Eligible patients had to be ≥ 18 years of age and have previously-untreated, histologically-confirmed advanced stage, epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with either optimal (≤1 cm residual disease) or suboptimal residual disease following surgery. Patients had to have a GOG Performance Status of ≤ 2 and been entered on study within 12-weeks postoperatively. Patients had to have adequate bone marrow function (absolute neutrophil count (ANC) ≥ 1,500/ul, platelets ≥ 100,000/ul), renal function (creatinine ≤ 1.5 × institutional upper limit normal (ULN)), hepatic function (bilirubin ≤ 1.5 × ULN, ALT, AST, and alkaline phosphatase ≤ 2.5 × ULN) and neurologic function (neuropathy, sensory and motor ≤ grade 1). Written informed consent consistent with all federal, state and local requirements was obtained from all patients before study entry.
On day 1 of each 21-day treatment cycle, PPX was administered as a 10 minute intravenous (IV) infusion, followed immediately by the IV administration of carboplatin over 30-minutes. Routine premedication to prevent hypersensitivity, nausea, or vomiting was not required. Patients could receive up to eight cycles of therapy. PPX was supplied by Cell Therapeutics, Inc. (Seattle, WA) in 20-ml vials containing 90 mg conjugated paclitaxel equivalent. Commercially available carboplatin (Paraplatin®, Bristol-Myers Squibb Oncology) was used.
Evaluation During Study
Pretreatment evaluation consisted of a history and physical examination, chest x-ray, complete blood count, prothrombin time, activated partial thromboplastin time, CA-125 testing, serum electrolytes, creatinine, liver function tests, electrocardiogram and a baseline imaging study (computed tomography scan or magnetic resonance imaging of the abdomen and pelvis). Complete blood counts were performed weekly, and CA-125 testing, serum electrolytes, creatinine and liver function tests were obtained prior to each cycle. Patients were also examined prior to every course. Measurable lesions noted at baseline were reevaluated after cycles 4 and 8. Response Evaluation Criteria in Solid Tumors (RECIST)17
and CA-125 levels18
were used to assess response. Only patients in the feasibility phase were evaluated for response.
In accordance with the NCI Common Toxicity Criteria, Version 2 (NCI-CTC), DLT was defined as either hematologic or non-hematologic toxicity which occurred in the first cycle during the dose-seeking phase (or in the first 4 cycles in the feasibility phase). Hematologic DLT included a dose delay of > 2 weeks due to failure to recover counts adequately (see Dose Adjustments), study-treatment-related febrile neutropenia (fever ≥ 38.5°C) when ANC is <1.0×109/L, Grade 4 neutropenia lasting ≥ 7 days and Grade 4 thrombocytopenia. Non-hematologic DLT included study-treatment-related grade 3 or 4 toxicities (excluding fatigue, hypersensitivity reaction, nausea and vomiting) or any drug-related death.
Initial treatment modifications consisted of cycle delay and dose reduction (). Subsequent cycles of therapy could not begin until the ANC was ≥ 1,500 cells/uL (NCI-CTC Grade 1) and the platelet count ≥ 75,000 cells/uL. Therapy could be delayed for a maximum of 2 weeks until these values were achieved. Two dose reductions of PPX were allowed for febrile neutropenia and/or grade 4 neutropenia lasting ≥ 7 days. Also, patients with grade 3 thrombocytopenia, or thrombocytopenia-associated bleeding that required a platelet transfusion, could have a one-time dose reduction of carboplatin. A second occurrence of grade 3 thrombocytopenia required a dose reduction of PPX. Dose modifications were not made for anemia. Patients could receive red blood cell transfusions and/or erythropoietin using standard supportive care guidelines. Other hematologic growth factors were not allowed.
Dose modification was required for any drug-related grade 3 or 4 non-hematologic toxicity. Treatment was discontinued in patients with persistent peripheral neuropathy ≥ grade 3. Patients with non-hematologic toxicity had to return to ≤ grade 1 before continuing therapy.
On days of pharmacokinetic evaluation, carboplatin was administered one hour after the PPX infusion. Up to 28 serial plasma specimens, 17 ultrafiltrate plasma specimens, and seven urine specimens were collected from each patient participating in the dose-seeking phase of the trial. Heparinized-blood was drawn during cycles 1 and 4 immediately before the 10-minute PPX infusion, at 20, 40 and 90 min, 3, 4, 6, 8, 12, 24, 36,and 48 hours after the start of PPX infusion, on days 8 and 15 during cycle 1, and before starting cycles 2 and 3. Plasma was prepared by centrifuging the blood at 2,000 × gravity for 15 minutes. Plasma ultrafiltrates were prepared from heparinized-blood drawn during cycles 1 and 4 immediately before carboplatin administration, 30 minutes after the start of the 30 minutes infusion and again 2, 3, 5, 7, 11, 23 and 35 hours post-infusion start by centrifuging the plasma through an Amicon Centrifree® YM-30 centrifugal filter device (Millipore Corporation, Bedford, MA). Total urine volume produced during six 4-hour time intervals and one 24-hour time interval, for a total of 48 hours during the first cycle, was collected commencing at the time of PPX administration. All specimens were stored at −70°C until testing
The concentrations of conjugated taxanes and unconjugated paclitaxel in the serial plasma specimens were determined by liquid chromatography-tandem mass spectrometry validated methods by Tandem Labs Salt Lake City, Utah. The quantification of carboplatin in plasma ultrafiltrate was performed by HPLC combined with inductively coupled plasma mass spectrometry by Elemental Research Inc, North Vancouver, British Columbia, Canada. Non-compartmental pharmacokinetic analyses were performed on the temporal profiles of conjugated taxanes and unconjugated paclitaxel in plasma and urine, and of carboplatin in plasma ultrafiltrate and urine using WinNonlin Enterprise ver 4.1software (Pharsight Corporation, Mountain View, CA).
The study was carried out in two phases. The dose-seeking phase was designed to find the MTD of the study regimen. Once an estimate of the MTD was established, the second “feasibility” phase was initiated. The purpose of the feasibility phase was to obtain more precise estimates of the toxicity of the study regimen, to be assured that the recommended dose from the escalation phase was not too toxic for incorporation into a phase III trial.
A two-stage sequential design was used to assess the feasibility of delivering multiple cycles of the study regimen. The decision rules for whether or not to advance to the next stage of the study are summarized in . Based on the estimated frequency of dose modification and/or delay with the two-drug combination of carboplatin and paclitaxel in Protocol GOG-158, the regimen in this study would be considered not
feasible for a phase III study if the true event (DLT) probability within the first 4 cycles of therapy was ≥ 40%19
. If the true event rate for this regimen was 40%, this design provided a 91% chance of classifying the regimen as not feasible, with a 58% chance reaching this conclusion before beginning the second stage. If the event rate was as low as 20%, the design provided a 91% chance of classifying the regimen as feasible and a 63% chance of reaching this conclusion before beginning the second stage.