Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Patients of Different Ages With Metastatic Breast Cancer

OBJECTIVES:

Primary

* To determine age-related changes in the pharmacokinetics (pK) of weekly paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel) in patients with metastatic breast cancer.
* To determine age-related changes in the pharmacodynamics (toxicity) of nab-paclitaxel in these patients.

Secondary

* To determine response and time to progression in these patients.
* To explore predictors of pK parameters in these patients.
* To explore predictors of the need for dose reduction, dose delays, or grade 3 or 4 toxicity in these patients.

OUTLINE: Patients are stratified by age in years (< 50 vs 50-60 vs 60-70 vs > 70).

Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes once daily on days 1, 8, and 15 as planned. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Blood is drawn for pharmacokinetic studies periodically during course 1.

Patients complete questionnaires regarding risk factors that would predict for pharmacokinetic parameters at baseline, prior to the third course of treatment, and at end of study. Data collected include medical characteristics, demographics, functional status, comorbidity, psychological status, social functioning and support, nutritional status, and cognition.

• paclitaxel albumin-stabilized nanoparticle formulation (Drug): 100 mg/m2 3 weeks on 1 week off
• pharmacological study (Other): Cycle 1, week 1 at 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 24 and 48 hours
• physiologic testing (Other): Prior to treatment, at the end of 2 cycles of therapy and upon completion of therapy
• questionnaire administration (Other): Prior to treatment, at the end of 2 cycles of therapy and upon completion of therapy
• study of socioeconomic and demographic variables (Other): Prior to treatment, at the end of 2 cycles of therapy and upon completion of therapy
• cognitive assessment (Procedure): Prior to treatment, at the end of 2 cycles of therapy and upon completion of therapy
• psychosocial assessment and care (Procedure): Prior to treatment, at the end of 2 cycles of therapy and upon completion of therapy

Primary outcomes

• Mean Area Under the Curve Over 24 Hours (AUC24) [Cycle 1, week 1 at 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours post treatment]: Mean of area under the curve over 24 hours (AUC24) reported as well as linear regression of AUC24 by age and chemotherapy toxicity risk score. Chemotherapy toxicity risk score is based on the following variables and the value assigned to them. Higher scores indicate more risk, range of 2-19: patient age (>=72 years); creatinine clearance (<34 mL/min); presence of amenia (<10 g/dL); hearing impairment; falls in the last 6 months; need for assistance with taking medications; limitations in walking one block; decreased social activities; chemotherapy dosing; number of chemotherapy drugs; cancer type
• Mean Clearance (CL) [Cycle 1, week 1 at 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours post treatment]: Mean CL reported as well as regression results of CL by age and chemotherapy toxicity risk score. Chemotherapy toxicity risk score is based on the following variables and the value assigned to them. Higher scores indicate more risk, range of 2-19: patient age (>=72 years); creatinine clearance (<34 mL/min); presence of amenia (<10 g/dL); hearing impairment; falls in the last 6 months; need for assistance with taking medications; limitations in walking one block; decreased social activities; chemotherapy dosing; number of chemotherapy drugs; cancer type

Secondary outcomes

• Grade 3 Toxicity Rate by Chemotherapy Toxicity Risk Score [Up to 2.5 years]: Comparison of presence of grade 3 toxicity rate by risk score distribution. Chemotherapy toxicity risk score is based on the following variables. Higher scores indicate more risk, range of 2-19: patient age (>=72 years); creatinine clearance (<34 mL/min); presence of amenia (<10 g/dL); hearing impairment; falls in the last 6 months; need for assistance with taking medications; limitations in walking one block; decreased social activities; chemotherapy dosing; number of chemotherapy drugs; cancer type Chemotherapy toxicity risk score category: Low risk score - toxicity risk score: 0-5 Medium risk score - toxicity risk score: 6-9 High risk score - toxicity risk score: 10-19
• Best Response [Assessed after every 2 cycles of therapy until progression, up to 2.5 years]: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.
• Median Event-free Survival (EFS) in Months [From the date treatment begins until the first date on which recurrence, progression or death due to any cause, assessed up to 3.5 years]: Median and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for EFS. EFS will be estimated using the product limit method of Kaplan and Meier. EFS is defined by time to disease recurrence, disease progression or death to due to any cause
• Number of Participants Requiring Dose Reductions [At the completion of treatment, up to 2.5 years]: Number of participants requiring a dose reduction is reported and analysis was performed using a student's 2 sample t test to determine the need of dose reductions based on age, AUC, and CL.
• Number of Participants With a Dose Omission [At the completion of treatment, up to 2.5 years]: Number of participants with a dose omission is reported and analysis was performed using a student's 2 sample t test to determine the need of dose omission based on age, AUC, and CL.
• Percent of Participants With a Grade 3 Toxicity [At the completion of treatment, up to 2.5 years]: Percent of participants experiencing a grade 3 toxicity is reported and analysis was performed using a student's 2 sample t test to determine the presence of grade 3 toxicity based on age, AUC, and CL.

Sex: All, ages: 18 Years to 120 Years

DISEASE CHARACTERISTICS:

Inclusion criteria:

* Diagnosis of metastatic breast cancer
* Any estrogen receptor, progesterone receptor, or HER-2/neu status allowed as long as the patient will receive paclitaxel albumin-stabilized nanoparticle formulation alone
* First- or second-line chemotherapy treatment for metastatic disease planned

Exclusion criteria:

* Untreated CNS metastases or symptomatic CNS metastases requiring escalating doses of corticosteroids

PATIENT CHARACTERISTICS:

* Karnofsky performance status 70-100%
* WBC ≥ 3,000/mm³
* ANC ≥ 1,500/mm³
* Platelet count ≥ 100,000/mm³
* Hemoglobin ≥ 9.0 g/dL
* AST and ALT ≤ 2.5 times upper limit of normal (ULN)
* Alkaline phosphatase ≤ 2.5 times ULN (unless bone metastases are present in the absence of liver metastases)
* Bilirubin ≤ 1.5 mg/dL
* Peripheral neuropathy ≤ grade 1
* Creatinine clearance ≥ 30 mL/min (calculated or 24-hour)
* Negative pregnancy test
* Fertile patients must use effective contraception
* Not pregnant or nursing
* No known history of allergic reactions to paclitaxel
* No serious or uncontrolled infection
* Ability to understand and the willingness to sign a written informed consent document

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* No ≥ grade 2 toxicity from prior therapy (other than alopecia)
* No taxane for adjuvant therapy or metastatic disease within the past 12 months
* No other concurrent investigational agents
* No other concurrent anticancer therapy

Participant flow

Outcome results

• Mean Area Under the Curve Over 24 Hours (AUC24) (Primary), Mean, µg/mL*hour: Nab-paclitaxel 4711 +/- 2777 (p 0.055)
• Mean Clearance (CL) (Primary), Mean, L/h: Nab-paclitaxel 37.16 +/- 14.81 (p 0.25)
• Grade 3 Toxicity Rate by Chemotherapy Toxicity Risk Score (Secondary), Count of participants, Participants: Nab-paclitaxel 5 (p 0.041)
• Best Response (Secondary), Count of participants, Participants: Nab-paclitaxel 12
• Median Event-free Survival (EFS) in Months (Secondary), Median, months: Nab-paclitaxel 5.7 (3.2 to 9.2)
• Number of Participants Requiring Dose Reductions (Secondary), Count of participants, Participants: Nab-paclitaxel 11 (p .38)
• Number of Participants With a Dose Omission (Secondary), Count of participants, Participants: Nab-paclitaxel 15 (p 0.15)
• Percent of Participants With a Grade 3 Toxicity (Secondary), Number, percentage of participants: Nab-paclitaxel 26 (13 to 42) (p 0.75)

Adverse events

Time frame: Up to 3.5 years

Serious adverse events by term

Other adverse events by term

84 more terms not shown.

• Results publication: Hurria A, Blanchard MS, Synold TW, Mortimer J, Chung CT, Luu T, Katheria V, Rotter AJ, Wong C, Choi A, Feng T, Ramani R, Doan CM, Brown J, Somlo G. Age-related changes in nanoparticle albumin-bound paclitaxel pharmacokinetics and pharmacodynamics: influence of chronological versus functional age. Oncologist. 2015 Jan;20(1):37-44. doi: 10.1634/theoncologist.2014-0202. Epub 2014 Dec 9. PMID 25492923

• Study Protocol and Statistical Analysis Plan (PDF, 2019-07-22)

• Mina Sedrak, MD, Principal investigator, City of Hope Medical Center

NIH grants: P30CA033572