A Study of Radium-223 in Combination With Tasquinimod in Bone-only Metastatic Castration-Resistant Prostate Cancer (Radium-223)
|ClinicalTrials.gov Identifier: NCT02396368|
Recruitment Status : Withdrawn (Phase III study results for the drug Tesquinimod were not promising so it was a drug development decision to stop using the drug)
First Posted : March 24, 2015
Last Update Posted : November 20, 2015
This is a Phase I/Ib study of Radium-223 in combination with Tasquinimod for patients with bone metastases from castration-resistant prostate cancer (CRPC).
The investigators propose to determine the spectrum of tolerability of the combination of tasquinimod and radium-223 and determine a dose for a subsequent randomized phase II study (first cohort) and the proportion of men with bone-specific alkaline phosphatase response (second cohort).
|Condition or disease||Intervention/treatment||Phase|
|Prostate Cancer Bone-only Metastatic Castration-Resistant Prostate Cancer (CRPC)||Drug: Tasquinimod Radiation: Radium 223||Phase 1|
This is a study of Radium-223 in combination with Tasquinimod. The target population is patients with bone metastases from castration-resistant prostate cancer intended for treatment with radium-223.
After baseline assessment, all subjects will receive six cycles of Radium-223 separated by an interval of 28 days. Radium-223 will be administered per FDA-approved dosing (six IV injections at a dose of 50kBq/kg of body weight, administered every 4 weeks). The treatment maintenance dose of tasquinimod will be a maximum of 1 mg of tasquinimod taken once daily with water (~200 mL). The initial target dose of tasquinimod is 0.5mg/day. All subjects will be followed up for 12 months after start of study treatment.
The investigators propose a phase I/Ib trial of the addition of tasquinimod to FDA-approved doses of radium-223 in men with symptomatic bone-only metastatic CRPC. The investigators anticipate that given their distinct mechanisms of action and non-overlapping toxicity profiles that additive or synergistic toxicity would be minimal. The investigators hypothesize that adding tasquinimod to radium therapy may result in improved measures of efficacy including reduction in total alkaline phosphatase, time to first skeletal-related event and PSA and radiographic progression-free survival.
In the Phase I portion of dose-escalation scheme, the dose escalation will follow a 3+3 design with intra-patient dose-escalation from 0.25mg/day of tasquinimod to a goal dose of either 0.25mg (dose-level -1), 0.5mg (dose-level 1), or 1.0mg/day (dose-level 2) based on individual tolerability.
Upon identifying a recommended Phase II combination dose-level of Radium-223 and tasquinimod, the investigators will move to the Phase Ib portion and open an expanded cohort of up to 35 additional patients to achieve a total of 38 patients treated at the recommended phase II dose-level (including those from the dose-escalation phase).
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||0 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I/Ib Study of Radium-223 in Combination With Tasquinimod in Bone-only Metastatic Castration-Resistant Prostate Cancer|
|Study Start Date :||March 2015|
|Estimated Primary Completion Date :||July 2017|
|Estimated Study Completion Date :||July 2017|
Experimental: Radium 223 and Tasquinimod
During dose level 1, tasquinimod will start at 0.25mg/day orally with a goal of 0.5mg/day. Dose level 2 will start at 0.25mg/day with a goal of 1mg/day.
Radium-223 will be administered per FDA-approved dosing (six IV injections at a dose of 50kBq/kg of body weight, administered every 4 weeks).
Tasquinimod is a quinoline-3-carboxamide analog that has demonstrated significant improvements in progression-free survival and overall survival in men with CRPC in a phase II trial.Tasquinimod will be administered at three dose levels (dose levels 1, 2, and -1). During dose level 1, tasquinimod will start at 0.25mg/day orally with a goal of 0.5mg/day. Dose level 2 will start at 0.25mg/day with a goal of 1mg/day. Dose level -1 will be 0.25mg/day without dose titration.
Radiation: Radium 223
Radium Ra 223 dichloride, an alpha particle-emitting pharmaceutical, is a radiotherapeutic drug. Radium 223 is supplied as a clear, colorless, isotonic, and sterile solution to be administered intravenously with pH between 6 and 8. Each milliliter of solution contains 1,000 kBq radium-223 dichloride (27 microcurie), corresponding to 0.53 ng radium-223, at the reference date. Radium is present in the solution as a free divalent cation.Radium-223 will be administered per FDA-approved dosing (six IV injections at a dose of 50kBq/kg of body weight, administered every 4 weeks).
- Safety of combining Radium-223 with tasquinimod [ Time Frame: Up to 18 months ]Safety of combining Radium-223 with tasquinimod will be assessed by the incidence and severity of toxicities (adverse events and serious adverse events).
- Bone-ALP response [ Time Frame: Up to 18 months ]Bone-specific alkaline phosphatase (serum bone markers) response will be described as percentage of change from baseline to 6 months or earlier for those who discontinue study therapy
- Time to radiographic or clinical progression or death, whichever comes first (progression free survival; PFS). [ Time Frame: Up to 18 months ]
Time to radiographic or clinical progression or death, whichever comes first (progression free survival; PFS). Based on RECIST version 1.1 and Prostate Cancer Working Group 2 (PCWG2) definitions including:
- Progression of soft tissue lesions according to RECIST 1.1
- Progression of bone lesions detected with bone scan according to PCWG2 criteria
- Radiologically-confirmed spinal cord compression or pathological fracture due to malignant progression
- Either of: time to first symptomatic SRE or symptomatic progression.
- Time to first symptomatic SRE [ Time Frame: Up to 18 months ]Time to first symptomatic SRE (defined as first use of XRT to relieve skeletal symptoms, new pathologic vertebral or nonvertebral bone fractures, spinal cord compression, or tumor -related orthopedic surgical intervention).
- Proportion of patients without symptomatic progression at 6 months [ Time Frame: 6 months ]
To determine proportion of patients without symptomatic progression at 6 months, defined as any one or more of:
- Regular consumption of narcotic analgesics (single IV dose or >10 of 14 days of oral narcotic use)
- Requirement for radiation therapy for control of tumor-related pain
- VAS pain rating of >4 due to cancer pain on two consecutive ratings
- Median change in the bone scan index (BSI) within patients at 12 weeks compared to baseline bone scan. [ Time Frame: 12 weeks ]
- PSA decline will be reported on all patients [ Time Frame: 12 weeks ]The percentage of change in PSA from baseline to 12 weeks.
- PSA progression (PSA progression free survival; PSA-PFS) [ Time Frame: Up to 18 months ]
PSA progression (PSA progression free survival; PSA-PFS) will be defined per the PCWG2 guidelines
- For those subjects showing an initial decline in PSA from baseline, is defined as an increase in PSA that is ≥25% and ≥2 ng/mL above the nadir, and which is confirmed by a second value 3 or more weeks later (i.e., a confirmed rising trend).
- For those subjects with no decline in PSA from baseline, is defined as an increase in PSA that is ≥25% and ≥2 ng/mL after 12 weeks.
- Time to death after start of study treatment months [ Time Frame: Up to 18 months ]Time to death after start of study treatment (overall survival; OS)
- Changes in bone markers [ Time Frame: Up to 18 months ]
Changes in other bone markers:
- Serum C-telopeptide(uCTX-1)
- N-terminal propeptide of procollagen type 1 (P1NP)
- Radium-223 micro-scale dosimetry in bone tissue [ Time Frame: Up to 18 months ]Radium-223 micro-scale dosimetry in bone tissue using bone biopsy material before and after treatment at 3 time points.
- The spatial distribution of Ra-223 in the patient's skeleton [ Time Frame: Up to 18 months ]Longitudinal whole-body planar gamma camera imaging will provide information on how tasquinimod impacts the overall skeletal distribution and uptake of Ra-223.
- The whole organ-level dosimetry of Ra-223 in the the patient's skeleton [ Time Frame: Up to 18 months ]Longitudinal whole-body planar gamma camera imaging will provide information on how tasquinimod impacts on the organ-level dosimetry and uptake of Ra-223.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02396368
|United States, Maryland|
|Johns Hopkins Hospital|
|Baltimore, Maryland, United States, 21205|
|Principal Investigator:||Mario Eisenberger, MD||Johns Hopkins University|