Feasibility of IV Tc-99m-tilmanocept for Imaging of M2-like TAMs in Metastatic Melanoma

This study in 20 patients is designed as a monocentric, open-label and uncontrolled, exploratory pilot study. Patients diagnosed with advanced melanoma (stage III-IV) and scheduled for anti-PD-1 immunotherapy will be recruited for this project. Patients will receive IV 250 µg Tilmanocept, labelled with 370 MBq of Tc-99m (bolus injection) according to the Navidea's protocol in our GMP certified radiopharmaceutical unit, before the first cycle of clinically scheduled immunotherapy. Scintigraphy images will be acquired dynamically from time of injection to +30 minutes. Quantitative SPECT/CT (xSPECT/CT, Siemens Symbia Intevo, Erlangen, Germany) imaging will be performed up to 1 hour p.i. to evaluate hyperaemia, and up to 3 hours p.i. to image and measure the CD206 receptor uptake. The data of the scans will be compared to immunohistochemistry results from biopsy staining for TAMs and M2-like TAMs and retrospectively with response to the immunotherapy to determine any correlation between M2-like TAMs and treatment response. For the planned retrospective comparison we will use the FDG - PET/CT data that is done after the immunotherapy as standard of care. We will analyse the lesion size and FDG - uptake in standard of care PET/CT of CD206+ and CD206 negative lesions in Tilmanocept SPECT/CT before and after immunotherapy to determine any correlation between CD206 related uptake and treatment response.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

* Female and male
* Age ≥ 18
* Diagnosis of having advanced melanoma , stage III-IV
* Scheduled for clinically indicated anti-PD-1 immunotherapy
* Informed Consent as documented by signature
* FDG PET/CT within 4 weeks before screening
* Biopsy available
* Minimum 3 lesions detected in FDG PET/CT

Exclusion Criteria:

* Age under 18
* Ocular melanoma
* Women who are pregnant or breast feeding,
* Intention to become pregnant during the course of the study,
* Previous enrolment into the current study,
* Enrolment of the investigator, his/her family members, employees and other dependent persons,
* Previous immunotherapy,
* History of any disease or relevant physical or psychiatric condition or abnormal physical finding which may interfere with the study objectives at the investigator judgment
* The subject has a known allergy to or has had an adverse reaction to dextran exposure
* Insufficient knowledge of project language, inability to give consent or to follow procedures
* The patient makes use of his/her "right not to know" and refuses to be informed about incidental findings

• BACKGROUNDDomingues B, Lopes JM, Soares P, Populo H. Melanoma treatment in review. Immunotargets Ther. 2018 Jun 7;7:35-49. doi: 10.2147/ITT.S134842. eCollection 2018. PMID 29922629
• BACKGROUNDHodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. doi: 10.1056/NEJMoa1003466. Epub 2010 Jun 5. PMID 20525992
• BACKGROUNDRobert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbe C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30. doi: 10.1056/NEJMoa1412082. Epub 2014 Nov 16. PMID 25399552
• BACKGROUNDRibas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. doi: 10.1016/S1470-2045(15)00083-2. Epub 2015 Jun 23. PMID 26115796
• BACKGROUNDLarkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. doi: 10.1056/NEJMoa1504030. Epub 2015 May 31.