A Phase I, Open Label, Dose Escalation Study of the Safety, Tolerability and Pharmacokinetic Properties of the Combination of Cilengitide and Paclitaxel in Patients With Advanced Solid Malignancies
Overview
- Phase
- Phase 1
- Status
- Completed
- Enrollment
- 13
- Locations
- 3
- Primary Endpoint
- Change in Cyr61 expression levels (Cohort II)
Overview
Brief Summary
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.
Detailed Description
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 Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Histologic proof of cancer that is now unresectable (solid tumors, excluding lymphoma)
- •For Cohort II only:
- •Histologic adenocarcinoma of the breast with manifestations of metastatic cancer or locally advanced, unresectable cancer
- •Estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2) receptor negative disease per local standards
- •Refractory to taxanes which is defined as one of the following:
- •Having relapsed during or within 12 months of completing adjuvant paclitaxel or docetaxel
- •Disease progression while on any taxane in the locally advanced, unresectable or metastatic breast cancer setting
- •Ability and willingness to undergo biopsy for biomarker testing prior to start of treatment
- •Disease must be measurable by imaging-based evaluation per Response Evaluation Criteria in Solid Tumors (RECIST) criteria (v1.1)
- •Up to 5 prior regimens of chemotherapy for metastatic disease are allowed
Exclusion Criteria
- •Known standard therapy for the patient's disease that is potentially curative or definitely capable of extending life expectancy
- •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
- •Any of the following prior therapies:
- •Chemotherapy =\< 21 days prior to registration
- •Mitomycin C/nitrosoureas =\< 42 days prior to registration
- •Immunotherapy =\< 14 days prior to registration
- •Biologic therapy =\< 14 days prior to registration
- •Prior investigational therapy =\< 28 days prior to registration
- •Full field radiation therapy =\< 28 days prior to registration or limited field radiation therapy \< 14 days prior to registration
- •Full field radiation encompasses the entire area of known disease involvement and surrounding uninvolved but at-risk areas, e.g. subtotal nodal (mantle and upper abdomen) or total nodal irradiation
Arms & Interventions
Treatment (cilengitide, paclitaxel)
Patients receive cilengitide 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.
Intervention: Cilengitide (Drug)
Treatment (cilengitide, paclitaxel)
Patients receive cilengitide 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.
Intervention: Laboratory Biomarker Analysis (Other)
Treatment (cilengitide, paclitaxel)
Patients receive cilengitide 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.
Intervention: Paclitaxel (Drug)
Treatment (cilengitide, paclitaxel)
Patients receive cilengitide 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.
Intervention: Pharmacological Study (Other)
Outcomes
Primary Outcomes
Change in Cyr61 expression levels (Cohort II)
Time Frame: Baseline to 21 days
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 until hematologic nadir for ANC
Time Frame: Up to 3 months
Time until hematologic nadir for WBC
Time Frame: Up to 3 months
Progression-free survival (PFS) (Cohort II)
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
Kaplan-Meier method will be used to estimate the distribution of PFS time.
Time to progression
Time Frame: Up to 3 months
Time until hematologic nadir for platelets
Time Frame: Up to 3 months
Incidence of grade 3+ adverse events, as graded using NCI CTCAE v 4.0
Time Frame: Up to 3 months
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.
Severity of all adverse events, graded according to NCI CTCAE v4.0
Time Frame: Up to 3 months
The severity of all adverse events (overall, by dose-level, and by tumor group) will be tabulated and summarized in this patient population.
Incidence of hematologic toxicity, including thrombocytopenia, neutropenia, and leukopenia, evaluated via the ordinal CTC
Time Frame: Up to 3 months
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.
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
Time Frame: Up to 3 months
The number of all adverse events (overall, by dose-level, and by tumor group) will be tabulated and summarized in this patient population.
Overall survival (OS) (Cohort II)
Time Frame: The time of registration to death due to any cause, assessed up to 3 months
Kaplan-Meier method will be used to estimate the distribution of OS time.
Response rate, defined as the proportion of patients whose tumor responds to treatment (Cohort II)
Time Frame: Up to 3 months
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 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
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
Time Frame: From start of the treatment until disease progression/recurrence, assessed up to 3 months
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).
Incidence of non-hematologic toxicity, evaluated via the ordinal Common Toxicity Criteria (CTC)
Time Frame: Up to 3 months
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 until any treatment related toxicity
Time Frame: Up to 3 months
Time until treatment related grade 3+ toxicity
Time Frame: Up to 3 months
Secondary Outcomes
- Incidence of toxicity, as assessed using PRO-CTCAE(Up to 3 months)