This phase I study sought to determine the toxicity profile, pharmacokinetics, and antitumor activity of giving carboplatin every 3 weeks and paclitaxel weekly in patients with relapsed ovarian cancer. Eligible patients with relapsed epithelial ovarian cancer and prior treatment with platinum- and paclitaxel-based therapy were treated with an escalating regimen of carboplatin (day 1) at an area under the curve (AUC) of 4–6 and 1-h infusions of paclitaxel (days 1, 8, and 15) at 50–80 mg/m 2 cycled at 3-week intervals. Pharmacokinetic studies were performed on the first day of cycles 1 and 2. All patients had a platinum-free interval of greater than 6 months from the most recent platinum treatment. A total of 77 cycles were administered to 16 patients, with a similar median number of cycles per patient at each dose level varying from 4.6 to 5.3. Febrile neutropenia and grade 4 thrombocytopenia were the dose-limiting toxicities at dose levels 3 and 4 after the third cycle, with no mucositis, nausea, vomiting, or peripheral neuropathy observed greater than grade 2. The maximum tolerated dose of carboplatin was an AUC of 5 and 80 mg/m 2 for paclitaxel. Pharmacokinetic analysis showed a marginal statistical difference with regard to reduced systemic paclitaxel concentration after cycle 2 compared with cycle 1 ( P = 0.06). Of nine patients evaluable for a radiographic response, the response rate was 66.6% with a complete response of 33.3%. All five patients with nonmeasurable disease achieved a biochemical response. The combination of carboplatin given every 3 weeks at an AUC of 5 and 1-h weekly paclitaxel at 80 mg/m 2 is a feasible and reasonably well-tolerated regimen and may have significant antitumor activity in relapsed ovarian cancer patients.
2073 Background: CT-2106 is a novel camptothecin (CPT) conjugate in which CPT is bound to a biodegradable water soluble poly-L-glutamic acid-glycine polymer. Conjugation of CPT to the polymer allows for greater stability in circulation, increased potential for exclusion from normal tissue, and enhanced permeability and retention in tumor tissue. CT-2106 has demonstrated significant anti-tumor activity in multiple human tumor cell lines in vivo, including lung and colon cancers. This study was designed to determine the pharmacokinetics of CT-2106 in patients with advanced malignancies. Methods: Patients were treated with CT-2106 as a 10 minute intravenous infusion every 21 days. Blood and urine samples were collected during treatment cycles 1 and 2. Samples were analyzed for conjugated and unconjugated CPT with validated HPLC/FD methods. Noncompartmental PK analysis of plasma concentration-time data was made by WinNonLin (Ver. 4.01). Results: Twenty-four patients have been treated. Conjugated CPT doses were 12 mg/m2 (3 patients), 25 mg/m2 (7), 50 mg/m2 (3), 75 mg/m2 (8), and 105 mg/m2 (3). Data is currently available from blood and urine samples from 17 patients (mean age 62.8, range 46–77). Plasma Cmax and AUC values for conjugated and unconjugated CPT indicate CT-2106 PK linearity from 12 to 75 mg/m2. The apparent termination t1/2 of unconjugated CPT is quite long -approximately 40 hours. Five days after the first administration (cycle 1), the excretion in urine of CT-2106 and unconjugated CPT accounted for 27.9% and 5.1% of the administered dose, respectively. The excretion pattern did not change during cycle 2. A major CPT conjugated species found in urine was glu-gly-CPT. Dose-limiting toxicities include: grade 3/4 neutropenia with concomitant grade 3 thrombocytopenia in 3 patients (105 mg/m2); grade 2 hematuria in 1 patient (25 mg/m2). Most adverse events have been mild or moderate. Conclusions: CT-2106 generates prolonged systemic exposures to unconjugated CPT in plasma; also, urine excretion levels of conjugated camptothecin are substantial. This study is ongoing to determine the MTD and collect further pharmacokinetc data. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cell Therapeutics, Inc.
2096 Background: : Chemotherapy is enhanced by multi-ATP-depleting therapy (Cancer Res. 60: 6776, 2000). Malignant tumors generally increase ATP production to increase cell division. In general, tumors make and consume (deplete) more ATP than normal tissues. If ATP production is equally inhibited in normal and tumor tissues, high ATP consumption (depletion) in tumors should deplete ATP to cytocidal levels, whereas the lower ATP consumption in normal cells should reduce ATP to tolerable levels. This rationale requires multiple ATP inhibitors inhibiting multiple biochemical pathways that produce ATP. Methods: Alanosine (AL), inhibitor of AMP synthesis, + 6-methylmercaptopurine riboside (MMPR), inhibitor of purine synthesis, preceded by PALA, a pyrimidine inhibitor; acronym, PALM. F16 blocks ATP synthesis by selectively accumulating in mitochondria of responsive breast cancers (Cancer Cell 2:29, 2002). Results: F16 alone was not effective. Taxotere alone (TXT), at MTD40, affects 100% PR of tumors. The addition of PALM (P100 AL250 M150), or PALM + F16 10, effects the same 100% P.R. at half the TXT dose (TXT20), suggesting clinical benefit at reduced normal tissue toxicities. Follow-up (120 days) demonstrates substantial tumor recurrence (43–50%) in Groups 1 and 2, and minimal recurrence (17%) in Group 3. Conclusions: A multi-ATP-depleting regimen (PALM + F16) + chemotherapy augments tumoricidal capability. Chemotherapy is at markedly lower doses, strongly suggesting lower toxic side-effects in the clinic. No significant financial relationships to disclose.
The objective of this study was to analyze retrospective populations with recurrent ovarian cancer to assess differences in CA-125 patterns during chemotherapy. The populations included all patients treated between January 1994 and January 2004, who received liposomal doxorubicin and topotecan, and all patients treated between July 1997 and June 2001, who received carboplatin. Prognostic variables were abstracted from the medical records. Eighty-nine patients received liposomal doxorubicin and topotecan therapy and 21 received carboplatin; of these, 59 (liposomal doxorubicin), 60 (topotecan), and 17 (carboplatin) patients had evaluable CA-125 patterns. Patients given liposomal doxorubicin were more likely to have received only one or two cycles of therapy (37/89 [42%]) than patients receiving either carboplatin (5/21 [24%]) or topotecan (20/89[22%]). In cycle 1, CA-125 increases in patients were carboplatin, 4/17 (24%); liposomal doxorubicin, 41/59 (69%); and topotecan, 11/60 (18%). In cycle 2, CA-125 increases were carboplatin, 2/16 (13%); liposomal doxorubicin, 19/37 (51%); and topotecan, 9/50 (18%). In cycle 3, CA-125 increases were carboplatin, 0/12 (0%); liposomal doxorubicin, 7/23 (30%); and topotecan, 6/38 (16%). Of patients having any CA-125 decrease and given two or more cycles, fewer declines were seen in those given liposomal doxorubicin precycle 2 (18/35[51%]) than in those given carboplatin (13/16[81%]) or topotecan (49/56[88%]). The most prominent delay in CA-125 decline was in patients given liposomal doxorubicin compared with those given topotecan or carboplatin. In the entire population, only 3 of 107 (2.8%) patients demonstrated first CA-125 decline precycle 4. Discontinuation of therapy solely on the basis of early CA-125 increase (precycle 3), particularly with liposomal doxorubicin chemotherapy, may exclude some patients who will benefit from continued therapy.
5541 Background: Over half of patients (pts) diagnosed with EOC are ≥ 65 yrs of age. GOG 172 showed a significant survival advantage with post-operative IPC in all women with newly diagnosed stage III EOC, regardless of age. Toxicity can be significant and there is limited data for pts ≥ 65 yrs. Methods: A descriptive intention-to-treat analysis of pts ≥ 65yrs treated with IPC for EOC at our center from 1994–2008. Medical records were reviewed retrospectively to detail toxicity (CTCAEv3.0), compliance and outcome. Results: 118 pts with a median age of 70 yrs (range 65–83), KPS 90% (range 70–90), and co-morbidities 2 (range 0–6) were treated with IPC: 27 pts (23%) as primary postoperative IPC (IV paclitaxel 135mg/m2 D1, IP cisplatin 75mg/m2 D2 & IP paclitaxel 60mg/m2 D8) and 91 pts (77%) as consolidation (IP cisplatin regimen, alone or combined with IV paclitaxel or with IP gemcitabine). Median no. of cycles was 3 (range 0–7) with 55% pts completed total no. planned. 18% were switched to IV treatment. 14% had treatment delays. 32% required dose reductions, 22% at cycle 1. Toxicities included: 32% had IP port complications, 42% functional decline, 43% new ≥ Gr1 neuropathy (4% Gr3), 12% Gr2 hearing impairment, 60% ≥ Gr1 nausea/vomiting (4% Gr3), 57% ≥ Gr1 diarrhea/constipation (0% Gr3), 37% ≥ Gr1 abdominal pain (2% Gr3). For evaluable pts, 78% had ≥ Gr1 electrolyte disturbance (5% Gr3–4), 71% ≥ Gr1 nephrotoxicity (5% Gr2; 1% Gr3), 20% ≥ Gr2 neutropenia (6%Gr3; 3% Gr4). Ca125 normalized in 90% (pts with elevated baseline Ca125). Kaplan-Meier estimated median PFI was 1.2yrs (95% CI: 1–1.6yrs). Conclusions: Rate of completed full IPC cycles and toxicity is similar to published data. IPC can be safely administered in pts ≥ 65yrs with adequate support and dose modifications. Older patients must be adequately represented in future prospective trials. No significant financial relationships to disclose.
