PHASE
I/II STUDY WITH THE MDR INHIBITORTM (BIRICODAR, VX-710) + DOXORUBICIN
(DOX) IN ANTHRACYCLINE RESISTANT ADVANCED SOFT TISSUE SARCOMA (STS)
Demetri GD,1 Morris D,2 Ernst S,2
Hings I,3 Blackstein M,4 Venner P,5 Plessis-Belair
D,6 Ette E,7 Harding MW,7 Hunt W,6
Bramwell VHC.8 1Dana Farber Cancer Institute,
2Tom Baker Cancer Centre, 3Montreal General Hospital,
4Mount Sinai Hospital, 5Cross Cancer Institute.
6BioChem Pharma, 7Vertex Pharmaceuticals Incorporated,
8London Regional Cancer Centre.
IncelTM restores drug sensitivity to both MDR1 and MRP expressing cells. A Phase I/II study Incel + DOX is complete. Phase I evaluated DOX at 60-75 mg/m2 to establish the optimal dose for Phase II. Patients (pts) and inclusion criteria: inoperable, locally advanced or metastatic STS; measurable disease; anthracycline resistant/refractory (documented progression on DOX defined as: appearance of new lesions, or >25% increase in measurable lesions within 8 weeks of study entry, or untreated GI stromal sarcoma/leiomyosarcoma metastatic to liver); < 225 mg/m2 cumulative DOX; adequate hematological, liver, and kidney function. In Phase I, IV bolus DOX at 60, 75 or 67.5 mg/m2 was administered 4 hr after initiation of a 72-hr CIV of Incel at 120 mg/m2/hr. Cycles were repeated q 3 weeks. Plasma samples were collected for determination of DOX pharmacokinetics.
Phase I: 14 pts were enrolled: demographics: 7M/7F, median age 55 (range 26-64); histologic subtypes: leiomyosarcoma (6 pts), GI stromal sarcoma (6 pts), MFH (1 pt), malignant schwannoma (1 pt); 6 pts DOX naïve, 8 pts with a median (range) cumulative prior DOX exposure of 150 mg/m2 (135-225 mg/m2). Cohorts of 3 pts received DOX at 60, 75 and then 67.5 mg/m2. No DLTs were observed at 60 mg/m2, but 2/3 pts at both 75 mg/m2 and the intermediate 67.5 mg/m2 dose experienced DLT (febrile neutropenia). Median (range) cycle 1 ANC nadirs for the 60, 67.5 and 75 mg/m2 cohorts were 0.6 (0.05-1.3), 0.2 (0.03-0.4), and 0 (0-1.8) x 109/L, respectively. Incel had no apparent effect on DOX AUCs, Vss, or clearance. Five additional pts were enrolled at 60 mg/m2; pts in the 67.5 and 75 mg/m2 cohorts continued treatment with dose reductions. Phase I established 120 mg/m2/hr Incel + 60 mg/m2 DOX as the appropriate dose for Phase II.
Phase II: 28 pts were enrolled, including 6 pts treated with 60 mg/m2 DOX in Phase I. Demographics- (17M/11F), median age 51.7 (range 23-5); histologic subtypes: leiomyosarcoma (9 pts), Gl stromal sarcoma (10 patients), MFH (1 pt), malignant schwannoma (1 pt), liposarcoma (1 pt), spindle cell sarcoma (2 pts), synovial sarcoma (2 pts), neurogenic sarcoma (1 pt), high-grade undifferentiated epithelioid tumor (1 pt), MFH (1 pt); 24 pts with metastatic disease; 10 pts DOX naïve, 18 pts with a mean (range) cumulative prior DOX exposure of 138 mg/m2 (60-225 mg/m2) over 2-3 cycles. A total of 106 cycles of Incel + 60 mg/m2 doxorubicin were administered. Response data for 25 evaluable pts are summarized below by tumor histology.
| Tumor Histology |
No.
Pts
|
Early
Progression
|
Stable
Disease
|
Partial
Response
|
|
|
||||
| Non-GI Stromal |
15
|
6
|
7
|
2
|
| GI Stromal |
10
|
9
|
1
|
0
|
| Overall |
25
|
15
|
8
|
2
|
One PR pt had a response duration of 53 wks and 2 pts (1 PR and 1 SD/minor response pt) had surgical resections with curative intent. Non-hematological side effects (asthenia, nausea, abdominal pain, vomiting, stomatitis, diarrhea, headache) were generally mild to moderate and reversible. Incel + DOX had minimal activity in the 10 pts with GI stromal sarcomas, but 2 PRs and 7 disease stabilizations were observed in the 15 patients (13.3% objective response rate) with non-GI stromal sarcomas who progressed on prior DOX. Incel + DOX should be further evaluated in non-GI stromal sarcoma pts.
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