An Evaluation of Tc 99m Tilmanocept by Intravenous (IV) and Subcutaneous (SC) Injection in Kaposi Sarcoma (KS)

This is a Manocept Platform prospective, single-center, open-label, non-randomized, dose escalation, comparative, safety study of intravenously and subcutaneously injected Tc 99m tilmanocept in the localization and detection of cutaneous and non-cutaneous KS tumor(s) in subjects with biopsy-confirmed KS. Three IV doses (µg/mCi) of tilmanocept will be evaluated in three cohort groups. One subcutaneous dose will be evaluated in cohort group 3.

This study is designed to evaluate the safety and tolerability of escalating doses of IV Tc 99m tilmanocept and to compare results obtained from IV and subcutaneous administrations of Tc 99m tilmanocept in the same subjects. Whole body planar as well as SPECT/CT imaging will be performed to provide greater resolution of areas of Tc 99m tilmanocept localization. A biopsy of a non-visceral KS lesion will be taken to correlate pathology with Tc 99m tilmanocept localization.

This study is designed to evaluate the use of Tc 99m tilmanocept as an imaging agent in HIV-positive subjects with known KS by evaluating localization in known and unknown cutaneous and non-cutaneous lesions.

• Tc99m-tilmanocept (Drug), also known as Lymphoseek: Tilmanocept is a radiotracer that accumulates in macrophages by binding to a mannose binding receptor that resides on the surface.

Primary outcomes

• To Determine the Safety of Escalating Doses of Tc 99m Tilmanocept in HIV Subjects With Biopsy-confirmed KS. [10 days after IV Tc 99m tilmanocept administration]: Cohort 1 (100 mcg/ 5mCi) was conducted first. A safety data review meeting was held after completion of Cohort 1 and again after completion of Cohort 2 at which the principal investigators and sponsor representatives reviewed the safety data to determine whether to proceed to the next cohort. All cohorts were evaluated for safety. Safety evaluations included AEs, clinical laboratory tests, vital signs, physical examinations, and ECGs. The data table includes the number of safety signals detected during the evaluation for each cohort.

Secondary outcomes

• Per Subject Localization Rate of Tc 99m Tilmanocept in at Least One KS Suspected or Confirmed Lesion by Planar and/or SPECT/CT Imaging [10 days after IV Tc 99m tilmanocept administration]: Presents Tc 99m tilmanocept KS lesion localization in each cohort. IV injections occurred in all three cohorts. SC injections occurred in cohort 3 only.
• Qualify and Quantify Tc 99m Tilmanocept Localization Intensity on Imaging With CD206 Locale and Quantity by Histology and IHC in Biopsied KS Lesions to Determine Optimal IV Dose. [10 days after IV Tc 99m tilmanocept administration]: Localization intensity for each biopsied and clinically defined lesion was to be determined by Planar and/or SPECT/CT imaging. The results would have been average pixel intensity and percentage above background. Note: Cohort 1 was completed before this outcome measure was introduced, therefore no cohort 1 subjects were evaluated for this outcome measure.
• Localization Concordance of Subcutaneous Injection and IV Injection [10 days after IV Tc 99m tilmanocept administration]: Per lesion/region concordance of IV vs subcutaneous Tc 99m localization with anatomical areas of active KS defined by confirmed diagnosis or clinical symptomology. Note: IV routes of administration are used in all three cohorts. Cohort 3 is the only SC route of administration.
• Exploratory: Quantify HHV8 in Biopsied KS Lesions. Mean and Standard Deviation Results. [10 days after IV Tc 99m tilmanocept administration]: Quantify HHV8 in biopsied KS lesions by using qPCR. Note: Cohort 1 was completed before this outcome measure was introduced, therefore no cohort 1 subjects were evaluated for this outcome measure. If there is identification of HHv8, that would confirm the presence of KS cells in the biopsied tissue.
• Exploratory: Quantify HHV8 in Biopsied KS Lesions. Median Results. [10 days after IV Tc 99m tilmanocept administration]: Quantify HHV8 in biopsied KS lesions by using qPCR. Note: Cohort 1 was completed before this outcome measure was introduced, therefore no cohort 1 subjects were evaluated for this outcome measure. If there is identification of HHv8, that would confirm the presence of KS cells in the biopsied tissue.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. The subject has provided written informed consent with HIPAA authorization before the initiation of any study-related procedures.
2. The subject is at least 18 years of age at the time of consent.
3. The subject is HIV positive.
4. The subject has a biopsy-confirmed diagnosis of KS and is classified into one of the categories below:

   1. Confirmed cutaneous KS/oral lesions without edema.
   2. Confirmed cutaneous KS/oral lesions with edema.
   3. Confirmed cutaneous KS/oral lesions with or without edema and suspected non-cutaneous KS due to clinical symptomology or confirmed non-cutaneous KS lesion(s).

Exclusion Criteria:

1. The subject is pregnant or lactating.
2. The subject has received chemotherapy or radiation therapy to KS sites within six weeks of enrollment.
3. The subject has known sensitivity to dextran.
4. The subject has received an investigational product within 30 days prior to the Tc 99m tilmanocept administration on Day 1.
5. The subject has received any radiopharmaceutical within 7 days prior to the administration of Tc 99m tilmanocept on Day 1.
6. Any condition that, in the clinical judgment of the treating physician, is likely to prevent the subject from complying with any aspect of the protocol or that may put the subject at unacceptable risk.

Participant flow

Outcome results

• To Determine the Safety of Escalating Doses of Tc 99m Tilmanocept in HIV Subjects With Biopsy-confirmed KS. (Primary), Number, Safety Signals: 100 mcg/5 mCi Tc99m-Tilmanocept 0; 100 mcg/10 mCi Tc99m-Tilmanocept 0; 200 mcg/5 mCi Tc99m-Tilmanocept 0
• Per Subject Localization Rate of Tc 99m Tilmanocept in at Least One KS Suspected or Confirmed Lesion by Planar and/or SPECT/CT Imaging (Secondary), Count of participants, Participants: 100 mcg/5 mCi Tc99m-Tilmanocept 4; 100 mcg/10 mCi Tc99m-Tilmanocept 1; 200 mcg/5 mCi Tc99m-Tilmanocept 0
• Qualify and Quantify Tc 99m Tilmanocept Localization Intensity on Imaging With CD206 Locale and Quantity by Histology and IHC in Biopsied KS Lesions to Determine Optimal IV Dose. (Secondary), Count of participants, Participants: 100 mcg/10 mCi Tc99m-Tilmanocept 4; 200 mcg/5 mCi Tc99m-Tilmanocept 6
• Localization Concordance of Subcutaneous Injection and IV Injection (Secondary), Count of units, Lesions: 100 mcg/5 mCi Tc99m-Tilmanocept 3; 100 mcg/10 mCi Tc99m-Tilmanocept 0; 200 mcg/5 mCi Tc99m-Tilmanocept 0
• Exploratory: Quantify HHV8 in Biopsied KS Lesions. Mean and Standard Deviation Results. (Secondary), Mean, HHV8 (RFU): 100 mcg/10 mCi Tc99m-Tilmanocept 1242.50 +/- 583.635; 200 mcg/5 mCi Tc99m-Tilmanocept 4392.50 +/- 4143.048
• Exploratory: Quantify HHV8 in Biopsied KS Lesions. Median Results. (Secondary), Median, HHV8 (RFU): 100 mcg/10 mCi Tc99m-Tilmanocept 1171.50 (606.0 to 2021.0); 200 mcg/5 mCi Tc99m-Tilmanocept 4463.50 (73.0 to 10507.0)

Adverse events

Time frame: 50 days

Other adverse events by term

• Cope, F.O., W. Metz, et al. Innovations in receptor-targeted precision imaging at Navidea: diagnosis up close and personal. Nature Outlook (31 October 2013); S125-S129.
• Results publication: Cope FO, Abbruzzese B, Sanders J, Metz W, Sturms K, Ralph D, Blue M, Zhang J, Bracci P, Bshara W, Behr S, Maurer T, Williams K, Walker J, Beverly A, Blay B, Damughatla A, Larsen M, Mountain C, Neylon E, Parcel K, Raghuraman K, Ricks K, Rose L, Sivakumar A, Streck N, Wang B, Wasco C, Williams A, Schlesinger LS, Azad A, Rajaram MVS, Jarjour W, Young N, Rosol T, McGrath M. Corrigendum to the inextricable axis of targeted diagnostic imaging and therapy: An immunological natural history approach [Nucl Med Biol 43 (2016) 215-225]. Nucl Med Biol. 2016 Dec;43(12):837. doi: 10.1016/j.nucmedbio.2016.10.001. No abstract available. PMID 27866590

• Study Protocol (PDF, 2019-02-01)
• Statistical Analysis Plan (PDF, 2020-07-30)
• Informed Consent Form (PDF, 2019-10-10)

• Michael Blue, MD, Study director, Navidea Biopharmaceuticals

NIH grants: R44CA192859