A dose-finding and pharmacokinetic study of IV vinflunine in combination with doxorubicin as first line treatment of metastatic breast cancer

Abstract Abstract #6124 Background: VFL is a novel bifluorinated tubulin-targeted agent of the vinca alkaloids class. In a phase II study in anthracycline and taxane pretreated MBC patients (pts), an ORR of 30% observed. Given activity shown by DXR or VFL in MBC, we conducted a phase I study of the combination, define maximum tolerated dose (MTD), recommended dose (RD), safety (NCI CTC 2.0), PK interaction and efficacy (Recist).&amp;#x2028; Methods: 2 schedules investigated (VFL D1 with DXR D1, every 3 weeks and VFL Ds 1 and 8, with DXR Ds 1 and 8, every 3 weeks). Eligibility: Pts with MBC, previously untreated for metastatic disease; could have received adj/neoadjuvant with anthracycline-containing regimen, cumulative doses &amp;lt; 250 mg/m² for DXR, 450 mg/m² for EPI. Dose escalation used 3+3 design; PK samples were obtained for VFL and DXR to investigate potential interaction.&amp;#x2028; &amp;#x2028; Results: 32 patients were enrolled (15 patients in schedule 1 and 17 in schedule 2) and received escalating doses of VFL and DXR.&amp;#x2028; In schedule 1, 2 dose levels (DL) were investigated; At DL VFL250/DXR50, 8 pts were treated with 6 patients evaluable for DLT, where 2 DLTs were identified consisting of neutropenia &amp;lt; 0.1x109/l &amp;gt; 3 days and a neutropenic infection; then this DL was considered MTD; at the DL VFL250/DXR40, 7 pts were treated without developing DLTs then considered RD. 73 cycles were administered (median 6); Most frequent haematological toxicity was neutropenia, gr 3 in 1 pt and gr 4 in 11 pts. Main non-haematological adverse events were: nausea 80%, fatigue 73.3%, constipation 40%, vomiting 40%, anorexia 33.3%, stomatitis 20%, dyspnea 13.3%. Clinical activity: 7 pts (46.7%) had PR, and 4 pts (26.7%) SD. No PK interaction was detected.&amp;#x2028; In schedule 2, at DL VFL150/DXR25, 6 of 9 pts were evaluable in whom 2 Gr 4 neutropenia &amp;gt; 7 days occurred, (DL considered as MTD). In the DL below VFL120/DXR25, 6 of 8 pts were evaluable, only 1 Gr 4 neutropenia &amp;gt; 7 days occurred, (DL considered RD). A total of 89 cycles (median 6) were administered; neutropenia was the main haematological toxicity, with Gr ¾ in 14 pts (82.4%); main non-haematological toxicities: fatigue 82.4%, constipation 76.5%, nausea 76.5%, vomiting 64.7%, stomatitis 41.2%, dyspnea 41.2%, anorexia 35.3%; no episode of Gr 4 occurred.&amp;#x2028; Among 17 treated pts, 8 (47.1%) had PR and 6 (35.3%) SD. PK analysis ongoing.&amp;#x2028; Conclusion: RD for schedule 1 is VFL250/DXR40 on day 1, Q3W, for schedule 2, VFL120/DXR25 on days 1 and 8, Q3W. Overall VFL/DXR combination is feasible and toxicity was manageable, where haematological toxicity was frequent but reversible. Promising antitumour activity was detected. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6124.</jats:p

Tolerability of sunitinib in combination with docetaxel and trastuzumab as first-line therapy for HER2+advanced breast cancer : Abstract #4120

Abstract Abstract #4120 Background: Trastuzumab (T) combined with docetaxel (D) is approved for the first-line treatment of HER2+ advanced BC (ABC). Sunitinib (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3 with single-agent activity in pts with previously treated ABC. The tolerability and preliminary antitumor activity of SU combined with D and T was investigated in this exploratory study as a first-line regimen for ABC.&amp;#x2028; Materials and methods: A target of 25 female pts (≥18 yrs, ECOG PS 0 or 1) with unresectable, locally recurrent or metastatic HER2+ BC are being enrolled. Starting doses for the 3 treatments are listed in the table below. The primary objective is safety. Secondary endpoints are PK and preliminary tumor activity according to RECIST. After discontinuation of D, responsive pts (PR or SD) can continue SU and T until PD.&amp;#x2028; &amp;#x2028; Results: As of May 2008, 18 pts were enrolled; 11 pts continue on study therapy and 7 have discontinued (5 due to PD; 1 due to pt decision; 1 due to G3 fatigue). Of the 18 pts enrolled, 16 are evaluable for safety and 11 for activity. Pts completed 75/96/98 cycles of D/SU/T, respectively, with a median of 5 cycles/pt for each drug (range: 1-13/1-12/1-13). The planned dose of SU (37.5 mg/d) was reduced to 25 mg/d in 6/16 pts due to G4 neutropenia (1); G3 febrile neutropenia (1); G3 fatigue (1); G2 hyperbilirubinemia (1); G2 hypertension (1); and G2 diarrhea (1). D was reduced in 4 pts due to febrile neutropenia (2) and G4 neutropenia (2). T was given q3w in 12 pts and wkly in 4 pts. T dosing was delayed by ≥4 days in 6 pts, 4 due to D dose delay and 2 due to AEs when D was already discontinued (G2 neutropenia and G3 fatigue). Overall, the most frequent AEs were fatigue (68.8%) and neutropenia (43.8%), consistent with the most common toxicities of D. No GI perforation or bleeding were reported. The most frequently reported severe AEs were neutropenia (1 G3 and 6 G4) and febrile neutropenia (5 G3). G-CSF was administered to 8 pts. Of the 11 pts evaluable for antitumor activity, 1 showed a confirmed CR, 7 a confirmed PR, 2 had PD and 1 was not evaluable.&amp;#x2028; Conclusions: The combination of SU 37.5 mg/d (Schedule 2/1) with D 75 mg/m2 q3w and T wkly/3-wkly, given as first-line treatment to HER2+ pts with ABC, shows manageable toxicities. The use of G-CSF appears beneficial. Preliminary antitumor activity is encouraging. Enrollment is ongoing. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4120.</jats:p

Breast cancer and renal insufficiency

Abstract Abstract #6086 Background:&amp;#x2028; The Belgian IRMA study (Renal Insufficiency and Anticancer Medications) reported the high prevalence of renal insufficiency (RI) in 1208 cancer patients, with a glomerular filtration rate (GFR) &amp;lt;90 ml/min for 64%. Furthermore, 78.1% were receiving potentially nephrotoxic drugs and 78.8% drugs necessitating dosage adjustment in case of renal dysfunction. We present here the results for the 510 BIRMA patients with breast cancer.&amp;#x2028; Methods:&amp;#x2028; Data were collected for patients presenting at one of the 7 BIRMA centers in March 2006: tumor, sex, age, weight, height, serum creatinine (SCR), bone metastasis (BM) and anticancer drugs (including dose modification). Glomerular Filtration Rate (GFR) was estimated by the aMDRD formula.&amp;#x2028; Results:&amp;#x2028; 510 breast cancer patients were included: mean age 58.7 years, weight 68.1 kg, height 161.6 cm, 4 men, 46.9% of patients had BM. The prevalence of elevated SCR (&amp;gt;=1.2 mg/dL) was 7.3%, of GFR&amp;lt;90 ml/min/1.73m² 67.8%, and of GFR&amp;lt;60 (threshold for many anticancer drugs to consider dose modification) 15.9% (Table). 86.6% of treated patients (n=486) were receiving at least one drug needing dosage adjustment in case of renal dysfunction and 73.4% received at least one potentially nephrotoxic drug. Furthermore, the prevalence of GFR&amp;lt;90/60 was 74.9/24.3% for breast cancer patients with BM (Table). When comparing the prevalence of GFR&amp;lt;90 between patients with or without BM (for patients with available GFR), the frequency of RI was significantly higher for BM patients (78.9 vs 69.9%, p=0.03).&amp;#x2028; Conclusions:&amp;#x2028; The results of the BIRMA study showed that RI is highly frequent in breast cancer patients in Belgium and that nearly 94% of the patients receive potentially nephrotoxic drugs and/or drugs for which dosage must be adjusted in RI. Furthermore, patients with BM had a higher rate of RI than patients without. These frequencies are higher compared to data from the NHANES study in the US general population, especially for breast cancer patients with a stage 3 RI for whom SCR was normal in 55.7% of the cases. This underlines that estimating renal function with formulae such as aMDRD is mandatory in every breast cancer patient, even when SCR is within the normal range.&amp;#x2028; &amp;#x2028; Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6086.</jats:p