First-in-Human Phase I Study of MP0250, a First-in-Class DARPin Drug Candidate Targeting VEGF and HGF, in Patients With Advanced Solid Tumors.

Purpose: A first-in-human study was performed with MP0250, a DARPin drug candidate. MP0250 specifically inhibits both vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) with the aim of disrupting the tumor microenvironment.

Patients And Methods: A multicenter, open-label, repeated-dose, phase I study was conducted to assess the safety, tolerability, and pharmacokinetics of MP0250 in 45 patients with advanced solid tumors.

Targeting angiogenesis in multiple myeloma by the VEGF and HGF blocking DARPin protein MP0250: a preclinical study.

The investigational drug MP0250 is a multi-specific DARPin molecule that simultaneously binds and neutralizes VEGF and HGF with high specificity and affinity. Here we studied the antiangiogenic effects of the MP0250 in multiple myeloma (MM). In endothelial cells (EC) isolated from bone marrow (BM) of MM patients (MMEC) MP0250 reduces VEGFR2 and cMet phosphorylation and affects their downstream signaling cascades.

Phase I/II study of cetuximab in combination with cisplatin or carboplatin and fluorouracil in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.

Purpose: This was an open, randomized, multicenter, phase I/II study to investigate the safety and tolerability of cetuximab in the first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN).

Patients And Methods: Treatment comprised cetuximab (initial dose 400 mg/m2 with subsequent weekly doses of 250 mg/m2) in combination with 3-week cycles of either cisplatin (100 mg/m2) or carboplatin (area under the curve, 5), each in combination with a 5-day infusion of fluorouracil (FU) at escalating doses of 600, 800, and 1,000 mg/m2/d. The study was divided into two phases: A, the first two cycles (6 weeks) focusing on the safety and tolerability of combination therapy; and B, the remaining time for those benefiting from therapy until disease progression or intolerable toxicity.

Decreased repopulation as well as increased reoxygenation contribute to the improvement in local control after targeting of the EGFR by C225 during fractionated irradiation.

Background And Purpose: Inhibition of repopulation and enhanced reoxygenation has been suggested to contribute to improvement of local tumour control after fractionated irradiation combined with inhibitors of the epidermal growth factor receptor (EGFR). The present study addresses this hypothesis in FaDu human squamous cell carcinoma. For this tumour model marked repopulation and incomplete reoxygenation during fractionated irradiation has previously been demonstrated.

Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck.

Purpose: To evaluate the efficacy and safety of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN).

Patients And Methods: Ninety-six eligible patients received cetuximab (initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2) followed by platinum chemotherapy at the same dose and schedule at which progressive disease was documented before entry onto the study.

Results: The response rate, based on an independently read assessment, in the intent-to-treat population was 10%, with a disease control rate (complete response, partial response [PR], and stable disease) of 53%.

Different classes of EGFR inhibitors may have different potential to improve local tumour control after fractionated irradiation: a study on C225 in FaDu hSCC.

Background And Purpose: Previous experiments reported from this laboratory have shown that simultaneous application of the selective epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitor BIBX1382BS during fractionated irradiation significantly prolonged growth delay of FaDu human squamous cell carcinoma but did not improve local tumour control. The present study investigates the effect of the EGFR monoclonal antibody (mAb) C225 on local tumour control of FaDu tumours after combined treatment with single dose and fractionated irradiation to address whether different classes of EGFR inhibitors have different potential to improve the outcome of radiotherapy in the same tumour model.

Material And Methods: In unirradiated tumours, C225 was given either once or 4 times i.

Phase I/II study of capecitabine and vinorelbine in pretreated patients with metastatic breast cancer.

Purpose: To define the maximum-tolerated dose (MTD) and to evaluate the dose-limiting toxicities (DLT) of the combination of capecitabine and vinorelbine in patients with metastatic breast cancer who relapse after adjuvant and/or first-line treatment. In addition, we aimed to obtain data on efficacy and safety at the recommended dose.

Patients And Methods: Patients with measurable metastatic breast cancer after failure of prior chemotherapy (including anthracyclines and/or taxanes) were eligible.

High-dose chemotherapy with autologous stem cell transplantation in patients with oligometastatic breast cancer.

The purpose of this prospective trial was to study a combined-modality treatment including local consolidation by surgery or radiotherapy and high-dose chemotherapy (HDC) followed by peripheral-blood stem-cell (PBSC) transplantation. In all, 48 patients with oligometastatic breast cancer amenable to local treatment after induction chemotherapy with epirubicin and cyclophosphamide or paclitaxel and cisplatin, depending on prior adjuvant chemotherapy, were enrolled. The median follow-up was 41 months (range, 7-85 months).

Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.

Background: The epidermal growth factor receptor (EGFR), which participates in signaling pathways that are deregulated in cancer cells, commonly appears on colorectal-cancer cells. Cetuximab is a monoclonal antibody that specifically blocks the EGFR. We compared the efficacy of cetuximab in combination with irinotecan with that of cetuximab alone in metastatic colorectal cancer that was refractory to treatment with irinotecan.

New systemic frontline treatment for metastatic colorectal carcinoma.

Options for first-line chemotherapy in patients with metastatic colorectal carcinoma have broadened considerably with the introduction of irinotecan and oxaliplatin. Furthermore, the oral fluoropyrimidine capecitabine has demonstrated efficacy in Phase III trials and recently was approved for first-line treatment in Europe and the United States. Capecitabine yielded similar median times to disease progression and median survival rates compared with bolus 5-fluorouracil (5-FU)/leucovorin (LV) (Mayo Clinic/North Central Cancer Treatment Group regimen), with superior and similar response rates, respectively.

Phase I study of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor.

Purpose: To investigate the safety and tolerability and to explore the pharmacokinetic and pharmacodynamic profile of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with solid tumors that express epidermal growth factor receptor (EGFR).

Patients And Methods: This was a phase I dose-escalation trial of EMD72000 in patients with advanced, EGFR-positive, solid malignancies that were not amenable to any established chemotherapy or radiotherapy treatment. EMD72000 was administered weekly without routine premedication until disease progression or unacceptable toxicity.

Capecitabine and irinotecan as first-line chemotherapy in patients with metastatic colorectal cancer: results of an extended phase I study.

Background: To define the maximum-tolerated dose (MTD) and to evaluate the dose-limiting toxicities (DLTs) of the combination of capecitabine and irinotecan in patients with metastatic colorectal cancer.

Patients And Methods: Thirty-seven patients with measurable metastatic colorectal cancer with no prior chemotherapy for metastatic disease were treated at three dose levels (DLs). For the first two dose levels, irinotecan (70 mg/m(2)) was administered once a week for 6 weeks in combination with 2 weeks of capecitabine at 1000 mg/m(2) (DL1) or 1250 mg/m(2) (DL2) twice daily, starting on days 1 and 22.

Irinotecan in the treatment of colorectal cancer: clinical overview.

Purpose And Methods: For more than three decades, the therapeutic options for patients with advanced colorectal cancer have almost exclusively been based on fluoropyrimidines. With the recognition that topoisomerase-I (TOP-I) is an important therapeutic target in cancer therapy, irinotecan, a semisynthetic TOP-I-interactive camptothecin derivative, has been clinically established in the treatment of colorectal cancer.

Results: Irinotecan was investigated as second-line chemotherapy after prior treatment with fluorouracil (FU)-based regimens in two large randomized phase III trials comparing irinotecan with either best supportive care or an infusional FU/leucovorin (LV) regimen.

Clinical phase I dose escalation and pharmacokinetic study of high-dose chemotherapy with treosulfan and autologous peripheral blood stem cell transplantation in patients with advanced malignancies.

A Phase I dose escalation and pharmacokinetic study of the alkylating cytotoxic agent treosulfan was conducted to evaluate the maximum tolerated dose and the dose-limiting toxicities in patients with advanced malignancies rescued by autologous peripheral blood stem cell transplantation. Twenty-two patients (15 ovarian and 7 other carcinomas/lymphomas) with a median age of 48 years were treated with 28 high-dose courses. Treosulfan was infused over 2 h at escalating doses from 20 to 56 g/m2, and pharmacokinetic parameters were analyzed.

Detection of germ-cell tumor cells in the peripheral blood by nested reverse transcription-polymerase chain reaction for alpha-fetoprotein-messenger RNA and beta human chorionic gonadotropin-messenger RNA.

By establishing sensitive nested reverse transcription-PCRs for the detection of mRNA of alpha-fetoprotein (AFP) and beta human chorionic gonadotropin (betahCG), we investigated the presence of circulating tumor cells in the peripheral blood of 119 patients with germ-cell tumor. A total of 336 blood samples obtained before and during therapy were examined with regard to clinical applicability. The overall ratio of positive PCR results was 26.

Ifosfamide-based drug combinations: preclinical evaluation of drug interactions and translation into the clinic.

Ifosfamide is an alkylating antineoplastic agent with documented activity against a variety of solid tumor types, most notably lung cancer, testicular cancer, and sarcoma. Ifosfamide has been included in various drug combination protocols, usually on an empirical basis. To gather more insight into the mechanisms that underlie these drug interactions and to develop guidelines for further improvement of clinical combination protocols, we performed a broad preclinical evaluation program of ifosfamide-based combination regimens using isobologram analysis of drug interactions.

Raltitrexed (Tomudex) in combination with 5-fluorouracil for the treatment of patients with advanced colorectal cancer: preliminary results from phase I clinical trials.

The potential of raltitrexed (Tomudex) in combination with 5-fluorouracil (5-FU) as treatment for advanced colorectal cancer has been investigated in two phase I clinical trials. In the first study, raltitrexed was combined with bolus 5-FU; patients received raltitrexed as a 15-min infusion followed 24 h later by bolus 5-FU every 3 weeks. In the second study, 5-FU was administered as a weekly 24-h infusion for 5 weeks of a 6-week cycle and raltitrexed was given 15-min prior to 5-FU on days 8 and 29.

Reversal of MDR1-associated resistance to topotecan by PAK-200S, a new dihydropyridine analogue, in human cancer cell lines.

Recent data suggest that expression of the membrane P170-glycoprotein (P-gp) may confer resistance to the topoisomerase-I-interactive agent topotecan. The present study describes the cellular effects of a new dihydropyridine analogue, PAK-200S, on P-gp-mediated resistance to topotecan in human breast and ovarian tumour cells. PAK-200S at a non-cytotoxic concentration of 2.

Treatment of patients with cisplatin-refractory testicular germ-cell cancer. German Testicular Cancer Study Group (GTCSG).

With the use of cisplatin-based combination chemotherapy, metastatic testicular germ-cell tumors can be cured in 70% to 80% of patients. The combination of cisplatin, etoposide and bleomycine (PEB) is considered standard therapy. Patients refractory to cisplatin-based chemotherapy have a markedly poor prognosis.

First-line high-dose chemotherapy compared with standard-dose PEB/VIP chemotherapy in patients with advanced germ cell tumors: A multivariate and matched-pair analysis.

Purpose: To compare first-line high-dose chemotherapy (HD-CT) with autologous blood stem-cell transplantation to standard-dose chemotherapy (SD-CT) in male patients with advanced germ cell tumors (GCTs), a matched-pair analysis was performed within a homogenous group of patients classified as having either Indiana advanced disease or a poor prognosis according to International Germ Cell Cancer Consensus Group (IGCCCG) criteria.

Patients And Methods: A multivariate analysis was performed that included 147 consecutive patients who had received sequential high-dose cisplatin, etoposide, and ifosfamide (VIP) therapy (HD-CT) in a German multicenter trial between 1993 and 1997 and 309 patients who had been treated with standard-dose cisplatin, etoposide, and bleomycin (PEB) or VIP chemotherapy (SD-CT) within two randomized trials at Indiana University between 1984 and 1992.

Results: Multivariate analysis demonstrated HD-CT to be significantly superior to SD-CT when adjustments were made for prognostic factors (P =.

Paclitaxel and UFT plus oral calcium folinate in pretreated metastatic breast cancer.

This phase I study was designed to determine the maximum tolerated dose (MTD) and dose-limiting side effects of combination treatment with paclitaxel (Taxol) and UFT (uracil and tegafur in a 4:1 molar ratio) plus oral calcium folinate (Orzel) for advanced metastatic breast cancer. After premedication, patients received paclitaxel as a 3-hour IV infusion (175 mg/m2) on day 1; UFT was administered orally at 300 mg/day (dose level 1), 400 mg/day (dose level 2), 500 mg/day (dose level 3), or 600 mg/day (dose level 4) in combination with 90 mg/day of calcium folinate in three divided doses for 14 days. Twenty patients with pretreated metastatic breast cancer have entered the trial so far.

Thrombopoietin serum levels at the start of mobilization, collection, and transfusion of autologous peripheral blood stem cells.

Thrombopoietin (TPO) serum levels in 14 patients (9 male and 5 female, mean age 36 years, range 16 to 55 years) with breast cancer (n = 5), testicular cancer (n = 7), or lymphoma (n = 2), undergoing high dose chemotherapy with peripheral blood stem cell (PBSC) transplantation, were evaluated at the first day of the mobilization chemotherapy (1), at the day of the first apheresis (2), and at the day of stem cell transfusion (3). All patients have been pretreated (one to four regimens) and received chemotherapy and granulocyte colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) both at 5 microg/kg body weight (bw). for stem cell mobilization.

Kinetic study of CD34+ cells during peripheral blood stem cell collections.

The impact of the separated volume on the yield of CD34+ cells during peripheral blood stem cell collections (PBSCC) remains controversial. We therefore studied the CD34+ cell concentration in the peripheral blood of patients (pts) during PBSCC as well as the total amount of CD34+ cells collected after each blood volume (BV) processed and engraftment data for each cycle of high dose chemotherapy (HD Ctx). A total of 21 PBSCC from 20 patients with different malignancies were analyzed.