SUPPLEMENTARY INFORMATION

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1 Supplementary Information S6 Intravenous delivery with therapeutic intent Therapy Antigen Target Study Special Feature Main Findings Antibody Population 131 I anti-p97 (p96.5 and 8.2) 1 p97 12 pts therapy 33 pts imaging Metastatic melanoma 90 Y B3 2 Anti-Lewis Y 33 pts Lewis Y positive: GI, non-small cell, ovarian bladder, breast 177 Lu-CC49 3 Tag 72 9 pts Breast, colon, lung 131 I KAb CEA 9 pts IV, pts IA 90 Y CC49 5 Tag72 34 pts Non-small cell lung cancer 131 I cg250 6 Carbonic Anhydrase IX 131 I cg250 7 Carbonic Anhydrase IX 33 pts Metastatic renal cell 15 pts Renal cell Phase I RIT, first monoclonal Fab therapy. Used specific and nonspecific antibody mci single and mci cumulative Phase I, 3 to 25 mci Y-90. Coinfusion with In- 111 Phase I 10 to 25 mci/m2 Phase I compared IV vs IA route mci Phase I +interferon +chelating agent and paclitaxel mci/m2y- 90 CC49 Phase I/II 30 to 90 mci/m2. Phase I dose escalation based on imaging scan dosimetry 50cGy, 75 cgy and 100 cgy whole body. Activity Tumor uptake is proportional to antigen content. Specific targeting (3.7 times> than control). Limited toxicity Pharmacokinetic similar for In-111 and Y of 24 treated stable. All HAMA response First 177Lu administration in pts. MTD 15 mci/m2. No antitumor response No survival benefit between routes. MTD marrow at 50 mci for IV and 75 mci for IA. Similar pharmacokinetics. DTPA allowed slightly higher Y- 90 CC49, MTD 17 mci/m2. Addition of paclitaxel required decreasing its dose MTD 90 mci/m2 hematologic. All had HAMA. 51% stable disease. No major responses. MTD 75 cgy, DLT at 100 cgy. Toxicity hematologic. No responses

2 131 I A5B7 8 CEA 12 pts GI adenocarcinoma 90 Y ct CEA 13 pts CEA positive: colon, lung, medullary, mucoepidermoi d 131 I A5B7 10 CEA 10 pts Colorectal, stomach, lung 90 Y capromab 11 PSMA(intracellula r domain) 8 pts Metastatic prostate cancer 131 I anti-cea (Fab )2 12 CEA 6 pts Limited liver metastasis from colon fractionated starting at 30 mci. Phase I 43.2 and 48.6 mci/m2 + vascular disrupting agent combretastatin-a4- phosphate (CA4P) 8, 12 and 16 mci/m2, used DTPA as chelating agent Repeated administration of murine antibody (2-4). Effect of cyclosporin A. Administered mci, IV 9mCi/m2 ( mCi), IV. 2 received EDTA mci, IV and 20Gy XRT 30% stable 70% progressed. MTD was hematologic. Combination therapy Was able to increase the activity with DTPA administration. DOTA conjugate on antibody compared to DTPA. Fractionated dose MTD 13.4 mci/m2. Smaller lesion had the highest uptake. Use of cyclosporine delayed timing and extent of immune response. Allowed more cycles. Myelosuppression is still dose limiting effect of repeat administration All tested developed HAMA. No CR or PR, 4SD, 4 Prog. Repeat diagnostic scan had altered biodistribution. Main toxicity myelosuppression. EDTA decreased myelosuppression Stable disuse in 3, 1 PR. Limited abnormalities in hepatic function. Feasible to

3 90 Y CC49 13 Tag72 12 pts Gastrointestinal 131 I Labetuzuma b (hmn- 14) 14 CEA 131 I chtnt- Double stranded 1/B 15 DNA and histone H1 antigens 23 pts Colorectal cancer metastatic liver 21 pts Metastatic colon 131 I NP-4 16 CEA 57 pts Metastatic CEA positive (colorectal, lung, pancreatic, breast, medullary, biliary, and salivary) 131 I COL-1 17 CEA 18 pts GI malignancy, CEA positive Bispecific (hmn-14 x m ) CEA 42 pts Medullary thyroid cancer Phase 1 dose escalation (0.3, 0.4 and 0.5mCi/kg) Post-surgical resection of liver mets received mci/m2 Phase 1 dose escalation (0.35 to 1.79 mci/kg) Activity based on marrow dose from 150cGy to 450 cgy capped at 250 mci. Repeat dosing. Dose escalation 10mCi/m2 10,25,50,65 and 75 mci/m2 Phase II multicenter. Anti- CEA with anti DTPA bispecific antibody. 131 Idi- DTPA 50.3 mci/m2 4-7 days after injection of bispecific (total activity range from 62.7 to 109 mci). combine therapy cgy to tumor. No responses, 2 stable disease. Validated on biopsy low tumorto-normal tissue ratio. Transient myelo suppression. OS median 68m. 51.3% alive at 5 years. Diseasefree progression 18 m. DLT hematologic. No CR or PR, 5 SD. Documented effect of HAMA on dosimetry and clearance. MTD hematologic. 1PR, 4 MR and 7 stable. Small tumor showed more favorable dosimetry. MTD 65, Ci/m2 hematologic. No non hematologic DLT. No response, 22% SD lasting 1.5 to 4 month. Stabilization plus objective response in 54.7%. Decrease in doubling time in 56.7%. Median progression-free survival 13.6m. Median OS 43.9m. Main toxicity hematologic

4 131 I HAb18 HAb18G/CD pts Metuximab 19 Hepatocellular cancer 131 I Metuximab F(ab`) I hepamab (DGDK-1) I OC-125 F(ab`)2 22 HAb18G/CD147 Membrane glycoprotein Cancer antigen125 (MUC16) 134 pts Hepatocellular carcinoma 32 pts Hepatocellular carcinoma 6 pts Ovarian cancer 90 Y-hMN- CEA 14 pts Medullary thyroid cancer Two arm, arterial RIT with 0.75mCi/kg+ Tumor arterial chemoembolizatio n in 68 pts median of 132 course of RIT and 152 TACE or Tumor arterial chemoembolizatio n alone in 70 pt 296 sessions of TACE Phase I/ II Dose escalation in 28 pt.25-1 mci/kg hepatic artery infusion Phase II 106 pt 0.75 mci/kg Phase I IV 20 to 100 mci Phase II patients with minimal residual disease after surgery and 1 or 2 chemotherapy regimen. IP RIT 120 mci 5-10 days after surgery Phase I. Stems cell harvested. Escalating dose 20 mci/m2 to 50 mci/m2 (total mci). Dosimetry based with limit to normal organs. Following 90Y hmn-14 docetaxel Median survival was extended to 26.7 m for combined vs m for TACE alone. Slightly higher hematologic toxicity in treated group with combined therapy. Prior RIT alone gave survival of 19 m. No DLT. MTD 0.75 mci/kg. 73 pts completed 2 cycles. PR 8,2%, MR and 58.9 SD. No DLT. Oneyear survival 31%. 70% AFPpositive patients dropped by > 50%. 84% showed improvement in ECOG performance status. Toxicity mainly hematologic with Grade 3 changes. Little therapeutic benefit. Main toxicity hematologic but with stem cell recovered. Non hematologic DLT at the 50mCi/m2 was cardiopulmonary. MTD 40 mci/m2 +docetaxel. 2MR, 1PR

5 131 I MN-14 F(ab`)2 24 CEA 15 pts Medullary thyroid carcinoma 131 I MN14 CEA 12 pts F(ab`)2 25 Medullary thyroid cancer 90 Y m MUC-1 9 pts Prostate and 8 pts Breast cancer 90 Y BrE-3 27 Glycoprotein of human milk fat globule 90 Y Cl ivatuzumab (hpam4) 28 Mucin antigen 6 pts Breast cancer 38 pts Pancreatic cancer given at 60 mg/m2. Activity based on bone marrow dose. Bone marrow dose of 140, 180, and 220 cgy. Median activity mci range from 99.2to 267 mci Dose escalated on normal organ dosimetry starting 90 cgy to kidney and 1200 cgy to lung and escalate by 300 cgy. Stem cell re-infused. 90 Y m170 alone or followed by paclitaxel (12 mci/m2 in prostate and 22mCi/m2 in breast). stem cell available 90 Y BrE or 9.25 mci/m2 90 Y hpam4 in combination weekly x 3. Dose escalation 6-15 mci/m2, with gemcitabine (200 mg/m2) DLT was hematologic. MTD 180cGy marrow. SD in 11 of 12 for >3 to 26 month. 1 decrease in tumor mass. 7 median of 55% reduction of tumor marker. Hematologic toxicity observed. All patients received their stem cell and recovered. 1 PR, 1 MR 10 SD. Among first study with transplant. Did not reach DLT PSA drop in 2 prostate cancer pts. 2 minor response in breast cancer. MTD not reached. 3 breast cancers pt required stem cell No DLT reached. HAMA response in 5 of 6. 3 of 6 had objective response although less than 8 wks. Maximum tolerated dose at 12 mci/m2 x3 cycle 19 mci/m2 x3 additional cycles. Fractionation allowed almost twice higher total dose. Median overall survival 7.7 m

6 References 1. Larson, S.M. et al. Localization of I-131-labeled p97-specific fab fragments in human melanoma as a basis for radiotherapy. J Clin Investigation. 72, (1983). 2. Pai-Scherf et al. Imaging and phase I study of In-111- and Y-90-labeled anti- Lewis(Y) monoclonal antibody B3. Clin Cancer Res. 6, (2000). 3. Mulligan, T. et al. Phase I study of intravenous Lu-177-labeled CC49 murine monoclonal antibody in patients with advanced adenocarcinoma. Clin Cancer Res, 1, 1447 (1995). 4. Sultana, A. et al. Randomised phase I/II trial assessing the safety and efficacy of radiolabelled anti-carcinoembryonic antigen I-131 KAb201 antibodies given intraarterially or intravenously in patients with unresectable pancreatic adenocarcinoma. BMC Cancer. 9, 66 (2009). 5. Forero, A. et al. Phase I study of Y-90-CC49 monoclonal antibody therapy in patients with advanced non-small cell lung cancer: effect of chelating agents and paclitaxel co-administration. Cancer Biother Radio. 20, (2005). 6. Divgi, C.R. et al. Phase I/II radioimmunotherapy trial with iodine-131-labeled monoclonal antibody G250 in metastatic renal cell carcinoma. Clin Cancer Res. 4, (1998). 7. Divgi, C.R. et al. Phase I clinical trial with fractionated radioimmunotherapy using I- 13-labeled chimeric G250 in metastatic renal cancer. J Nucl Med. 45, (2004). 8. Meyer, T. et al. A phase I trial of radioimmunotherapy with I-131-A5B7 anti-cea antibody in combination with combretastatin-a4-phosphate in advanced gastrointestinal carcinomas. Clin Cancer Res. 15, (2009). 9. Wong, J.Y.C. et al. A phase I radioimmunotherapy trial evaluating (90)yttriumlabeled anti-carcinoembryonic antigen (CEA) chimeric T84,66 in patients with metastatic CEA-producing malignancies. Clin Cancer Res. 6, (2000). 10. Ledermann, J.A. et al. A phase-i study of repeated therapy with radiolabelled antibody to carcinoembryonic antigen using intermittent or continuous administration of cyclosporin A to suppress the immune response. Int J Cancer. 47, (1991). 11. Kahn, D. et al. A phase II study of [90Y] yttrium-capromab pendetide in the treatment of men with prostate cancer recurrence following radical prostatectomy. Cancer Biother Radio. 14, (1999). 12. Buchegger, F. et al. Radioimmunotherapy of colorectal cancer liver metastases: combination with radiotherapy. Ann NY Acad Sci. 910, (2000). 13. Tempero, M. et al. High-dose therapy with iodine-131-labeled monoclonal antibody CC49 in patients with gastrointestinal cancers: a phase I trial. J Clin Oncol. 15, (1997). 14. Liersch, T. et al. Phase II trial of carcinoembryonic antigen radioimmunotherapy with 131I-labetuzumab after salvage resection of colorectal metastases in the liver: fiveyear safety and efficacy results. J Clin Oncol. 23, (2005). 15. Street, H.H. et al. Phase I study of 131I-chimeric(ch) TNT-1/B monoclonal antibody for the treatment of advanced colon cancer. Cancer Biother Radio. 21, (2006).

7 16. Behr, T.M. et al. Phase I/II clinical radioimmunotherapy with an iodine-131-labeled anti-carcinoembryonic antigen murine monoclonal antibody IgG. J Nucl Med. 38, (1997). 17. Yu, B. et al. Phase I trial of iodine 131-labeled COL-1 in patients with gastrointestinal malignancies: influence of serum carcinoembryonic antigen and tumor bulk on pharmacokinetics. J Clin Oncol. 14, (1996). 18. Salaun, P.Y. et al. Phase II trial of anticarcinoembryonic antigen pretargeted radioimmunotherapy in progressive metastatic medullary thyroid carcinoma: biomarker response and survival improvement. J Nucl Med. 53, (2012). 19. Wu, L. et al. Hepatic artery injection of (1)(3)(1)I-labelled metuximab combined with chemoembolization for intermediate hepatocellular carcinoma: a prospective nonrandomized study. Eur J Nucl Med Mol Imag. 39, (2012). 20. Chen, Z.N. et al. Targeting radioimmunotherapy of hepatocellular carcinoma with iodine (I-131) metuximab injection: clinical phase I/II trials. Int J Radiat Oncol Biol Phys. 65, (2006). 21. Chen, S.L. et al. Phase I clinical trial of targeted therapy using I-131-hepama-1 mab in patients with hepatocellular carcinoma. Cancer Biother Radio. 19, (2004). 22. Mahe, M.A. et al. A phase II study of intraperitoneal radioimmunotherapy with iodine-131-labeled monoclonal antibody OC-125 in patients with residual ovarian carcinoma. Clin Cancer Res. 5, 3249s-3253s (1999). 23. Sharkey, R.M. et al. A phase I trial combining high-dose 90Y-labeled humanized anti-cea monoclonal antibody with doxorubicin and peripheral blood stem cell rescue in advanced medullary thyroid cancer. J Nucl Med. 46, (2005). 24. Juweid, M.E. et al. Phase I/II trial of I-131-MN-14 F(ab)(2) anti-carcinoembryonic antigen monoclonal antibody in the treatment of patients with metastatic medullary thyroid carcinoma. Cancer. 85, (1999). 25. Juweid, M.E. et al. Initial experience with high-dose radioimmunotherapy of metastatic medullary thyroid cancer using 131I-MN-14 F(ab)2 anti-carcinoembryonic antigen MAb and AHSCR. J Nucl Med. 41, (2000). 26. Richman, C.M. et al. High-dose radioimmunotherapy combined with fixed, low-dose paclitaxel in metastatic prostate and breast cancer by using a MUC-1 monoclonal antibody, m170, linked to indium-111/yttrium-90 via a cathepsin cleavable linker with cyclosporine to prevent human anti-mouse antibody. Clin Cancer Res. 11, (2005). 27. DeNardo, S.J. et al. Radioimmunotherapy for breast cancer using indium- 111/yttrium-90 BrE-3: results of a phase I clinical trial. J Nucl Med. 38, (1997). 28. Ocean, A.J. et al. Fractionated radioimmunotherapy with (90) Y-clivatuzumab tetraxetan and low-dose gemcitabine is active in advanced pancreatic cancer: A phase 1 trial. Cancer. 118, (2012).