Robert J. Stagg

A randomized trial of continuous intravenous versus hepatic intraarterial floxuridine in patients with colorectal cancer metastatic to the liver: the Northern California Oncology Group trial.

In 1983, the Northern California Oncology Group (NCOG) instituted a randomized trial of intravenous (IV) versus intraarterial (IA) floxuridine (FUDR) administered via an implantable pump for patients with colorectal cancer metastatic to the liver. The study objectives were to compare the hepatic response rate, time to hepatic progression, and toxicity for the two treatment arms. The study design, which allowed patients failing IV FUDR to crossover to the IA arm, prevents a meaningful comparative analysis of survival. Patients with liver-only metastases (N = 143) were randomized, 76 to the IV arm and 67 to the IA arm, and 115 patients (65 IV, 50 IA) were fully evaluable. Of the 65 patients in the IV arm, 28 crossed over to IA treatment after failing IV FUDR. The dose-limiting toxicity of IV FUDR was diarrhea, whereas biliary toxicity limited both the dose and duration of IA FUDR therapy. Of the first 25 patients treated with IA FUDR at a dose of .3 mg/kg/day, 10 developed radiographically evident biliary strictures, and three developed permanent jaundice. With reduction of the initial IA FUDR dose to .2 mg/kg/day, and adoption of a policy of early dosage reduction, treatment interruption, or termination of therapy for persistent elevations in alkaline phosphatase, only two further cases of serious biliary toxicity occurred. However, 26 of the 50 IA FUDR patients ultimately had therapy terminated because of drug toxicity rather than disease progression. When compared with systemic infusion, infusion into the hepatic artery greatly enhanced the antitumor activity of FUDR against colorectal liver metastases. Although biliary toxicity is the most serious limitation of this form of therapy, biliary stricture and jaundice usually can be averted through careful monitoring of liver enzymes and early dosage reduction.

Multicenter phase II study of iodine-131 tositumomab for chemotherapy- relapsed/refractory low-grade and transformed low-grade B-cell non-Hodgkin's lymphomas

PURPOSE This multicenter phase II study evaluated the efficacy, dosimetry methodology, and safety of iodine-131 tositumomab in patients with chemotherapy-relapsed/refractory low-grade or transformed low-grade non-Hodgkins lymphoma (NHL). PATIENTS AND METHODS Patients received a dosimetric dose that consisted of 450 mg of anti-B1 antibody followed by 35 mg (5 mCi) of iodine-131 tositumomab. Serial total-body gamma counts were then obtained to calculate the patient-specific millicurie activity required to deliver the therapeutic dose. A therapeutic dose of 75 cGy total-body dose (attenuated to 65 cGy in patients with platelet counts of 101,000 to 149,000 cells/mm(3)) was given 7 to 14 days after the dosimetric dose. RESULTS Forty-five of 47 patients were treated with a single dosimetric and therapeutic dose. Twenty-seven patients (57%) had a response. The response rate was similar in patients with low-grade (57%) or transformed low-grade (60%) NHL. The median duration of response was 9.9 months. Fifteen patients (32%) achieved a complete response (CR; 10 CRs and five clinical CRs), including five patients (50%) with transformed low-grade NHL. The median duration of CR was 19.9 months, and six patients have an ongoing CR. Treatment was well tolerated, with the principal toxicity being hematologic. The most common nonhematologic toxicities that were considered to be possibly related to the treatment included mild to moderate fatigue (32%), nausea (30%), fever (26%), vomiting (15%), infection (13%), pruritus (13%), and rash (13%). Additionally, one patient developed human-antimouse antibodies. CONCLUSION Iodine-131 tositumomab produced a high overall response rate, and approximately one third of patients had a CR despite having chemotherapy-relapsed or refractory low-grade or transformed low-grade NHL.

Chemoembolization for hepatocellular carcinoma.

Fifty-one patients with unresectable hepatocellular carcinoma (HCC) were treated with Gelfoam (absorbable gelatin sterile powder; The Upjohn Co, Kalamazoo, MI) chemoembolization. A mixture of Gelfoam powder, contrast media, and three drugs (doxorubicin, mitomycin, and cisplatin) was injected under fluoroscopic guidance via a percutaneous catheter into the hepatic artery until stagnation of blood flow was achieved. Of the 51 patients, 50 are assessable for response, and all are assessable for toxicity and complications. The median percent of liver replacement was 50% (range, 15% to 95%). By conventional response criteria, there were 12 partial responses (PRs) (24%), 13 minor responses (MRs) (26%), 12 stabilization of disease (SD) (24%), and 13 (26%) progressive disease (PD). Tumor liquefaction was noted on computed tomographic (CT) scan in 35 of 50 patients (70%). Of the 34 patients with elevated alpha-fetoprotein (AFP), 23 (68%) had a greater than 50% reduction following treatment. Responding patients were re-treated at the time of tumor progression if they still met the entry criteria. The median survival of assessable patients from the time of treatment was 207 days and from the diagnosis of the primary was 302 days. Fourteen patients remain alive at 3 months to 3 years following treatment. The vast majority of patients had transient pain, fever, nausea, and elevation in liver enzymes. Ascites developed in 14 patients. There were two treatment-related deaths: one from tumor hemorrhage and one from liver failure. Chemoembolization appears to have significant activity in patients with hepatocellular carcinoma and is relatively well tolerated.

Toxicities and complications of implanted pump hepatic arterial and intravenous floxuridine infusion

Toxicities and complications were prospectively analyzed in patients with liver metastases receiving hepatic intra‐arterial (IA) and systemic intravenous (IV) floxuridine (FUDR) with the Infusaid (Intermedics‐Infusaid Corp., Norwood, MA) implantable pump. Among 55 patients treated with IA FUDR (0.3–0.1 mg/kg/day × 14, every 28 days), elevations in liver enzyme values, not attributable to disease progression, developed in 96% of patients. Serious biliary toxicity occurred in 31 patients (56%). In 16, biliary sclerosis was documented radiographically and was diagnosed clinically in 15 additional patients. Ten patients were hospitalized for biliary toxicity, including five who required cholecystectomy for acalculous cholecystitis. Because of the high reported incidence of serious gastroduodenal toxicity after IA FUDR infusion, our procedure for hepatic arterial cannulation was designed to eliminate misperfusion of the stomach and duodenum with drug; none of our patients experienced FUDR‐associated gastroduodenal ulceration or bleeding. Cyclic IV FUDR (0.05–0.15 mg/kg/day × 14, every 28 days) was administered to 31 participants of the Northern California Oncology Group trial (3L‐82‐1) of IV versus IA FUDR. Dose‐limiting toxicity was diarrhea. Serious toxicities were: protracted diarrhea (three), dermatitis (two), tear duct stenosis (two), and stomatitis (two). Three patients were hospitalized for toxicity. No hematologic or biliary toxicity occurred. The optimal route for treatment of hepatic metastases with continuous FUDR infusion has not yet been established. Systemic IV infusion has low morbidity, but preliminary response data need to be substantiated in controlled clinical trials before there can be widespread clinical application. High response rates for IA infusion have been previously documented. Morbidity due to acalculous cholecystitis and gastroduodenal ulceration can now be avoided. Despite significant progress in characterization of hepatobiliary toxicity, it remains dose‐limiting. Continuous IA FUDR infusion should remain under the aegis of dedicated treatment centers until standardized protocols with diminished toxicity are established.

Hepatic Arterial Chemotherapy for Colorectal Cancer Metastatic to the Liver

Hepatic metastases of colorectal origin are resistant to radiation and immunotherapy. Traditional intravenous chemotherapy produces responses in 10% to 30% of patients, and surgical resection is feasible in approximately 20% of patients who have a solitary or unilobar lesion. Infusion of cytotoxic agents into the hepatic artery, introduced 2 decades ago, is the most promising form of therapy for unresectable hepatic metastases. Fluorouracil, floxuridine, and mitomycin have been most commonly administered by hepatic arterial infusion. The recent development of a totally implantable pump has allowed prolonged ambulatory infusion of chemotherapeutic agents into the hepatic artery. We review the recent data on the pharmacology, therapeutic outcome, administration techniques, and complications of hepatic arterial chemotherapy. Future trials in this area should use uniform stratification variables and standardized criteria for evaluating response, time to progression, and survival.

A First-in-Human Phase I Study of the Anticancer Stem Cell Agent Ipafricept (OMP-54F28), a Decoy Receptor for Wnt Ligands, in Patients with Advanced Solid Tumors

Purpose: Wnt signaling is implicated in tumor cell dedifferentiation and cancer stem cell function. Ipafricept (OMP-54F28) is a first-in-class recombinant fusion protein with the extracellular part of human frizzled 8 receptor fused to a human IgG1 Fc fragment that binds Wnt ligands. This trial evaluated ipafricept in patients with solid tumors. Experimental design: A 3+3 design was used; ipafricept was given intravenously every 3 weeks. The objectives were determination of dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and preliminary efficacy. Results: 26 patients were treated in seven dose-escalation cohorts (0.5, 1, 2.5, 5, 10, 15, and 20 mg/kg). No further dose escalation was pursued as PK modeling indicated that the target efficacious dose was reached at 10 mg/kg, and fragility fractures occurred at 20 mg/kg. Most common related grade 1 and 2 adverse events (AEs; ≥20% of patients) were dysgeusia, decreased appetite, fatigue, and muscle spasms. Ipafricept-related grade 3 TEAEs included hypophosphatemia and weight decrease (1 subject each, 3.8%). Ipafricept half-life was ∼4 days and had low incidence of antidrug antibody formation (7.69%) with no impact on drug exposure. Six patients had β-C-terminal telopeptide (β-CTX) doubling from baseline, which was reversible. PD modulation of Wnt pathway genes in hair follicles occurred ≥2.5 mg/kg. Two desmoid tumor and a germ cell cancer patient experienced stable disease for >6 months. Conclusions: Ipafricept was well tolerated, with RP2D of 15 mg/kg Q3W. Prolonged SD was noted in desmoid tumor and germ cell cancer patients. Clin Cancer Res; 23(24); 7490–7. ©2017 AACR.

Hepatic intra-arterial methylene blue injection during endoscopy: a method of detecting gastroduodenal misperfusion in patients receiving hepatic intra-arterial chemotherapy via an implanted pump

Colorectal cancer is the third most common malignancy in the United States, with about 150,000 newly diagnosed cases per year.1 About half of all patients ultimately develop liver metastases and in 50% of those liver involvement is the dominant clinical problem.2,~ Resection of hepatic metastases is only feasible in about 10% of patients and systemic chemotherapy produces responses in 15 to 35% of patients. Hepatic intra-arterial (HIA) chemotherapy has been used to treat patients with metastatic colorectal carcinoma confined to the liver since the early 1960s.s The theoretical advantage of this route of drug delivery is its ability to enhance anti-tumor effect by increasing drug exposure at the tumor site and to minimize toxicity by decreasing systemic drug exposure. The availability of the totally implantable pump in the early 1980s greatly facilitated prolonged outpatient administration of HIA chemotherapy. Numerous phase II and III trials have documented the activity of this therapy.9-19 In order to safely and effectively deliver HIA chemotherapy, complete hepatic perfusion and the absence of gastrointestinal misperfusion must be achieved. This requires both proper catheter placement and surgical division of all vessels that supply the distal stomach and duodenum which arise from the hepatic artery distal to the point of cannulation.20 Intra-operatively, fluorescein injection into the pump sidepores with inspection of the liver and gastroduodenum using a Woods lamp is done to assure proper catheter placement. A post-operative, hepatic perfusion study (comparing an intra-arterial technetium-99m macroaggregated albumin scan to an intravenous technetium-99m sulfur colloid scan)20 has been routinely used to further verify the perfusion pattern. Hepatic artery infusion computerized tomography can also be

A phase I/II study of alternating constant rate infusion floxuridine with constant rate infusion vinblastine for the treatment of metastatic renal cell carcinoma

Background. Metastatic renal cell carcinoma (RCC) is largely chemoresistant. The efficacy of cell cycle specific chemotherapeutic agents, particularly those with short half‐lives, may be enhanced by the use of constant rate infusion schedules. Infusional floxuridine has been demonstrated to have a response rate of approximately 20%. Infusional vinblastine has not been tested extensively in patients with metastatic RCC. The sequential use of these agents was designed to increase efficacy and limit toxicity.

Abstract A084: DENALI: a 3-arm double-blind randomized phase 2 study of carboplatin, pemetrexed, and placebo (CPP) versus carboplatin, pemetrexed, and either 1 or 2 truncated courses of demcizumab (CPD) in patients with non-squamous non-small cell lung cancer (NSCLC)

Introduction: Delta-like ligand 4 (DLL4) is a ligand that activates the Notch pathway, which is important for cancer stem cell (CSC) survival. Demcizumab is a humanized, anti-DLL4 antibody that has been shown using an in vivo tumorigenicity limiting dilution assay to inhibit tumor growth and decrease CSC frequency in minimally passaged human xenograft models. In addition, inhibition of DLL4 has also been shown in preclinical studies to cause dysfunctional sprouting of new vessels, resulting in an antiangiogenic effect. Data from a phase 1b study of carboplatin (C), pemetrexed (P), and demcizumab (D) in patients with 1st-line metastatic non-squamous NSCLC led to this double-blind randomized 3-arm placebo (Pl)-controlled phase 2 study. Methods: Patients with non-squamous NSCLC were randomized (1:1:1) to 1st-line therapy with either Arm 1 -CPPl, Arm 2 -CPD with a single 70-day truncated course of demcizumab or Arm 3 - CPD with two 70-day truncated courses of demcizumab (second course starting on Day 168). CP were given at usual dose and schedule; P/D was given IV on days 1 and 15 in cycles 1-3 and 7-9. The primary endpoint was response rate and secondary endpoints included progression-free survival, survival, safety, immunogenicity, pharmacokinetics, and biomarkers of Notch signaling and CSCs in blood, hair follicles, and tumor cells. The primary study analyses compared CPPl to the two pooled CPD arms. Results: 82 patients were randomized and all 82 were treated. The median age was 61, the male/female ratio was 40/42, 80 pts had adenocarcinoma, 0 pts harbored EGFR mutation or ALK rearrangement, and 15 were KRAS mutated. The response/clinical benefit rates were 52%/92% and 28%/79% in the CPPl and pooled CPD arms, respectively (response p value = 0.04). The median progression-free survival (PFS) was 8.7 months (95% CI: 5.4-12.5) in the CPPl arm and 5.5 months (95% CI: 4.1-6.9) in the pooled CPD arms (HR = 2.3; 95%CI: 1.1-4.8). The interim median overall survival (OS) for the CPPl and pooled CPD arms was not reached (95% CI: 16.0—NR) and 15.5 months (95% CI: 8.3-NR) (HR= 2.4; 95% CI: 0.94-6.1), respectively. CPD was generally well tolerated with nausea, fatigue, constipation, anemia, and hypertension being the most common reported toxicities. The incidences of the Grade 3 or greater toxicities of special interest with demcizumab therapy were hypertension (8% vs 25%), pulmonary hypertension (0% vs 0%), heart failure (0% vs. 0%), and bleeding (0% vs. 3.4%) in the CPPl and pooled CPD arms, respectively. Conclusions: The addition of either 1 or 2 truncated courses of demcizumab to 1st-line carboplatin and pemetrexed did not improve the efficacy compared to CPPl in patients with 1st-line metastatic NSCLC. CPD therapy was generally well tolerated. Citation Format: Brett Hughes, Andrew Dean, Ben Markman, Luke Dreisbach, Mariano Provencio, Libero Ciuffreda, Rachel Dear, Peter Graze, Alforia Nadal, Baerin Houghton, Teresa Moran, Rachel Roberts, Grace Dy, Taus Alvaro, Alex Martinez Marti, Rainer Brachmann, Robert Stagg, Ramaswamy Govindan. DENALI: a 3-arm double-blind randomized phase 2 study of carboplatin, pemetrexed, and placebo (CPP) versus carboplatin, pemetrexed, and either 1 or 2 truncated courses of demcizumab (CPD) in patients with non-squamous non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A084.