PK and Safety Study of Paclitaxel Injection Concentrate for Nano-dispersion Administered Weekly

• Determination of Maximum Tolerated Dose (MTD) during dose escalation [ Time Frame: One 21-day treatment cycle ] [ Designated as safety issue: Yes ]
  MTD for PICN will be determined as dose below the dose at which DLT (Dose Limiting Toxicity) is seen for ≥ 2 subjects
  
  

• Establishing pharmacokinectic profile at each dose level for PICN [ Time Frame: One 21-day treatment cycle ] [ Designated as safety issue: No ]
  Plasma levels of PICN will be determined and PK parameters viz., Cmax, AUC0-t, AUC0-∞, MRT, Tmax, t½, Kel, Vd, Cl for PICN will be evaluated
  
  

Drug: Paclitaxel Injection Concentrate for Nanodispersion

PICN infusion will be prepared by diluting 5% dextrose Injection to obtain a nano-dispersion and infused using conventional PVC infusion systems.

PICN will be administered as 30-minute intravenous infusion on days 1, 8, and 15 of each 4-week cycle - once a week for 3 weeks, followed by 1 week of rest (one cycle)until disease progression, development of unacceptable toxicities, non-compliance, inter-current illness that prevents treatment continuation, withdrawal of consent, or change in subject condition that render the subject unacceptable for further treatment.

This is a phase I study of PICN that will use the standard '3+3'dose-escalation design to determine the MTD and recommend phase II dose of PICN administered once a week for 3 weeks, followed by 1 week of rest. PICN will be administered as 30-minute intravenous infusion on days 1, 8, and 15 of each 4-week cycle - once a week for 3 weeks, followed by 1 week of rest (one cycle). Next cycle dosing will open on day 28 after laboratory investigations are done of the previous cycle. Subjects will continue therapy until disease progression, development of unacceptable toxicities, non-compliance, inter-current illness that prevents treatment continuation, withdrawal of consent, or change in patient condition that render the patient unacceptable for further treatment. There are 6 dose levels planned for dose escalation. The dose escalation plan is as follows: Three subjects will be treated at the initial dose level for PICN. If no Cycle-1 dose-limiting toxicities (DLTs) are observed, 3-new subjects will be treated at the next dose level. If one of three subjects experiences a DLT at any given dose level, three additional subjects will be treated at that same dose. If a DLT occurred in at least two subjects at any dose level, dose escalation will be halted, and the next three subjects enrolled will be treated at the preceding lower dose level. MTD will be defined as the highest PICN dose at which DLT (Dose Limiting Toxicity) is seen in <2 subjects out of 6. Subjects who fail to complete 1 cycle of study treatment for non-treatment related reasons will be replaced.

AEs will be monitored across all cycles per CTCAE 4.0 and disease response will be assessed by imaging at baseline and on day 1 of cycle 3, 5, and 7 as per RECIST 1.1. Upon study completion, subjects will be followed for toxicities for 4 weeks, or longer if there are unresolved ≥ grade 3 toxicities at the end of the 4-week period. Subjects removed from study for unacceptable adverse events will be followed until resolution (≤ grade 2) or stabilization of the adverse events. Blood samples for pharmacokinetic studies will be collected at pre-planned time-points.