A First-In-Human Phase I Study of sEphB4-HSA in Patients With Advanced Solid Tumors With Expansion at the Maximum Tolerated Dose (MTD) or Recommended Phase II Dose (RP2D).
18 Years
N/A
Both
Unspecified Adult Solid Tumor, Protocol Specific
Trial Information
A First-In-Human Phase I Study of sEphB4-HSA in Patients With Advanced Solid Tumors With Expansion at the Maximum Tolerated Dose (MTD) or Recommended Phase II Dose (RP2D).
PRIMARY OBJECTIVES:
I. To establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of
sEphB4-HSA.
II. To describe the dose limiting toxicities and adverse event profile of sEphB4-HSA in
patients with advanced solid tumors.
III. To describe the pharmacokinetics of sEphB4-HSA. IV. To describe the anti-tumor activity
of sEphB4-HSA as manifested by responses to treatment.
V. To obtain preliminary evaluation of effect of sEphB4-HSA on absolute circulating tumor
cell (CTC) numbers as compared with pre-treatment levels using pre- and during treatment
CTC. Exploratory evaluation of effect of sEphB4-HSA on downstream protein mediators of the
Ephrin pathway (pAKT, pSrc) and their transcriptional target genes (rgs5 and psenen) will be
performed.
VI. To collect pilot information to identify a dose or doses with biologic activity.
Biologic activity after treatment with sEphB4-HSA will be defined as evidence of
drug-on-target effect as manifested by reduction in absolute CTC numbers. Other exploratory
evaluations of drug-on-target effect such as increase in transcript levels of psenen or rgs5
may be considered in the assessment of biologic activity.
OUTLINE: This is a dose-escalation study. Patients will be assigned to receive recombinant
EphB4-HSA fusion protein intravenously (IV) over 60 minutes in one of the following
treatment schedules:
1. Weekly treatment - administered on days 1, 8, 15, and 22. Courses repeat every 28 days
in the absence of disease progression or unacceptable toxicity.
2. Every 2 weeks treatment - administered on days 1 and 15. Courses repeat every 28 days
in the absence of disease progression or unacceptable toxicity.
3. Every 3 weeks treatment - administered on day 1. Courses repeat every 21 days in the
absence of disease progression or unacceptable toxicity.
Inclusion Criteria:
- Patient must have an advanced (metastatic or recurrent) pathologically proven solid
tumor which has not responded to standard therapy or which has progressed following
standard therapy for advanced disease and/or for which no standard therapy is known
to be effective
- Patient must agree, as part of the informed consent, to provide blood and tumor
samples for molecular correlates, pharmacokinetics and pharmacodynamics; archival
tumor tissue is mandatory, patients without it are excluded
- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance score of
0-1
- Patients must have a life expectancy of at least 12 weeks
- Patients or their legal representatives must be able to comprehend and provide
written informed consent
- White blood count (WBC) >= 3,000/μl
- Absolute neutrophil count (ANC) >= 1,500/μl
- Platelet count >= 100,000/μl
- Serum creatinine =< 1.5 X upper limit of normal (ULN) for reference lab
- Creatinine Clearance of >= 60 (as calculated by Cockcroft-Gault formula
- Serum bilirubin =< 1.5 mg/dL
- Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels =<
3X the ULN for the reference lab (=< 5X the ULN if there is evidence of hepatic
involvement by malignant disease)
- Patients must be recovered to grade 1 from the effects (excluding alopecia) of any
prior therapy for their malignancies
- Women of childbearing potential (WOCBP) and male patients with WOCBP partner must be
using an adequate method of contraception to avoid pregnancy throughout the study and
for up to 12 weeks after the last dose of investigational product in such a manner
that the risk of pregnancy is minimized
- WOCBP must have a negative serum test (minimum sensitivity 25 IU/L or equivalent
units of human chorionic gonadotropin [HCG]) within 72 hours prior to the start of
investigational product
- Patients enrolled into the expansion cohort must have accessible tumor for biopsy,
and must agree to having 2 biopsies done for fresh frozen tissue collection
Exclusion Criteria:
- Undergoing or have undergone in the past 4 weeks (28 days) any other therapy for
their cancer, including radiation therapy and adjuvant therapy
- Have a major systemic infection requiring antibiotics 72 hours or less prior to the
first dose of study drug
- Have untreated central nervous system (CNS) metastases; 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
- Have active hepatitis B or C
- 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 sEphB4HSA or
places the patient at undue risk for treatment related complications
- 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
- Pregnant or lactating
- On any dose of warfarin or are on full dose anticoagulation with other agents,
including low molecular weight heparin, antithrombin agents, antiplatelet 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
- Had any active bleeding in the last =< 4 weeks or have an otherwise known bleeding
diathesis
Type of Study:
Interventional
Study Design:
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Toxicities observed at each dose level utilizing the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0
Outcome Description:
Summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by CTCAE and nadir or maximum values for the laboratory measures), time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize toxicities and side effects by dose and by course.
Outcome Time Frame:
At least 4 weeks after the start of the first course
Safety Issue:
Yes
Principal Investigator
Anthony El-Khoueiry
Investigator Role:
Principal Investigator
Investigator Affiliation:
USC/Norris Comprehensive Cancer Center
Authority:
United States: Food and Drug Administration
Study ID:
0C-11-3
NCT ID:
NCT01642342
Start Date:
September 2012
Completion Date:
September 2015
Related Keywords:
- Unspecified Adult Solid Tumor, Protocol Specific
- Neoplasms
Name | Location |
|---|---|
| USC Norris Comprehensive Cancer Center | Los Angeles, California 90089 |
