Dose Escalation Study to Evaluate Safety, Dosimetry, and PD of the HER2-Directed Radioligand CAM-H2 in Patients With Advanced HER2+ Breast, Gastric, GEJ, and Other HER2+ Solid Tumors (trial ID: NCT04467515)

Introduction: CAM-H2 is a novel radiopharmaceutical comprising of a single-domain antibody which binds to HER2, and that is covalently linked to the beta particle-emitting radioisotope I-131. The dose escalation phase of this study has a 3+3 design and was set up to assess safety, dosimetry, and PD of ascending doses of CAM-H2.

Methods: Subjects with advanced/ metastatic HER2+ breast (BC), gastric, and GEJ cancers who were refractory to standard of care treatment, and who had at least 1 measurable lesion, as defined by RECIST v 1.1, or RANO-BM and who had a life expectancy of at least 6 months were eligible for the study.

Eligible patients were enrolled in cohorts to receive ascending doses of 50 mCi (1.85 GBq), 100 mCi (3.70 GBq) and 150 mCi (5.55 GBq) of CAM-H2 in cycles of 2 doses, administered 4 weeks apart. Imaging (SPECT/ CT and planar WB) was conducted after each dose in cycle 1, at 5 hrs, 24 hrs, 48 hrs and 168 hrs post CAM-H2 administration, to evaluate distribution, organ/ target lesion uptake and dosimetry.

Results: 18 subjects were screened, of whom 13 proceeded to treatment. Of these, 9 were diagnosed with HER2+ BC (3 had brain metastases), 3 had GEJ cancer and 1 had gastric cancer. 3 were administered at least 1 dose of 50 mCi CAM-H2, 3 at least 1 dose of 100 mCi CAM-H2 and 7 at least 1 dose of 150 mCi CAM-H2. These subjects were all heavily pre-treated prior to entry into the study. BC subjects had a median of 9 (range 3-15) prior systemic treatments and non-BC subjects a median of 4 (range 2-5). All BC subjects, and 60% of non-BC subjects, had undergone prior radiotherapy.

22 TEAE were reported in 6 subjects that were related to the study drug. Of these, 2 grade 3 TEAEs were experienced by 2 subjects. These included:

• Decrease in platelet count – patient had history of thrombocytopenia prior to and during screening. Their platelet count declined after receiving their 1st dose of CAM-H2 and then increased following the 2nd dose.

• Pneumonitis – this subject had a history of cough, lung disease and chest wall pain and was admitted to hospital the day following their 1st dose of CAM-H2. As this was a potentially study drug related SAE, it was a DLT.

One additional SAE was reported but was not study drug related.

All subjects had measurable tumor uptake on post treatment imaging. Dosimetry was carried out after the 1st and 2nd doses of CAM-H2. The results have been normalized to reflect expected values if a 150mCi dose (potential therapeutic dose) of CAM-H2 was administered. Tumor absorbed dose ranged from 0.8-17.5 Gy (mean uptake 3.7 and median uptake 2.8 Gy). Bone marrow absorbed dose ranged from 0.3-1.3 Gy (mean and median 0.5 Gy).

Conclusions: CAM-H2 demonstrated an acceptable safety profile at 50 mCi, 100 mCi and 150 mCi. Based on the dosimetry data gathered, bone marrow could be the dose limiting organ although we have not seen significant clinical signs of haematological toxicity. It is possible that bone marrow values may be artificially high due to spill over from the neighbouring kidney uptake as measurements are taken from the lumbar spine.

Imaging data confirms that CAM-H2 is highly specific, reaches, and is retained in, HER2+ tumors, which supports a proof of mechanism for the single domain antibody-radioligand platform.

To date, limited evidence of efficacy has been observed. This is likely due to the relatively low single and cumulative radiation doses that have been achieved in the target lesions so far. The tumor absorbed range was wide suggesting enrichment of patient population through molecular imaging pathologic HER2 positivity should be considered for future study designs.

If the hypothetical effective cumulative dose can be successfully administered (900 mCi), extrapolated dosimetry data suggests that the tumor absorbed dose could be in the range of 5-105 Gy (mean uptake 22.3 Gy: median uptake 17.1 Gy).

The safety data generated, would allow higher dose levels in future clinical trials.