A Phase Ib multicenter, dose-escalation study of the polyamine analogue PG-11047 in combination with gemcitabine, docetaxel, bevacizumab, erlotinib, cisplatin, 5-fluorouracil, or sunitinib in patients with advanced solid tumors or lymphoma.

PURPOSE: Polyamines are absolutely essential for maintaining tumor cell proliferation. PG-11047, a polyamine analogue, is a nonfunctional competitor of the natural polyamine spermine that has demonstrated anticancer activity in cells and animal models of multiple cancer types. Preclinical investigations into the effects of common chemotherapeutic agents have revealed overlap with components of the polyamine metabolic pathway also affected by PG-11047. This report describes a Phase Ib clinical trial investigating PG-11047 in combination with cytotoxic and anti-angiogenic chemotherapeutic agents in patients with advanced refractory metastatic solid tumors or lymphoma. METHODS: A total of 172 patients were assigned to treatment arms based on cancer type to receive the appropriate standard-of-care therapy (gemcitabine, docetaxel, bevacizumab, erlotinib, cisplatin, 5-fluorouracil (5-FU), or sunitinib as directed) along with once weekly intravenous infusions of PG-11047. PG-11047 dose escalation ranged from 50 to 590 mg. RESULTS: The maximum tolerated dose (MTD) of PG-11047 in combination with bevacizumab, erlotinib, cisplatin, and 5-FU was 590 mg. Dose-limiting toxicities (DLTs) in these groups were rare (5 of 148 patients). Overall partial responses (PR) were observed in 12% of patients treated with PG-11047 and bevacizumab, with stable disease documented in an additional 40%. Stable disease occurred in 71.4% of patients in the 5-FU arm, 54.1% in the cisplatin arm, and 33.3% in the erlotinib arm. Four of the patients receiving cisplatin + PG-11047 (20%) had unconfirmed PRs. MTDs for gemcitabine, docetaxel, and sunitinib could not be determined due to DLTs at low doses of PG-11047 and small sample size. CONCLUSIONS: Results of this Phase Ib trial indicate that PG-11047 can be safely administered to patients in combination with bevacizumab, erlotinib, cisplatin, and 5-FU on the once weekly dosing schedule described and may provide therapeutic benefit. The manageable toxicity profile and high MTD determination provide a safety profile for further clinical studies.

Phase I study of pemetrexed and pegylated liposomal doxorubicin in patients with refractory breast, ovarian, primary peritoneal, or fallopian tube cancer.

PURPOSE: Pemetrexed and pegylated liposomal doxorubicin (PLD) are clinically active as single agents and preclinically synergistic. This phase I, open-label trial evaluated the maximum tolerated dose (MTD) and safety of pemetrexed followed by PLD in patients with breast or gynecologic cancers. PATIENTS: Using 3 + 3 dose escalation, cohorts of 3-9 patients received escalating doses of pemetrexed 400-500 mg/m(2) on days 1 and 15 and PLD 30-45 mg/m(2) on day 1 of a 28-day cycle. All patients received folic acid and vitamin B(12) until 21 days after last pemetrexed dose. Patients continued until dose-limiting toxicity (DLT) or progression (PD). RESULTS: From 11/05 to 2/08, 29 patients entered treatment; median age: 60.6 years (range, 47.5-80.1); ECOG PS 0/1: 27.6%/72.4%; primary disease site: ovarian (55.2%), breast (34.5%), peritoneum (10.3%); prior therapies: chemotherapy (100.0%), surgery (72.4%), hormones/biologics (35%), and radiation (20.7%). Pemetrexed/PLD dose levels: L1 = 400/30 (n = 4), L2 = 400/35 (n = 6), L3 = 500/35 (n = 9), L4 = 500/40 (n = 7), and L5 = 500/45 (n = 3). Treatment-related grade 3-4 toxicities: hematologic-neutropenia (86.2%), leukopenia (58.6%), thrombocytopenia (48.3%), anemia (41.4%); nonhematologic-mucosal inflammation (24.1%), febrile neutropenia (24.1%), hand-foot syndrome (13.8%), hypokalaemia (10.3%). Reasons for discontinuation: PD (48.3%), toxicity (27.6%), patient request (13.8%), and investigator request (10.3%). EFFICACY: 5 ovarian patients (20.8%) achieved partial response; median time to progression (TTP) was 6.1 months (range, 1.2-12.5). CONCLUSION: Pemetrexed plus PLD was reasonably tolerated in this heavily-pretreated population. MTD: pemetrexed 500 mg/m(2) and PLD 40 mg/m(2) may be carried forward to phase II studies in specific patient populations. TTP in platinum-refractory ovarian patients was greater than expected.

Sequential interleukin 3 and granulocyte-macrophage-colony stimulating factor therapy in patients with bone marrow failure with long-term follow-up of responses.

BACKGROUND: Interleukin-3 (IL-3) and granulocyte-macrophage-colony stimulating factor (GM-CSF) have synergistic, hematopoietic growth-promoting activity in preclinical studies. Because of the paucity of effective therapies for patients with chronic bone marrow failure states, the authors studied the biologic activity of sequential IL-3/GM-CSF in such patients. METHODS: IL-3 was given subcutaneously for 5 days (at escalating doses of 0.15 microg/kg, 0.3 microg/kg, 0.6 microg/kg, 1.2 microg/kg, 2.5 microg/kg, 5.0 microg/kg, 10.0 microg/kg, or 15.0 microg/kg per day), and GM-CSF for was given subcutaneously for 9 days (at a dose of 5 microg/kg per day; Phase I 3 + 3 design) followed by 14 days of rest (total, 2 courses), then maintenance therapy. RESULTS: The majority of 38 evaluable patients had aplastic anemia or myelodysplastic syndrome. Most patients (79%) had neutrophil responses. Ten patients (26%), all of whom were treated with IL-3 doses >/= 1.2 microg/kg per day, had platelet responses, with a median increase of 132 x 10(9)/L (range, 41-180 x 10(9)/L) over baseline in responders. Six patients (16%) had trilineage recovery, which could be durable (the longest ongoing at 6.5 years after therapy completion). The most common toxicities were low-grade fever, headache, and fatigue. The maximum tolerated doses were IL-3 at 10 microg/kg per day and GM-CSF at 5 microg/kg per day. CONCLUSIONS: Sequential IL-3/GM-CSF effectively raised blood counts in some patients with bone marrow failure at doses that were tolerated well. These results indicate that early-acting growth factors can induce durable, multilineage responses in a subset of individuals with bone marrow failure.