To evaluate the safety, tolerability, dose limiting toxicity (DLT), and maximum tolerated
dose (MTD), of FS102(BMS-986186) when administered intravenously (IV) to subjects with
relapsed or refractory solid tumors that overexpress HER2 and who have no standard treatment
options.
This is a Phase 1, open-label, multiple dose escalation study in subjects with solid tumors
that over express HER2.
Subjects with locally un-resectable and/or metastatic solid cancers that over express human
epidermal growth factor tyrosine kinase receptor 2 (HER2) by standard clinical pathology
criteria and who have no standard treatment options will be enrolled into a series of
escalating dose cohorts.
Within each dose cohort, subjects will receive weekly (± 1 day) or less frequent IV (Q3W)
infusions of FS102 during an initial 28-day (4-week) DLT observation period. During the DLT
observation period, subjects will be assessed for safety, tolerability, dose limiting
toxicity, PK, immunogenicity, and clinical disease response. Following assessment by the
Investigator, subjects without clinical disease progression and without unacceptable toxicity
will be eligible to continue receiving FS102 for up to six 21 (Q3W) to 28-day (weekly)
cycles.
Continuation Phase. Subjects who complete six 21-28-day cycles of treatment will be evaluated
for entry into an extended Continuation Phase of the study. Subjects will be eligible for
continuation if:
- They demonstrate no evidence of disease progression;
- In the opinion of the Investigator they are deemed reasonably likely to continue to
benefit from treatment; and
- They have not experienced any toxicity requiring discontinuation. During the
Continuation Phase, subjects will continue to receive FS102 at the same dose they were
originally assigned, unless modified downward for earlier toxicity. No dose escalation
within subjects will be permitted.
Treatment may continue until one of the following criteria applies:
- Disease progression;
- Intervening illness that prevents further administration of treatment;
- Unacceptable adverse events;
- Significant subject non-compliance with protocol;
- Pregnancy;
- Subject decides to withdraw from study;
- General or specific changes in the subject's condition that render the subject
unacceptable for further treatment in the judgment of the Investigator; or
- Sponsor decides to end the study.
For more information regarding BMS clinical trial participation, please visit
www.BMSStudyConnect.com
Inclusion Criteria:
1. Signed written informed consent obtained prior to performing any study procedure,
including screening procedures.
2. Men and women ≥ 18-years-old on the day of signing informed consent.
3. Subjects must have histologically or cytologically confirmed solid tumor malignancy
that is unresectable/locally advanced and/or metastatic and for which standard
curative or palliative measures are not available or are no longer effective (for all
subjects, histologic or cytologic proof of malignancy based on prior primary cancer
pathology is acceptable).
4. Subjects must have HER2-positive tumors and written clinical pathology report
documentation of HER2 status available for Sponsor's Medical Monitor review.
1. Assessment of HER2 status in subjects with breast cancer should follow the 2013
American Society of Clinical Oncology (ASCO)/College of American Pathologists
(CAP) criteria (Wolff et al, 2013) as practicable.
2. Assessment of HER2 status in subjects with gastric and gastroesophageal junction
adenocarcinoma should follow the criteria published by Rüschoff et al (2012) as
practicable.
3. Assessment of HER2 status in subjects with non-breast/non-gastric cancers may
follow local institutional criteria. These criteria should be made available to
the Sponsor.
4. All subjects with breast and gastric/gastroesophageal junction cancers should
have HER2 testing performed using an assay kit/methodology specifically
FDA-approved for their cancer type as practicable.
5. Subjects for whom the clinical pathology report includes only IHC as 3+ (does not
reflex to ISH) may enroll without a written report of ISH determined HER2 copy
number, provided the investigative site confirms that archival tissue is
available.
5. Subjects with breast cancer must have been treated with at least two FDA-approved
anti-HER2 directed therapies (more than two is also permissible), and subjects with
gastric and gastroesophageal junction cancers must have been treated with at least one
FDA-approved anti-HER2 directed therapy (more than one is also permissible); and all
subjects must have refractory or relapsed/progressive disease during or following
their last prior anti-HER2 directed therapy.
1. Subjects enrolling in the study who have non-breast, non-gastric,
non-gastroesophageal junction cancers do not require any prior treatment with
anti-HER2 therapy if there is no FDA-approved anti-HER2 agent for their specific
cancer type, but they must have refractory or relapsed/progressive disease during
or following their last prior anti-cancer therapy.
2. For all subjects, prior post-operative adjuvant administration of anti-HER2
therapy is permissible.
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 and estimated
life expectancy ≥ 3 months.
7. Any prior cumulative doxorubicin dose must be ≤ 360 mg/m2; prior cumulative epirubicin
dose must be ≤ 720 mg/m2.
8. Adequate organ function as defined below:
1. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5
upper limit of normal (ULN); if liver function abnormalities are due to the
underlying malignancy, then AST and ALT must be ≤ 5 ULN;
2. Total serum bilirubin ≤ ULN unless due to Gilbert's Syndrome;
3. Serum creatinine ≤ 1.25 x ULN; or if serum creatinine > 1.25 ULN, then calculated
(Cockcroft-Gault formula, glomerular filtration rate (GFR) ≥ 60 mL/min;
4. Hemoglobin ≥ 9.0 g/dL and not requiring > 1 unit red blood cell transfusion per
month; subjects receiving therapeutic erythropoietin preparations in accordance
with the FDA product label are eligible to enroll;
5. Absolute neutrophil count ≥ 1,500/mm3 (not supported by growth factors in the
preceding 21 days);
6. Platelet count ≥ 100,000/mm3 (without platelet transfusion or growth factor
support in the preceding 7 days);
7. Activated partial thromboplastin time (aPTT) ≤ 1.25 ULN and international
normalized ratio (INR) ≤ 1.3 (unless the subject is receiving therapeutic
anticoagulants);
8. Left ventricular ejection fraction (LVEF) determined by 2 dimensional
echocardiogram (2D Echo) or multi-gated acquisition scan (MUGA) ≥ 50% or ≥ local
institutional lower limit normal (LLN) whichever is higher.
9. Serum magnesium, calcium, and phosphorus must be within normal reference ranges
as per local tests. [If initial screening results are outside of normal reference
range, the Investigator may initiate appropriate measures to correct. However
administration of FS102 may not proceed until the specified electrolytes have
normalized.]
9. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of HCG) during screening for
eligibility assessments and enrollment and within 24 hours prior to the start of study
drug.
10. Women must not be breastfeeding
11. WOCBP must agree to follow instructions for method(s) of contraception for the
duration of treatment with study drug FS102 plus 30 days (duration of ovulatory cycle)
for a total of 30 days post-treatment completion.
12. Males who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception for the duration of treatment with study drug FS102 plus 90
days (duration of sperm turnover) for a total of 90 days post-treatment completion.
13. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt
from contraceptive requirements. However they must still undergo pregnancy testing as
described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on
the importance of pregnancy prevention and the implications of an unexpected pregnancy.
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on
the use of highly effective methods of contraception. Highly effective methods of
contraception have a failure rate of < 1% when used consistently and correctly.
At a minimum, subjects must agree to the use of two methods of contraception, with one
method being highly effective and the other method being either highly effective or less
effective as listed below.
Exclusion Criteria:
1. Primary brain or other central nervous system malignancy.
2. Any history of leptomeningeal metastasis.
3. Active brain metastasis or treatment for brain metastasis within 1 month of scheduled
dosing day 1.
a. Dose of corticosteroid, if any, for brain metastasis must be tolerated in terms of
glucose tolerance ≤ Grade 2 (symptomatic; dietary modification or oral agent
indicated) and hyperglycemia ≤ Grade 2 (fasting glucose value >160 - 250 mg/dL [> 8.9
- 13.9 mmol/L]).
4. History of second or other 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 primary solid tumor treated with curative intent and no known active
disease present and no treatment administered during the last 3 years.
5. Receipt of any investigational treatment within 4 weeks of scheduled dosing day 1.
6. Receipt of cytotoxic chemotherapy within 3 weeks (6 weeks for nitrosoureas and
mitomycin C) of scheduled dosing day 1.
7. Receipt of radiation therapy within 3 weeks of scheduled dosing day 1, unless the
radiation comprised a limited field to non-visceral structures (eg, a limb bone
metastasis).
8. Receipt of treatment with immunotherapy (including interferons, interleukins,
immunoconjugates), biological therapies (including monoclonal antibodies or other
engineered proteins), targeted small molecules (including but not limited to kinase
inhibitors), hormonal therapies (except for gonadotropin releasing hormone
agonists/antagonists for prostate cancer which may be continued while on study) within
3 weeks of scheduled dosing day 1.
9. Receipt of trastuzumab, pertuzumab, or ado-trastuzumab emtansine within 4 weeks of
scheduled dosing day 1.
10. Receipt of lapatinib within 7 days of scheduled dosing day 1.
11. Is concurrently enrolled in another therapeutic clinical trial involving ongoing
therapy with any investigational or marketed product or placebo.
12. Exclusionary concurrent medical conditions:
1. Hypertension which is not controlled to systolic < 160 mm Hg and diastolic < 90
mm Hg;
2. Myocardial infarction, unstable angina, coronary artery bypass graft, coronary
artery angioplasty or stent placement within 12 months before scheduled dosing
day 1;
3. History of congestive heart failure;
4. History of absolute decrease in LVEF of ≥ 16 absolute percentage points, or ≥ 10
absolute percentage points and crossing from > LLN to < LLN on prior anti-HER2
therapy, even if asymptomatic and the LVEF decrease recovered;
5. Abnormal 12-lead electrocardiogram (ECG) judged to be clinically significant by
the Investigator;
6. Hemorrhagic, embolic, or thrombotic stroke within 6 months of scheduled dosing
day 1;
7. Prior bone marrow or stem cell transplant;
8. Previously known infection with human immunodeficiency virus (HIV); or, hepatitis
B or C requiring treatment;
9. Any active infection requiring the use of parenteral anti-microbial agents or
that is > Grade 2;
10. Non-malignant interstitial lung disease;
11. Dyspnea of any cause requiring supplemental oxygen therapy;
12. Significant traumatic injury or major surgery (major surgery means opening of a
body cavity, eg, thoracotomy, laparotomy, laparoscopic organ resection, and major
orthopedic procedures, eg, joint replacement, open reduction and internal
fixation) within 21 days of scheduled dosing day 1;
13. Any other acute or chronic medical or psychiatric condition (including alcohol
and illicit substance abuse) or laboratory abnormality that could increase the
risk associated with study participation or could interfere with the
interpretation of the study results and, in the judgment of the Investigator or
Medical Monitor, would render the subject inappropriate for participation in the
study.
13. Has not recovered from the adverse effects of previous anti-cancer treatments to
pre-treatment baseline or Grade 1, except for alopecia, anemia (hemoglobin must meet
the present study inclusion criterion), and peripheral neuropathy (which must have
recovered to ≤ Grade 2).
14. Hypersensitivity/infusion reaction to monoclonal antibodies, other therapeutic
proteins, or allergy to any component/excipient of FS102 finished drug product
(arginine, glycine, phosphoric acid, or polysorbate 80) and the reaction could not be
controlled or prevented on subsequent infusion with standard therapies such as
anti-histamines, 5-HT3 antagonists, or corticosteroids.
15. Subjects who are pregnant or breast feeding.
16. Subjects who are unable or unwilling to comply with all study requirements for
clinical visits, examinations, tests, and procedures.
