Phase I clinical trial design

UNLABELLED Gastrin-releasing peptide receptors (GRP-R) are upregulated in many cancers, including prostate, breast, and lung. We describe a new radiolabeled bombesin (BBN) analog for imaging and systemic radiotherapy that has improved pharmacokinetics (PK) and better retention of radioactivity in the tumor. METHODS DO3A-CH2CO-G-4-aminobenzoyl-Q-W-A-V-G-H-L-M-NH2 (AMBA) was synthesized and radiolabeled. The human prostate cancer cell line PC-3 was used to determine the binding (Kd), retention, and efflux of 177Lu-AMBA. Receptor specificity was determined by in vitro autoradiography in human tissues. PK and radiotherapy studies were performed in PC-3 tumor-bearing male nude mice. RESULTS 177Lu-AMBA has a high affinity for the GRP-R (Kd, 1.02 nmol/L), with a maximum binding capacity (Bmax) of 414 fmol/10(6) cells (2.5 x 10(5) GRP-R/cell). Internalization was similar for 177Lu-AMBA (76.8%), 177Lu-BBN8 (72.9%), and 125I-[Tyr4]-BBN (74.9%). Efflux was markedly lower for 177Lu-AMBA (2.9%) ...

Subtraction hybridization applied to a 'differentiation therapy' model of cancer employing human melanoma cells resulted in the cloning of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24). Initial studies confirm an inverse correlation between ...

Preclinical and in vitro studies have determined that copper is an important cofactor for angiogenesis. Tetrathiomolybdate (TM) was developed as an effective anticopper therapy for the initial treatment of Wilson's disease, an autosomal recessive disorder that leads to abnormal copper accumulation. Given the potency and uniqueness of the anticopper action of TM and its lack of toxicity, we hypothesized that TM would be a suitable agent to achieve and maintain mild copper deficiency to impair neovascularization in metastatic solid tumors. Following preclinical work that showed efficacy for this anticopper approach in mouse tumor models, we carried out a Phase I clinical trial in 18 patients with metastatic cancer who were enrolled at three dose levels of oral TM (90, 105, and 120 mg/day) administered in six divided doses with and in-between meals. Serum ceruloplasmin (Cp) was used as a surrogate marker for total body copper. Because anemia is the first clinical sign of copper def...

Regulatory bodies and scholars have traditionally conceptualized biomedical research on healthy subjects in the same way as research on patients. Guidelines and regulations have portrayed payment to a healthy subject as a potential constraint, or "undue influence," on the subject's free consent. In this essay we suggest an alternative way of conceptualizing research on healthy subjects, which sees the basic issue not as one of undue influence but as one of justice. Healthy subjects generally enroll in research protocols not for humanitarian
reasons but for the money they will receive. Many of these protocols are conducted by profit-driven corporations. Yet current guidelines and regulations prohibit subjects from negotiating for fair payment for the risks, discomforts and inconveniences they undergo, and IRBs are not staffed adequately to monitor the subject's safety. We propose to remedy the situation by regulating payment to healthy subjects as a labor relation.

The study aimed to demonstrate satisfactory inter-UK transit of cold storage clinical trial material. The product environment had to be maintained between 0 and 8 degrees C throughout transit until delivery. Straightforward, low cost and simplified shipping arrangements were sought that would be appropriate for small-scale Phase I clinical trial activities. A laboratory test defined an optimal three frozen gel pack configuration to maintain refrigerated environmental conditions for dummy product packs in a single type and size of insulated shipper. The internal environment was temperature monitored at 30-min intervals in all tests. Twelve Glasgow to London transits were then studied over 2 years to include all seasonal temperature variations. A configuration using three frozen gel packs and 4 h pre-chill of the transit container maintained the internal environment at 0-8 degrees C for up to 48 h during autumn, winter and spring. A modified four frozen gel pack configuration was suit...