Prostatic Neoplasms, Castration-Resistant
Conditions
Keywords
CRPC, Metastatic, Chemotherapy naïve, Chemo-naïve, Prostate cancer, mCRPC, Chemotherapy-naïve, Chemo naïve
Brief summary
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.
Detailed description
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.
Interventions
DRUGTasquinimod
A patient initially received 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.
DRUGPlacebo
Placebo capsules were identical to tasquinimod capsules in appearance and excipients but excluded the active compound (tasquinimod).
Sponsors
Ipsen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
20 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Radiological Progression-Free Survival (PFS) | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years | PFS was defined as the time from the date of randomisation to the date of radiological progression (confirmed by the central imaging assessment) or death due to any cause. Radiological progression was defined by any of the following criteria: progression of soft tissue lesions evaluated by computed tomography (CT) or magnetic resonance imaging (MRI) scan according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 criteria; progression of bone lesions detected with bone scan according to Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria; or radiologically confirmed spinal cord compression or pathological fracture due to malignant progression. The primary endpoint was centrally and independently evaluated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Local Assessment of Radiological PFS | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years | The Investigator was to evaluate radiological disease progression in accordance with the criteria defined for the primary endpoint. |
| Time to Symptomatic PFS Based on Local Assessment | Every 3 months | Symptomatic PFS, defined as the time from the date of randomisation to the date of appearance of pain (using pain visual analogue scale (VAS)) at a site with documented disease and analgesic use, or skeletal-related events, or death due to prostate cancer, whichever occurred first. |
| Overall Survival | From randomisation up to 3 years | An overall survival event was defined as death due to any cause. The number of participants with overall survival events is reported. |
| Quality of Life (QoL) | Every 3 months | QoL measured by the Functional Assessment of Cancer Therapy Prostate Module (FACT-P) questionnaire and by the EuroQol 5-Dimension QoL Instrument (EQ-5D). Due to the early termination of the study, a simplified data analysis (primary endpoint and overall survival) was performed to fulfil the requirement from regulatory authorities for early termination studies. Therefore, no analyses were performed on this secondary efficacy endpoint. |
| Tasquinimod Pharmacokinetic (PK) Profile | Up to 216 hours after a single dose and during the double blind treatment period (Day 15, 29, 57 and 127) | Tasquinimod PK profile: 1. Following a single 1 mg dose of tasquinimod given to a subgroup of 12 Asian-Chinese patients (ancillary study). 2. At steady state conditions based on limited sampling strategy. Following termination of the study the PK analyses were not performed. |
| Time From Randomisation to Further Treatment for Prostate Cancer | Every 6 months during the follow-up period | The need for any anti-tumour prostate cancer treatments was to be recorded during the Follow-up Period, with the time to further treatment to subsequently be derived. |
Countries
China, South Korea, Taiwan
Participant flow
Recruitment details
Patients were recruited across 36 centres. The first patient first visit was on 24 January 2014. The last patient was randomised into the study on 16 April 2015; however, early termination of the study was announced on the same day. Due to a necessary visit for 1 patient, the last patient last visit of the study was on 26 May 2015.
Pre-assignment details
229 patients were screened, of whom 146 were randomised (96 tasquinimod, 50 placebo).
Participants by arm
| Arm | Count |
|---|---|
| Tasquinimod One capsule (0.25, 0.50 or 1 mg), taken orally once a day with water and food (preferably the main evening meal).
A patient initially received 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. | 96 |
| Placebo One capsule, taken orally once a day with water and food (preferably the main evening meal).
Placebo capsules were identical to tasquinimod capsules in appearance and excipients but excluded the active compound (tasquinimod). | 50 |
| Total | 146 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double Blind Treatment Period | Physician Decision | 1 | 0 |
| Double Blind Treatment Period | Poor tolerability | 7 | 2 |
| Double Blind Treatment Period | Progressive disease for bone lesion | 1 | 0 |
| Double Blind Treatment Period | Sponsor's request | 70 | 34 |
| Double Blind Treatment Period | Subject planning to withdraw | 1 | 0 |
| Double Blind Treatment Period | Symptomatic disease progression | 8 | 3 |
| Double Blind Treatment Period | Withdrawal by Subject | 8 | 5 |
| Open-Label Treatment Period | Poor tolerability | 0 | 1 |
| Open-Label Treatment Period | Sponsor's request | 0 | 4 |
| Open-Label Treatment Period | Symptomatic disease progression | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Tasquinimod | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 121 Participants | 80 Participants | 41 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants | 16 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 146 Participants | 96 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment China | 103 Participants | 69 Participants | 34 Participants |
| Region of Enrollment Korea, Republic of | 33 Participants | 22 Participants | 11 Participants |
| Region of Enrollment Taiwan | 10 Participants | 5 Participants | 5 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 146 Participants | 96 Participants | 50 Participants |
| Status of Visceral Metastases Absence | 140 Participants | 92 Participants | 48 Participants |
| Status of Visceral Metastases Presence | 6 Participants | 4 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 76 / 94 | 30 / 50 |
| other Total, other adverse events | 52 / 94 | 19 / 50 |
| serious Total, serious adverse events | 19 / 94 | 5 / 50 |
Outcome results
Primary
Time to Radiological Progression-Free Survival (PFS)
PFS was defined as the time from the date of randomisation to the date of radiological progression (confirmed by the central imaging assessment) or death due to any cause. Radiological progression was defined by any of the following criteria: progression of soft tissue lesions evaluated by computed tomography (CT) or magnetic resonance imaging (MRI) scan according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 criteria; progression of bone lesions detected with bone scan according to Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria; or radiologically confirmed spinal cord compression or pathological fracture due to malignant progression. The primary endpoint was centrally and independently evaluated.
Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years
Population: ITT population: All randomised patients. Patients were allocated to the treatment they were randomised to. This population consisted of all randomised patients regardless of whether or not the patient received any dose of the study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tasquinimod | Time to Radiological Progression-Free Survival (PFS) | 11.00 months |
| Placebo | Time to Radiological Progression-Free Survival (PFS) | 7.53 months |
p-value: 0.02795% CI: [0.182, 0.903]Log Rank
Secondary
Local Assessment of Radiological PFS
The Investigator was to evaluate radiological disease progression in accordance with the criteria defined for the primary endpoint.
Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years
Population: No data collected due to the early termination of the study. Therefore, no analyses performed on this secondary efficacy endpoint.
Secondary
Overall Survival
An overall survival event was defined as death due to any cause. The number of participants with overall survival events is reported.
Time frame: From randomisation up to 3 years
Population: ITT population: All randomised patients. Patients were allocated to the treatment they were randomised to. This population consisted of all randomised patients regardless of whether or not the patient received any dose of the study treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tasquinimod | Overall Survival | Number of deaths | 2 Participants |
| Tasquinimod | Overall Survival | Number of censored observations | 94 Participants |
| Placebo | Overall Survival | Number of deaths | 2 Participants |
| Placebo | Overall Survival | Number of censored observations | 48 Participants |
p-value: 0.44895% CI: [0.065, 3.355]Log Rank
Secondary
Quality of Life (QoL)
QoL measured by the Functional Assessment of Cancer Therapy Prostate Module (FACT-P) questionnaire and by the EuroQol 5-Dimension QoL Instrument (EQ-5D). Due to the early termination of the study, a simplified data analysis (primary endpoint and overall survival) was performed to fulfil the requirement from regulatory authorities for early termination studies. Therefore, no analyses were performed on this secondary efficacy endpoint.
Time frame: Every 3 months
Secondary
Tasquinimod Pharmacokinetic (PK) Profile
Tasquinimod PK profile: 1. Following a single 1 mg dose of tasquinimod given to a subgroup of 12 Asian-Chinese patients (ancillary study). 2. At steady state conditions based on limited sampling strategy. Following termination of the study the PK analyses were not performed.
Time frame: Up to 216 hours after a single dose and during the double blind treatment period (Day 15, 29, 57 and 127)
Population: No data collected due to the early termination of the study. Therefore, no analyses performed on this secondary efficacy endpoint.
Secondary
Time From Randomisation to Further Treatment for Prostate Cancer
The need for any anti-tumour prostate cancer treatments was to be recorded during the Follow-up Period, with the time to further treatment to subsequently be derived.
Time frame: Every 6 months during the follow-up period
Population: No data collected due to the early termination of the study. Therefore, no analyses performed on this secondary efficacy endpoint.
Secondary
Time to Symptomatic PFS Based on Local Assessment
Symptomatic PFS, defined as the time from the date of randomisation to the date of appearance of pain (using pain visual analogue scale (VAS)) at a site with documented disease and analgesic use, or skeletal-related events, or death due to prostate cancer, whichever occurred first.
Time frame: Every 3 months
Population: No data collected due to the early termination of the study. Therefore, no analyses performed on this secondary efficacy endpoint.