First-in-human phase II trial of the botanical formulation PHY906 with capecitabine as second-line therapy in patients with advanced pancreatic cancer.

BACKGROUND: Preclinical studies showed a Chinese botanical formula, PHY906, has synergistic anti-tumor activity with capecitabine. Our phase I study determined maximal tolerated dose of capecitabine 1,500 mg/m(2) BID day 1-7 and PHY906 800 mg BID day 1-4 every 2 weeks. We conducted this phase II study to explore the efficacy of capecitabine and PHY906 in patients with advanced pancreatic cancer who were previously treated with gemcitabine-based regimens. METHODS: Patients with pancreatic cancer and an Eastern Cooperative Oncology Group performance status of 0-2 received PHY906 and capecitabine. Toxicity was assessed per NCI-CTCAE v3.0 and response per response evaluation criteria in solid tumors q 6 weeks. Correlative studies of cytokines, chemokines and growth factors were tested using a cytometric bead array. Quality of life was assessed by utilizing Edmonton symptom assessment system. The primary objective was overall survival. RESULTS: The study enrolled 25 patients. Median progression-free survival (mPFS) was 10.1 weeks (range 0.4-54.1) and median overall survival (mOS) was 21.6 weeks (range 0.4-84.1). Eighteen patients received at least 2 cycles, and achieved mPFS of 12.3 weeks and mOS of 28 weeks. Six-month survival rate was 44 % (11/25). Unsupervised clustering of patients grouped those with shortened survival together by their cytokine profile showed that only IL-6 had a significant difference (p < .001) between short- and long-term survivors. CONCLUSIONS: Capecitabine plus PHY906 provides a safe and feasible salvage therapy after gemcitabine failure for APC. Role of IL-6 in tumor progression and tumor cachexia needs to be investigated with respect to its relation to pathophysiology of pancreatic cancer and development of anti-IL-6 therapeutics.

Rechallenge with cisplatin in a patient with pancreatic cancer who developed a hypersensitivity reaction to oxaliplatin. Is skin test useful in this setting?

CONTEXT: A recent meta-analysis suggests that the addition of oxaliplatin or cisplatin to gemcitabine can lead to improved survival in patients with advanced pancreatic cancer, especially those with a good performance status. In an event of a platinum hypersensitivity reaction, the particular platinum salt is likely discontinued. Desensitization has shown benefit anecdotically but it is an intensive process. We present a case in which platinum-containing therapy was able to continue in a patient with metastatic pancreatic cancer following a hypersensitivity reaction to oxaliplatin, by switching to cisplatin after a negative intradermal skin test. CASE REPORT: A 58-year-old gentleman with metastatic pancreatic adenocarcinoma received biweekly cycles of gemcitabine in combination with oxaliplatin. During the fifth cycle, he experienced a grade 2 hypersensitivity reaction including erythema and lip numbness, for which he was medicated with antihistaminics and corticosteroids. Cycles 6 and 7 of oxaliplatin were tolerated over 4 h infusion with pretreatment of H1, H2 blockers and corticosteroids. During the 8th cycle, the patient developed a grade 3 hypersensitivity reaction manifesting as facial flushing, sweating, symptomatic bronchospasm, cyanotic lips and chest tightness. Symptoms resolved with antihistaminics, corticosteroids and epinephrine. Although oxaliplatin treatment was discontinued, the patient's response to the platinum therapy merited a cisplatin rechallenge. An intradermal skin test was administered with negative result, allowing for a regimen change to biweekly gemcitabine and cisplatin. The patient has tolerated multiple additional cycles with further decrease in tumor size and tumor markers. CONCLUSIONS: Intradermal skin tests can be useful tools for effectual rechallenge. Literature review reveals scarce data of intradermal skin tests used to rechallenge cisplatin to patients with oxaliplatin hypersensitivity reaction, and our case is the first apparent example for a patient with advanced pancreatic cancer. Despite the possibility of platinum cross-reactivity, rechallenge can be considered if patients have responded to the therapy and are treated in a supervised environment.