(P 321) PHASE 1B TRIAL OF CAMSIRUBICIN, A NOVEL DOXORUBICIN ANALOG, WITH CONCOMITANT PEGFILGRASTIM FOR ADVANCED SOFT TISSUE SARCOMA TO IDENTIFY A NEW MAXIMUM TOLERATED DOSE/RECOMMENDED PHASE 2 DOSE.

Objective: Doxorubicin is the 1st line treatment for many patients with advanced soft tissue sarcoma (ASTS). The clinical benefit of doxorubicin is limited by having to terminate treatment once a lifetime cumulative dose is reached due to the increased risk of irreversible cardiotoxicity. Camsirubicin HCl (camsirubicin) has been engineered to modify doxorubicin side chains that have been implicated in mediating cardiotoxicity, while still retaining antitumor activity. Resulting from this is the hypothesis that camsirubicin can take advantage of the known dose-response of this class of drug and be administered without restrictions on cumulative dose due to avoidance or reduction in cardiotoxicity.

The objective of this phase 1b study is to identify a new maximum tolerated dose (MTD)/RP2D when camsirubicin is administered with concomitant pegfilgrastim and to assess the safety and anti-tumor activity of this regimen.

Methods: Like most anthracyclines, camsirubicin exhibits the dose limiting toxicity of neutropenia as demonstrated in a previously completed phase 1 trial, which identified 265 mg/m2 every 21 days (Q21D) as the recommended phase 2 dose (RP2D). A single arm phase 2 study administered camsirubicin at the RP2D with concomitant pegfilgrastim to minimize neutropenia which allowed administration of camsirubicin for up to 16 cycles (with cumulative doses >5000 mg/m2) with no evidence of irreversible cardiotoxicity. Given the lack of toxicity at the RP2D administered with concomitant pegfilgrastim in that phase 2 study, the current phase 1b study has been designed to dose escalate beyond the original RP2D in the presence of pegfilgrastim.

Results: Data will be presented describing the safety and antitumor activity of camsirubicin at dose levels greater than the 265 mg/m2 previously evaluated with concomitant pegfilgrastim. To date, the first four dose levels (ranging between 265 and 520 mg/m2) have been accrued and demonstrate very good tolerability and early signs of clinical benefit. Multiple patients have had stable disease after 4 cycles, and the study’s first dosed patient (who has received 11 cycles) continues on study drug with stable disease. No subjects in the first 3 dose cohorts have demonstrated signs or symptoms of cardiac dysfunction, clinically significant neutropenia, or study drug-related Grade 3 adverse events. We anticipate subject data for an additional 1-2 dose levels, as this trial is still in progress at the time of this abstract’s submission.

Conclusion: Camsirubicin, a novel doxorubicin analog, can be given at doses higher than a previously reported RP2D when given with concomitant pegfilgrastim. The objective of this ongoing study is to continue to increase the dose and define a new MTD/RP2D in the presence of pegfilgrastim. The hypothesis is that higher per cycle and cumulative doses of camsirubicin will lead to an increase in tumor response and clinical benefit when compared to doxorubicin, where the cumulative dose is restricted. The identification of a new RP2D for camsirubicin will allow direct comparison to doxorubicin in subjects with advanced soft tissue sarcoma as well as other cancer types where doxorubicin is currently used.