Paclitaxel (Page 5 of 15)

Non-Small Cell Lung Carcinoma (NSCLC)

In a Phase 3 open-label randomized study conducted by the ECOG, 599 patients were randomized to either paclitaxel (T) 135 mg/m2 as a 24-hour infusion in combination with cisplatin (c) 75 mg/m2 , paclitaxel (T) 250 mg/m2 as a 24-hour infusion in combination with cisplatin (c) 75 mg/m2 with G-CSF support, or cisplatin (c) 75 mg/m2 on day 1, followed by etoposide (VP) 100 mg/m2 on days 1, 2, and 3 (control). Response rates, median time to progression, median survival, and 1-year survival rates are given in the following table. The reported p-values have not been adjusted for multiple comparisons. There were statistically significant differences favoring each of the paclitaxel plus cisplatin arms for response rate and time to tumor progression. There was no statistically significant difference in survival between either paclitaxel plus cisplatin arm and the cisplatin plus etoposide arm.

Table 6. Efficacy Parameters in the Phase 3 First-Line NSCLC Study

a Etoposide (VP) 100 mg/m2 was administered IV on days 1, 2, and 3.

b Compared to cisplatin/etoposide.

T135/24 c75 (n=198) T250/24 c75 (n=201) VP100 a c75 (n=200)
• Response
— rate (percent) 25 23 12
— p-valueb 0.001 <0.001
• Time to Progression
— median (months) 4.3 4.9 2.7
— p-valueb 0.05 0.004
• Survival
— median (months) 9.3 10.0 7.4
— p-valueb 0.12 0.08
• 1-Year Survival
— percent of patients 36 40 32

In the ECOG study, the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire had 7 subscales that measured subjective assessment of treatment. Of the 7, the Lung Cancer Specific Symptoms subscale favored the paclitaxel 135 mg/m2 /24 hour plus cisplatin arm compared to the cisplatin/etoposide arm. For all other factors, there was no difference in the treatment groups.

The adverse event profile for patients who received paclitaxel in combination with cisplatin in this study was generally consistent with that seen for the pooled analysis of data from 812 patients treated with single-agent paclitaxel in 10 clinical studies. These adverse events and adverse events from the Phase 3 first-line NSCLC study are described in the ADVERSE REACTIONS section in tabular (Tables 10 and 15) and narrative form.

AIDS-Related Kaposi’s Sarcoma

Data from 2, Phase 2 open-label studies support the use of paclitaxel as second-line therapy in patients with AIDS-related Kaposi’s sarcoma. Fifty-nine of the 85 patients enrolled in these studies had previously received systemic therapy, including interferon alpha (32%), DaunoXome® (31%), DOXIL® (2%), and doxorubicin containing chemotherapy (42%), with 64% having received prior anthracyclines. Eighty-five percent of the pretreated patients had progressed on, or could not tolerate, prior systemic therapy.1

In Study CA139-174, patients received paclitaxel at 135 mg/m2 as a 3-hour infusion every 3 weeks (intended dose intensity 45 mg/m2 /week). If no dose-limiting toxicity was observed, patients were to receive 155 mg/m2 and 175 mg/m2 in subsequent courses. Hematopoietic growth factors were not to be used initially. In Study CA139-281, patients received paclitaxel at 100 mg/m2 as a 3-hour infusion every 2 weeks (intended dose intensity 50 mg/m2 /week). In this study patients could be receiving hematopoietic growth factors before the start of paclitaxel therapy, or this support was to be initiated as indicated; the dose of paclitaxel was not increased. The dose intensity of paclitaxel used in this patient population was lower than the dose intensity recommended for other solid tumors.

All patients had widespread and poor-risk disease. Applying the ACTG staging criteria to patients with prior systemic therapy, 93% were poor risk for extent of disease (T1), 88% had a CD4 count <200 cells/mm3 (I1), and 97% had poor risk considering their systemic illness (S1).

All patients in Study CA139-174 had a Karnofsky performance status of 80 or 90 at baseline; in Study CA139-281, there were 26 (46%) patients with a Karnofsky performance status of 70 or worse at baseline.

Table 7. Extent of Disease at Study Entry Percent of Patients
Prior Systemic Therapy (n=59)
Visceral ± edema ± oral ± cutaneous 42
Edema or lymph nodes ± oral ± cutaneous 41
Oral ± cutaneous 10
Cutaneous only 7

Although the planned dose intensity in the 2 studies was slightly different (45 mg/m2 /week in Study CA139-174 and 50 mg/m2 /week in Study CA139-281), delivered dose intensity was 38 to 39 mg/m2 /week in both studies, with a similar range (20-24 to 51-61).

Efficacy

The efficacy of paclitaxel was evaluated by assessing cutaneous tumor response according to the amended ACTG criteria and by seeking evidence of clinical benefit in patients in 6 domains of symptoms and/or conditions that are commonly related to AIDS-related Kaposi’s sarcoma.

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