5 (end of infusion), 2, 4, 8, 24, 48, 72, 168, and 240 hours after the start of the PT01 IV infusion. Cycle 1 and Beyond, prepose and .5 hour post infusion.
Safety Issue:
Description:
Measure:The total clearance of the PT01 from plasma (CL)
Time Frame:Cycle 0 Day 1: predose PT01 (Hour 0) and at 0.5 (end of infusion), 2, 4, 8, 24, 48, 72, 168, and 240 hours after the start of the PT01 IV infusion. Cycle 1 and Beyond, prepose and .5 hour post infusion
Safety Issue:
Description:
Measure:Duration of arginine reduction <10% of baseline.
Time Frame:Cycle 0 Day 1: predose PT01 (Hour 0) and at 0.5 (end of infusion), 2, 4, 8, 24, 48, 72, 168, and 240 hours after the start of the PT01 IV infusion. Cycle 1 and Beyond, prepose and .5 hour post infusion.
Safety Issue:
Description:
Measure:The absolute-percent of arginine reduction from baseline
Time Frame:Cycle 0 Day 1: predose PT01 (Hour 0) and at 0.5 (end of infusion), 2, 4, 8, 24, 48, 72, 168, and 240 hours after the start of the PT01 IV infusion. Cycle 1 and Beyond, prepose and .5 hour post infusion
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Athenex, Inc.

Last Updated

October 21, 2019