A Proof of Concept Study of Maintenance Therapy With Tasquinimod in Patients With Metastatic Castrate-resistant Prostate Cancer Who Are Not Progressing After a First Line Docetaxel Based Chemotherapy

Study Overview
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Brief Summary
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The purpose of this study is to confirm that tasquinimod used as maintenance therapy is active and tolerable in patients with metastatic castrate-resistant prostate cancer not progressing after a first chemotherapy with docetaxel.

Official Title
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A Randomised, Double-Blind, Placebo-Controlled Proof Of Concept Study Of Maintenance Therapy With Tasquinimod In Patients With Metastatic Castrate-Resistant Prostate Cancer Who Are Not Progressing After A First Line Docetaxel Based Chemotherapy

Conditions
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Metastatic Castrate Resistant Prostate Cancer

Intervention / Treatment
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* Drug: Tasquinimod
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically documented prostate cancer with evidence of metastatic disease on radiological evaluation, with or without symptoms (defined according to the BPI scale, with use of analgesics or narcotics) Has received a first line docetaxel based chemotherapy (as a monotherapy) every 3 weeks schedule of administration with corticosteroids for a minimum of 6 cycles with a cumulative dose ≥360 mg/m2. Any combination with investigational or non investigational agent is prohibited Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Docetaxel-related adverse effects must have been resolved to NCI-CTCAE v4.03 (Common Toxicity Criteria for Adverse Effects) Grade ≤1. Chemotherapy-induced alopecia and Grade 2 peripheral neuropathy are allowed No progressive disease at the end of docetaxel treatment defined according to RECIST criteria, no new lesion(s) assessed by bone scan and no elevated prostate specific antigen (PSA) for the three last tests with PSA3≤PSA2≤PSA1. The time between each PSA test should be preferably at least 14 days, however, a minimum of 7 days is acceptable. Note: PSA value can be rounded to the nearest whole number if PSA>10 ng/mL. If the PSA3 value is above the PSA2, a fourth PSA test will be performed. The PSA4 value should be below or equal to PSA2 Last dose of docetaxel administered between 21 and 42 days before randomisation Chemical or surgical castration verified by levels of serum testosterone ≤50 ng/dL (1.75 nmol/L) Exclusion Criteria: Has concurrent use of other anticancer agents or treatments, with the following exceptions: ongoing treatment with luteinising hormone-releasing hormone agonists or antagonists, denosumab or bisphosphonate (e.g., zoledronic acid) is permitted if started ≥4 weeks prior to Screening. Ongoing treatment should be kept at a stable dose regimen Has ongoing treatment with warfarin Had prior radiation therapy since starting docetaxel. Exceptions may be made for palliative non-myelosuppressive radiation therapy administered more than 2 weeks prior to randomisation Had prior strontium, samarium or radium therapy or prior treatment with tasquinimod, or any agents with antiangiogenic properties Has ongoing treatment with corticosteroids at >10 mg/day prednisolone equivalent Has prostate cancer pain that warrants the initiation of radiotherapy or chemotherapy Has known brain or epidural metastases. Patients with previous medullary cord compression without any neurological deficit could be included Has a history of other malignancies, except adequately treated non-melanoma skin cancer or other solid tumours curatively treated, without evidence of disease for >5 years

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tasquinimod<br>1 capsule daily, taken orally with water and food (0.25 mg initially then dose escalated to 0.5 mg or 1 mg per day) until disease progression or toxicity or patient's willingness to stop. | Drug: Tasquinimod<br>* A patient's dose will escalate from one level to the next, once tolerability of the current dose is established. If tolerability issues arise at 0.5 or 1 mg/day, patients will have their dose reduced to 0.25 or 0.5 mg/day, respectively.<br>|
| Placebo Comparator: Placebo<br>1 capsule daily, taken orally with water and food until disease progression or toxicity or patient's willingness to stop. | Drug: Placebo<br>* Placebo capsules are identical to tasquinimod capsules in appearance and excipients but exclude the active compound (tasquinimod), to be taken orally once a day with water and food<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Radiological Progression Free Survival [PFS] | The time from the date of randomisation to the date of radiological progression or death due to any cause. Radiological progression was defined - Using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for soft tissue lesions (Eisenhauer, EJC 2009), as at least a 20% relative and a 5 mm absolute increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters recorded on study (including Screening or the appearance of one or more new lesions) for target Lesions. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions - Using Prostate Cancer Clinical Working Group in March 2008 (PCWG2) criteria for bone lesions (Scher, JCO 2008). Progression was defined as appearance of 2 or more bone lesions. | Every 8 weeks until disease progression documentation (approximately up to 2.5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival Based on Number of Subjects Who Died | Overall survival is defined as the time from randomisation to death due to any cause. The number of participants who died is presented since the Median was not reached for this assessment. Tasquinimod: Patients censored = 63, Patients at risk (t=0) = 71 Placebo: Patients censored = 67, Patients at risk (t=0) = 73 | Every 3 months after study treatment stop until death (approximately up to 2.5 years) | 
| Time to Progression Free Survival [PFS] on Next-line Therapy (PFS 2) | The time from the date of randomisation to the date of radiological progression free survival [PFS] on next-line therapy (PFS 2) or death due to any cause. Radiological progression was defined - Using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for soft tissue lesions (Eisenhauer, EJC 2009), as at least a 20% relative and a 5 mm absolute increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters recorded on study (including Screening or the appearance of one or more new lesions) for target Lesions. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions - Using Prostate Cancer Clinical Working Group in March 2008 (PCWG2) criteria for bone lesions (Scher, JCO 2008). Progression was defined as appearance of 2 or more bone lesions. | Every 3 months after study treatment stop (follow-up) until progression under the next line therapy (approximately up to 2.5 years) | 
| Symptomatic PFS Based on Number of Subjects Who Had Symptomatic Progression or Death | Symptomatic PFS is defined as the time from the date of randomisation to the date of symptomatic progression or death due to prostate cancer, whichever occurs first [symptomatic progression as assessed by Brief Pain Inventory (BPI) and analgesic use]. Symptomatic progression was defined by the occurrence of pain with documented disease, skeleton related adverse events. The median symptomatic PFS for placebo and tasquinimod groups was not reached. Tasquinimod: Patients censored = 48, Patients at risk (t=0) = 71 Placebo: Patients censored = 54, Patients at risk (t=0) = 73 | Every 8 weeks until symptomatic or radiological progression documentation (approximately up to 2.5 years) | 
| Time to Further Anticancer Treatment for Prostate Cancer | Time from randomisation to further treatment for prostate cancer | Every 3 months after study treatment stop until further anticancer therapy for prostate cancer (approximately up to 2.5 years) | 
| Time to Deterioration in Functional Assessment of Cancer Therapy - Prostate (FACT-P) | End of Study visit (within 14 days of last dose of study treatment) Impact of tasquinimod on health related quality of life (QoL) - Analysis of time to deterioration in FACT-P The FACT-P measurement system is a validated collection of health related quality of life (HRQOL) questionnaires used to assess HRQOL in men with prostate cancer. It is appropriate for use with patients with any form of cancer and extensions of it have been used and validated in other chronic illness condition. The FACT-P is a self-administered 39-item scale comprising five domains: physical well-being, social/family well-being, functional well-being, emotional well-being and additional concerns. The individual subscale scores range from 0 to a high between 24 and 48 and the total score ranges between 0 and 156, with higher scores representing better Quality of Life (QoL) | Up to End of Study visit (approximately up to 2.5 years) | 
| Change From Baseline of EuroQol-5 Dimension QoL Instrument (EQ-5D) VAS Score | Baseline is defined as last measurement collected prior to the first dose of study drug. End of Study visit (within 14 days of last dose of study treatment) The EQ-5D, a 5-item scale useful in health resource utilisation and cost comparisons between treatment groups designed for self-completion by patients consists of two pages [EQ-5 descriptive system and EQ Visual Analogue Scale(VAS)]. The EQ-5 descriptive system comprises five dimensions: mobility, self care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, severe problems. The EQ-VAS records the respondent's self-rated health on a vertical VAS. The respondents are asked to mark health status on the day of the interview on a 10cm vertical scale with end points of 0 to100. There are notes at the both ends of the scale that the bottom rate(0) corresponds to the worst health you can imagine, and the highest rate(100) corresponds to the best health you can imagine | Baseline and End-of-study Visit (approximately up to 2.5 years) | 
| Safety Profile of Tasquinimod | Number of subjects reporting adverse events | At regular intervals during the study treatment period and every 3 months during the follow-up until death (approximately up to 2.5 years) |