Phase I Study Evaluating 161Tb-PSMA Therapy in Adult Patients With Metastatic Clear Cell Renal Cell Carcinoma

Patients with mccRCC will be selected, treated and followed-up as described below:

Selection step - 68Ga-PSMA PET:

A selection step at screening is mandatory for all patients in order to evaluate the PSMA expression in tumor lesions through 68Ga-PSMA PET and according to local imaging review. Only patients with PSMA expressing tumors according to eligibility criteria define din the protocol will be eligible to the treatment step.

Treatment step:

Eligible patients will be treated with escalating doses of 161Tb-PSMA-1 (from 7.4 GBq ± 10% to 11.5GBq ± 10%), intravenously (IV) for 4 cycles administered every 6 weeks. Three DL are expected to be assessed in the dose escalation part from 7.4 to 11.5 GBq ± 10%.

Dose Levels 161Tb-PSMA, IV, Q6W, 4 doses :

• DL-1 5.5 GBq ± 10% Q6W
• DL1 (starting activity) 7.4 GBq ± 10% Q6W
• DL2 9.5 GBq ± 10% Q6W
• DL3 11.5 GBq ± 10% Q6W

Assessment step:

To assess tumor response according to RECIST V1.1, imaging will be performed at baseline, W9-10, W24, then every 12 weeks up to 1 year after the first administration and every 24 weeks afterwards until progression, death or overall study completion, whichever is earliest. Survival status will be documented for all patients until death or overall study completion at least 12 months after the last patient. Moreover, to study the distribution of the 161Tb-PSMA-1 in standard organs and tumor lesions, repeated SPECT-CT acquisitions will be performed on all patients treated in the dose escalation part.

Inclusion criteria

• I1. Male or female patients aged ≥ 18 years at time of informed consent signature.
• I2. Patient with histologically confirmed diagnosis of metastatic clear cell renal cell carcinoma (mccRCC) progressing during or after at least 2 lines of therapy including at least 1 line of anti-VEGFR and 1 line of immunotherapy.
• I3. Patient with documented radiological disease progression at the time of inclusion with measurable disease as per RECIST v1.1.
• I4. Patient with positive PSMA-PET (68Ga-PSMA-PET) (see Appendix 6):

• For patient with only extrahepatic disease: ≥ 50% of positive extrahepatic lesions
• For patient with both extra-hepatic and liver metastasis: ≥ 50% of positive extrahepatic metastatic lesions and ≥ 80 % of positive supracentimetric liver metastatic lesions.
• For patient with only liver metastatic lesions: ≥ 80 % of positive supracentimetric lesions
• I5. Life expectancy ≥ 6 months.
• I6. Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1, with a Karnofsky Performance Status (KPS) ≥ 80%.
• I7. Adequate organ function according to laboratory values defined below:

Haematological function :

• Peripheral absolute neutrophil count (ANC) ≥1.5 x 109 /L
• Platelet count ≥ 100 x 109/L
• Hemoglobin ≥ 9.0 g/dL (without transfusion within 7 days)

Renal and hepatic function :

• Serum creatinine or creatinine clearance according to CKD-EPI

o ≤ 1.5 X upper limit of normal (ULN) OR ≥ 40 mL/min/1.73m2

• Total bilirubin

o ≤ 1.5 X ULN with the following exception: Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be enrolled

• Aspartate aminotransferase (ASAT) and Alanine aminotransferase (ALAT) ≤ 1.5 X ULN (up to 3x ULN in case of liver metastases)

• I8. Women of child-bearing potential must have a negative pregnancy test at screening (within 72 hours prior C1D1) and must agree to use 1 highly effective form of contraception from the time of the treatment period and of the negative pregnancy test up to 6 months after the last administration of IMP. Effective forms of contraception are listed in Appendix 5.
• I9. Fertile males must use a highly effective contraception during dosing period and through 6 months after final administration of study.
• I10. Patient should be able and willing to comply with study visits and procedures as per protocol.
• I11. Patient should understand, sign, and date the written voluntary informed consent form at the screening visit prior to any protocol-specific procedures performed.
• I12. Covered by a medical insurance.

Exclusion criteria

• E1. Patients with known active central nervous system (CNS) metastases and/or epidural metastases and/or leptomeningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to C1D1 and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids (at doses higher than 10 mg/d of methylprednisolone or equivalent) for at least 4 weeks prior to C1D1.
• E2. Patients previously treated with any radiopharmaceutical.
• E3. Persisting AEs related to previous anti-cancer therapy which were not resolved to grade ≤ 1 (except: anemia provided that criterion I7 is met) and /or any persistent immune-related AEs >1 (except adequately controlled irAE, e.g.: with replacement therapy for endocrine irAE) using NCI CTCAE V6.0.
• E4. History, within 2 years, of cancer other than renal cancer, except for basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or localized prostate cancer.
• E5. History of idiopathic pulmonary fibrosis, non-infectious pneumonitis, interstitial lung disease that required steroids or has current pneumonitis, interstitial lung disease, drug-induced pneumonitis, or evidence of active pneumonitis.
• E6. Prior therapy or needs to be treated with a forbidden concomitant/concurrent therapies/procedures including (see protocol for minimal wash out period to C1D1 and use during treatment) :
• Any anticancer treatment (immunotherapy, chemotherapy) or investigational therapy
• Targeted therapy including antiangiogenic therapy
• Radiotherapy
• Major surgery
• Growth factors targeting the myeloid lineage (e.g., G-CSF, GM-CSF, M-CSF) or growth factors targeting the erythroid lineage (e.g., erythropoietin)
• Live or live-attenuated vaccine. Note: killed vaccines are allowed.
• E7. Patients with clinically significant hematuria, hematemesis or hemoptysis exceeding 0.5 teaspoon (2.5mL) of red blood, as well as those with a history of coagulopathy or other significant bleeding (e.g., pulmonary hemorrhage) within the 3 months prior to the initiation of the study treatment. Patients receiving anticoagulation medication will be eligible only if the dosage and route of administration have remained stable for at least 2 weeks prior to C1D1.
• E8. Patients with an active uncontrolled infection.
• E9. Pregnant or breastfeeding women.