I. A. M. Mandjes

Phase I clinical and pharmacokinetic study of PNU166945, a novel water-soluble polymer-conjugated prodrug of paclitaxel.

Intravenous administration of paclitaxel is hindered by poor water solubility of the drug. Currently, paclitaxel is dissolved in a mixture of ethanol and Cremophor EL; however, this formulation (Taxol®) is associated with significant side effects, which are considered to be related to the pharmaceutical vehicle. A new polymer-conjugated derivative of paclitaxel, PNU166945, was investigated in a dose-finding phase I study to document toxicity and pharmacokinetics. A clinical phase I study was initiated in patients with refractory solid tumors. PNU16645 was administered as a 1-h infusion every 3 weeks at a starting dose of 80 mg/m2, as paclitaxel equivalents. Pharmacokinetics of polymer-bound and released paclitaxel were determined during the first course. Twelve patients in total were enrolled in the study. The highest dose level was 196 mg/m2, at which we did not observe any dose-limiting toxicities. Hematologic toxicity of PNU166945 was mild and dose independent. One patient developed a grade 3 neurotoxicity. A partial response was observed in one patient with advanced breast cancer. PNU166945 displayed a linear pharmacokinetic behavior for the bound fraction as well as for released paclitaxel. The study was discontinued prematurely due to severe neurotoxicity observed in additional rat studies. The presented phase I study with PNU166945, a water-soluble polymeric drug conjugate of paclitaxel, shows an alteration in pharmacokinetic behavior when paclitaxel is administered as a polymer-bound drug. Consequently, the safety profile may differ significantly from standard paclitaxel.

Phase II trial of topically applied miltefosine solution in patients with skin-metastasized breast cancer.

SummarySkin deposits from breast cancer can present serious therapeutic problems, especially when resistant to conventional therapy. Topical application of a cytotoxic drug may represent an attractive new treatment modality devoid of major systemic toxicity. Miltefosine was selected because of its efficacy in breast cancer models. A mixture of alkylated glycerols of various chain lengths and water was used as the pharmaceutical vehicle to dissolve and to further facilitate tissue penetration of miltefosine. In our Institute a phase II study was performed to determine the efficacy and tolerability of topically applied miltefosine in patients with cutaneous metastases from breast cancer. Thirty-three patients in total entered the trial. A 6% miltefosine solution was applied once daily in the first week and twice daily in the following weeks. The planned minimum treatment duration was 8 weeks. We found an overall response rate of 43% for 30 evaluable patients, composed of 23% complete response and 20% partial response. The median response duration was 18 weeks, range 8–68. Toxicity consisted mainly of localized skin reactions, which could be controlled by a paraffin-based skin cream and, where appropriate, by dose modification. No systemic toxicities were observed. We conclude that topical miltefosine is an effective treatment modality in patients with skin metastases from breast cancer.

Phase I and pharmacological study of sequential intravenous topotecan and oral etoposide.

We performed a phase I and pharmacological study to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of a cytotoxic regimen of the novel topoisomerase I inhibitor topotecan in combination with the topoisomerase II inhibitor etoposide, and to investigate the clinical pharmacology of both compounds. Patients with advanced solid tumours were treated at 4-week intervals, receiving topotecan intravenously over 30 min on days 1-5 followed by etoposide given orally twice daily on days 6-12. Topotecan-etoposide dose levels were escalated from 0.5/20 to 1.0/20, 1.0/40, and 1.25/40 (mg m-2 day-1)/(mg bid). After encountering DLT, additional patients were treated at 3-week intervals with the topotecan dose decreased by one level to 1.0 mg m-2 and etoposide administration prolonged from 7 to 10 days to allow further dose intensification. Of 30 patients entered, 29 were assessable for toxicity in the first course and 24 for response. The DLT was neutropenia. At doses of topotecan-etoposide 1.25/40 (mg m-2)/(mg bid) two out of six patients developed neutropenia grade IV that lasted more than 7 days. Reduction of the treatment interval to 3 weeks and prolonging etoposide dosing to 10 days did not permit further dose intensification, as a time delay to retreatment owing to unrecovered bone marrow rapidly emerged as the DLT. Post-infusion total plasma levels of topotecan declined in a biphasic manner with a terminal half-life of 2.1 +/- 0.3 h. Total body clearance was 13.8 +/- 2.7 l h-1 m-2 with a steady-state volume of distribution of 36.7 +/- 6.2 l m-2. N-desmethyltopotecan, a metabolite of topotecan, was detectable in plasma and urine. Mean maximal concentrations ranged from 0.23 to 0.53 nmol l-1, and were reached at 3.4 +/- 1.0 h after infusion. Maximal etoposide plasma concentrations of 0.75 +/- 0.54 and 1.23 +/- 0.57 micromol l-1 were reached at 2.4 +/- 1.2 and 2.3 +/- 1.0 h after ingestion of 20 and 40 mg respectively. The topotecan area under the plasma concentration vs time curve (AUC) correlated with the percentage decrease in white blood cells (WBC) (r2 = 0.70) and absolute neutrophil count (ANC) (r2 = 0.65). A partial response was observed in a patient with metastatic ovarian carcinoma. A total of 64% of the patients had stable disease for at least 4 months. The recommended dose for use in phase II clinical trials is topotecan 1.0 mg m-2 on days 1-5 and etoposide 40 mg bid on days 6-12 every 4 weeks.

Neoadjuvant chemotherapy adaptation and serial MRI response monitoring in ER-positive HER2-negative breast cancer.

Background:Changing the neoadjuvant chemotherapy regimen in insufficiently responding breast cancer is not a standard policy. We analysed a series of patients with ‘luminal’-type breast cancer in whom the second half of neoadjuvant chemotherapy was selected based on the response to the first half.Methods:Patients with oestrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2−) breast cancer received three courses of neoadjuvant dose-dense doxorubicin and cyclophosphamide (ddAC). Three further courses of ddAC were administered in case of a ‘favourable response’ on the interim magnetic resonance imaging (MRI) and a switch to docetaxel and capecitabine (DC) was made in case of an ‘unfavourable response’, using previously published response criteria. The efficacy of this approach was evaluated by tumour size reductions on serial contrast-enhanced MRI, pathologic response and relapse-free survival.Results:Two hundred and forty-six patients received three courses of ddAC. One hundred and sixty-four patients (67%) had a favourable response at the interim MRI, with a mean tumour size reduction of 31% after the first three courses and 34% after the second three courses. Patients with unfavourable responsive tumours had a mean tumour size reduction of 12% after three courses and received three courses of DC rather than ddAC. This led to a mean shrinkage of 27%.Conclusion:The tumour size reduction of initially less responsive tumours after treatment adaptation adds further evidence that a response-adapted strategy may enhance the efficacy of neoadjuvant chemotherapy.

Paclitaxel, carboplatin, and trastuzumab in a neo-adjuvant regimen for HER2-positive breast cancer.

To evaluate a nonanthracycline‐containing regimen consisting of 24 weekly administrations of paclitaxel, carboplatin, and trastuzumab as neo‐adjuvant therapy for human epidermal growth factor receptor 2 (HER2)‐positive breast cancer. Patients with stage II or III breast cancer, including inflammatory disease, with HER2 overexpression (immunohistochemistry and/or fluorescent in situ hybridization) were treated with 24 weekly administrations of paclitaxel 70 mg/m2, carboplatin AUC = 3 mg/mL/minute, and trastuzumab 2 mg/kg (loading dose 4 mg/kg). In cycles 7, 8, 15, 16, 23, and 24, only trastuzumab was given. The primary end point was pathologic complete response (pCR) in both breast and axilla. Of 61 evaluable patients, 61% had stage II disease and 75% were node‐positive. The median NRI (Neoadjuvant Response Index, a measure of the degree of downstaging by chemotherapy) of all patients was 0.86. Twenty‐seven (44%) had a NRI of 1.0, which corresponds to pCR in breast and lymph nodes. The most commonly reported grade 3/4 toxicities were neutropenia (72%) and thrombocytopenia (36%). Dose reduction was necessary in 51% of the patients. A weekly carboplatin–paclitaxel–trastuzumab neo‐adjuvant regimen is highly active in HER2‐positive breast cancer with an acceptable toxicity profile. A multicenter phase 2 trial has recently reached its accrual target and will serve as a basis for a subsequent randomized phase 3 study comparing this regimen to a similar regimen preceded by anthracyclines.

Toxicity of dual HER2-blockade with pertuzumab added to anthracycline versus non-anthracycline containing chemotherapy as neoadjuvant treatment in HER2-positive breast cancer: The TRAIN-2 study

BACKGROUND The addition of pertuzumab to neoadjuvant trastuzumab-based chemotherapy improves pathologic complete response rates in HER2-positive breast cancer. However, increased toxicity has been reported with the addition of pertuzumab, and this may differ between various chemotherapy backbone regimens. We evaluated toxicities of pertuzumab when added to either FEC-T (5-fluorouracil, epirubicin, cyclophosphamide, trastuzumab) or weekly paclitaxel, trastuzumab, carboplatin (PTC). METHODS The TRAIN-2 study is a neoadjuvant randomized controlled trial in stage II and III HER2-positive breast cancer (NCT01996267). Patients are randomly assigned to receive either three cycles of FEC-T plus pertuzumab or three cycles of PTC plus pertuzumab, followed by six cycles of PTC plus pertuzumab in both arms. Toxicities are described per treatment arm according to the Common Toxicity Criteria for Adverse Events version 4.03. RESULTS This analysis includes 110 patients balanced over both treatment arms. Neutropenia was the most common hematologic toxicity, with grade 3-4 occurring in 53% in the FEC-T-arm and in 51% in the PTC-arm. Febrile neutropenia occurred in 9% in the FEC-T arm and did not occur in the PTC-arm. Secondary G-CSF prophylaxis was used in 35-40% of patients. Asymptomatic ejection fraction decrease grade 2 was observed in 24% in the FEC-T-arm and 11% in the PTC-arm. The most common grade 3-4 non-hematologic toxicity was diarrhea (5% in the FEC-T-arm and 18% in the PTC-arm). CONCLUSIONS Pertuzumab in combination with FEC-T mostly causes neutropenia, and when added to PTC mostly causes diarrhea. Significant cardiac toxicity is rare with both regimens, and toxicity is overall well manageable.

Copy number profiling by array comparative genomic hybridization identifies frequently occurring BRCA2-like male breast cancer

Genomic aberrations can be used to subtype breast cancer. In this study, we investigated DNA copy number (CN) profiles of 69 cases of male breast cancer (MBC) by array comparative genomic hybridization (aCGH) to detect recurrent gains and losses in comparison with female breast cancers (FBC). Further, we classified these profiles as BRCA1‐like, BRCA2‐like or non‐BRCA‐like profiles using previous classifiers derived from FBC, and correlated these profiles with pathological characteristics. We observed large CN gains on chromosome arms 1q, 5p, 8q, 10p, 16p, 17q, and chromosomes 20 and X. Large losses were seen on chromosomes/chromosome arms 1p, 6p, 8p, 9, 11q, 13, 14q, 16q, 17p, and 22. The pattern of gains and losses in estrogen receptor positive (ER+) MBC was largely similar to ER+ FBC, except for gains on chromosome X in MBC, which were uncommon in FBC. Out of 69 MBC patients, 15 patients (22%) had a BRCA2‐like profile, of which 2 (3%) were also BRCA1‐like. One patient (1%) was only BRCA1‐like; the remaining 53 (77%) patients were classified as non‐BRCA‐like. BRCA2‐like cases were more often p53 accumulated than non‐BRCA‐like cases (P = 0.014). In conclusion, the pattern of gains and losses in ER+ MBC was largely similar to that of its ER+ FBC counterpart, except for gains on chromosome X in MBC, which are uncommon in FBC. A significant proportion of MBC has a BRCA2‐like aCGH profile, pointing to a potentially hereditary nature, and indicating that they could benefit from a drug regimen targeting BRCA defects as in FBC.

Independent replication of polymorphisms predicting toxicity in breast cancer patients randomized between dose-dense and docetaxel-containing adjuvant chemotherapy

Introduction Although pharmacogenomics has evolved substantially, a predictive test for chemotherapy toxicity is still lacking. We compared the toxicity of adjuvant dose-dense doxorubicin-cyclophosphamide (ddAC) and docetaxel-doxorubicin-cyclophosphamide (TAC) in a randomized multicenter phase III trial and replicated previously reported associations between genotypes and toxicity. Results 646 patients (97%) were evaluable for toxicity (grade 2 and higher). Whereas AN was more frequent after ddAC (P < 0.001), TAC treated patients more often had PNP (P < 0.001). We could replicate 2 previously reported associations: TECTA (rs1829; OR 4.18, 95% CI 1.84-9.51, P = 0.001) with PNP, and GSTP1 (rs1138272; OR 2.04, 95% CI 1.13-3.68, P = 0.018) with PNP. Materials and methods Patients with pT1-3, pN0-3 breast cancer were randomized between six cycles A60C600 every 2 weeks or T75A50C500 every 3 weeks. Associations of 13 previously reported single nucleotide polymorphisms (SNPs) with the most frequent toxicities: anemia (AN), febrile neutropenia (FN) and peripheral neuropathy (PNP) were analyzed using logistic regression models. Conclusions In this independent replication, we could replicate an association between 2 out of 13 SNPs and chemotherapy toxicities. These results warrant further validation in order to enable tailored treatment for breast cancer patients.

Abstract 3134: Neoadjuvant chemotherapy in ER+HER2- breast cancer: Response prediction based on immunohistochemical and molecular characteristics

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Introduction: A pathological complete remission (pCR) is rarely achieved by neoadjuvant chemotherapy (NAC) in ER+HER2- tumors. Therefore, its use might be questionable in specific groups of this tumor type. To select which patients benefit and which could be withheld from NAC, we tested standard pathology and molecular markers in ER+HER2- breast tumors. Methods: Pre-treatment biopsies were available from 211 ER+HER2- tumors, which had been treated with NAC. mRNA expression and aCGH data were available for 132 tumors. We determined progesterone receptor (PR)expression, endocrine responsiveness, histology, proliferation, molecular subtypes and BRCAness aCGH profiles. We correlated these data with chemotherapy response using pCR rates and the neoadjuvant response index (NRI). Results: PR-negative tumors (n = 65, 30.8%) and Luminal B type tumors (n=43, 20.4%) responded significantly better to NAC than other tumors, for both pCR breast and the NRI as outcome measure ([table 1][1]). The associations remained significant in multivariate analysis. However, even in the subgroup of patients with the lowest response rate (tumors with both a positive PR and of the Luminal A type (n=58, 44 %)), the majority showed downstaging (median NRI=0.25)([table 1][1]). For endocrine responsiveness and the BRCAness aCGH profile only an association with pCR breast was observed. Histology (lobular versus ductal) and proliferation did not show an association with chemotherapy response ([table 1][1]). Discussion: PR expression and molecular subtype are associated with a better response to NAC. However, both markers had only weak predictive power and it was not possible to identify a subgroup with no or only minimal chemotherapy benefit. Therefore, the decision to refrain patients from NAC in ER+HER2- breast tumors should not be based on predictive markers, but exclusively on estimates of prognosis. ![Figure][2] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3134. doi:10.1158/1538-7445.AM2011-3134 [1]: #F1 [2]: pending:yes

P3-14-17: Paclitaxel, Carboplatin, and Trastuzumab in a Neoadjuvant Regimen for HER2−Positive Breast Cancer: The TRAIN Study.

Background: Treatment with trastuzumab is highly active in HER2 positive breast cancer, although cardiotoxicity is a well known side effect. The cardiotoxicity of trastuzumab may be aggravated by combined treatment with anthracyclines. Consequently, treatment with trastuzumab is often delayed pending the administration of anthracyclines. Both in vitro and in vivo data suggest that trastuzumab synergizes with a range of chemotherapeutic drugs, including taxoid drugs and carboplatin. In addition, prolonged pre-operative treatment leads to higher pathologic complete remission (pCR) rates. We report the results of a fase 2 trial integrating trastuzumab at the start of a non-anthracycline containing weekly paclitaxel-carboplatin based neo-adjuvant chemotherapy regimen in HER2−positive breast cancer. Patients and methods: One-hundred patients with stage II or III breast cancer, including inflammatory disease, with HER2 overexpression (immunohistochemistry and/or in situ hybridization) were treated with 24 weekly administrations of paclitaxel 70 mg/m2, carboplatin AUC=3 mg.ml-1.min, and trastuzumab 2 mg/kg (loading dose 4 mg/kg). In cycles 7, 8, 15, 16, 23, and 24 only trastuzumab was given. The primary end point was pathologic complete response (pCR) in both breast and axilla. The trial was preceded by an initial pilot cohort of 55 patients treated with the same regimen. Results: Final efficacy and safety results of all patients included in the phase 2 trial will be reported at the meeting. In the pilot cohort of 55 similarly treated patients, 33% had stage II disease, 69% was clinically node positive, and 49% was ER and PgR negative. Twenty-four patients (41%) had a pCR in breast and lymph nodes. pCR in ER negative patients was 67%, pCR in ER positive patients was 21%. The most commonly reported grade 3/4 toxicities were neutropenia (30%) and thrombocytopenia (27%). Dose reduction was required in 24% of the patients. Grade 3/4 left ventricular systolic dysfunction was not observed. Conclusion: A weekly carboplatin-paclitaxel-trastuzumab neo-adjuvant regimen is highly active in HER2 positive breast cancer with a good safety profile. A subsequent multicenter phase 3 trial will compare this regimen to a similar 16 week regimen preceded by 4 cycles of anthracyclines plus cyclophosphamide. The study protocol was developed at the joint ECCO-AACR-EORTC-ESMO Workshop on Methods in Clinical Cancer Research in Flims, Switserland. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-17.