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First-in-human safety, imaging and dosimetry of [68Ga]Ga-DPI-4452, a novel CA IX-targeting peptide, in patients with clear cell renal cell carcinoma

  • Michael S Hofman,
  • Ben Tran,
  • Darren R. Feldman,
  • Anna Pokorska-Bocci,
  • Solen Pichereau,
  • Jonathan Wessen,
  • Mohammad B. Haskali,
  • Richard Sparks,
  • Olena Vlasyuk,
  • Ivana Galetic

Research Funding

Debiopharm International SA

Background

Carbonic anhydrase IX (CA IX) is overexpressed in clear cell renal cell carcinoma (ccRCC) and is associated with aggressive tumor behavior, treatment resistance and overall poor outcomes. DPI-4452 is a first-in-class, cyclic peptide that binds with high affinity to CA IX. Radiolabeling DPI-4452 with gallium-68 ([68Ga]Ga-DPI-4452) or lutetium-177 ([177Lu]Lu-DPI-4452) is an innovative, theranostic approach for identifying and treating patients with CA IX-expressing tumors. Compared with existing antibody approaches, a radiolabeled peptide may confer better characteristics for both PET-CT imaging and therapy. This first-in-human study (NCT05706129) is evaluating the theranostic potential of [68Ga]Ga-DPI-4452 and [177Lu]Lu-DPI-4452 in patients with unresectable metastatic ccRCC, colorectal cancer or pancreatic ductal adenocarcinoma tumors. Here we report safety, tolerability, pharmacokinetics, dosimetry and imaging characteristics of [68Ga]Ga-DPI-4452 from the completed ccRCC imaging cohort.

Methods

The DPI-4452 peptide contains a DOTA cage and is radiolabelled with [68Ga]Ga. Following intravenous injection of [68Ga]Ga-DPI-4452, patients underwent serial PET-CT imaging, urine and blood sampling to assess imaging characteristics, biodistribution, and dosimetry of [68Ga]Ga-DPI-4452. Patients were followed for 7 days post-injection for safety observations.

Results

A mean activity of 185 MBq [68Ga]Ga-DPI-4452 was administered to 3 patients with ccRCC. No clinically significant toxicities were observed. PET-CT images showed rapid and sustained tumor uptake over 4 h, as well as rapid renal elimination. At 1 h, the maximum tumor standardized uptake value (SUVmax) across 36 lesions ranged from 6.8 to 211.6, with a mean of 64.6. Seventeen of these lesions (found in lymph nodes, lung, pancreas, parotid gland and other sites) were not detectable on prior contrast-enhanced CT. OLINDA dosimetry estimates revealed that the organs receiving the highest absorbed doses (mean [SD] mGy/MBq) were stomach wall (0.33 [0.10]), small intestine wall (0.33 [0.08]) and gallbladder wall (0.21 [0.12]), with a mean whole body effective dose of 0.06 [0.02] mSv/MBq. Absorbed doses in the kidney, liver and bone marrow were low. Over 80% of total administered radioactivity cleared from the bloodstream within 1 h.

Conclusions

[68Ga]Ga-DPI-4452 provides exceptional images in patients with ccRCC without clinically significant toxicity. Very high SUVs and tumor-to-background ratios suggest potential for use in both diagnostics and patient selection for therapy. The tumor retention and rapid elimination support potential of [177Lu]Lu-DPI-4452 radioligand therapy. Clinical trial information: NCT05706129.