Geoffrey Chong

A Phase I Trial of Humanized Monoclonal Antibody A33 in Patients with Colorectal Carcinoma: Biodistribution, Pharmacokinetics, and Quantitative Tumor Uptake

Purpose: To determine the in vivo characteristics of huA33, a CDR-grafted humanized antibody against the A33 antigen, we have conducted an open-label, dose escalation, biopsy-based phase I trial of huA33 in patients with colorectal carcinoma. Experimental Design: Patients with colorectal carcinoma were infused with [131I]huA33 (400 MBq: 10 mCi) and [125I]huA33 (40 MBq: 1 mCi) 1 week before surgery. There were four huA33 dose levels (0.25, 1.0, 5.0, and 10 mg/m2). Adverse events, pharmacokinetics, biodistribution, tumor biopsies, and immune responses to huA33 were evaluated. Results: There were 12 patients entered into the trial (6 males and 6 females; age range, 39-66 years). No dose-limiting toxicity was observed. The biodistribution of huA33 showed excellent uptake of [131I]huA33 in metastatic colorectal carcinoma. Pharmacokinetic analysis showed no significant difference in terminal half-life (T1/2β) between dose levels (mean ± SD, 86.92 ± 22.12 hours). Modeling of colon uptake of huA33 showed a T1/2 of elimination of 32.4 ± 8.1 hours. Quantitative tumor uptake ranged from 2.1 × 10−3 to 11.1 × 10−3 %ID/g, and tumor/normal tissue and tumor/serum ratios reached as high as 16.3:1 and 4.5:1, respectively. Biosensor analysis detected low-level human anti-human antibody responses in four patients following huA33 infusion. Conclusions: huA33 shows selective and rapid localization to colorectal carcinoma in vivo and penetrates to the center of large necrotic tumors, and colon elimination half-life of huA33 is equivalent to basal colonocyte turnover. The excellent targeting characteristics of this humanized antibody indicate potential for the targeted therapy of metastatic colorectal cancer in future trials.

Specific Targeting, Biodistribution, and Lack of Immunogenicity of Chimeric Anti-GD3 Monoclonal Antibody KM871 in Patients With Metastatic Melanoma: Results of a Phase I Trial

PURPOSE KM871 is a chimeric monoclonal antibody against the ganglioside antigen GD3, which is highly expressed on melanoma cells. We conducted an open-label, dose escalation phase I trial of KM871 in patients with metastatic melanoma. PATIENTS AND METHODS Seventeen patients were entered onto one of five dose levels (1, 5, 10, 20, and 40 mg/m2). Patients received three infusions of KM871 at 2-week intervals, with the first infusion of KM871 trace-labeled with indium-111 (111In) to enable assessment of biodistribution in vivo. Biopsies of metastatic melanoma sites were performed on days 7 to 10. RESULTS Fifteen of 17 patients completed a cycle of three infusions of KM871. No dose-limiting toxicity was observed during the trial; the maximum-tolerated dose was therefore not reached. Three patients (at the 1-, 5-, and 40-mg/m2 dose levels) developed pain and/or erythema at tumor sites consistent with an inflammatory response. No normal tissue uptake of 111In-KM871 was observed, and tumor uptake of 111In-KM871 was observed in all lesions greater than 1.5 cm (tumor biopsy 111KM871 uptake results: range, 0.001% to 0.026% injected dose/g). The ratio of maximum tumor to normal tissue was 15:1. Pharmacokinetic analysis revealed a 111In-KM871 terminal half-life of 7.68 +/- 2.94 days. One patient had a clinical partial response that lasted 11 months. There was no serologic evidence of human antichimeric antibody in any patient, including one patient who received 16 infusions over a 12-month period. CONCLUSION This study is the first to demonstrate the biodistribution and specific targeting of an anti-GD3 antibody to metastatic melanoma in patients. The long half-life and lack of immunogenicity of KM871 makes this antibody an attractive potential therapy for patients with metastatic melanoma.

A Phase I Biodistribution and Pharmacokinetic Trial of Humanized Monoclonal Antibody Hu3s193 in Patients with Advanced Epithelial Cancers that Express the Lewis-Y Antigen

Purpose: We report a first-in-man trial of a humanized antibody (hu3S193) against the Ley antigen. Experimental Design: Patients with advanced Ley-positive cancers received four infusions of hu3S193 at weekly intervals, with four dose levels (5, 10, 20, and 40 mg/m2). The first infusion of hu3S193 was trace labeled with Indium-111, and biodistribution, pharmacokinetics, tumor uptake, and immune response were evaluated in all patients. Results: A total of 15 patients (7 male/8 female; age range, 42-76 years; 6 breast, 8 colorectal cancer, and 1 non–small-cell lung cancer) were entered into the study. Transient grade 1 to 2 nausea and vomiting was observed following infusion of hu3S193 at the 40mg/m2 dose level only. There was one episode of dose-limiting toxicity with self-limiting Common Toxicity Criteria grade 3 elevated alkaline phosphatase observed in one patient with extensive liver metastases. The biodistribution of 111In-hu3S193 showed no evidence of any consistent normal tissue uptake, and 111In-hu3S193 uptake was observed in cutaneous, lymph node, and hepatic metastases. Hu3S193 displayed a long serum half-life (T1/2β = 189.63 ± 62.17 h). Clinical responses consisted of 4 patients with stable disease and 11 patients with progressive disease, although one patient experienced a 89% decrease in a lymph node mass, and one patient experienced inflammatory symptoms in cutaneous metastases, suggestive of a biological effect of hu3S193. No immune responses (human anti-human antibody) to hu3S193 were observed. Conclusion: Hu3S193 is well tolerated and selectively targets tumors, and the long half-life and biological function in vivo of this antibody makes it an attractive potential therapy for patients with Ley-expressing cancers.

Phase I Trial of 131I-huA33 in Patients with Advanced Colorectal Carcinoma

Purpose: Humanized monoclonal antibody A33 (huA33) targets the A33 antigen which is expressed on 95% of colorectal cancers. A previous study has shown excellent tumor-targeting of iodine-131 labeled huA33 (131I-huA33). Therefore, we did a phase I dose escalation trial of 131I-huA33 radioimmunotherapy. Experimental Designs: Fifteen patients with pretreated metastatic colorectal carcinoma each received two i.v. doses of 131I-huA33. The first was an outpatient trace-labeled “scout” dose for biodistribution assessment, followed by a second “therapy” dose. Three patients were treated at 20, 30, and 40 mCi/m2 dose levels, and six patients at 50 mCi/m2 to define the maximum tolerated dose. Results: Hematologic toxicity was 131I dose-dependent, with one episode of grade 4 neutropenia and two episodes of grade 3 thrombocytopenia observed at 50 mCi/m2. The maximum tolerated dose was determined to be 40 mCi/m2. There were no acute infusion-related adverse events, and gastrointestinal toxicity was not observed despite uptake of 131I-huA33 in bowel. Seven patients developed pruritus or rash, which was not related to 131I dose. There was excellent tumor-targeting of 131I-huA33 shown in all patients. The serum T1/2β of 131I-huA33 was (mean ± SD) 135.2 ± 46.9 hours. The mean absorbed tumor dose was 6.49 ± 2.47 Gy/GBq. Four patients developed human anti-human antibodies. At restaging, 4 patients had stable disease, whereas 11 patients had progressive disease. Conclusion: Radioimmunotherapy using 131I-huA33 shows promise in targeting colorectal tumors, and is deliverable at a maximum tolerated dose of 40 mCi/m2. Further studies of 131I-huA33 in combination with chemotherapy are planned.

Longitudinal assessment of quality of life in rectal cancer patients with or without stomas following primary resection.

PURPOSE: The purpose of this study was to assess the longitudinal impact of stoma formation on the health-related quality of life of rectal cancer patients treated with adjuvant chemotherapy. METHODS: Health-related quality of life data was prospectively collected in a randomized trial designed to compare 24 weeks of bolus 5-fluorouracil/leucovorin with 12 weeks of continuous 5-fluorouracil in patients with resected Dukes B and C colorectal cancer. Health-related quality of life data was collected at baseline, during adjuvant treatment, and at one and three years after completion of chemotherapy. RESULTS: Between 1993 and 2003, 186 rectal cancer patients were enrolled. One hundred thirty-nine patients had anterior resection, of whom 46 had a temporary defunctioning colostomy. Forty-seven patients had abdominoperineal resection with formation of a permanent colostomy. There was no significant difference in global health-related quality of life between patients with and patients without a stoma at any time point. However, during adjuvant treatment, role (P = 0.04) and social (P = 0.005) functioning were significantly worse in stoma patients than in nonstoma patients. Moreover, the impairment in social functioning persisted at one (P = 0.03) and three years (P = 0.04) after adjuvant chemotherapy. CONCLUSION: Our results demonstrate important adverse effects of either temporary or permanent stoma formation on subsequent health-related quality of life in patients with rectal cancer.

Improving long-term outcomes for patients with liver metastases from colorectal cancer.

Despite improved screening and adjuvant therapy for primary colorectal cancers, synchronous and metachronous liver metastases remain a significant problem for patients with this disease. Approximately 40% of patients who develop metastatic disease have tumor confined to the liver, which has driven interest in regional therapies targeting the liver. These include chemotherapy delivered via hepatic arterial infusion (HAI), destructive therapies such as radiofrequency ablation (RFA), and surgical metastasectomy. Surgical techniques for liver resection have improved significantly during the last decade; therefore, this has become an attractive method for rendering suitable patients macroscopically disease free. Studies showing prolonged diseasefree survival, overall survival—and possibly cure—in selected patients have demonstrated the efficacy of this approach. Systemic chemotherapy has been shown to downsize a proportion of initially unresectable liver metastases to the point of resectability. Adam et al reported a single-institution series of 872 patients with colorectal liver metastases who were assessed for resectability: 171 (19.6%) had resectable disease initially and underwent immediate surgery; 701 patients who had unresectable disease initially were treated with preoperative chemotherapy, which was mainly oxaliplatin based. After restaging, 95 patients (13.6%) were considered resectable, and underwent surgery. The actuarial 5-year survival for this downstaged group was 34%, with the survival curve almost exactly replicating that of patients who had initially resectable disease who underwent immediate surgery. This nonrandomized, yet innovative comparison has been a major rationale in support of surgery for patients with initially unresectable disease that responds adequately to preoperative chemotherapy. Response to this therapy is also predictive for long-term outcome. Adam et al found that patients who had liver metastasectomy after tumor progression on preoperative chemotherapy had significantly poorer survival than responders or those with tumor stabilization. Postoperative therapy is an accepted and rational component of treatment for patients requiring preoperative downsizing before resection. However, even patients with initially resectable liver metastases may benefit from postoperative therapy. The largest study was performed by the Federation Francophone de Cancerologie Digestive, which randomly assigned 167 patients to intravenous fluorouracil (FU)/leucovorin (LV) or observation after complete liver metastasectomy. Preliminary results suggested a nonstatistically significant trend toward improved disease-free and overall survival. An Intergroup study of 109 patients compared postoperative HAI floxuridine plus continuousinfusion intravenous FU versus observation. Although there was no difference in overall survival, both time to recurrence and time to recurrence in the liver were prolonged in the postoperative therapy arm. Additional support for the notion of more intensive postoperative therapy was provided by a study that demonstrated improved 2-year survival for patients randomly assigned to postoperative HAI floxuridine plus systemic FU versus systemic FU alone. Long-term follow-up has confirmed superior progression-free survival and a trend to improved overall survival for the combination arm. There are few prospective trials of preoperative systemic chemotherapy for patients with unresectable liveronly metastases. Pozzo et al conducted a single-institution nonrandomized study that comprised 40 patients with unresectable disease defined by local criteria. These criteria were more than six metastases (or three per lobe; 14 patients); more than 5 cm diameter of at least one lesion if six metastases (or three per lobe; 10 patients); and contiguity with at least two hepatic veins, inferior vena cava or liver hilum (14 patients). The response rate to irinotecan/FU/ LV) was 47.5%, and 13 (32.5%) patients underwent R0 liver resection. Six cycles of postoperative chemotherapy were administered to all patients who underwent resection JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 36 DECEMBER 2

Programmed cell death-1 inhibition in lymphoma

Cancers can evade the host immune system by inducing upregulation of immune inhibitory signals. Anti-programmed cell death-1 (PD-1) monoclonal antibodies block these inhibitory signals allowing the host to mount an immune response against malignant cells. This class of drugs is active in solid tumours, where upregulation of cell-surface PD-1 ligand proteins is nearly uniform. Because lymphoma is a malignancy of immune system cells, the role of the PD-1 pathway in these neoplasms is more complex. However, early clinical trials using PD-1 inhibitors have shown significant clinical activity in various subtypes of relapsed lymphoma. In this Review, we assess the scientific literature on the role of the PD-1 pathway in lymphoma, the relevant clinical data for PD-1 inhibition, and future strategies for this next generation of anticancer agents.

Gemcitabine, cisplatin and methylprednisolone (GEM-P) with or without Rituximab in relapsed and refractory patients with diffuse large B cell lymphoma (DLBCL)

Abstract This is the first report of the combination of gemcitabine, cisplatin and methylprednisolone (GEM-P) with Rituximab (GEM-PR) for diffuse large B-cell lymphoma (DLBCL). Thirty-nine patients with relapsed or refractory DLBCL in this study received GEM-P with (n = 24) or without Rituximab (n = 15) 64% patients had Stage III/V disease. The overall response rate (ORR) was 59% (95% CI 42.1–74.4); 11/39 (28%) patients attained complete response. Patients received a median of two cycles (1–4) of treatment. For GEM-PR group, the ORR was 67% (95% CI 45–84%) compared to 47% (95% CI 21–73%) in GEM-P alone. one-year progression-free survival was 51% (95% CI 28–69%) in GEM-PR group compared to 27% (95% CI 8–49%) in GEM-P alone (P = 0.04). GEM-P is an effective second-line regimen in patients with relapsed or refractory DLBCL and the addition of Rituximab appears to further improve outcomes.

Early treatment intensification with R-ICE and 90Y-ibritumomab tiuxetan (Zevalin)-BEAM stem cell transplantation in patients with high risk diffuse large B-cell lymphoma patients and positive interim PET after 4 cycles of R-CHOP-14

In the treatment of diffuse large B-cell lymphoma, a persistently positive [18F]fluorodeoxyglucose positron emission tomography (PET) scan typically carries a poor prognosis. In this prospective multi-center phase II study, we sought to establish whether treatment intensification with R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) chemotherapy followed by 90Y-ibritumomab tiuxetan–BEAM (BCNU, etoposide, cytarabine, and melphalan) for high-risk diffuse large B-cell lymphoma patients who are positive on interim PET scan after 4 cycles of R-CHOP-14 (rituximab, cyclophosphamide, doxorubicin, and prednisone) can improve 2-year progression-free survival from a historically unfavorable rate of 40% to a rate of 65%. Patients received 4 cycles of R-CHOP-14, followed by a centrally-reviewed PET performed at day 17–20 of cycle 4 and assessed according to International Harmonisation Project criteria. Median age of the 151 evaluable patients was 57 years, with 79% stages 3–4, 54% bulk, and 54% International Prognostic Index 3–5. Among the 143 patients undergoing interim PET, 101 (71%) were PET-negative (96 of whom completed R-CHOP), 42 (29%) were PET-positive (32 of whom completed R-ICE and 90Y-ibritumomab tiuxetan-BEAM). At a median follow up of 35 months, the 2-year progression-free survival for PET-positive patients was 67%, a rate similar to that for PET-negative patients treated with R-CHOP-14 (74%, P=0.11); overall survival was 78% and 88% (P=0.11), respectively. In an exploratory analysis, progression-free and overall survival were markedly superior for PET-positive Deauville score 4 versus score 5 (P=0.0002 and P=0.001, respectively). Therefore, diffuse large B-cell lymphoma patients who are PET-positive after 4 cycles of R-CHOP-14 and who switched to R-ICE and 90Y-ibritumomab tiuxetan-BEAM achieved favorable survival outcomes similar to those for PET-negative R-CHOP-14-treated patients. Further studies are warranted to confirm these promising results. (Registered at: ACTRN12609001077257).

Phase I Imaging and Pharmacodynamic Trial of CS-1008 in Patients With Metastatic Colorectal Cancer

PURPOSE CS-1008 (tigatuzumab) is a humanized, monoclonal immunoglobulin G1 (IgG1) agonistic antibody to human death receptor 5. The purpose of this study was to investigate the impact of CS-1008 dose on the biodistribution, quantitative tumor uptake, and antitumor response in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Patients with mCRC who had received at least one course of chemotherapy were assigned to one of five dosage cohorts and infused with a weekly dose of CS-1008. Day 1 and day 36 doses were trace-labeled with indium-111 ((111)In), followed by whole-body planar and regional single-photon emission computed tomography (SPECT) imaging at several time points over the course of 10 days. RESULTS Nineteen patients were enrolled. (111)In-CS-1008 uptake in tumor was observed in only 12 patients (63%). (111)In-CS-1008 uptake and pharmacokinetics were not affected by dose or repeated drug administration. (111)In-CS-1008 biodistribution showed gradual blood-pool clearance and no abnormal uptake in normal tissue. No anti-CS-1008 antibody development was detected. One patient achieved partial response (3.7 months duration), eight patients had stable disease, and 10 patients had progressive disease. Clinical benefit rate (stable disease + partial response) in patients with (111)In-CS-1008 uptake in tumor was 58% versus 28% in patients with no uptake. An analysis of individual lesions showed that lesions with antibody uptake were one third as likely to progress as those without antibody uptake (P = .07). Death-receptor-5 expression in archived tumor samples did not correlate with (111)In-CS-1008 uptake (P = .5) or tumor response (P = .6). CONCLUSION Death-receptor-5 imaging with (111)In-CS-1008 reveals interpatient and intrapatient heterogeneity of uptake in tumor, is not dose dependent, and is predictive of clinical benefit in the treatment of patients who have mCRC.