A phase I clinical and pharmacokinetic study of capecitabine (Xeloda®) and irinotecan combination therapy (XELIRI) in patients with metastatic gastrointestinal tumours

Capecitabine is a highly active oral fluoropyrimidine that is an attractive alternative to 5-fluorouracil in colorectal cancer treatment. The current study, undertaken in 27 patients with gastrointestinal tumours, aimed to assess the toxicity and potential for significant pharmacokinetic interactions of a combination regimen incorporating capecitabine with 3-weekly irinotecan (XELIRI). Irinotecan (200 and 250 mg m−2) was administered as a 90-min infusion on day 1 in combination with escalating capecitabine doses (700–1250 mg m−2 twice daily) administered on days 2–15 of a 3-week treatment cycle. Pharmacokinetics were characterised on days 1 and 2 of the first two cycles. A total of 103 treatment cycles were administered. The principal dose-limiting toxicities were diarrhoea and neutropenia. Capecitabine 1150 mg m−2 twice daily with irinotecan 250 mg m−2 was identified as the maximum-tolerated dose and capecitabine 1000 mg m−2 with irinotecan 250 mg m−2 was identified as the recommended dose for further study. Analyses confirmed that there were no significant pharmacokinetic interactions between the two agents. The combination was clinically active, with complete and partial responses achieved in heavily pretreated patients. This study indicates that XELIRI is a potentially feasible and clinically active regimen in patients with advanced gastrointestinal cancer

Phase I study of humanized monoclonal antibody AVE1642 directed against the type 1 insulin-like growth factor receptor (IGF-1R), administered in combination with anticancer therapies to patients with advanced solid tumors

BACKGROUND: Type 1 insulin-like growth factor receptor (IGF-1R) mediates resistance to chemotherapy and targeted agents. This study assessed the safety, pharmacokinetics (PK), and tolerability of humanized IGF-1R antibody AVE1642 with other cancer treatments. PATIENTS: Patients with advanced solid tumors received three weekly AVE1642 dosed at 6 mg/kg, chosen following previous study, with 75 (cohort A) or 100 mg/m(2) (B) docetaxel, 1250 mg/m(2) gemcitabine/100 mg erlotinib (C1), or 60 mg/m(2) doxorubicin (D1). Blood samples were assayed for PK, IGFs, and IGF-BP3. RESULTS: Fifty-eight patients received 317 AVE1642 infusions. The commonest adverse events were diarrhea (37/58 patients), asthenia (34/58), nausea (30/58), and stomatitis (21/58). Dose-limiting toxic effects in cohorts C1 (diarrhea) and D1 (neutropenia) prompted addition of cohorts C2 (1000 mg/m(2) gemcitabine/75 mg erlotinib) and D2 (50 mg/m(2) doxorubicin). Grade 3-4 hyperglycemia (three cases) accompanied steroid premedication for docetaxel administration. No PK interactions were detected. There were three partial responses in cohorts B (melanoma) and C (leiomyosarcoma, two cases) and 22 stabilizations ≥12 weeks, giving a control rate of 25/57 (44%). On treatment IGF-II rose by 68 ± 25 ng/ml in patients discontinuing treatment <12 weeks, and fell by 55.5 ± 21 ng/ml with disease control (P < 0.001). CONCLUSION: AVE1642 was tolerable with 75-100 mg/m(2) docetaxel and 1000 mg/m(2) gemcitabine/75 mg erlotinib, achieving durable disease control in 44%, with an association between IGF-II and response

P3-16-08: A Phase 2, Randomized Open-Label Study of Iniparib, Administered Either Weekly or Twice-Weekly in Combination with Gemcitabine Plus Carboplatin in Patients with mTNBC.

Abstract Background Iniparib (BSI-201) is an investigational anticancer agent whose precise mechanism of action is under active investigation. In breast cancer cell lines and xenograft models of triple-negative breast cancer (TNBC), iniparib exhibits anti-proliferative activity and potentiates the cell cycle effects of some DNA damaging agents. In a randomized, open-label phase 2 study in pts with metastatic TNBC (mTNBC), iniparib combined with gemcitabine (G) and carboplatin (C) (GC) improved efficacy outcomes compared with GC alone. A confirmatory phase 3 study with GCI failed to meet pre-specified criteria for PFS and OS; however, an exploratory subset analysis demonstrated a potential benefit amongst 2nd/3rd line pts (O'Shaughnessy et al. ASCO 2011). Here we report results of a randomized phase 2 study (NCT01045304) in pts with mTNBC, which assesses efficacy and pharmacokinetics (PK) of iniparib administered either biw or qw in combination with GC. Patients and methods: Eligible pts (N=163; median age 49 yrs) had documented and measurable TNBC, ECOG PS 0–1, normal organ/marrow function, and had received ≤2 prior chemotherapy (CT) regimens for metastatic disease. Pts were randomized (1:1) to receive G (1,000 mg/m2, IV, d 1, 8) plus C (AUC 2, IV, d 1, 8) and iniparib either biw (5.6 mg/kg, IV d 1,4,8,11) or qw (11.2 mg/kg, IV d 1,8) on a 21 d cycle. Pts were stratified according to prior CT for mTNBC (0 vs. 1–2). The primary efficacy endpoint was overall response rate (ORR; CR + PR); secondary endpoints included: clinical benefit rate (CBR; CR + PR + SD for 24 weeks), PFS, OS and PK. Results: At the time of analysis, 23% of patients were still on treatment. The median number of cycles administered per patient was 6 in both arms; exposure to iniparib was identical. Safety data are not fully validated. All pts experienced at least 1 treatment emergent adverse event (TEAE). Grade (Gr) ≥3 TEAEs occurred in 94% and 85% of pts in the biw and qw arms, respectively. TEAEs Gr ≥3 occurring in ≥5% of pts regardless of relationship to study drug (biw vs qw) are as follows: blood and lymphatic 71% vs 67%; hepatobiliary 7.5% vs 9.8%; asthenia/fatigue 7.5% vs 11%; GI 8.8% vs 8.5%; infections 7.5% vs 3.7%; respiratory, thoracic and mediastinal 5% vs 8.5%, metabolism and nutrition 4% vs 6%. For response data see table. No major difference was observed in drug exposure (based on AUC within one cycle) between the two dosing regimens. Conclusion: Dosing of GCI on a qw schedule produced a similar ORR to that obtained with the biw schedule. A comparable safety profile in both arms, and consistency with results of previous studies, suggests that the weekly combination of GCI may be an appropriate schedule for further studies evaluating this combination. OS and PFS data are not yet mature; updated efficacy and safety data will be presented. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-08.</jats:p