Paclitaxel Protein-Bound Particles For Injectable Suspension (Albumin-Bound) (Page 7 of 10)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) has not been studied.

Paclitaxel was clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). Paclitaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay.

Administration of paclitaxel formulated as albumin-bound particles to male rats at 42 mg/m2 on a weekly basis (approximately 16% of the daily maximum recommended human exposure on a body surface area basis) for 11 weeks prior to mating with untreated female rats resulted in significantly reduced fertility accompanied by decreased pregnancy rates and increased loss of embryos in mated females. A dose of 42 mg/m2 also reduced male reproductive organ weights, mating performance, and sperm production. Testicular atrophy/degeneration was observed in single-dose toxicology studies in animals administered paclitaxel formulated as albumin-bound particles at doses lower than the recommended human dose; doses were 54 mg/m2 in rodents and 175 mg/m2 in dogs. Similar testicular degeneration was seen in monkeys administered three weekly doses of 108 mg/m2 paclitaxel formulated as albumin bound particles.

Administration of paclitaxel prior to and during mating produced impairment of fertility in male and female rats. Paclitaxel caused reduced fertility and reproductive indices, and increased embryo-fetal toxicity.

14 CLINICAL STUDIES

14.1 Metastatic Breast Cancer

Data from 106 patients accrued in two single arm open label studies and from 460 patients enrolled in a randomized comparative study were available to support the use of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) in metastatic breast cancer.

Single Arm Open Label Studies
In one study, Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) was administered as a 30-minute infusion at a dose of 175 mg/m2 to 43 patients with metastatic breast cancer. The second trial utilized a dose of 300 mg/m2 as a 30-minute infusion in 63 patients with metastatic breast cancer. Cycles were administered at 3-week intervals. Objective responses were observed in both studies.

Randomized Comparative Study This multicenter trial was conducted in 460 patients with metastatic breast cancer. Patients were randomized to receive Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) at a dose of 260 mg/m2 given as a 30-minute infusion, or paclitaxel injection at 175 mg/m2 given as a 3-hour infusion. Sixty-four percent of patients had impaired performance status (ECOG 1 or 2) at study entry; 79% had visceral metastases; and 76% had > 3 sites of metastases. Fourteen percent of the patients had not received prior chemotherapy; 27% had received chemotherapy in the adjuvant setting, 40% in the metastatic setting and 19% in both metastatic and adjuvant settings. Fifty-nine percent received study drug as second or greater than second-line therapy. Seventy-seven percent of the patients had been previously exposed to anthracyclines.

In this trial, patients in the Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) treatment arm had a statistically significantly higher reconciled target lesion response rate (the trial primary endpoint) of 21.5% (95% CI: 16.2% to 26.7%), compared to 11.1% (95% CI: 6.9% to 15.1%) for patients in the paclitaxel injection treatment arm. See Table 11. There was no statistically significant difference in overall survival between the two study arms.

Table 11: Efficacy Results from Randomized Metastatic Breast Cancer Trial
a Reconciled Target Lesion Response Rate (TLRR) was the prospectively defined protocol specific endpoint, based on independent radiologic assessment of tumor responses reconciled with investigator responses (which also included clinical information) for the first 6 cycles of therapy. The reconciled TLRR was lower than the investigator Reported Response Rates, which are based on all cycles of therapy.b From Cochran-Mantel-Haenszel test stratified by 1st line vs. > 1st line therapy.c Prior therapy included an anthracycline unless clinically contraindicated.

Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) 260 mg/m2

Paclitaxel Injection 175 mg/m2

Reconciled Target Lesion Response Rate (primary endpoint)a

All randomized patients

Response Rate [95% CI]

50/233 (21.5%) [16.19% – 26.73%]

25/227 (11.1%) [6.94% – 15.09%]

p-valueb

0.003

Patients who had failed combination chemotherapy or relapsed within 6 months of adjuvant chemotherapyc

Response Rate [95% CI]

20/129 (15.5%) [9.26% – 21.75%]

12/143 (8.4%) [3.85% – 12.94%]

14.2 Non-Small Cell Lung Cancer

A multicenter, randomized, open-label study was conducted in 1052 chemotherapy naive patients with Stage IIIb/IV non-small cell lung cancer to compare Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) in combination with carboplatin to paclitaxel injection in combination with carboplatin as first-line treatment in patients with advanced non-small cell lung cancer. Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m2 , following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound)/paclitaxel infusion. Treatment was administered until disease progression or development of an unacceptable toxicity. The major efficacy outcome measure was overall response rate as determined by a central independent review committee using RECIST guidelines (Version 1.0).

In the intent-to-treat (all-randomized) population, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1, and 73% were current or former smokers. Patients received a median of 6 cycles of treatment in both study arms.

Patients in the Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound)/carboplatin arm had a statistically significantly higher overall response rate compared to patients in the paclitaxel injection/carboplatin arm [(33% versus 25%) see Table 12]. There was no statistically significant difference in overall survival between the two study arms.

Table 12: Efficacy Results from Randomized Non-Small Cell Lung Cancer Trial (Intent-to-Treat Population)
CI = confidence interval; DoR= Duration of response.

Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) (100 mg/m2 weekly) + carboplatin (N=521)

Paclitaxel Injection (200 mg/m2 every 3 weeks) + carboplatin (N=531)

Overall Response Rate (ORR)

Confirmed complete or partial overall response, n (%)

170 (33%)

132 (25%)

95% CI

28.6, 36.7

21.2, 28.5

P-value (Chi-Square test)

0.005

Median DoR in months (95% CI)

6.9 (5.6, 8.0)

6.0 (5.6, 7.1)

Overall Response Rate by Histology

Carcinoma/Adenocarcinoma

66/254 (26%)

71/264 (27%)

Squamous Cell Carcinoma

94/229 (41%)

54/221 (24%)

Large Cell Carcinoma

3/9 (33%)

2/13 (15%)

Other

7/29 (24%)

5/33 (15%)

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2024. All Rights Reserved.