Topotecan Hydrochloride for Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Topotecan Hydrochloride for Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: United States
Condition: Ovarian Cancer, Small Cell Lung Cancer
Class: Miscellaneous antineoplastics
Form: Intravenous (IV), Powder
Ingredients: Topotecan hydrochloride, Mannitol, Tartaric acid, Hydrochloric acid, Sodium hydroxide

Pharmaceutical Information

Drug Substance

Proper  name: Topotecan hydrochloride
Chemical name: 

S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3’,4’:6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione monohydrochloride.

Molecular formula and molecular mass: C23H23N3O5·HCl
457.9 g/moL
Structural formula:  
Physicochemical properties:  
Description: 

Topotecan hydrochloride is a light yellow to greenish powder. It is soluble in water and melts with decomposition at 223º to 225ºC.

Clinical Trials

Ovarian Cancer

Study Demographics and Trial Design

Topotecan hydrochloride was studied in four clinical trials of 453 patients with metastatic ovarian carcinoma.

Patients in these four studies received an initial dose of 1.5 mg/m2 given by intravenous infusion over 30 minutes for the first five consecutive days of a 21-day course.

In a randomized Phase III study, topotecan hydrochloride was compared with paclitaxel in patients with recurrent ovarian cancer who had failed initial treatment with a platinum containing regimen. This study treated 112 patients with topotecan hydrochloride (1.5 mg/m2/day for the first 5 consecutive days of a 21-day course) and 114 patients with paclitaxel (175 mg/m2 over 3 hours on day one of a 21-day course).

Response rates, response duration (measured from the time of documented response), time to progression, time to response and survival for the comparative study are provided in Table 1.

Study Results

Patients receiving topotecan hydrochloride achieved a higher response rate (21% vs. 14%, p = 0.196) than those receiving paclitaxel; a longer duration of response (median of 26 vs. 22 weeks, Hazard-ratio = 0.778, p = 0.476); a longer time to progression (median of 19 vs. 15 weeks, Hazard-ratio = 0.764, p = 0.0718); and a longer estimated median survival (63 vs. 53 weeks, Hazard-ratio = 0.986, p = 0.9315).

However, the median time to response was longer with topotecan hydrochloride compared to paclitaxel: median of 8 vs. 6 weeks (Hazard-ratio = 0.615, p = 0.1465). Consequently there is a risk of underestimating the expected efficacy of topotecan hydrochloride for injection if patients are withdrawn from treatment prematurely.

Table 1 Comparative Efficacy Parameters of Topotecan Hydrochloride vs. Paclitaxel in Ovarian Cancer
Parameter Topotecan Hydrochloride (n=112) Paclitaxel (n=114)
Complete Response Rate (%)
Partial Response Rate (%)
Overall Response Rate (%)
95% CI
4.5
16.1
20.5
(13.1, 28.0)
2.6
11.4
14.0
(7.7, 20.4)
(p-value) (0.196)
Response Duration (weeks)
Median
95% CI

26*
(22.1, 32.9)

22*
(16.0, 34.6)
Hazard-ratio (p-value) 0.778 (0.476)
Time to Progression (weeks)
Median
95% CI

19
(12.1, 23.6)

15
(11.9, 18.3)
Hazard-ratio (p-value) 0.764 (0.0718)
Time to Response (weeks)
Median
Range

8.0*
3.1 to 19.0

6.0*
2.4 to 12.3
Hazard-ratio (p-value) 0.615 (0.1465)
Survival (weeks)
Median
Range

63
0.7 to 122.1

53
0.6 to 129.9
Hazard-ratio (p-value) 0.97 (0.87)

*topotecan (n=23) paclitaxel (n=16)

Patients who failed on the initial arm of this study were allowed to switch to the alternate treatment. Eight of 61 (13.1%) patients who received topotecan hydrochloride after paclitaxel responded. Five of 49 (10.2%) patients who received paclitaxel after topotecan hydrochloride responded.

Topotecan hydrochloride was active in ovarian cancer patients who had developed resistance to platinum-containing therapy, defined as tumour progression while on, or tumour relapse within 6 months after completion of a platinum-containing regimen. One complete and seven partial responses were seen in 60 patients, for a response rate of 13%. In the same study, there were no complete responders and only four artial responders on the paclitaxel arm, for a response rate of 7%.

Topotecan hydrochloride remained active in patients who did not respond to or eventually failed paclitaxel, as shown by the responders in this trial and the trial in platinum and paclitaxel failures (see below).

The safety profile for paclitaxel in this study was consistent with the product’s monograph; the safety profile for topotecan hydrochloride in this study was consistent with that observed in all 453 patients from the four ovarian clinical trials.

The three additional studies were open-labelled and non-comparative in design. The first study enrolled 111 patients with recurrent ovarian cancer who had failed one prior platinum-containing regimen. The response rate was 14% (95% CI: = 7.9% - 20.9%). The median duration of response was 16 weeks (range: 4.6 to 41.9 weeks). The time to progression was 11 weeks (range: 0.7 to 72.1 weeks). The median survival was 52 weeks (range: 1.4 to 72.3 weeks).

A second open study enrolled 139 patients with recurrent ovarian cancer who had failed one (62 patients) or two (77 patients) prior regimens containing platinum and paclitaxel. The response rates in this study for evaluable patients were 12.9% and 16.9%, respectively. Median response duration was 18.1 weeks. Median time to progression was 12 weeks (range: 0.6 – 52.7 weeks). Median survival was 51.3 weeks for patients failing first-line therapy.

The third open study enrolled 30 patients with recurrent ovarian cancer who had failed one or two prior platinum-containing regimens. The response rate was 13% (95% CI: = 3.8 - 30.7%). The median duration of response was 28 weeks (range: 16 - 59 weeks).

Small Cell Lung Cancer

Study Demographics and Trial Design

Topotecan hydrochloride was studied in 426 patients with recurrent or progressive small cell lung cancer in one randomized Phase III, comparative study and in three non-randomized, Phase II studies.

In a randomized, Phase III, comparative trial, 107 patients were treated with topotecan hydrochloride (1.5 mg/m2/day x 5 days starting on day one of a 21-day course) and 104 patients were treated with CAV (1000 mg/m2 cyclophosphamide, 45 mg/m2 doxorubicin, 2 mg vincristine administered sequentially on day one of a 21 day course). All patients were considered sensitive to first-line chemotherapy (responders who then subsequently progressed ≥ 60 days after completion of first-line therapy). A total of 77% of patients treated with topotecan hydrochloride and 79% of patients treated with CAV received platinum/etoposide with or without other agents as first-line chemotherapy.

Response rates, response duration, time to progression, and survival are shown in Table 2.

Table 2 Efficacy of Topotecan Hydrochloride vs. CAV (cyclophosphamide-doxorubicin-vincristine) in Small Cell Lung Cancer Patients Sensitive to First-Line Chemotherapy
Parameter Topotecan Hydrochloride (n=107) CAV (n=104)
Complete Response Rate
Partial Response
RateOverall Response Rate
95% Confidence Interval*
0.0%
24.3%
24.3%
16.17 to 32.43%
1.0%
17.3%
18.3%
10.84 to 25.7%
(p-value) (0.285)
Response Duration (weeks)
Median
95% Confidence interval
n=26
14.4
13.1 to 18.0
n=19
15.3
13.1 to 23.1
Hazard-ratio (topotecan hydrochloride: CAV)
(p-value)
1.42
(0.30)
Time to Progression (weeks)
Median
95% Confidence Interval

13.3
11.4 to 16.4

12.3
11.0 to 14.1
Hazard-ratio (topotecan hydrochloride: CAV)
(p-value)
0.92
(0.55)
Survival (weeks)
Median
95% Confidence Interval

25.0
20.6 to 29.6

24.7
21.7 to 30.3
Hazard-ratio (topotecan hydrochloride: CAV)
(p-value)
1.04
(0.80)

This calculation for duration of response was based on the interval between first response and time to progression.

*95% confidence interval for the difference in the rate of response (6.0%) was -6.0 to 18%.

The time to response was similar in both arms: topotecan hydrochloride median of 6 weeks (range 2.4 to 15.7) versus CAV median of 6 weeks (range 5.1 to 18.1).

Palliation of disease-related symptoms was greater in patients who received topotecan hydrochloride than in patients who received CAV. These clinically important improvements occurred at a higher rate in 8 of 9 symptoms in patients treated with topotecan hydrochloride. Symptom improvement was statistically significant in 5 of 9 symptoms. These data are presented in Table 3.

Patients treated with topotecan hydrochloride also experienced a longer time to worsening in 7 of 9 disease-related symptoms (shortness of breath, anorexia, interference with daily activity, cough, insomnia, hoarseness and fatigue). Time to worsening of chest pain and hemoptysis were similar for both treatment groups. Statistically significant differences in the length of time to worsening of shortness of breath (p = 0.046) and anorexia (p = 0.003) were noted, with the topotecan hydrochloride group worsening at a slower rate.

Table 3 Percentage of Patients with Symptom Improvement+: Topotecan Hydrochloride versus CAV in Patients with Small Cell Lung Cancer
Symptom Topotecan Hydrochloride (n = 107) CAV (n=104) Pearson chi-square p-value
n++ (%) n++ (%)
Shortness of Breath 68 (27.9) 61 (6.6) 0.002
Interference with Daily Activity 67 (26.9) 63 (11.1) 0.023
Fatigue 70 (22.9) 65 (9.2) 0.032
Hoarseness 40 (32.5) 38 (13.2) 0.043
Cough 69 (24.6) 61 (14.8) 0.160
Insomnia 57 (33.3) 53 (18.9) 0.085
Anorexia 56 (32.1) 57 15.8) 0.042
Chest Pain 44 (25.0) 41 (17.1) 0.371
Hemoptysis 15 (26.7) 12 (33.3) 0.706

+ Defined as improvement sustained over at least 2 courses compared to baseline.

++ Number of patients with baseline and at least one post-baseline assessment.

Topotecan hydrochloride (1.5 mg/m2/day x 5 days starting on day one of a 21-day course) was also studied in three open-label, non- comparative trials in 319 patients with recurrent or progressive small cell lung cancer after treatment with first-line chemotherapy. In all three studies, patients were stratified as either sensitive (responders who then subsequently progressed ≥ 90 days after completion of first-line therapy) or refractory (no response to first-line chemotherapy or who responded to first-line therapy and then progressed within 90 days of completing first-line therapy).

In one study, the median response rate was 15.4% for sensitive (n = 52) and 2.1% for refractory patients (n = 47). Median time to response was 6.1 weeks (sensitive) and 5.4 weeks (refractory). The median duration of response was 23.1 weeks (sensitive) and 24.9 weeks (refractory). Median time to progression was 13.1 weeks (sensitive) and 9.6 weeks (refractory). Median survival time was 28.3 weeks (sensitive) and 21.4 weeks (refractory). Disease-related symptoms resolved or improved versus baseline in 20% of patients (n = 65), remained unchanged in 60%, or worsened in 20%.

In an EORTC (European Organization for Research and Treatment of Cancer) Study, the median response rate was 31.1% for sensitive (n = 45) and 7.3% for refractory patients (n = 55). Median time to response was 7 weeks for sensitive and 5.6 weeks for refractory patients. The median duration of response was 20.7 weeks (sensitive) and 30.7 weeks (refractory). Median time to progression was 17.7 weeks (sensitive) and 8.3 weeks (refractory). Median survival was 35.6 weeks (sensitive) and 20.9 weeks (refractory).

In a third study, the median response rate was 11.3% for sensitive (n = 71) and 2.1% for refractory patients (n = 48) . Median time to response was 5.6 weeks (sensitive) and 5.7 weeks (refractory). The median duration of response was 21.9 weeks (sensitive) and 22.0 weeks (refractory). Median time to progression was 10.3 weeks (sensitive) and 6.4 weeks (refractory). Median survival time was 26.4 weeks (sensitive) and 15.9 weeks (refractory).

Detailed Pharmacology

Pharmacokinetics

Metabolism

Topotecan undergoes pH dependant hydrolysis, with the equilibrium favouring the ring-opened hydroxy-acid form at physiologic pH. The metabolism of topotecan in humans has not been extensively studied. However in rats and dogs, approximately 4% and 17% of the dose, respectively, was excreted as N-desmethyl derivatives of topotecan and its ring opened hydroxy -acid form. In vitro studies in rat, dog and human liver microsomes indicate that the rate of metabolism of topotecan to the N-demethylated metabolite in human microsomes is between that in rat and dog liver microsomes.

No other metabolite of topotecan has been identified. A major route of clearance of topotecan was by hydrolysis of the lactone ring to form the ring-opened hydroxy-acid.

Drug Interactions

When given in combination with cisplatin (cisplatin day 1, topotecan days 1 to 5), the clearance of topotecan was reduced on day 5 compared to day 1 (19.1 L/h/m2 compared to 21.3 L/h/m2).

In vitro, topotecan did not inhibit human P450 enzymes CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, or CYP4A nor did it inhibit the human cytosolic enzymes dihydropyrimidine or xanthine oxidase. Following 14 days of intravenous dosing in rats at doses up to 1.36 mg/m2 topotecan free base, no inductive effect was observed on P450 enzymes 1A, 2B, 3A, and 4A.

Microbiology

Not applicable.

Toxicology

The toxicity of topotecan in animals has been predictive of the toxicity observed thus far in patients, where neutropenia (the most common dose-limiting toxicity) was often associated with thrombocytopenia and anemia.

Carcinogenicity

Carcinogenicity studies are not generally performed with antineoplastic agents and have not been performed for topotecan.

Mutagenicity

Topotecan was not mutagenic in bacterial mutagenicity tests using Salmonella typhimurium and Escherichia coli. Topotecan was genotoxic in mammalian cells (mouse lymphoma cells and human lymphocytes) in vitro and in mouse bone marrow cells in vivo. Similar findings have been observed for other topoisomerase I inhibitor, CPT-11.