Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study.

BACKGROUND: HannaH (NCT00950300) was a phase III, randomized, international, open-label study that compared pharmacokinetics (PK), efficacy, and safety of two different trastuzumab formulations [subcutaneous (s.c.) and intravenous (i.v.)] in HER2-positive, operable, locally advanced, or inflammatory breast cancer in the neoadjuvant/adjuvant setting. The co-primary end points, to show noninferiority of s.c. versus i.v. trastuzumab in terms of serum concentration (Ctrough) and pathologic complete response (pCR) were met; safety profiles were comparable at 12 months' median follow-up. Secondary end points included safety and tolerability, PK profile, immunogenicity, and event-free survival (EFS). We now report updated safety and efficacy data after a median follow-up of 20 months. PATIENTS AND METHODS: Patients (N = 596) were treated with eight cycles of neoadjuvant chemotherapy, administered concurrently with 3-weekly s.c. trastuzumab (fixed dose of 600 mg) or the standard weight-based i.v. method. Following surgery, patients continued trastuzumab treatment to complete 1 year of therapy. Updated analyses of PK, efficacy, safety, and immunogenicity data were carried out. RESULTS: s.c. trastuzumab was generally well tolerated and the incidence of adverse events (AEs), including grade 3 or 4 AEs, between treatment groups was comparable. A slightly higher incidence of serious AEs (SAEs), mainly due to infections, was reported with s.c. treatment {64 [21.5%; 95% confidence interval (CI) 17.0%-26.7%] versus 42 (14.1%; 95% CI 10.4%-18.6%) in the i.v. group}; however, the differences were small and often based on rare events, with no observable pattern across reported events. An early analysis of EFS showed rates of 95% in both groups 1 year postrandomization. Exploratory analyses did not reveal an association between toxicity and body weight or exposure. CONCLUSIONS: Overall, the safety profile of s.c. trastuzumab was consistent with the previously published data from HannaH and the known safety profile of i.v. trastuzumab. EFS rates were comparable between the i.v. and s.c. groups. CLINICAL TRIAL NUMBER: NCT00950300.

Immunotherapy of metastatic malignant melanoma by a vaccine consisting of autologous interleukin 2-transfected cancer cells: outcome of a phase I study.

We performed a phase I trial to evaluate the safety and tolerability of repeated skin injections of IL-2-transfected autologous melanoma cells into patients with advanced disease. Cell suspensions, propagated from excised metastases, were IL-2 gene transfected by adenovirus-enhanced transferrinfection and X-irradiated prior to injection. Vaccine production was successful in 54% of the patients. Fifteen patients (37%) received two to eight skin vaccinations of either 3 x 10(6) (intradermal) or 1 x 10(7) (half intradermal, half subcutaneous) transfected melanoma cells per vaccination (secreting 140-17,060 biological response modifier program units of IL-2/10(6) cells/24 hr). Analyses of safety and efficacy were carried out in 15 and 14 patients, respectively. Overall, the vaccine was well tolerated. All patients displayed modest local reactions (erythema, induration, and pruritus) and some experienced flu-like symptoms. Apart from newly appearing (4 of 14) and increasing (5 of 14) anti-adenovirus and newly detectable anti-nuclear antibody titers (1 of 15), recipients developed de novo or exhibited increased melanoma cell-specific delayed-type hypersensitivity (DTH) reactions (8 of 15) and vitiligo (3 of 15) and showed signs of tumor regression (3 of 15). This supports the idea of a vaccine-induced or -amplified anti-cancer immune response. None of the patients exhibited complete or partial regressions, but five of them experienced periods of disease stabilization. Three of these individuals received more than the four planned vaccinations and their mean survival time was 15.7 +/- 3.5 months as compared to 7.8 +/- 4.6 months for the entire patient cohort. These data indicate that IL-2-producing, autologous cancer cells can be safely administered to stage IV melanoma patients and could conceivably be of benefit to patients with less advanced disease.

A computer module for the continuous monitoring of cardiac output in the operating theatre and the ICU.

A new pulse contour method to determine stroke volume and cardiac output continuously in patients on a beat-to-beat basis from the aortic pressure wave has been implemented in the form of a simple, inexpensive, fully automatic computing module for a commercially available patients monitoring system (Philips Medical Systems). Its reliability has been tested and shown in a computer analog, in experimental studies in 10 dogs (not reported here), in 22 hemodynamic studies on 20 young healthy volunteers and during 41 days in 20 postsurgical patients in the ICU, the most important result being that erros figures (15 and 19% respectively in the two human studies) are of the same order as when two standard methods, Fick and dye dilution are compared. The clinical studies have further indicated the easy applicability of the module 1 degree in the monitoring of critically ill patients in ICU's, 2 degrees as a monitor of the systemic circulation during anesthesia, and 3 degrees as a tool for studying the hemodynamic effects of pharmacological agents. The instrument consitutes no burden to the patients and has, several times during the course of the evaluation, provided an early warning of a deteriorating hemodynamic status of the patient to the physician.

The effect of splenopentin (DA SP-5) on in vitro myelopoiesis and on AZT-induced bone marrow toxicity.

Splenopentin (DA SP-5) is a pentapeptide corresponding to the amino acid sequence 32-36 (Arg-Lys-Glu-Val-Tyr) of the splenic hormone splenin. We examined the influence of DA SP-5 on bone marrow progenitor cell (BMC) proliferation. DA SP-5 acts as a co-stimulant for recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) in the induction of human BMC derived colony formation in vitro (colony-forming units). When exposed to DA SP-5 and thereafter to AZT and rHuGM-CSF, BMCs show a colony-forming response similar to that after cultivation with the rHuGM-CSF alone. In contrast, when exposed to AZT and rHuGM-CSF (and not preincubated with DA SP-5) the colony formation was reduced. A similar pentapeptide thymopentin (Arg-Lys-Asp-Val-Tyr) did not influence colony formation by human BMCs. We assume that DA SP-5 could support therapeutic effects of rHuGM-CSF.

Splenopentin (DAc-SP-5) accelerates the restoration of myelopoietic and immune systems after sublethal radiation in mice.

In 1981 a new splenic hormone was described by Audhya et al. (Biochemistry, 20, 6195-6200, 1981). At first designated as thymopoietin III, the complete amino acid sequence had been described as splenin in 1984. For the pentapeptide corresponding to amino acids 32-36 of splenin was shown to be active in immunological systems. The synthetic pentapeptide splenopentin (DAc-SP-5) and the sequence 32-36 of splenin are identical. In this study the recovery of immunocompetence in mice following sublethal irradiation is shown to be enhanced by DAc-SP-5. The treatment effects of DAc-SP-5 were verified by splenic plaque-forming response to a T-cell dependent antigen and in the hematopoietic colony-forming assay. These effects were associated with an accelerated recovery of leukocyte counts in peripheral blood and spleen without significant changes in the relation between leukocyte and lymphocyte subpopulations. Furthermore, in comparison to control animals DAc-SP-5 treated mice showed in the first weeks postexposure a significantly higher number of bone marrow derived cells as well as granulocyte-macrophage and macrophage colony-forming cells (GM-CFC and M-CFC). Therefore, DAc-SP-5 may be a useful substance for treating secondary forms of bone marrow depression.