(P 184) PHASE 1B TRIAL OF CAMSIRUBICIN, A NOVEL DOXORUBICIN ANALOG, WITH CONCOMITANT PEGFILGRASTIM IN SUBJECTS WITH ADVANCED SOFT TISSUE SARCOMA TO IDENTIFY A NEW MTD/RP2D

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. The hypothesis is 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 five dose levels (ranging between 265 and 650 mg/m2) have been accrued. No dose-limiting toxicities have been observed, and camsirubicin has demonstrated very good tolerability and early signs of clinical benefit. The majority of patients have had stable disease, including all three at the 520mg/m2 dose level. One patient at the 520 mg/m2 dose level, with unresectable cancer at study entry, was deemed eligible for tumor resection after 6 cycles of camsirubicin treatment and a corresponding 21% reduction in tumor dimensions. This patient underwent successful surgical resection of the cancer with clear margins. No subjects to date have demonstrated signs or symptoms of drug-related cardiac dysfunction. This trial continues to show less frequent and less severe alopecia and oral mucositis with camsirubicin compared to what has been seen in recent ASTS clinical trials with doxorubicin. We anticipate availability of subject data for additional dose levels at the time of the conference, as the trial is still in progress at the time of this abstract’s submission.

Conclusion: : Camsirubicin, a novel doxorubicin analog, when given with concomitant pegfilgrastim can be given at doses higher than the previously reported RP2D. 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 ASTS as well as other cancer types where doxorubicin is currently used.