Study Of Tasquinimod In Asian Chemo-Naïve Patients With Metastatic Castrate-Resistant Prostate Cancer

The primary objective was to confirm the effect of tasquinimod in delaying disease progression or death as compared with placebo in chemo-naïve patients with metastatic castrate-resistant prostate cancer (mCRPC).

Secondary objectives included further evaluation of the safety profile of tasquinimod, comparison of clinical benefits (such as overall survival and symptoms) of tasquinimod with placebo, to evaluate the quality of life impact and to determine the pharmacokinetics of tasquinimod.

The study involved a 4-week Screening Period, Baseline Visit (Day 1) where the patient was randomised, followed by a Double Blind Treatment Period. Patients initially received tasquinimod (or corresponding placebo) at a 0.25 mg/day dose which was then titrated through 0.5 mg/day (from Day 15) to a maximum of 1 mg/day (from Day 29). If tolerability issues arose at 0.5 or 1 mg/day, patients had their dose reduced to 0.25 or 0.5 mg/day, respectively. The Double Blind Treatment Period continued until the death of the patient or any criterion for withdrawal from study treatment was reached. Any placebo treated patients with radiological disease progression confirmed by the central imaging assessment, who remained asymptomatic or mildly symptomatic were, at the Investigator's discretion, given the option to continue on active treatment (tasquinimod) during an Open-Label Treatment Period, following the same titration rule described above until progression under active treatment. All other patients stopped study treatment.

An End-of-Study Treatment/Withdrawal Visit was to be performed within 14 days after the last dose of study treatment and patients were then to be followed up every 6 months until 80% of the patients had died or 2 years after the last patient was randomised, whichever occurred last.

A PK ancillary study was to be performed in a subgroup of 12 Asian-Chinese patients before randomisation; however, due to the early termination of this study, only some samples were analysed and no PK analyses were performed.

Eligibility Criteria:
Inclusion Criteria:

1. Asian male aged at least 20 years at the time of signing the informed consent form.
2. Histologically confirmed diagnosis of adenocarcinoma of the prostate.
3. Evidence of metastatic disease (bone and/or visceral), excluding node lesion only, on radiographic examination, whether from bone scan (bone lesions) or other imaging modality (CT scan/MRI).
4. Chemical or surgical castration verified by levels of serum testosterone ≤50 ng/dL (1.75 nmol/L).
5. Evidence of progressive disease after castration levels of testosterone had been achieved, defined by any of the following criteria:

   * Increasing serum Prostate Specific Antigen (PSA) levels, with the most recent value ≥2 ng/mL (increasing levels must have been confirmed by three consecutive PSA measurements, within 15 months prior to the start of study treatment. The time between each PSA test should have been preferably at least 14 days, however a minimum of 7 days was acceptable. The third value was used for study selection).
   * Progression of soft tissue metastasis documented within 6 weeks prior to randomisation (CT scan or MRI).
   * Progression of bone disease (at least one new bone lesion as measured by bone scan within the 12 weeks prior to the start of study treatment).
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
7. Laboratory values as follows:

   * Haemoglobin ≥90 g/L (≥9 g/dL).
   * Absolute neutrophil count ≥1500/μL.
   * Platelets ≥100,000/μL.
   * Serum creatinine ≤1.5 times the upper limit of normal (ULN).
   * Total bilirubin ≤1.5 times ULN.
   * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 times ULN (≤5 times ULN if liver metastases were present).
   * Serum amylase ≤ULN (if serum amylase \>ULN, pancreatic amylase and serum lipase should have been analysed. If both pancreatic amylase and serum lipase were \>ULN, patient excluded).
8. If sexually active with partner of childbearing potential, patient agreed to use adequate contraceptive method (barrier contraceptive with spermicide) while receiving study treatment and until 14 days after the stop of study treatment or had been previously vasectomised.
9. No evidence (within last 5 years) of prior malignancies (except successfully treated basal cell or squamous cell carcinoma of the skin).
10. Able to swallow and retain oral medication.
11. Able to adhere to the study visit schedule and other protocol requirements.
12. Ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to cooperate with the Investigator and to comply with the requirements of the entire study.
13. Able to sign and date the written informed consent after being informed of the full nature and purpose of the study, including possible risks and side effects, and given ample time and opportunity to read and understand this information.

Exclusion Criteria:

1. Cytotoxic chemotherapy for the treatment of prostate cancer within 2 years prior to the start of study treatment.
2. Previous anticancer therapy using radiation, biologics or vaccines and including sipuleucel-T (Provenge®) within 4 weeks prior to the start of study treatment and abiraterone, TAK700 or MDV3100 within 2 weeks prior to the start of study treatment. Before inclusion, abiraterone, TAK700 or MDV3100 related adverse effect must have been resolved to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 Grade ≤1. If radiation therapy was applied after Baseline scan, a new Baseline scan needed to be done at least 4 weeks after the radiation therapy.
3. Therapy with antiandrogens within 4 weeks (within 6 weeks for bicalutamide e.g. Casodex®) prior to the start of study treatment.
4. Concurrent use of other anticancer agents or treatments, with the exception of ongoing treatment with luteinising hormone-releasing hormone (LHRH) agonists or antagonists, denosumab (Prolia®) or bisphosphonate (e.g. zoledronic acid), which were allowed. Ongoing treatment was to be kept at a stable schedule; however, if medically required, a change of dose, compound, or both was allowed.
5. Any treatment modalities involving major surgery within 4 weeks prior to the start of study treatment.
6. Prostate cancer pain that required ongoing treatment with narcotic analgesics or warranted the initiation of radio- or chemotherapy.
7. Both of the following criteria:

   * Visceral metastasis.
   * Bone lesions both on and outside of the spinal axis.
8. PSA \>100 ng/mL.
9. Ongoing treatment with warfarin.
10. Maintenance treatment with corticosteroids corresponding to a prednisolone or prednisone dose above 10 mg/day. The dose must have been stable for at least 5 days.
11. Systemic exposure to ketoconazole or other strong cytochrome P450 (CYP) 3A4 isozyme inhibitors or inducers within 14 days prior to the start of study treatment. Systemic exposure to amiodarone was not allowed within 1 year prior to the start of study treatment.
12. Ongoing treatment with sensitive CYP1A2 substrate or CYP1A2 substrate with narrow therapeutic range at the start of study treatment.
13. Ongoing treatment with CYP3A4 substrate with narrow therapeutic range at the start of study treatment.
14. Simultaneous participation in any other study involving treatment with investigational drugs or having received treatment with investigational drugs less than 4 weeks prior to the start of study treatment.
15. Myocardial infarction, percutaneous coronary intervention, acute coronary syndrome, coronary artery bypass graft, New York Heart Association (NYHA) class III/IV congestive heart failure, cerebrovascular accident, transient ischaemic attack, or limb claudication at rest, within 6 months prior to start of study treatment, history of venous thrombo-embolic disease within 3 months prior to randomisation and ongoing symptomatic dysrhythmias, unstable angina, uncontrolled hypertension, and uncontrolled atrial or ventricular arrhythmias.
16. History of pancreatitis.
17. Known brain or epidural metastases.
18. Known positive serology for human immunodeficiency virus (HIV) (patients with known history of HIV were excluded because of potential for unforeseen toxicity and morbidity in an immunocompromised host).
19. Chronic hepatitis with advanced, decompensated hepatic disease or cirrhosis of the liver or history of a chronic viral hepatitis or known viral hepatitis carrier (patients who had recovered from hepatitis were allowed to enter the study) with abnormal liver function.
20. Patients with active tuberculosis (TB), or with known, untreated latent TB (country-specific TB therapy should have been given for at least 30 days prior to the start of study treatment and the patient should have intended to complete the entire course of that therapy).
21. Any condition, including other active or latent infections, medical or psychiatric conditions, or the presence of laboratory abnormalities, which could have confounded the ability to interpret data from the study or placed the patient at unacceptable risk if he participated in the study.
22. Any patient who in the opinion of the Investigator should not have participated in the study.