Maybe, just maybe INCEL isn't *clinicaly* dead, as some investors proclaimed!
Few responded in P-refractory OC and improvement in response to M + P in HRPC.
[Proceedings of the 1999 AACR · NCI · EORTC International Conference]
Copyright © 1999 by the American Association for Cancer Research
#530 A Phase II study of IncelTM (biricodar, VX-710) + paclitaxel in women with advanced ovarian cancer refractory to paclitaxel therapy. Seiden M, Swenerton K, Matulonis U, Rose P, Batist G, Verma S, Oza A, Popadiuk C, Bessette P, Angers E, Ette E, Harding MW, Charpentier D. Massachusetts General Hospital, Boston MA, BCCA, Vancouver, BC, Dana Farber Cancer Institute, Boston MA, Macdonald Women's Hospital, Cleveland, OH, Jewish General Hospital, Montreal QC, ORCC, Ottawa, ON, Princess Margaret Hospital, Toronto, ON, H Bliss Murphy Cancer Center, St John, NF, CUSE, Fleurimont, QC, BioChem Pharma, Laval, QC, Vertex Pharmaceuticals Incorporated, Cambridge MA, CHUM, Pavillon Notre-Dame, Montreal, QC.
Incel/VX-710 is a potent inhibitor of multidrug resistance mediated by P-glycoprotein (P-gp) and MRP expression. Varying levels of P-gp and MRP are expressed (40 and 60%, respectively) in patients (pts) with advanced ovarian cancer. We initiated a Phase II study to evaluate safety, pharmacokinetics and efficacy of Incel + paclitaxel (P) in advanced ovarian cancer pts refractory to prior P therapy. Inclusion criteria; 2 prior regimens for pts with advanced ovarian carcinoma; progressive disease on P, or documented progressive within 4 months of prior P therapy; bi-dimensional measurable disease; ECOG performance status 2; normal renal, liver and bone marrow function. Pts receive a 24-hr Incel infusion (120 mg/m2/hr) with 3-hr P at 80 mg/m2 (P AUC and time >0.05 µM comparable to 3 hour 175 mg/m2 P). Endpoints; response rate, response duration and CA125 levels. As of July 1999, 34 patients have enrolled and >100 cycles of Incel/P have been administered. Safety data is available for 22 pts. Incel/P has been well tolerated. Myelosuppression is the principal toxicity. Median (range) cycle 1 WBC and ANC nadirs were 2.05 (0.7-6.3) and 0.49 (0.02-3.85) x 109/L, respectively. The most frequent non-hematological toxicities (nausea, vomiting, asthenia, neuropathy, fever, diarrhea) were mild to moderate. Among the 1st 25 evaluable pts, 14/25 received 4-9 treatment cycles and only 7 pts terminated with PD after 1-2 cycles. Significant CA125 decreases (ranging from 40-90%) were observed in 56% of pts (14/25; 4 pts with >50% and 9 with >75% reductions, respectively) that were sustained for up to 18 weeks. One CR, 2 PRs and 2 MRs (>30% tumor shrinkage) have been observed thus far and 9 pts continue on therapy. Incel/P therapy results in objective responses in strictly defined P refractory ovarian carcinoma pts and in sustained CA125 reductions in a high percentage of pts.
[Proceedings of the 1999 AACR · NCI · EORTC International Conference]
Copyright © 1999 by the American Association for Cancer Research
#531 A Phase II study of the safety, pharmacokinetics and efficacy of Incel (biricodar, VX-710) in combination with mitoxantrone (M) and prednisone (P) in hormone refractory prostate cancer (HRPC). Einstein Jr A, Lush R, Rago R, Ko Y-J, Bubley G, Henner WD, Beer T, Chatta G, Shepard R, Unger P, Merica EA, Ette E, Harding MW, Dalton WS. Moffitt Cancer Center, Tampa, FL, Beth Israel Deaconess Hospital, Boston MA, Oregon Health Sciences University, Portland OR, Arkansas Cancer Research Ctr, Little Rock, AR, Greater Baltimore Medical Ctr, Baltimore, MD, Vermont Ctr Cancer Medicine, Burlington, VT, and Vertex Pharmaceuticals Incorporated, Cambridge, MA.
Incel is a potent inhibitor of multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) and MRP expression. Prostate tumors have a high incidence of MRP expression and a variable incidence of P-gp. Since mitoxantrone (M) and prednisone (P) are both substrates for MDR transporters, we initiated a Phase II study of Incel + M/P in HRPC patients (pts). Endpoints: primary--serum PSA response rate; secondary--response duration, pain reduction, analgesic consumption and QOL measures. Inclusion criteria: progressive HRPC (defined as new lesions, new disease related pain, or a 50% increase in PSA within 6 weeks of study entry); testosterone <30 ng/ml; no prior chemotherapy; ECOG performance status 0-3; adequate organ function. Pts receive Incel (120 mg/m2/hr) as a 72 hr CIVI with M (12 mg/m2) administered 4 hrs after starting Incel and P (5 mg bid) administered throughout study treatment. As of July 1999, 40 pts have been enrolled and >130 courses of Incel + M/P have been administered. Six pts received a cycle of M/P alone then Incel + M/P with intensive pharmacokinetics sampling. Pharmacokinetic analysis (n = 6) shows that Incel does not alter M clearance [median (range) of 0.35 (0.13-0.97) and 0.38 (0.11-0.54) L/h/kg for M/P alone and Incel + M/P, respectively]. Incel + M/P has been well tolerated. Transient Gr 1/2 nausea & vomiting and Gr 1/2 neutropenia are the principal treatment toxicities: 5 pts experienced an uncomplicated febrile neutropenic episode, 3 pts had Gr 3 nausea/vomiting, and 1 pt had Grade 3 ataxia. Among 25 evaluable pts, 10 achieved PSA responses: 8 with >80% PSA reductions sustained for up to 27 wks, and 2 active pts at >50% with PSAs continuing to decline. Twenty evaluable pts have discontinued therapy (6 with PD and 9 with SD, 5 PSA response pts are in follow-up), 14 pts are too early to assess, and 6 non-evaluable pts discontinued prematurely. Incel + M/P can produce substantial and prolonged PSA reductions in HRPC pts and may improve responses and response duration compared to M/P alone. |
