A Phase II study of the polyamine analog N1,N11-diethylnorspermine (DENSpm) daily for five days every 21 days in patients with previously treated metastatic breast cancer.

PURPOSE: Polyamines are ubiquitous intracellular polycationic molecules essential for cell growth and differentiation. Polyamine analogs down-regulate ornithine decarboxylase, induce spermidine/spermine N1-acetyltransferase, deplete natural polyamine pools, inhibit growth, and induce programmed cell death in breast cancer models. This study evaluated the activity of the first-generation analog DENSpm in women with metastatic breast cancer. EXPERIMENTAL DESIGN: The overall accrual goal was 34 patients (30 evaluable) in a two-stage design. The second stage of accrual was to proceed if > or =2 among first 15 evaluable patients were progression free at 4 months. The primary objective was to determine whether > or =20% of metastatic breast cancer patients treated with DENSpm as second- or third-line therapy remained progression free after 4 months. RESULTS: Sixteen patients (median age, 52 years; range, 34-65; median performance status, 1; range, 0-1) enrolled in the first stage received 43 cycles (median, 2; range, 1-6) of 100 mg/m2 DENSpm as a 15-min infusion i.v. on days 1-5 every 21 days. All 16 patients were evaluable for toxicity; 15 were evaluable for response. All patients had disease progression by 4 months, and the study closed after the first stage of accrual. The main toxicities included grade 1-2 abdominal pain, transient perioral numbness, nausea, and grade 1 thrombocytopenia. Two patients had grade 3 abdominal pain during cycle 2 infusion: one was hospitalized, and another was subsequently retreated at 80% dose without pain recurrence. CONCLUSIONS: Although this dose and administration schedule of DENSpm was quite tolerable, no evidence of clinical activity was detected. Encouraging preclinical activity of polyamine analogs alone and in combination with cytotoxic drugs supports the continued evaluation of newer-generation polyamine analogs for the treatment and prevention of breast cancer.

A phase 2 trial of immunotherapy with mitumprotimut-T (Id-KLH) and GM-CSF following rituximab in follicular B-cell lymphoma.

We evaluated the efficacy and safety of patient-specific immunotherapy with mitumprotimut-T idiotype keyhole limpet hemocyanin and granulocyte-monocyte colony-stimulating factor (GM-CSF) following rituximab in patients with follicular B-cell lymphoma. Patients with previously untreated or relapsed/refractory CD20+ follicular lymphoma received 4 weekly infusions of rituximab and those with a complete response (CR), partial response (PR), or stable disease received mitumprotimut-T and GM-CSF injections subcutaneously. Courses were given monthly for 6 doses, every 2 months for 6 doses, and then every 3 months until disease progression. Computed tomography scans were obtained every 3 to 6 months and reviewed centrally. The primary endpoint was event-free survival (EFS). Among 103 patients treated with rituximab, 92 (54 relapsed/refractory and 38 previously untreated) received mitumprotimut-T/GM-CSF; median age was 53 years, 91% had stage III to IV disease, and 59% had failed earlier therapy. The premitumprotimut-T objective response rate was 47% (2 CRs, 41 PRs). During the mitumprotimut-T treatment phase, 16 patients converted to CR resulting in an overall objective response rate of 60% (18 CRs, 37 PRs). Median EFS was 15.2, 20.8, and 13.5 months for all, treatment-naive, and relapsed/refractory disease patients, respectively. Anti-Id cellular immune responses were detected in 13 of 18 (72%) patients and humoral immune responses in 17 of 83 (20%) patients. Adverse events were usually mild-to-moderate. The most common adverse event was injection site reactions. Mitumprotimut-T/GM-CSF-induced anti-Id cellular immune responses in most patients. The occurrence of late CRs and favorable EFS suggested a clinical benefit of active immunotherapy and led to a placebo-controlled phase 3 trial.

Placebo-controlled phase III trial of patient-specific immunotherapy with mitumprotimut-T and granulocyte-macrophage colony-stimulating factor after rituximab in patients with follicular lymphoma.

PURPOSE: To evaluate patient-specific immunotherapy with mitumprotimut-T (idiotype keyhole limpet hemocyanin [Id-KLH]) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in CD20(+) follicular lymphoma. PATIENTS AND METHODS: Patients with treatment-naive or relapsed/refractory disease achieving a complete response (CR), partial response (PR), or stable disease (SD) with four weekly rituximab infusions were randomly assigned to mitumprotimut-T/GM-CSF or placebo/GM-CSF, with doses given monthly for six doses, every 2 months for six doses, and then every 3 months until disease progression (PD). Randomization was stratified by prior therapy (treatment-naive or relapsed/refractory) and response to rituximab (CR/PR or SD). The primary end point was time to progression (TTP) from randomization. RESULTS: A total of 349 patients were randomly assigned; median age was 54 years, 79% were treatment naive, and 86% had stage III/IV disease. Median TTP was 9.0 months for mitumprotimut-T/GM-CSF and 12.6 months for placebo/GM-CSF (hazard ratio [HR] = 1.384; P = .019). TTP was comparable between the two arms in treatment-naive patients (HR = 1.196; P = .258) and shorter with mitumprotimut-T/GM-CSF in relapsed/refractory disease (HR = 2.265; P = .004). After adjusting for Follicular Lymphoma International Prognostic Index (FLIPI) scores, the difference in TTP between the two arms was no longer significant. Overall objective response rate, rate of response improvement, and duration of response were comparable between the two arms. Toxicity was similar in the two arms; 76% of adverse events were mild or moderate, and 94% of patients had injection site reactions. CONCLUSION: TTP was shorter with mitumprotimut-T/GM-CSF compared with placebo/GM-CSF. This difference was possibly due to the imbalance in FLIPI scores.

Phase II trial of idiotype vaccination in previously treated patients with indolent non-Hodgkin's lymphoma resulting in durable clinical responses.

PURPOSE: To evaluate idiotype (Id) vaccination as a single agent in previously treated patients with indolent non-Hodgkin's lymphoma. PATIENTS AND METHODS: Patients underwent biopsy for determination of their lymphoma-specific Id sequence. Recombinant Id protein was manufactured and covalently linked with keyhole limpet hemocyanin (KLH) to generate Id/KLH. Patients received Id/KLH 1 mg on day 1 subcutaneously, with granulocyte-macrophage colony-stimulating factor 250 mug on days 1 to 4, monthly for 6 months. Booster injections were administered until progression. Both clinical and immune responses were evaluated. RESULTS: Thirty-two previously treated patients received at least one injection of Id/KLH, and 31 were assessed for efficacy. Responses were observed in four patients (one complete response and three partial responses). Median time to onset of response was 5.9 months (range, 2.3 to 14.1 months). Median duration of response has not been reached but should be at least 19.4 months (range, 10.4 to 27.2+ months). Median time to progression is 13.5 months. The most common adverse events were mild to moderate injection site reactions. Six (67%) of nine patients tested demonstrated a cellular immune response, and four (20%) of 20 patients demonstrated an antibody response against their Id. CONCLUSION: This trial demonstrates that Id/KLH alone can induce tumor regression and durable objective responses. Further study of Id/KLH is recommended in other settings where efficacy may be further enhanced as in first-line therapy or after cytoreductive therapy.

Ametantrone acetate: anthracenedione diacetate, NSC-287513

El acetato de ametantrona es el compuesto padre de una serie de antracenodionas actualmente sometidois a pruebas clínicas en los Estados Unidos. Se sintetizaron estos compuestos en un intento de eliminar la toxicidad cardíaca asociada con antibióticos antraciclínicos sin sacrificar la actividad clínica. El acetato dea meyantrona parece funcionar como un agente intercalador. En sistemas de tumores murinos, la droga produce curas en leucemias P388 y L1210, melanoma B16 y carcinoma de colon 26. En perros, los objetivos principales de la toxicidad fueron la médula ósea, el tejido linfoide, la vía gastrointestinal y los testículos. La droga no es activa por vía orla. El acetato de ametantrona muestra una curva dósis/repuesta de inclinación relativamente alta. La administración intravenosa rápida en ratones produce convulsiones instantáneas y muerte. Aunque menos frecuente y menos severa que la toxicidad producida por antraciclinas, pudo demostrarse toxicidad cardíaca en ratones, ratas, conejos y perros. El acetato de ametantrona es un compuesto de un azul intenso que imparte color azul a la orina, la materia fecal, la piel y a los órganos internos. El período de vida media plasmático de la droga es aproximadamente dos horas. Se han comenzado tres estudios clínicos Fase 1: dos utilizan un régimen de una sola dósis y uno un régimen de 5 días. Hasta la fecha se han notado muy pocas respuestas. La toxicidades más importantes han sido leucopenia, decoloración azul de la piel, alopecia e hipotensión ortostática. La dósis inicial recomendada para estudios fase 2 de una sola dósis en pacientes de alto riesgo es 140 mg/m2

Phase 1 and 2 trials of diaziquone (AZQ) in patients with brain tumors: a clinical review

La diaziquona es una aziridinilobenzoquinona con acción alquilante y lipofilicidad que permite que la droga cruce la barrera hematoencefálica. Este comupuesto muestra un espectro amplio de actividades en rumores murinos, incluyendo actividad curativa contra varios tumores endoencefálicos implantados (ependimoblastoma). Este artículo revisa la información clínica disponible sobre diaziquona en pacientes con tumores cerebrales. En diez estudios Fase1, se observaron indicadores de actividad SNC en tumores metástaticos y primarios en varios pacientes. En cuatro estudios preliminares Fase 2, se administró la droga cada cuatro semanas a pacientes con tumores cerebrales. El regimen de tratamiento y las respuestas fueron las siguientes: 22.5 a 27.5 mg/m2 cada 4 semanas produjo 5 respuestas parciales (PR) en 29 casos evaluables (EC); de 6 a 8 mg/m2qd x 5,4 PR/16 EC; 20 mg/m2 (días 1, 8), 4 PR/15 EC; 17.5 mg/m2 (días 1,8), 1 PR/20 EC. Se observaron remisiones prolongadas y estabilización de la enfermedad en algunos de estos pacientes, la mayoría de los cuales habían sido previamente tratados con radioterapia y quimioterapia. La toxicidad más signficativa fue la hipoplasia de la médula ósea. Al parecer, la actividad máxima de diaziquona es contra los tumores cerebrales primarios y en futuras evaluaciones este compuesto debe ser la primera droga en la quimioterapia

The phase I trial

Los objetivos del estudio del estudio Fase 1 en el desarrollo de drogas anticancer son: determinar la dósis más alta tolerada, programas de administración, patrones de toxicidad, propiedades farmacoquinéticas, y si fuera posible, potencial terapéutico. Su diseño depende grandemente de datos obtenidos en el desarrollo preclínico. Muchos protocolos requieren una dósis inicial a nivel de 1/10 de la dósis letal en ratones (en mg/m2), escalando por etapas, siguiendo un esquema tipo Fibonacci, y administrando la droga una vez o diariamente por cinco días cada tres o cuatro semanas. Los estudios Fase 1 se limitan a pacientes con función hepática y renal relativametne buena y con neoplasias clínicamente estables que han sido confirmadas histológicamente y son resistentes a teapia convencional. Los hallazgos correlacionados dósis/programa con niveles plasmáticos/toxicidad son incorporados en el diseño de estudios terapéuticos subsiguientes