ESMO @ ECC 2013: Primary Endpoint Unmet in a Phase III Trial of First-Line Treatment with Palifosfamide plus Doxorubicin in Patients with Metastatic Soft Tissue Sarcoma

Palifosfamide/doxorubicin had a similar toxicity profile to placebo/doxorubicin in the PICASSO 3 study.

Although results from a phase II trial of palifosfamide looked promising, disappointing findings were reported for the phase III PICASSO 3 trial of palifosfamide as the first-line treatment of patients with metastatic soft tissue sarcoma (mSTS). The study did not meet its primary endpoint of progression-free survival (PFS), despite showing a statistically non-significant trend towards improved PFS of 3.1 weeks.

Findings were presented 1 October, 2013 by Dr Christopher Ryan of the Knight Cancer Institute, Oregon Health & Science University,  Portland, USA during the Soft Tissue and Bone Sarcoma Proffered Papers Session (Abstract E17-3125) at the 17th ECCO – 38th ESMO – 32nd ESTRO Congress. The European Cancer Congresses are organised in joint partnership with ESSO, EACR, EONS and SIOPE as a forum for the latest in oncology research and to offer multidisciplinary and multi-professional educational opportunities in oncology. The 2013 Congress convened in Amsterdam, The Netherlands from 27 September until 1 October.

Palifosfamide: Mechanism of action

As a bi-functional DNA alkylating agent, Palifosfamide has potential activity against multiple tumour types, including mSTS. Importantly, palifosfamide is the active metabolite of ifosfamide and able to bypasses resistance pathways and does not manifest the toxic metabolites associated with prodrug activation.

PICASSO 3: The study design

The PICASSO 3 study was designed to evaluate the safety and efficacy of palifosfamide when added to doxorubicin compared to doxorubicin and placebo. The PFS per RECIST v1.1 as assessed by independent, blinded radiographic review, was the primary endpoint with secondary endpoints of overall survival, response rate, quality of life, safety and tolerability. PICASSO 3 was conducted at 113 clinical centres worldwide.

Patients with measurable mSTS, centrally confirmed by independent pathology review, who had not received previous chemotherapy for metastatic disease were eligible for the study. The trial stratified 447 enrolled patients by histological type and age and randomly assigned  them 1:1 to receive doxorubicin at 75 mg/m(i.v. ; n=226)  on day 1 plus either 150 mg/m2 palifosfamide by i.v. or placebo  (n=221) on days 1, 2 and 3 every 21 days for up to 6 cycles. No crossover was allowed.

Synovial disease was reported in 6% of patients, 34% had leiomyosarcoma and 60% of patients presented with other sarcomas. Twenty-six percent of patients were aged 65 years or older.

PICASSO 3: The study results

The PFS was similar between treatment arms with a small prolongation benefit shown with adjunct palifosfamide. Median PFS was 5.98 months (95% confidence interval [CI] 5.31, 6.20) for palifosfamide/ doxorubicin  compared with 5.23 months (95%CI 4.13, 5.90) for placebo/doxorubicin (hazard ratio [HR] 0.87; p = 0.18). An interim analysis showed that median overall survival favoured placebo and was 15.91 months for palifosfamide/ doxorubicin compared to 16.89 months with placebo/ doxorubicin (HR 1.05; p = 0.74) .

Subgroup analyses of PFS and OS by stratum are ongoing.

Palifosfamide was well tolerated and showed a safety profile in combination with doxorubicin that was comparable with other palifosfamide clinical trials in soft tissue sarcoma. The adverse event (AE) profiles were similar in both treatment arms with an increase in the rate of febrile neutropenia of 17.8% observed for palifosfamide/ doxorubicin over 9.8% for placebo/doxorubicin. Other commonly reported AEs were nausea, constipation, fatigue, vomiting, diarrhoea, and anemia. Grade ≥3 AEs were neutropenia, febrile neutropenia, nausea, anemia, constipation and dehydration.

Patient health-related quality of life (QoL) was maintained with palifosfamide/doxorubicin, as demonstrated in patient reported QoL questionnaires.

The authors concluded that, although PICASSO 3 did not meet its primary endpoint, patients with mSTS receiving first-line palifosfamide/doxorubicin showed 3.1 weeks improvement in median PFS compared with placebo/doxorubicin. They also noted that palifosfamide/doxorubicin had a similar toxicity profile to placebo/doxorubicin in this phase III trial setting.

PICASSO 3 was sponsored by ZIOPHARM Oncology.