Phase II studies of polymer-doxorubicin (PK1, FCE28068) in the treatment of breast, lung and colorectal cancer

Abstract

Abstract. Phase I studies of [N-(2-hydroxypropyl)methacrylamide] (HPMA) copolymer-doxorubicin previously showed signs of activity coupled with 5-fold decreased anthracycline toxicity in chemotherapy-refractory patients. Here we report phase II studies using a similar material (FCE28068) in patients with breast (n=17), non-small cell lung (NSCLC, n=29) and colorectal (n=16) cancer. Up to 8 courses of PK1 (280 mg/m 2 doxorubicin-equivalent) were given i.v., together with 123 Ilabelled imaging analogue. Toxicities were tolerable, with grade 3 neutropenia more prominent in patients with breast cancer (4/17, 23.5% compared with 5/62, 8.1% overall). Of 14 evaluable patients with breast cancer 3 had partial responses (PR), all anthracycline-naïve patients. In 26 evaluable patients with NSCLC, 3 chemotherapy-naïve patients had PR. In contrast, none of the 16 evaluable patients with colorectal cancer responded. Imaging of 16 patients (5 with breast cancer, 6 NSCLC, 5 colorectal cancer) showed obvious tumour accumulation in 2 metastatic breast cancers, although unfortunately no images were obtained from patients who responded. These results show 6/62 PR with limited side effects, supporting the concept that polymer-bound therapeutics can have modified and improved anticancer activities and suggesting the approach should be explored further for breast cancer and NSCLC.

Recent progress in nanomedicine: therapeutic, diagnostic and theranostic applications

“…injection [34]. Figure 2O extends these findings to the clinical situation, showing that also in patients with head-and-neck tumors and with large subclavicular breast cancer metastases, the EPR-mediated accumulation of radiolabeled HPMA copolymer-based doxorubicin (PK1) can be clearly visualized and quantified [50]. Similarly, Figure 2Q-R show that also for radiolabeled Doxil, (i.e.…”

“…from different types of sarcomas (R), thereby enabling patient preselection and (more) personalized nano-chemotherapeutic treatments. Images are adapted, with permission, from [30,[32][33][34][38][39][40][41][42][50][51][52]. Rationale for image-guided and personalized nanomedicine.…”

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

“…They are based on the traditional cytotoxic drugs (e.g. platinates [145,146], doxorubicin [147,148], camptothecin and analogues [149][150][151][152][153][154][155][156][157][158][159], paclitaxel/docetaxel [160][161][162][163][164], methotrexate [165], and irinotecan [166,167]). Xyotax (CT-2103 or OPAXIO), a PGA-paclitaxel conjugate, and NKTR-102, a polymer conjugate of irinotecan, are both currently in phase III clinical trials, being the conjugates closest to approval and market availability [164,[166][167][168].…”

Characterizing EPR-mediated passive drug targeting using contrast-enhanced functional ultrasound imaging

“…Here, we therefore set out to visualize and quantify the tumor accumulation of near-infrared-fluorophore (NIRF) labeled polymeric drug carriers based on N-(2-hydroxypropyl)-methacrylamide HPMA copolymers are prototypic and routinely used macromolecular drug carriers, which have been extensively employed for EPR-mediated passive drug targeting [15][16][17]. As for other long-circulating nanocarriers, however, such as for liposomes, the tumor accumulation of HPMA copolymers varies quite considerably, both in animal models and in patients, from barely detectable, to up to 5% of the injected dose [18][19][20][21]. In spite of this conceptual shortcoming, HPMA copolymers have been extensively used over the years, to improve the tumor-directed delivery of many different low-molecular-weight drugs, including e.g.…”

“…As for other long-circulating nanocarriers, however, such as for liposomes, the tumor accumulation of HPMA copolymers varies quite considerably, both in animal models and in patients, from barely detectable, to up to 5% of the injected dose [18][19][20][21]. In spite of this conceptual shortcoming, HPMA copolymers have been extensively used over the years, to improve the tumor-directed delivery of many different low-molecular-weight drugs, including e.g.…”