Study of SXL01 in Patients With Metastatic Castration-Resistant Prostate Cancer (PROSTIRNA)

This is a single site, open-label, non-randomized, dose escalation phase I study designed to evaluate the safety, the tolerability and the Recommended Phase II Dose (RP2D) of SXL01, a synthetic small interfering ribonucleic acid (RNA) targeting the androgen receptor messenger RNA (mRNA), in patients with metastatic castration-resistant prostate cancer.

A standard method "3+3" will be used for dose escalation. A maximum of 30 patients will complete the dose-escalation phase of the study; 12 additional patients will be included at the RP2D in the expansion phase.


Eligibility Criteria:
Inclusion Criteria:

1. Males age 18-80 years.
2. ECOG performance status 0 - 1.
3. Life expectancy of more than 3 months.
4. Histologically confirmed prostate adenocarcinoma without neuroendocrine differentiation or small cell feature.
5. Metastatic prostate cancer deemed to be unresponsive or refractory to hormone therapy.
6. Detectable metastases by bone scan, CT scan or MRI.
7. Surgically or medically castrated, with testosterone levels of \< 50 ng/dL (\< 2.0 nM). If the patient is being treated with LHRH agonists (patient who have not undergone orchiectomy), this therapy must have been initiated at least 4 weeks prior to Cycle 1 Day 1 and must be continued throughout the study.
8. Documented prostate cancer progression as assessed by the investigator with one of the following:

   8.1. PSA progression defined by a minimum of two raising PSA levels with an interval of \>1 week between each determination. The PSA values at the screening visit must be ≥ 1 µg/l (1 ng/mL).

   8.2. Radiographic progression of soft tissue disease by modified RECIST criteria 1.1 or of bone metastasis with two or more documented new bone lesions on a bone scan with or without PSA progression.
9. Adequate hepatic, renal, and hematologic function: AST/ALT ≤ 2.5 X ULN; Normal bilirubin or ≤ 1.5 ULN in case of Gilbert's syndrome; Serum creatinine CL\> 60 mL/min by the Cockcroft-Gault formula; Hemoglobin ≥ 10 g/dL; Absolute neutrophil count ≥ 1500/mm3, Platelet count ≥ 100,000/mm3.
10. Patients must have recovered from the toxic effects of prior therapy (except alopecia) to NCIC CTCAE version 4.03 grade ≤1 and to baseline laboratory values as defined in inclusion criteria 9.
11. If sexually active, willing to use barrier contraception during the treatment phase of the protocol.
12. Written informed consent and any locally required authorization (e.g., Social security for France (Health Insurance)) obtained from the patient prior to performing any protocol-related procedures, including screening evaluations.
13. Patient willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

Exclusion Criteria:

1. BMI ≥ 30.
2. Evidence of brain metastasis.
3. Patient seropositive for HIV and/or hepatitis B antigen positive and/or Hepatitis C antibody.
4. Patient with history of autoimmune disease with the exception of vitiligo, psoriasis and controlled diabetes.
5. Active suspected or prior documented autoimmune disease (including inflammatory bowel disease, celiac disease, irritable bowel syndrome, Wegener's granulomatosis and Hashimoto's thyroiditis).
6. Patient with history of another malignancy, except for the following: skin cancers (melanoma excluded), previously treated cancer with no sign of disease for at least 3 years.
7. Patient with concurrent infection or concurrent chronic or acute illness such as pulmonary (asthma or COPD), cardiac (NYHA class III or IV) or hepatic disease, or other illness considered by the principal investigator to constitute an unwarranted high risk for investigational drug administration will be excluded.
8. Patient who has got a medical condition contraindicated for subcutaneous administration.
9. Chronic systemic corticosteroid use within 4 weeks of the first administration of SXL01 (more than 2 weeks for a dose \> 0.5 mg/kg of prednisolone).
10. Treatment with any hormonal therapy or androgen antagonist, including flutamide, bicalutamide, nilutamide, ketoconazole, diethylstilbestrol, Abiraterone, or enzalutamide, within 4 weeks of the first administration with the exception of GnRH agonists.
11. Patients requiring a continuous curative anti-coagulant treatment.
12. Patients requiring a continuous bisphosphonate or denosumab treatment at inclusion. Note: the use of bisphosphonate and denosumab during the course of the study will be allowed.
13. Planned to initiate any other anti-tumor therapies during the study.
14. Radiation therapy or surgery within 4 weeks of the first administration of SXL01.
15. Mental impairment (psychiatric illness/social situations) that may compromise the ability of the patient to give informed consent and comply with the requirements of the study.
16. Patient who has forfeited his/her freedom by administrative or legal award or who is under guardianship.