A Phase 1b, open-label, dose escalation study of PRS-343 in combination with atezolizumab in
patients with HER2-positive advanced or metastatic solid tumors.
This is a multicenter, open-label Phase 1b study to determine the MTD and RP2D and to assess
the safety and efficacy of PRS-343 administered in combination with atezolizumab, a PD-L1
antibody, in previously treated advanced or metastatic HER-2 positive solid tumors (e.g.,
bladder, breast and gastrointestinal). The study will include a dose escalation period
followed by an expansion period. PRS-343 and atezolizumab will be given intravenously once
every three weeks (Q3W).
All available safety data, emerging PK, pharmacodynamic data, and dose limiting toxicities
(DLTs) will be considered in guiding the Safety Committee's decisions regarding subsequent
doses to be tested during the escalation phase of the study. Once the MTD and RP2D have been
established, an expansion cohort will be enrolled.
One treatment cycle is defined as 21 days (3 weeks).
Inclusion Criteria:
1. Signed written informed consent obtained prior to performing any study procedure,
including screening procedures.
2. Men and women ≥18 years.
3. Histologically or cytologically confirmed diagnosis of previously treated locally
advanced and/or metastatic HER2+ solid tumor malignancy considered likely to respond
to a HER2-targeted CD137 agonist (e.g. gastric/gastroesophageal/esophageal, breast,
bladder).
4. HER2+ status documented by clinical pathology report.
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.
6. Estimated life expectancy of at least 3 months.
7. Measurable disease according to RECIST v1.1.
8. Adequate organ function as defined below:
9. Serum AST and ALT ≤ 2.5 X ULN or ≤ 5 X ULN in the presence of liver metastases.
10. Total serum bilirubin ≤ 1.5 X ULN.
11. Serum creatinine ≤ 2 X ULN OR calculated glomerular filtration rate (GFR) by
Cockcroft-Gault formula ≥ 30 mL/min.
12. Hemoglobin ≥ 9 g/dL.
13. ANC ≥ 1500/mm3.
14. Platelet count ≥ 75,000/mm3.
15. Left ventricular ejection fraction (LVEF) determined by echocardiogram or multi-gated
acquisition scan ≥ 50%.
16. Any prior cumulative doxorubicin dose must be ≤ 360 mg/m2; prior cumulative epirubicin
dose must be ≤ 720 mg/m2.
17. Women of childbearing potential must have a negative serum or urine pregnancy test
within 96 hours prior to start of study treatment.
18. Women must not be breastfeeding.
19. Women of childbearing potential must agree to follow instruction for method(s) of
contraception for the duration of treatment with study drug PRS 343 and atezolizumab
plus 5 months post-treatment completion.
20. 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 treatment 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
virus (HBV) or hepatitis C virus (HCV) (unless patients are HBV DNA / HCV RNA
negative).
8. Any severe infection within 28 days prior to Cycle 1 Day 1, including but not limited
to hospitalization for complications of infection, bacteremia, or severe pneumonia or
active tuberculosis.
9. Administration of live, attenuated vaccines within 28 days before Cycle 1 Day 1 or
anticipated need of vaccination with live attenuated vaccine during the study.
10. Need for the treatment of bacterial infection with oral or intravenous (IV)
antibiotics within 14 days prior to Cycle 1 Day 1.
11. History of infusion reactions to any component/excipient of PRS-343.
12. History of infusion reactions to any component/excipient of atezolizumab.
13. History of severe hypersensitivity reactions to monoclonal antibodies (mAbs).
14. 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).
15. 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.
16. Prior organ transplantation including allogeneic or autologous stem-cell
transplantation.
17. 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) nausea and diarrhea if anti-emetic and anti-diarrheal treatment hasn't been
exhausted.
18. Concurrent or previous other malignancy within 5 years of study entry with the
exception of cured basal or squamous cell skin cancer, superficial bladder cancer,
prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other
noninvasive or indolent malignancy.
19. Receipt of investigational treatment within 3 weeks of scheduled Cycle 1 Day 1 (C1D1)
dosing.
20. Receipt of cytotoxic chemotherapy within 3 weeks (6 weeks for nitrosoureas and
mitomycin C) of scheduled C1D1 dosing.
21. Receipt of radiation therapy within 3 weeks of scheduled Day 1 dosing, unless the
radiation comprised a limited field to non-visceral structures (e.g., limb bone
metastasis).
22. Receipt of treatment with immunotherapy, biological therapies, hormonal therapies
within 3 weeks of scheduled C1D1 dosing.
23. Treatment with targeted small molecules within 5 half-lives of scheduled C1D1 dosing.
24. Receipt of trastuzumab or ado-trastuzumab emtansine or any other experimental drug
that engages the same epitope as trastuzumab within 4 weeks of scheduled C1D1 dosing.
25. Receipt of atezolizumab or any other experimental drug that engages the same epitope
as atezolizumab within 4 weeks of scheduled C1D1 dosing.
26. Concurrent enrollment in another therapeutic clinical trial.
27. Major surgery within 3 weeks of scheduled C1D1 dosing.
