Clinical Trials /

PRS-343 in HER2-Positive Solid Tumors

NCT03330561

Description:

A multi center, open-label, Phase 1 dose escalation study with expansion cohort is designed to determine the MTD, RP2D and dosing schedule of PRS-343 in patients with HER2+ advanced or metastatic solid tumors.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: PRS-343 in HER2-Positive Solid Tumors
  • Official Title: A Phase 1, Open-Label, Dose Escalation Study of PRS-343 in Patients With HER2-Positive Advanced or Metastatic Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: PRS-343-PCS_04_16
  • NCT ID: NCT03330561

Conditions

  • HER2-positive Breast Cancer
  • HER2-positive Gastric Cancer
  • HER2-positive Bladder Cancer
  • HER2-positive Solid Tumor

Interventions

DrugSynonymsArms
PRS-343HER2/41BB BispecificPRS-343

Purpose

A multi center, open-label, Phase 1 dose escalation study with expansion cohort is designed to determine the MTD, RP2D and dosing schedule of PRS-343 in patients with HER2+ advanced or metastatic solid tumors.

Detailed Description

      The study will evaluate PRS-343 administered by intravenous (IV) infusion every 3 weeks
      (Schedule 1) initially. If safety, PK, and PD data suggest a different dosing schedule should
      be evaluated, Schedule 2 or 3 (dosing every 2 weeks or every 4 weeks in a 28-day cycle,
      respectively) may be conducted. Separate MTDs may be determined for each schedule evaluated.
      Dose-limiting toxicities (DLTs) will be reported during the first cycle of each schedule
      (e.g., 21 days after the first dose in Cycle 1 for Schedule 1). Patients will be monitored
      for safety throughout the study. Dosing will continue until criteria for study drug
      discontinuation are met (disease progression or withdrawal from the study).

      Patients with unknown HER2 status will be consented separately in a pre-screening visit in
      order to undergo HER2 testing prior to screening. All patients will be evaluated at screening
      (Day 28 to 1) and baseline (Day 1 predose).

      Once the MTD has been established, an expansion cohort of up to 30 additional patients with
      locally advanced or metastatic HER2+ solid tumors considered likely to respond to a HER2
      targeted CD137 agonist (e.g. gastric/gastroesophageal/esophageal, breast, bladder) may be
      enrolled. The expansion cohort will be enrolled at the MTD and/or at a lower dose level if
      safety/PD/PK/efficacy data support further evaluation of a lower dose level in order to
      determine the RP2D. The RP2D may be equivalent to or lower than the MTD.

      An End-of-Treatment Visit will be performed at the time of treatment discontinuation.
      Patients will be evaluated 30 days after the End-of-Treatment Visit or prior to starting
      subsequent therapy, if sooner, at the Safety Follow-up Visit to assess any ongoing AEs as
      outlined in the protocol.

      Patients will be assessed for tumor response/progression per RECIST v1.1
    

Trial Arms

NameTypeDescriptionInterventions
PRS-343Experimental
  • PRS-343

Eligibility Criteria

        Inclusion Criteria:

          1. Signed written informed consent obtained prior to performing any study procedure,
             including pre-screening and screening procedures.

          2. Men and women ≥18 years.

          3. Dose escalation: Histologically or cytologically confirmed diagnosis of
             unresectable/locally advanced and/or metastatic HER2+ solid tumor malignancy and for
             which standard therapies are not available, are no longer effective, are not
             tolerated, or have been declined by the patient.

             Expansion cohort: Locally advanced or metastatic HER2+ solid tumors considered likely
             to respond to a HER2-targeted CD137 agonist (e.g. gastric/gastroesophageal/esophageal,
             breast, bladder).

          4. Dose escalation and expansion cohort: HER2+ tumors documented by clinical pathology
             report:

               1. Assessment of HER2 status in patients with breast cancer should follow the 2013
                  American Society of Clinical Oncology (ASCO)/College of American Pathologists
                  (CAP) criteria (37) as practicable.

               2. Assessment of HER2 status in patients with gastric and gastroesophageal junction
                  adenocarcinoma should follow the criteria published by Ruschoff et al. (38) as
                  practicable.

               3. Assessment of HER2 status in patients with non-breast/non-gastric cancers may
                  follow local institutional criteria. These criteria should be made available to
                  the Sponsor.

               4. All patients with breast and gastric/gastroesophageal junction cancers should
                  have HER2 testing performed using a FDA approved test in a Clinical Laboratory
                  Improvement Amendments (CLIA)-certified laboratory.

               5. Patients for whom the clinical pathology report includes only IHC as 3+ (does not
                  reflex to ISH) may enroll without written report of ISH determined HER2 copy
                  number, provided the investigational site confirms that archival tissue is
                  available.

          5. Patients with breast cancer and gastric and gastroesophageal junction cancer must have
             received at least 1 prior HER2 targeted therapy for advanced/metastatic disease.

          6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.

          7. Estimated life expectancy of at least 3 months.

          8. Dose Escalation: Evaluable or measurable disease according to RECIST v1.1 Expansion
             Cohort (additional 30 patients) Measurable disease according to RECIST v1.1.

          9. Adequate organ function as defined below:

               1. Serum AST and ALT ≤ 3 X ULN

               2. Total serum bilirubin ≤ 1.5 X ULN

               3. Serum creatinine ≤ 1.5 X ULN OR calculated glomerular filtration rate (GFR) by
                  Cockcroft-Gault formula ≥ 50 mL/min

               4. Hemoglobin ≥ 9 g/dL

               5. ANC ≥ 1500/mm3

               6. Platelet count ≥ 75,000/mm3

               7. Left ventricular ejection fraction (LVEF) determined by echocardiogram or
                  multi-gated acquisition scan ≥ 50%

         10. Any prior cumulative doxorubicin dose must be ≤ 360 mg/m2; prior cumulative epirubicin
             dose must be ≤ 720 mg/m2.

         11. Women of childbearing potential must have a negative serum or urine pregnancy test
             within 96 hours prior to start of study drug.

         12. Women must not be breastfeeding.

         13. Women of childbearing potential must agree to follow instruction for method(s) of
             contraception for the duration of treatment with study drug PRS-343 plus 90 days
             post-treatment completion.

         14. Males who are sexually active with women of childbearing potential must agree to
             follow instructions for method(s) of contraception for the duration of treatment with
             study drug PRS 343 plus 90 days post-treatment completion.

        Exclusion criteria:

          1. Known uncontrolled central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Note: Patients with previously treated brain metastases may participate
             provided they are stable (without evidence of progression by imaging for at least 4
             weeks prior to the first dose of study treatment and any neurologic symptoms have
             returned to baseline), have no evidence of new or enlarging brain metastases, and are
             clinically stable off steroids for at least 7 days prior to study treatment.
             Carcinomatous meningitis precludes a patient from study participation regardless of
             clinical stability.

          2. History of acute coronary syndromes, including myocardial infarction, coronary artery
             bypass graft, unstable angina, coronary angioplasty or stenting within past 24 weeks.

          3. History of or current Class II, III or IV heart failure as defined by the New York
             Heart Association (NYHA) functional classification system (Appendix B).

          4. History of ejection fraction drop below the lower limit of normal with trastuzumab
             and/or pertuzumab.

          5. Medical, psychiatric, cognitive or other conditions that compromise the patient's
             ability to understand the patient information, to give informed consent, to comply
             with the study protocol or to complete the study.

          6. Any severe concurrent disease or condition (includes active infections, cardiac
             arrhythmia, interstitial lung disease) that in the judgment of the investigator would
             make study participation inappropriate for the patient.

          7. Previously known infection with human immunodeficiency virus (HIV); or hepatitis B or
             hepatitis C infection.

          8. History of infusion reactions to any component/excipient of PRS-343.

          9. Systemic steroid therapy (>10 mg daily prednisone or equivalent) or any other form of
             immunosuppressive therapy within 7 days prior to the first dose of study treatment
             (Note: topical, inhaled, nasal and ophthalmic steroids are not prohibited).

         10. Autoimmune disease that has required systemic treatment in the past (i.e., with use of
             disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement
             therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy
             for adrenal or pituitary insufficiency, etc.) is allowed.

         11. Has not recovered from the adverse effect of previous anticancer treatments to
             pre-treatment baseline or Grade 1 except for alopecia, anemia (hemoglobin must meet
             the study inclusion criteria) and peripheral neuropathy (which must have recovered to
             ≤ Grade 2).

         12. History of a second primary cancer with the exception of 1) curatively treated
             non-melanomatous skin cancer, 2) curatively treated cervical or breast carcinoma in
             situ, or 3) other malignancy with no known active disease present and no treatment
             administered during the last 2 years.

         13. Receipt of investigational treatment within 3 weeks of scheduled Cycle 1 Day 1 (C1D1)
             dosing.

         14. Receipt of cytotoxic chemotherapy within 3 weeks (6 weeks for nitrosoureas and
             mitomycin C) of scheduled C1D1 dosing.

         15. Receipt of radiation therapy within 3 weeks of scheduled C1D1 dosing, unless the
             radiation comprised a limited field to non-visceral structures (e.g., limb bone
             metastasis).

         16. Receipt of treatment with immunotherapy, biological therapies, targeted small
             molecules, hormonal therapies within 3 weeks of scheduled C1D1 dosing.

         17. Receipt of trastuzumab or ado-trastuzumab emtansine within 4 weeks of scheduled C1D1
             dosing.

         18. Concurrent enrollment in another therapeutic clinical trial.

         19. Major surgery within 3 weeks of scheduled C1D1 dosing.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence and severity of AEs graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4
Time Frame:Up to 36 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Peak Plasma Concentration (Cmax)
Time Frame:Up to 36 months
Safety Issue:
Description:
Measure:Area under the plasma concentration versus time curve (AUC)
Time Frame:Up to 36 months
Safety Issue:
Description:
Measure:Time to maximum dose concentration (Tmax)
Time Frame:Up to 36 months
Safety Issue:
Description:
Measure:Terminal half life (t1/2)
Time Frame:Up to 36 months
Safety Issue:
Description:
Measure:Tumor responses as defined by the Response Evaluation in Solid Tumors (RECIST) v.1.1
Time Frame:Up to 36 months
Safety Issue:
Description:
Measure:Duration of response
Time Frame:Up to 36 months
Safety Issue:
Description:
Measure:Disease control rate
Time Frame:Up to 36 months
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Pieris Pharmaceuticals, Inc.

Trial Keywords

  • HER2-positive breast cancer
  • HER2 -positive gastric cancer
  • HER2-positive bladder cancer
  • Pieris
  • PRS-343
  • Anticalin
  • Bi-specific
  • 4-1BB
  • CD137
  • HER2

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