Beatriz Pardo

Phase I clinical and pharmacokinetic study of kahalalide F administered weekly as a 1-hour infusion to patients with advanced solid tumors.

Purpose: A dose-escalation, phase I study evaluated the safety, pharmacokinetics, and efficacy of a weekly 1-h regimen of kahalalide F, a cyclic depsipeptide isolated from the marine mollusk Elysia rufescens, in adult patients with advanced solid tumors and no standard treatment available. Experimental Design: Patients received an i.v. 1-h infusion of kahalalide F once weekly until disease progression or unacceptable toxicity. The starting kahalalide F dose was 266 μg/m2, and dose escalation proceeded based on the worst toxicity found in the previous cohort. Results: Thirty-eight patients were enrolled at three Spanish institutions and received once-weekly kahalalide F 1-h infusions at doses between 266 and 1,200 μg/m2. Dose-limiting toxicities consisted of transient grade 3/4 increases in transaminase blood levels. The maximum tolerated dose for this kahalalide F schedule was 800 μg/m2, and the recommended dose for phase II studies was 650 μg/m2. No accumulated toxicity was found. One patient with malignant melanoma had unconfirmed partial response, one patient with metastatic lung adenocarcinoma had minor response, and six patients with different types of metastatic solid tumors had stable disease for 2.8 to 12.7 months. The noncompartmental pharmacokinetics of this kahalalide F schedule was linear and showed a narrow distribution and short body residence. The transaminitis associated with kahalalide F was dose dependent. Conclusions: The maximum tolerated dose was 800 μg/m2. Dose-limiting toxicities with weekly kahalalide F 1-h i.v. infusions were transient grade 3/4 increases in blood transaminase levels, and 650 μg/m2 was declared the recommended dose for phase II studies. This schedule showed a favorable safety profile and hints of antitumor activity.

Volasertib Versus Chemotherapy in Platinum-Resistant or -Refractory Ovarian Cancer: A Randomized Phase II Groupe des Investigateurs Nationaux pour l'Etude des Cancers de l'Ovaire Study

PURPOSE Volasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase. This phase II trial evaluated volasertib or single-agent chemotherapy in patients with platinum-resistant or -refractory ovarian cancer who experienced failure after treatment with two or three therapy lines. PATIENTS AND METHODS Patients were randomly assigned to receive either volasertib 300 mg by intravenous infusion every 3 weeks or an investigators choice of single-agent, nonplatinum, cytotoxic chemotherapy. The primary end point was 24-week disease control rate. Secondary end points included best overall response, progression-free survival (PFS), safety, quality of life, and exploratory biomarker analyses. RESULTS Of the 109 patients receiving treatment, 54 received volasertib and 55 received chemotherapy; demographics were well balanced. The 24-week disease control rates for volasertib and chemotherapy were 30.6% (95% CI, 18.0% to 43.2%) and 43.1% (95% CI, 29.6% to 56.7%), respectively, with partial responses in seven (13.0%) and eight (14.5%) patients, respectively. Median PFS was 13.1 weeks and 20.6 weeks for volasertib and chemotherapy (hazard ratio, 1.01; 95% CI, 0.66 to 1.53). Six patients (11%) receiving volasertib achieved PFS fore more than 1 year, whereas no patient receiving chemotherapy achieved PFS greater than 1 year. No relationship between the expression of the biomarkers tested and their response was determined. Patients treated with volasertib experienced more grade 3 and 4 drug-related hematologic adverse events (AEs) and fewer nonhematologic AEs than did patients receiving chemotherapy. Discontinuation resulting from AEs occurred in seven (13.0%) and 15 (27.3%) patients in the volasertib and chemotherapy arms, respectively. Both arms showed similar effects on quality of life. CONCLUSION Single-agent volasertib showed antitumor activity in patients with ovarian cancer. AEs in patients receiving volasertib were mainly hematologic and manageable.

TGFβ Controls Ovarian Cancer Cell Proliferation

There have been no major improvements in the overall survival of ovarian cancer patients in recent decades. Even though more accurate surgery and more effective treatments are available, the mortality rate remains high. Given the differences in origin and the heterogeneity of these tumors, research to elucidate the signaling pathways involved is required. The Transforming Growth Factor (TGFβ) family controls different cellular responses in development and cell homeostasis. Disruption of TGFβ signaling has been implicated in many cancers, including ovarian cancer. This article considers the involvement of TGFβ in ovarian cancer progression, and reviews the various mechanisms that enable the TGFβ signaling pathway to control ovarian cancer cell proliferation. These mechanistic explanations support the therapeutic use of TGFβ inhibitors in ovarian cancer, which are currently in the early phases of development.

A phase I clinical and pharmacokinetic study (LIPOTEC - GP PHARM/DOXO 01) of a new liposomal doxorubicin given as 3-week schedule in patients with solid tumors

As a dose-finding phase I study of a new liposomal formulation of doxorubicin (LipD), patients (n = 39; median age: 60 years; range, 41–75; median ECOG performance status, 1; range, 0–2) with refractory cancer had a starting dose of LipD administered at 30 mg/m2 as a 1-hour iintravenous infusion. Cycle duration was 21 days. At the recommended dose (RD), patients received a first cycle of nonliposomal doxorubicin (non-LipD) to evaluate intrapatient pharmacokinetic differences between non-LipD and LipD. The most frequent diagnosis was head and neck tumor (7 patients). Tolerance and safety of dose levels of 30, 40, 50, 60, 70, 80, and 90 mg/m2 were evaluated. A total of 131 cycles were administered (median per patient, 3; range, 1–6). Of the 39 patients, 8 completed the planned six cycles. Febrile neutropenia was dose limiting and defined the toxic dose of LipD as 70 mg/m2. Other significant toxicities included asthenia (G2: 31%; G3: 8%), neutropenia (G3: 35%; G4: 29%), thrombopenia (G3: 15%; G4: 2%), anemia (G1–G2: 67%; G3–G4: 5%), mucositis (G1–G2: 32%, G3: 4%), and acute allergic reactions (G1–G2: 36%). Comparison of pharmacokinetic profiles of non-LipD and LipD showed that higher exposure was achieved with LipD. Stable disease was observed in 14 patients. We conclude that the LipD regimen, given as a 1-hour infusion every 3 weeks, is well tolerated and has a favorable pharmacokinetic profile. The recommended dose is 70 mg/m2 with prophylactic antihistamines and corticoids to preempt allergic reaction.

Abstract 5587: Phase I study of PM00104 in combination with carboplatin in patients (pts) with advanced solid tumors

Background: PM00104 (Zalypsis ® ) is a synthetic alkaloid related to Jorumycin with a strong antitumor activity against a wide variety of tumor lines. In vivo data of synergism between PM00104 and a platinum compound against human gastric and bladder xenografts prompted this study. Objectives: To identify the maximum tolerated dose (MTD) and the recommended dose (RD) of C given on day (d) 1 followed by PM00104 as a 1-hour i.v. infusion on d1, every three weeks. Secondary objectives were safety and feasibility of the treatment, pharmacokinetic (PK) analysis and antitumor activity. Methods: 20 pts with metastatic or advanced solid tumors were enrolled in a 3+3 dose escalation study design. If a dose-limiting toxicity (DLT) was deemed associated with prior treatment, separate expansions into two cohorts of either heavily or mildly pretreated (HP or MP) patients were to be conducted at each dose level (DL). HP was defined as any of the following: > 2 lines of chemotherapy, > 6 cycles of an alkylating agent or of a C-based regimen, therapy with mitomycin-C, therapy with any nitrosourea, high-dose therapy, or irradiation of areas bearing > 25% bone marrow. Results: Median age was 60 (34-73) years; male/female, 10:10; ECOG 0/1, 10:10. Most frequent cancers were colon and breast. After recruitment of 3 evaluable pts at DL1 (3 AUC C and 2 mg/m 2 PM00104), 1 DLT was found in 1 HP pt. Thus, the stratification of each cohort was started. As one patient in the MP cohort also experienced a DLT, both cohorts had to be expanded to include 6 evaluable pts. No more DLTs emerged and it was decided to treat a new cohort of MP pts at DL2 (4 AUC C and 2 mg/m 2 PM00104), while recruitment of HP pts was put on hold. Because 2 out of 6 MP pts at DL2 had DLTs, this dosing was declared the MTD and DL1 the RD. All 4 DLTs (HP, 1 out of 6 pt; MP, 3 out of 14 pts) consisted of grade 4 thrombocytopenia regardless of the intensity of the pretreatment. Grade 3-4 toxicities (including the aforementioned DLTs) were found in 11 pts and comprised mainly neutropenia (n=11), and thrombocytopenia (n=8), followed by nausea, vomiting, and diarrhea (all grade 3 in 1 pt), fatigue (n=1) and C-related hypersensitivity (n=1). Preliminary PK parameters showed similar characteristics to single-agent PM00104 (n=19): mean AUC, 80.53 h·ng/ml; Cmax, 29.84 ng/ml; CL, 47.80 L/h; Vdss, 630 L. Target AUC 3 (n=13) and 4 (n=6) for C were 2.6 and 3.7 mg/ml·min, respectively. No PK interactions were detected for PM00104 or for C. One pt with triple negative breast cancer achieved a partial response (time to progression, 11.6 months), and 3 pts had disease stabilizations > 3 months (colorectal, head and neck, and tumor of unknown origin). Conclusion The intensity (heavy or mild) of prior antitumor treatment seems not to have a major impact in dose escalation. The RD for this schedule was 3 AUC C and 2 mg/m 2 PM00104, however the combination suggests an overlapping toxicity that hampers dose escalation of either of the compounds. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5587. doi:1538-7445.AM2012-5587

Tomografía de emisión de positrones como método diagnóstico y guía para la cirugía de resección en la recidiva de cáncer de colon

Resumen La elevada frecuencia de recidivas tumorales en el cancer colorrectal hace que, al evaluar sus posibilidades terapeuticas quirurgicas, se efectuen estudios (eco/TAC/RMN) capaces de determinar el grado de diseminacion de la enfermedad. La tomografia de emision de positrones (PET) permite una mejor estadificacion de la extension de la recidiva metastasica, tal como se demuestra en los dos casos que presentamos (uno con una segunda recidiva ganglionar mesenterica y otro con recidiva exclusivamente hepatica), lo que permitio en ambos casos una exeresis de dicha recidiva con caracter radical. Queda por definir el impacto de la PET sobre los resultados de esta cirugia de rescate en el cancer colorrectal.