This phase I trial studies the side effects and the best dose of cilengitide when given together with paclitaxel weekly in treating patients with solid tumors that have spread nearby or to other areas of the body and cannot be removed by surgery. Cilengitide may stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as paclitaxel, work in different ways to the stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving cilengitide together with paclitaxel may kill more tumor cells.
PRIMARY OBJECTIVES: I. To determine the maximally tolerated dose (MTD) of cilengitide and paclitaxel at weekly dose schedule. (Cohort I) II. To describe the toxicities associated with cilengitide and paclitaxel. III. To describe any antitumor activity of cilengitide and paclitaxel at weekly dose schedule. IV. To characterize pharmacokinetics (PK) of cilengitide and paclitaxel with the proposed schedule and correlate PK parameters to clinical outcome. (Cohort I) V. To examine the effect of cilengitide and paclitaxel on circulating cysteine-rich, angiogenic inducer, 61 (Cyr61) using a novel "sandwich enzyme-linked immunosorbent assay (ELISA)" and to correlate this effect with clinical response. (Cohort II) VI. To evaluate the information obtained through use of items from the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) in Phase I studies. VII. To determine if tumor tissue expression of alpha v beta 3 (αvβ3) and CYR61 correlate with therapeutic response to cilengitide with paclitaxel. (Cohort II) OUTLINE: This is a dose-escalation study of cilengitide. Patients receive cilengitide intravenously (IV) over 1 hour on days\* 1, 8, and 15 and paclitaxel IV over 1 hour on days 1, 8, and 15. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. NOTE: \*Some patients receive cilengitide IV over 1 hour on days 1, 2, 8, 9, 15, and 16. After completion of study treatment, patients are followed up for 3 months.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
13
Mayo Clinic in Arizona
Scottsdale, Arizona, United States
Mayo Clinic in Florida
Jacksonville, Florida, United States
Mayo Clinic
Rochester, Minnesota, United States
Best response, defined to be complete response (CR) or partial response (PR) as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population (overall and by tumor group).
Time frame: From start of the treatment until disease progression/recurrence, assessed up to 3 months
Change in Cyr61 expression levels (Cohort II)
At the end of each cycle, the percent change in serum Cyr61 expression from pre-treatment levels will be determined for each patient. For each patient, a times series plot of the percent change in serum Cyr61 expression from pre-treatment levels will be constructed and visually inspected for trends across time as well as for differences between those who respond to treatment (CR or PR by RECIST criteria) and those who do not.
Time frame: Baseline to up to 3 months
Change in Cyr61 expression levels (Cohort II)
A Wilcoxon rank sum test will be used to assess the percent change in Cyr61expression level after one cycle of treatment from pretreatment levels differs between those who progress within 120 days (within the first 6 cycles of treatment) and those who remain progression-free at least 120 days.
Time frame: Baseline to 21 days
Incidence of grade 3+ adverse events, as graded using NCI CTCAE v 4.0
The number and severity of grade 3+ adverse events (overall, by dose-level, and by tumor group) will be tabulated and summarized in this patient population.
Time frame: Up to 3 months
Incidence of hematologic toxicity, including thrombocytopenia, neutropenia, and leukopenia, evaluated via the ordinal CTC
Assessed using continuous variables as the outcome measures (primarily nadir) as well as categorization via CTC standard toxicity grading. Overall toxicity incidence as well as toxicity profiles by dose level, patient and tumor site will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.
Time frame: Up to 3 months
Incidence of non-hematologic toxicity, evaluated via the ordinal Common Toxicity Criteria (CTC)
Overall toxicity incidence as well as toxicity profiles by dose level, patient and tumor site will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.
Time frame: Up to 3 months
MTD of cilengitide and paclitaxel, defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least 1/3 of patients as graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0
Time frame: 3 weeks
Number of all adverse events, graded according to the NCI CTCAE v4.0
The number of all adverse events (overall, by dose-level, and by tumor group) will be tabulated and summarized in this patient population.
Time frame: Up to 3 months
Overall survival (OS) (Cohort II)
Kaplan-Meier method will be used to estimate the distribution of OS time.
Time frame: The time of registration to death due to any cause, assessed up to 3 months
Progression-free survival (PFS) (Cohort II)
Kaplan-Meier method will be used to estimate the distribution of PFS time.
Time frame: The time of registration to documentation of disease event where a disease event is local/regional/distant progression, contralateral breast disease, second primary disease or death due to any cause, assessed up to 3 months
Response rate, defined as the proportion of patients whose tumor responds to treatment (Cohort II)
Calculated as the number of eligible patients whose tumor meets the criteria for a CR or PR on two consecutive evaluations at least 6 weeks apart divided by the number of eligible patients with metastatic breast cancer refractory to taxanes who begin treatment. A 95% binomial confidence interval will be constructed for the true response rate.
Time frame: Up to 3 months
Severity of all adverse events, graded according to NCI CTCAE v4.0
The severity of all adverse events (overall, by dose-level, and by tumor group) will be tabulated and summarized in this patient population.
Time frame: Up to 3 months
Time to progression
Time frame: Up to 3 months
Time to treatment failure
Time frame: Time from registration to documentation of progression, unacceptable toxicity, or refusal to continue participation by the patient, assessed up to 3 months
Time until any treatment related toxicity
Time frame: Up to 3 months
Time until hematologic nadir for ANC
Time frame: Up to 3 months
Time until hematologic nadir for platelets
Time frame: Up to 3 months
Time until hematologic nadir for WBC
Time frame: Up to 3 months
Time until treatment related grade 3+ toxicity
Time frame: Up to 3 months
Incidence of toxicity, as assessed using PRO-CTCAE
The PRO-CTCAE will be summarized descriptively, and the dropout rate will be used for feasibility study. Informal comparison and correlation of the PRO-CTCAE symptoms with their corresponding items in clinician reported CTCAE will be conducted in an exploratory manner. Chi-squared tests will be used without adjustment for multiple comparisons.
Time frame: Up to 3 months
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