Abstract Background: Death receptor 5 (DR5) is a member of the TNFR superfamily that initiates the extrinsic apoptotic pathway by activating caspases. CS-1008 is a humanised, monoclonal IgG1 agonistic antibody to human DR5 created by CDR grafting of the murine antibody TRA-8. The aim of this study was to investigate the impact of CS-1008 dose on biodistribution, quantitative tumor uptake and anti-tumor response in patients with mCRC. Methods: Pts with mCRC who had received at least 1 course of chemotherapy (CT) were treated with weekly IV CS-1008 infusions in 5 non-sequential cohorts (Co). Different loading doses were used on days 1 and 8 (Co 1: 0.2 and 6 mg/kg; Co 2: 1 and 6 mg/kg; Co 3: 2 and 6 mg/kg; Co 4: 4 and 4mg/kg; Co 5: 6 and 2 mg/kg), followed by a weekly CS-1008 dose of 2 mg/kg. Cycle 1 encompassed 7 wks of therapy (D1 and D36 doses trace-labeled with 111In); additional weekly CS-1008 was scheduled as 4-wk cycles. Primary endpoints were to determine (1) the influence of CS-1008 dose on initial biodistribution, pharmacokinetic (PK) and tumor uptake of 111In-CS-1008 following single infusion; (2) changes in biodistribution, PK and tumor uptake following sequential doses. Secondary endpoints were to determine (1) anti-tumor response; (2) changes in tumor metabolism; (3) serum apoptosis biomarkers and serum tumor response markers. Results: Nineteen pts with a median age of 64 years and 2-6 prior CT lines were enrolled as follows: Co 1, 2 pts; Co 2, 4 pts; Co 3, 5 pts; Co 4, 3 pts; and Co 5, 5 pts. Twelve pts showed tumor uptake of 111In-CS-1008, 3 at each of the 1, 2, 4 and 6 mg/kg D1 dose levels. 111In-CS-1008 uptake in tumor was variable: some pts showed no uptake, in others uptake was observed in all measurable lesions. Liver metastases showed poor uptake of CS-1008. No significant differences were observed in tumor uptake between D1 and D36, and no effect of dose on tumor uptake was seen. DR5 expression in archived samples did not correlate with 111In-CS-1008 uptake, nor with clinical outcome. 111In-CS-1008 biodistribution showed gradual blood pool clearance and no discernible abnormal uptake in normal tissue. CS-1008 PK was not affected by dose or repeated drug administration. At restaging, there were 8 SD, 1 PR and 10 PD. The duration of PR was 3.7 months (mos). The mean duration of SD was 4 mos (range, 2.6-6.7 mos). Among the group of pts who showed CS-1008 uptake in tumor, 58% had clinical benefit (SD or PR), compared with 28% of pts in the group with no tumor uptake. The lesions that showed CS-1008 uptake were less likely to progress even in pts with overall PD at restaging. Conclusions: 111In-CS-1008 uptake in tumor predicts SD or PR. Tumor DR5 expression, assessed by 111In-CS-1008 imaging, reveals real-time heterogeneous DR5 expression, both on a per pt and on a lesion by lesion basis, and appears to be a promising predictive imaging biomarker of clinical benefit in pts with mCRC receiving CS-1008. Citation Format: Marika Ciprotti, Niall C. Tebbutt, Fook T. Lee, Sze T. Lee, Dave C. McKee, Graeme J. O'Keefe, Sylvia J. Gong, Geoffrey Chong, Hui K. Gan, Wendie Hopkins, Bridget Chappell, Nancy Y. Guo, Fiona E. Smyth, Archie N. Tse, Mendel Jansen, Manabu Matsumura, Rira Watanabe, Robert A. Beckman, Jon Greenberg, Andrew M. Scott. A phase I imaging and pharmacodynamic trial of CS-1008 in patients (pts) with metastatic colorectal cancer (mCRC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1174. doi:10.1158/1538-7445.AM2013-1174
2520 Background: ABT-806 is a humanized antibody targeting a conformationally exposed epitope only available when tumor Epidermal Growth Factor Receptor (EGFR) is overexpressed or (EGFRvIII) mutated. A prior trial treated 8 patients (pts) with a chimeric homologue (single-dose 5-40 mg/kg), with a minor response in one squamous cell carcinoma of skin pt. A prior phase 1A study of ABT-806 treated 26 pts (2-24 mg/kg IV q2w), with prolonged SD in one head and neck (H&N) cancer pt. No pt had a typical EGFR-inhibitor rash. The current study gathers further ABT-806 clinical data, assesses ABT-806i dosimetry in normal and malignant tissues and examines its relationship to clinical and PK/PD data. Methods: Pts with advanced tumors likely to express EGFR, ECOG 0-2, measurable disease and adequate organ function were enrolled. ABT-806i scans comprised ABT-806i 5-7mCi injection followed by whole body and regional SPECT scans over one week. Cohort (C) 1 pts (n=6) had ABT-806i scans alone. C2 pts (n=12) had ABT-806i scans at baseline and at week 6 (after 3 fortnightly doses of ABT-806; 6 pts at 18 mg/kg and 6 at 24 mg/kg). Subjects with PR/SD could receive ABT-806 on an extension study until progression. Results: 18 pts (M:F 11:7; median age 57 yrs) with tumors of H&N (6), colon (3), lung (2), brain (2), bladder (1), cervical (1) and other (3) were treated. An H&N pt had a confirmed PR whilst 5 pts had SD (lasting 37 and 24 wks in an adrenal carcinoma and H&N pt respectively). Two potential toxicities were seen at 24mg/kg on the extension study: equivocal rash (G1; three transient lesions on nose) and allergic reaction (Sweet’s syndrome, G2). Dosimetry in C1 pts confirmed safe radiation exposure levels to normal tissues. Many pts showed high, specific tumor uptake of ABT-806i, including 1 pt with an intracranial tumor. ABT-806i uptake was not significantly affected by concurrent ABT-806 treatment. Ongoing analyses of how ABT-806i uptake correlates with tumor EGFR and clinical response may inform the recommended phase 2 dose of ABT-806. Conclusions: The high therapeutic index and specificity of ABT-806 merits further investigation as monotherapy or an antibody-drug conjugate. ABT-806i may have utility as a bioimaging agent. Clinical trial information: NCT01472003.
Abstract Background: The development of antibody therapeutics for imaging and payload delivery is complex, and intact IgG have long half-lives that impact on tumor:blood ratios and tumor penetrance. Smaller molecular weight antibody constructs (eg diabodies) have been developed for improved penetrance into tumor, faster blood clearance, and enhanced tumor: normal tissue uptake, however renal uptake may impact on imaging and therapeutic effects. Through a novel pegylation strategy to surface disulphides, a diabody to TAG-72 (AVP0458) has been generated, and produced under cGMP for a first-in-human clinical trial. Materials and Methods: We have conducted a phase I, open label, first-in-human trial of PEG-AVP0458. The primary study objective was the safety of single dose of I-124 PEG-AVP0458 in patients (pts) with TAG-72 +ve relapsed / metastatic prostate or ovarian cancer. Secondary study objectives were evaluation of the biodistribution, tumor targeting, pharmacokinetics (PK) and immunogenicity of I-124 PEG-AVP0458. Pts were infused with I-124 PEG-AVP0458 (3-5mCi) at one of two dose levels (1mg/m2 and 10mg/m2), and imaged sequentially over a one week period. Safety, PK, and immunogenicity was assessed up to 30 days post infusion. Results: Six pts (1F:5M; age range 62-85yrs; 1 ovarian cancer, 5 prostate cancer) were entered into the study, 3 at each dose level. I-124 PEG-AVP0458 was well tolerated, with no infusion-related adverse events, and no serious adverse events observed. There was consistent biodistribution on PET imaging of I-124 PEG-AVP0458, with no normal tissue uptake. High tumor uptake was evident in metastatic disease in liver and lymph nodes, with lesion uptake seen within 1-2 days post injection. PK analysis showed a T½β of 46.8 ± 12.4 hrs. There was no impact of protein dose on biodistribution, tumor uptake or PK. No immunogenicity to PEG-AVP0458 was evident. Conclusions: I-124 PEG-AVP0458 is safe, and demonstrates excellent, rapid targeting of tumor in vivo, with no specific normal organ uptake, and high tumor: blood ratios. This data demonstrates the feasibility of using pegylated diabodies for imaging and for delivery of radioisotopes (RIT) or cytotoxic drug payloads (ADC) in cancer patients. Citation Format: Andrew M. Scott, Timothy Akhurst, Fook-Thean Lee, Marika Ciprotti, Ian Davis, Andrew Weickhardt, Hui Gan, Pece Kocovski, Nancy Guo, Linda Mileshkin, Scott Williams, Declan Murphy, Rod Hicks, Kunthi Pathmaraj, Sze Ting Lee, Graeme O'Keefe, Sylvia Gong, Maggie Oh, Michael Wheatcroft, Peter J. Hudson. Phase I safety and biodistribution study of 124I-PEG-AVP0458 diabody in patients with TAG-72 positive ovarian and prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT238. doi:10.1158/1538-7445.AM2015-CT238
The ability of recombinant antibodies to adequately penetrate into tumours is a key factor in achieving therapeutic effect; however, the behaviour of antibodies at a cellular level in tumours is poorly understood. The purpose of this study was to investigate those factors that influence the macroscopic and microscopic intratumoural distribution of an IgG1-humanized antibody, huA33, in colorectal tumours.Twelve patients were infused with radiolabelled huA33 at 7 days prior to elective surgery for colorectal carcinoma. Macroscopic huA33 uptake was determined by both gamma well counter and autoradiography measurements of the resected tumour specimens. Microscopic uptake was then quantitated at a cellular level and compared to vascular penetrance. The impact of variation in tumour antigen (GPA33) expression, tumour size, specimen type (primary vs metastatic), presence of macroscopic necrosis, and tumour vasculature on huA33 uptake were examined.The I-huA33 uptake in whole tumour sections was (mean ± SD) 5.13 ± 2.71 × 10(-3)% injected dose per gram (ID/g). GPA33 was expressed in all viable tumour cells, and huA33 uptake was excellent regardless of tumour size and specimen type. In tumours with macroscopically evident central necrosis (n = 5), huA33 uptake in tumour necrotic centres was lower than in viable peripheries (0.606 ± 0.493 vs 2.98 ± 2.17 × 10(-3)%ID, p = 0.06). However, when corrected for low cell viability in necrotic centres, uptake of huA33 at the cellular level was highly comparable to that in the more viable tumour periphery (7.10 ± 5.10 × 10(-9) vs 3.82 ± 3.67 × 10(-9)%ID/cell, p = 0.4). In the five patients who exhibited macroscopic necrosis in their tumours, huA33 showed excellent tissue penetration, with a maximum penetration distance of 26 μm in peripheral tumour regions and 118 μm in central regions. No correlation was observed between (131)I-huA33 uptake in tumour on a cellular basis and tumour vascularity.In patients with colorectal carcinoma, monoclonal antibody huA33 effectively targets viable tumour cells in all cellular milieus examined, including effective penetration into necrotic tumour centres, a novel and therapeutically important finding.
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