The application of adjuvant autologous antravesical macrophage cell therapy vs. BCG in non-muscle invasive bladder cancer: a multicenter, randomized trial

<p>Abstract</p> <p>Introduction</p> <p>While adjuvant immunotherapy with Bacille Calmette Guérin (BCG) is effective in non-muscle-invasive bladder cancer (BC), adverse events (AEs) are considerable. Monocyte-derived activated killer cells (MAK) are discussed as essential in antitumoural immunoresponse, but their application may imply risks. The present trial compared autologous intravesical macrophage cell therapy (BEXIDEM^®) to BCG in patients after transurethral resection (TURB) of BC.</p> <p>Materials and methods</p> <p>This open-label trial included 137 eligible patients with TaG1-3, T1G1-2 plurifocal or unifocal tumours and ≥ 2 occurrences within 24 months and was conducted from June 2004 to March 2007. Median follow-up for patients without recurrence was 12 months. Patients were randomized to BCG or mononuclear cells collected by apheresis after ex vivo cell processing and activation (BEXIDEM). Either arm treatment consisted of 6 weekly instillations and 2 cycles of 3 weekly instillations at months 3 and 6. Toxicity profile (primary endpoint) and prophylactic effects (secondary endpoint) were assessed.</p> <p>Results</p> <p>Patient characteristics were evenly distributed. Of 73 treated with BCG and 64 with BEXIDEM, 85% vs. 45% experienced AEs and 26% vs. 14% serious AEs (SAE), respectively (p < 0.001). Recurrence occurred significantly less frequent with BCG than with BEXIDEM (12% vs. 38%; p < 0.001).</p> <p>Discussion</p> <p>This initial report of autologous intravesical macrophage cell therapy in BC demonstrates BEXIDEM treatment to be safe. Recurrence rates were significantly lower with BCG however. As the efficacy of BEXIDEM remains uncertain, further data, e.g. marker lesions studies, are warranted.</p> <p>Trial registration</p> <p>The trial has been registered in the ISRCTN registry <url>http://isrctn.org</url> under the registration number ISRCTN35881130.</p

Phase I Trial of Consolidative Radiotherapy with Concurrent Bevacizumab, Erlotinib and Capecitabine for Unresectable Pancreatic Cancer

<div><p>Purpose</p><p>To determine the safety, tolerability and maximum tolerated dose (MTD) of addition of erlotinib to bevacizumab and capecitabine-based definitive chemoradiation (CRT) in unresectable pancreatic cancer.</p><p>Methods</p><p>Seventeen patients with CT-staged, biopsy-proven unresectable pancreatic cancer were enrolled between 3/2008 and 10/2010. Prior chemotherapy was permitted. Two patients each were enrolled at dose levels (DLs) 1–4 and 9 patients at DL 5. All patients received 50.4 Gy (GTV only) in 28 fractions with concurrent capecitabine, bevacizumab and erlotinib. Dose of each drug was escalated in 5 DLs using the continual reassessment method. Bevacizumab was escalated from 5mg/Kg q2weeks (DLs 1–4) to 10mg/Kg q2weeks (DL 5); daily erlotinib from 100mg/day (DLs 1–2) to 150 mg/Kg (DLs 3–5); and capecitabine from 400mg/m² twice daily on days of radiation (DL 1) to 650mg/m² (DLs 2–3) to 825 mg/m² (DLs 4–5). Reassessment for potential resection was performed 6–8 weeks later.</p><p>Results</p><p>Sixteen patients received gemcitabine-based chemotherapy prior to CRT. With a median clinical follow-up of 10 months, no grade 3 toxicities were observed in DLs 1–4. Three (33%) patients at DL 5 developed a grade 3 acute toxicity (2 diarrhea, 1 rash). No grade 4 or 5 toxicities were seen. DL 4 was selected as the MTD; therefore, the recommended doses in combination with radiation are: bevacizumab, 5mg/Kg q2weeks; erlotinib, 150 mg/Kg daily; and capecitabine, 825mg/m² BID. Median survival was 17.4 months. Of the five patients who underwent resection, 4 were originally deemed locally advanced and 1 was borderline resectable. Three patients had excellent pathological response (2 complete response and 20% viable tumor) at surgery, and the 2 patients with complete response are still alive at 61 and 67 months of follow up with no local or distant failures.</p><p>Conclusions</p><p>This chemoradiation regimen at the recommended dose levels is safe and tolerable for patients with unresectable pancreatic cancer and merits further evaluation.</p></div

CONSORT flow diagram of phase I trial.

<p>CONSORT flow diagram of phase I trial.</p

Exclusion criteria.

<p>Exclusion criteria.</p

Kaplan-Meier estimates of (a) overall survival, (b) distant progression-free survival and (c) local progression-free survival from start of chemoradiation therapy.

<p>Kaplan-Meier estimates of (a) overall survival, (b) distant progression-free survival and (c) local progression-free survival from start of chemoradiation therapy.</p

Individual toxicity grade.

<p>Individual toxicity grade.</p

Toxicity by dose level.

<p>Toxicity by dose level.</p