PRIMARY OBJECTIVES:
I. To establish the maximum tolerated dose (MTD) and recommended phase II dosing (RP2D) of
intravesical sEphB4-HSA administration.
II. To describe the dose limiting toxicities and adverse event profile of intravesical
sEphB4-HSA administration in patients with bladder carcinoma in situ (CIS) and/or high grade
T1/Ta bladder cancer (BCa).
III. To describe the pharmacokinetics of intravesical sEphB4-HSA administration.
IV. To explore the anti-tumor activity of intravesical sEphB4-HSA administration as
manifested by responses to treatment.
OUTLINE: This is a dose-escalation study.
Participants receive sEphB4-HSA intravesically over 2 hours on days 1, 8, 15, 22, 29, and 36
in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, participants are followed up at 30 days, and again at 3
and 6 months.
Inclusion Criteria:
- Patients with bladder CIS, or completely resected high grade Ta/T1 lesions that are
BCG unresponsive; unresponsive is BCG refractory and/or BCG relapsing
- BCG refractory: persistent high-grade disease at 6 months despite receiving at
least 5-6 induction instillations and at least one maintenance (two of three
instillations) in a 6 month period
- BCG relapsing: recurrence of high-grade disease after achieving a disease-free
state at 6 months after receiving at least 5-6 induction instillations and at
least one maintenance (two of three instillations) in a 6 month period
- Eastern Cooperative Oncology Group performance status 0 to 2
- Written informed consent and Health Insurance Portability and Accountability Act
(HIPAA) authorization for release of personal health information
- NOTE: HIPAA authorization may be included in the informed consent or obtained
separately
- Females must not be breastfeeding
- Patients must be willing to undergo additional radiologic imaging while on study
- Leukocytes >= 3,000/mcL
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcl
- Total bilirubin =< 1.5 X institutional upper limit of normal
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal
- Creatinine =< 1.5 X institutional upper limit of normal
- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation, and for 90 days following completion of therapy;
should a woman become pregnant or suspect she is pregnant while participating in this
study, she should inform her treating physician immediately
- Female of child-bearing potential is any woman (regardless of sexual orientation,
having undergone a tubal ligation, or remaining celibate by choice) who meets the
following criteria:
- Has not undergone a hysterectomy or bilateral oophorectomy; or
- Has not been naturally postmenopausal for at least 12 consecutive months
(i.e., has had menses at any time in the preceding 12 consecutive months)
- Ability to understand and the willingness to sign a written informed consent
- Absence of concomitant upper tract urothelial carcinoma (i.e. cancer within the kidney
or ureter) as evidenced on computed tomography (CT) urogram and no visible lesion
and/or biopsy proven evidence of urothelial carcinoma within the prostatic urethra
(i.e. biopsy proven presence of cancer within the prostatic urethra)
- Patient has a desire to preserve organ, understanding the risks of delaying standard
of care
- Patient is ineligible, declines, or is considered ineligible to undergo radical
cystectomy
Exclusion Criteria:
- If they are undergoing or have undergone in the past 4 weeks (28 days) any other
therapy for their cancer, including radiation therapy and chemotherapy
- If they have a major systemic infection requiring antibiotics 72 hours or less prior
to the first dose of study drug
- If they have untreated central nervous system (CNS) metastasis; patients whose CNS
metastases have been treated by surgery or radiotherapy, who are no longer on
corticosteroids, and who are neurologically stable may be enrolled in the dose
escalation portion of the trial
- If they have New York Heart Association (NYHA) class 3 or 4; myocardial infarction,
acute coronary syndrome, diabetes mellitus with ketoacidosis or chronic obstructive
pulmonary disease (COPD) requiring hospitalization in the preceding 6 months; or any
other intercurrent medical condition that contraindicates treatment with sEphB4-HSA or
places the patient at undue risk for treatment related complications
- If they have any other condition, including mental illness or substance abuse, deemed
by the investigator to be likely to interfere with a patient?s ability to sign
informed consent, cooperate and participate in the study, or interferes with the
interpretation of the results
- If they are pregnant or lactating
- If they are on any dose of warfarin or are on full dose anticoagulation with other
agents, including low molecular weight heparin, antithrombin agents, anti-platelet
agents and full dose aspirin within 7 days prior to first dose of study drug; patients
on prophylactic doses of low-molecular weight heparin are allowed
- If they have had any active bleeding in the last =< 4 weeks or have an otherwise known
bleeding diathesis
- Patients may not be receiving any other investigational agents
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to agent(s) or other agents used in study
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements
- Patients must not be pregnant or nursing due to the potential for congenital
abnormalities and the potential of this regimen to harm nursing infants
- Evidence of a history of a stroke or myocardial infarction within the last 6 months
prior to study enrollment
- Previous intravesical immunotherapy less than 3 months before study entry; Note: if a
patient is eligible for the study but has had intravesical immunotherapy within the
past 3 months, they can enroll in the study and initiation of treatment of the drug
will be delayed until a minimum of 90 days has passed since the previous treatment
- Renal and hepatic function values exceeding 2 times the upper normal value
- Patients who cannot hold instillation for 2 hours
- Patients who cannot tolerate intravesical dosing or intravesical surgical manipulation
