DEFINE: Dose Escalation For INtraprostatic LEsions

Sponsor

Ottawa Hospital Research Institute (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05851547

Collaborator

Knight Therapeutics (USA) Inc (Industry)

Enrollment

Arm

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

External beam radiotherapy combined with androgen deprivation therapy is a standard treatment option for localized prostate cancer. The current standard involves delivering radiotherapy uniformly throughout the prostate gland in daily fractions, five days per week, for approximately four weeks. In this study, radiotherapy will be delivered using an ultra-hypofractionated approach in three larger fractions on alternating days over one week Multiparametric magnetic resonance imaging will be used to guide focal dose escalation to parts of the gland harboring tumor, which could potentially reduce the risk of cancer recurrence compared to standard dose of radiotherapy. The aim of this study is to confirm that this approach can be delivered safely, that is, with rates of urinary and bowel side effects at 1 year of follow-up that are not significantly greater than the current standard.

Condition or Disease	Intervention/Treatment	Phase
Prostatic Neoplasms	Radiation: Prostate SBRT with Focal Boost Drug: Triptorelin Injection	Phase 2

Detailed Description

External beam radiotherapy (RT) in combination with androgen deprivation therapy (ADT) is a standard definitive treatment for localized prostate cancer. It confers long-term oncologic outcomes equivalent to those of radical prostatectomy. The current standard approach for prostate RT consists of uniform irradiation of the entire gland. This technique employs computed tomography (CT) images for planning, in which disease is not readily apparent. Multiparametric magnetic resonance imaging (mpMRI) of the prostate allows for accurate visualization of clinically significant tumour foci within the prostate gland. It thereby permits selective escalation of dose to tumours within the gland - a so-called focal boost or "microboost" - with the aim of improving treatment efficacy.

The current standard approach to prostate RT involves delivery of treatment in daily fractions, five days per week, over four weeks. Prostate cancer appears to exhibit an uncommon fractionation sensitivity among solid tumours. A consequence of this is that hypofractionation - that is, delivery of RT with larger fraction sizes - may further improve the therapeutic ratio. A number of large-scale studies have shown promise for an ultra-hypofractionated approach (that is, larger than 5-Gy fractions) in the treatment of localized prostate cancer.

There is an unmet need for innovations in radiotherapy that further reduce the risk of relapse without increasing toxicity or compromising health-related quality of life and that reduce the treatment burden. Both focal intraprostatic boosts - informed by mpMRI findings - and ultra-hypofractionation represent promising approaches to achieve this objective. To date, the optimal regimen that combines these two innovations remains to be explored. In this trial, we will investigate in a single-arm prospective cohort the safety of an mpMRI-defined focal boost technique with a convenient and radiobiologically compelling ultra-hypofractionated radiotherapy regimen (consisting of three fractionas delivered over one week) for localized unfavourable intermediate and high-risk localized prostate cancer.

This is a single-arm prospective trial conducted in patients with unfavourable intermediate-risk or high-risk localized prostate cancer. Treatment consists of ultra-hypofractionated intensity-modulated, image-guided prostate radiotherapy delivered to 27 Gy in 3 fractions (1 fraction per day every other day, over a 5 day period) to uninvolved regions, with up to 39 Gy in 3 fractions delivered to mpMRI-defined intraprostatic lesions, assuming normal tissue dosimetric criteria can be safely met. Radiotherapy will be combined with concurrent/adjuvant androgen deprivation therapy (6 months duration in patients with intermediate-risk disease and 24 months for patients with high-risk disease). There will be follow-up assessments for toxicity, quality of life, and biochemical control. The primary endpoint will be prevalence of grade ≥ 2 genitourinary or gastrointestinal toxicity at 12 months.

Primary Objective The primary objective is to determine whether, in a population of men with unfavourable intermediate-risk or high-risk localized prostate cancer receiving a combination of three-fraction ultra-hypofractionated RT and adjuvant androgen deprivation therapy, an mpMRI-defined focal boost can be delivered with acceptable GU and GI toxicity at 1 year of follow-up.

Secondary Objectives

The secondary objectives are to evaluate, in a population of men with unfavourable intermediate-risk or high-risk localized prostate cancer, the effects of an mpMRI-defined focal boost on:

Health-related quality of life
Biochemical disease-free survival

Study Design

Study Type:

Interventional

Anticipated Enrollment :

54 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Prostate radiotherapy of 27 Gy in 3 fractions to uninvolved regions, up to 39 Gy in 3 fractions to mpMRI-defined intraprostatic lesions, with concurrent/adjuvant androgen deprivation therapy (6 months intermediate risk, 24 months for high risk)Prostate radiotherapy of 27 Gy in 3 fractions to uninvolved regions, up to 39 Gy in 3 fractions to mpMRI-defined intraprostatic lesions, with concurrent/adjuvant androgen deprivation therapy (6 months intermediate risk, 24 months for high risk)

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase II Study of the Use of MRI-defined Focal Boosts With Stereotactic Body Radiotherapy for Localized Prostate Cancer

Anticipated Study Start Date :

Jun 1, 2023

Anticipated Primary Completion Date :

Jun 1, 2027

Anticipated Study Completion Date :

Jun 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Prostate SBRT with Focal Boost and Androgen Deprivation Therapy Stereotactic body radiotherapy to 27 Gy in 3 fractions to uninvolved regions of the prostate glad and up to 39 Gy in 3 fractions to mpMRI-defined intraprostatic lesions, with concurrent/adjuvant androgen deprivation therapy (6 months for intermediate risk, 24 months for high risk)	Radiation: Prostate SBRT with Focal Boost Prostate stereotactic body radiotherapy delivered to 27 Gy in 3 fractions on alternating days to uninvolved regions with up to 39 Gy in 3 fractions delivered to mpMRI-defined intraprostatic lesions Other Names: Ultrahypofractionated prostate radiotherapy with integrated microboost Drug: Triptorelin Injection Six months of androgen deprivation therapy for intermediate-risk localized prostate cancer and 24 months for high-risk localized prostate cancer Other Names: Androgen Deprivation Therapy

Arm

Intervention/Treatment

Experimental: Prostate SBRT with Focal Boost and Androgen Deprivation Therapy

Stereotactic body radiotherapy to 27 Gy in 3 fractions to uninvolved regions of the prostate glad and up to 39 Gy in 3 fractions to mpMRI-defined intraprostatic lesions, with concurrent/adjuvant androgen deprivation therapy (6 months for intermediate risk, 24 months for high risk)

Radiation: Prostate SBRT with Focal Boost

Prostate stereotactic body radiotherapy delivered to 27 Gy in 3 fractions on alternating days to uninvolved regions with up to 39 Gy in 3 fractions delivered to mpMRI-defined intraprostatic lesions

Other Names:

Ultrahypofractionated prostate radiotherapy with integrated microboost

Drug: Triptorelin Injection

Six months of androgen deprivation therapy for intermediate-risk localized prostate cancer and 24 months for high-risk localized prostate cancer

Other Names:

Androgen Deprivation Therapy

Outcome Measures

Primary Outcome Measures

Genitourinary and gastrointestinal toxicity [Up to 2 years]
Number of patients with grade 2 or greater genitourinary or gastrointestinal toxicity as measured by Common Terminology Criteria for Adverse Events (CTCAE ) version 5.0 and Radiation Therapy Oncology Group radiation toxicity scale

Secondary Outcome Measures

Bowel and urinary quality of life [Up to 2 years]
Measured by Expanded Prostate Cancer Index Composite (EPIC)-26 bowel and urinary domains
Disease-free survival [2 years]
Number of patients free of biochemical recurrence (defined according to the Phoenix definition as an increase in serum PSA that is ≥ 2 ng/mL above the nadir value observed following radiotherapy) or death from any cause

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically confirmed adenocarcinoma of the prostate
Unfavourable intermediate-risk or high-risk localized disease
Unfavourable intermediate-risk prostate cancer is defined as intermediate-risk prostate cancer [that is, no high-risk features and one or more intermediate-risk factors: T2b-T2c, Gleason 3+4 (grade group 2) or Gleason 4+3 (grade group 3), or PSA 10-20 μg/L] and one or more of the following: 2 or 3 intermediate-risk factors; Gleason 4+3 (grade group 3); ≥ 50% biopsy cores positive
High-risk localized prostate cancer is defined as at least one of the following: T3a-T3b; Gleason ≥ 8 (grade group 4 or grade group 5); PSA > 20 μg/L
3 Tesla prostate MRI done no more than 12 months prior to enrollment
ECOG performance status 0-2
Age ≥ 18 years
Written informed consent
The participant has planned androgen deprivation therapy that meets one of the following criteria:
Patients with intermediate-risk localized prostate cancer who have planned androgen deprivation therapy consisting of up to 6 months of triptorelin with or without bicalutamide; OR patients with high-risk localized prostate cancer who have planned androgen deprivation therapy consisting of up to 24 months of triptorelin with or without bicalutamide.
Completion of all appropriate investigations prior to enrollment

Exclusion Criteria:

Evidence of pelvic nodal metastases or distant metastases (AJCC Stage T1-4 N1 M0-1 or T1-4 N0 M1 disease)
Discordance between pre-enrollment prostate MRI and prostate biopsy findings, defined as biopsy cores with Gleason Gleason ≥ 4+3 (grade group ≥ 3) adenocarcinoma with no corresponding tumour focus seen on MRI
Androgen deprivation therapy commenced more than 60 days prior to enrollment
Intention to electively treat the pelvic lymph nodes with radiotherapy
Other active malignancy within the previous three years (except adequately treated nonmelanomatous carcinoma of the skin or low-grade superficial bladder carcinoma)
Prior pelvic radiotherapy
Contraindication to pelvic radiotherapy
Any history, past or present, of inflammatory bowel disease
Unilateral or bilateral hip arthroplasty
Trans-urethral resection of the prostate (TURP) performed within 6 months of anticipated start date of radiotherapy
Patients must not concurrently participate in any other therapeutic prostate cancer trial.