Trial Information

A Phase II Study of Weekly Docetaxel and Topotecan in Patients With Platinum-Resistant, Recurrent Epithelial Ovarian Cancer

Each year more than 28,000 women are diagnosed with epithelial ovarian cancer (EOC). Over
70% of these women will present with advanced (stage III, IV) disease. The current
treatment for newly diagnosed advanced EOC involves cytoreductive surgery followed by
chemotherapy. The standard chemotherapy in the primary setting is a combination of a
taxane; either paclitaxel or docetaxel and a platinum agent; either cisplatin or
carboplatin. Although high initial responses are seen with these primary therapies, most
will recur. Salvage chemotherapy thus becomes the mainstay of treatment for many patients
with this disease. The goals of salvage therapy are to maximize tumor response while
maintaining quality of life with minimal toxicity. As a consequence, there are a number of
agents that have been studied in this recurrent setting with significant antitumor activity.
Two such novel agents, topotecan and docetaxel are the basis of this phase I, II study.

Patients can be grouped into prognostic categories based on their responses to primary
therapy. Those with persistent disease or recurrence within 6 months of treatment are
deemed platinum resistant and those achieving a greater than 6 month progression free
interval are deemed platinum sensitive. This distinction is important because those that
are platinum sensitive have an improved overall survival and higher response rates to
salvage chemotherapy. The magnitude of this response increases with an increasing
progression free interval. The response of these patients to reintroducing either platinum
or paclitaxel has been established. Thigpen et. al. showed a 44% overall response rate(ORR)
to paclitaxel infused over 24 hours in 16 patients with a platinum free interval of greater
than or equal to 6 months. Kavanagh et. al. demonstrated a 21% partial response rate (PR)
to the reintroduction of carboplatin after taxane treatment in 26 patients with a 12-month
platinum-free intraval following platinum-refractory ovarian cancer.

Topotecan has been shown to have similar activity as paclitaxel as a second line therapy
with non-cross resistance. Topotecan is usually administered in a daily infusion over 30
minutes in doses of 1.5 mg/m2/d x 5 consecutive days every 21 days. In an effort to
decrease toxicity and maintain response rates, weekly schedules of topotecan have been
explored. Homesley et. al. conducted a phase I trial with single agent weekly topotecan
evaluating dosages from 1.5 to 6 mg/m2/wk. The recommended phase II dosage for weekly
topotecan was determined to be 4 mg/m2/wk. Dose limiting toxicities consisted of 70
non-hematologic events in 32 of 35 evaluable patients, primarily consisting of grade 1 or 2
chronic fatigue (16%) and gastrointestinal (nausea and vomiting [23%]) with the majority
(80%) being grade 1 in severity. Dose limiting myelotoxicity and thrombocytopenia were not
an issue at the weekly dosages evaluated in this trial. Morris and colleagues at Wayne
State University are currently studying weekly topotecan in platinum sensitive patients and
have reported a 40% partial response rate with 35% having stable disease. Myelotoxicity was
infrequent and included grade 3 or 4 neutropenia in 1.1% and grade 3 anemia in 1.8%.
Nonhematologic toxicity included grade 3 fatigue in 17% of patients.

Abu-Rustum et. al. conducted a phase I trial of weekly paclitaxel (60 -100 mg/m2 over
1-hour) in platinum resistant patients (n = 18 patients, recommended phase II dose 80
mg/mg/wk). Dose limiting toxicity was defined as two or more patients with treatment delay
or grade 3 toxicity at the same dose level. Treatment was delayed in 2 of 3 patients at the
100 mg/m2 dose level due to ANC < 1500. In addition they reviewed Memorial Sloan
Kettering's previous data with weekly paclitaxel (60 to 100 mg/m2/wk) in platinum resistant
patients and found an overall response rate (either documented tumor shrinkage or decrease
in serum CA-125 levels) of 28% (ORR in 13 of 45 patients). In a follow up phase II trial,
Markman et. al. reported a 25% objective response rate in 13 of 51 platinum resistant
patients (4 by decreasing CA-125 and 9 by 50% reduction in tumor volume). Only 1% (13 of
887 dosages) required a dose modification due to toxicity with weekly paclitaxel at 80
mg/m2/wk. Weekly paclitaxel is an active second-line regimen and is generally well
tolerated.

In advanced, platinum-refractory ovarian cancer, docetaxel administered every 3 weeks has
demonstrated substantial single-agent efficacy with response rates ranging from 24% to 40%
and an overall survival of 8 to 10.4 months. Neutropenia was the predominant Grade 3 /4
toxicity, followed by fluid retention, hypersensitivity reactions and diarrhea.

The combination of docetaxel and carboplatin has been studied as first-line therapy for the
treatment of epithelial ovarian cancer. A phase II study by Markman et.al. utilized
docetaxel 60 mg/m2 plus carboplatin AUC 6 every 3 weeks demonstrated an overall response
rate of 81%. The most common hematologic toxicity was Grade 4 neutropenia (64%), while
neutropenic fever was observed in only 6% of those patients. The most common non-hematologic
toxicity was a mild hypersensitivity reaction (34%) that did not prevent patients from
completing their planned therapy.

Preliminary results have recently been reported from a randomized phase III trial comparing
docetaxel (75 mg/m2/1 hr infusion) to paclitaxel (175 mg/m2/3 hr infusion) in combination
with carboplatin (AUC 5 as calculated by 51Cr-EDTA secretion) every 3 weeks as first-line
chemotherapy following surgery for Stage Ic-IV ovarian cancer. Both combinations
demonstrated very high overall response rates of 65% and 62%, respectively, and an estimated
1 year disease free survival is approximately 60% for both treatment groups. With regard to
toxicity, the occurrence of Grade 2-4 sensory neurotoxicity was significantly increased in
patients receiving paclitaxel (30%) compared to docetaxel (11%; p<.001) and accounted for
the majority of toxicity related treatment withdrawal in the paclitaxel group. The most
common severe side effect was myelosuppression with Grade 3 or 4 neutropenia occurring in
84% of patients treated with paclitaxel and 94% of patients treated with docetaxel (p<.001).
Febrile neutropenia was noted in 10% of patients treated with docetaxel, compared to 2% of
patients treated with paclitaxel (p<.001). However, there was no difference in septic
mortality between the two treatment arms.

In order to decrease the incidence of hematological toxicity associated with docetaxel
administered every three weeks, clinicians have explored the use of docetaxel on a weekly
schedule. There have been numerous published reports examining the role of weekly docetaxel
(single agent and in combination chemotherapy regimens) in wide range of solid tumors
including breast, NSCLC, prostate and ovarian. Weekly administration of docetaxel resulted
in substantial clinical activity, was well tolerated and resulted in a decreased incidence
of hematologic toxicity (grade 3/4 neutropenia and leukopenia each reported in ≤16% of
patients; grade 3/4 anemia and thrombocytopenia in ≤13% and ≤3% of patients, respectively.
Acute toxicities were uncommon, as was peripheral neuropathy. Prolonged treatment with
weekly docetaxel results in chronic toxicities, including asthenia (fatigue), edema, tearing
(excessive lacrimation or epiphora), and nail changes. Chronic toxicities have been most
prominent when docetaxel has been administered on a continuous weekly basis, i.e., without a
break. Toxicities appeared to be delayed in onset or avoided by providing treatment breaks.
The current strategy is treating weekly 2 out of 3 weeks on an every 21-day cycle or weekly
3 out of 4 weeks on an every 28-day cycle. The reduced incidence of myelosuppression may
enhance the feasibility and tolerability of weekly docetaxel-containing combination
regimens.

Burris and colleagues have enrolled 36 patients in a phase I study of weekly docetaxel (20,
25, 30 mg/m2/wk) and weekly topotecan (2.0, 3.0, 3.5 to 4 mg/m2/wk) for solid tumors. The
combination of weekly docetaxel 30 mg/m2/wk plus topotecan 3 mg/m2/wk on days 1, 8 and 15
every 28 days resulted in no dose-limiting toxicities and no dose reductions or treatment
omissions were warranted during cycle 1 of therapy. Non-hematologic toxicities consisted of
grade 1 and 2 nausea, vomiting, fatigue and weakness. Dose-limiting toxicity was documented
for weekly docetaxel 30 mg/m2/wk plus topotecan 4 mg/m2/wk with two patients experiencing
day 15 dose omissions (one patients with platelets 53 K and ANC 500 and one patient with
platelets 27 K who was previously treated with oxaliplatin. Eleven patients have been
treated to date with weekly docetaxel 30 mg/m2/wk plus topotecan 3.5 mg/m2/wk. Two patients
were non-evaluable, one due to rapidly progressive disease and one due to noncompliance. Of
the nine evaluable patients, five patients experienced dose-limiting toxicities as follows,
(1) cycle 1 day 15 (C1D15) held due to platelets 33K in a heavily pretreated patient,
including previous oxaliplatin, (2) C1D15 dose decreased due to grade 3 diarrhea, (3) C1D8
held due to grade 3-4 nausea and vomiting (may have been disease related), (4) C1D15 held
due to platelets 49 K (74 yo, heavily pretreated including previous XRT), (5) C1D15 held due
to platelets 43K and declining creatinine clearance of 43 ml/min (3 prior regimens,
including XRT, PS 2 and history of thrombocytopenia). One additional patient is planned to
complete this dose level, to provide 10 evaluable patients. Of the 36 patients receiving 76
cycles of therapy, myelosuppression was brief and reversible with no febrile neutropenia.
Per verbal communication from Dr. Burris, the recommended phase II dose will be docetaxel 30
mg/m2/wk plus topotecan 3.5 mg/m2/wk on days 1, 8 and 15 every 28 days for minimally
pretreated patients.

Given the results of these data and the goal to increase response rates in platinum
resistant recurrent EOC patients it would seem prudent to evaluate the safety and efficacy
of weekly docetaxel 30 mg/m2/wk plus weekly topotecan 3.5 mg/m2/wk via a phase II trial.
Results of this trial will be important by expanding our current knowledge base utilizing
weekly scheduling of chemotherapeutic agents in regard to toxicities and response rates in
platinum resistant EOC.