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.
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
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,
4. Dose escalation and expansion cohort: HER2+ tumors documented by clinical pathology
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
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
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
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
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.
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
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
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)
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
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
18. Concurrent enrollment in another therapeutic clinical trial.
19. Major surgery within 3 weeks of scheduled C1D1 dosing.