Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

RADAR Trial - Randomised Androgen Deprivation and Radiotherapy

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
National Health and Medical Research Council, Australia
Hunter Medical Research Institute (HMRI)
Health Research Council, New Zealand
Abbott
Novartis Pharmaceuticals
Cancer Society of New Zealand
University of Newcastle, Australia
Radiation Oncology, Calvary Mater Newcastle, Australia
Information provided by (Responsible Party):
Trans-Tasman Radiation Oncology Group (TROG)
ClinicalTrials.gov Identifier:
NCT00193856
First received: September 12, 2005
Last updated: November 18, 2014
Last verified: November 2014

September 12, 2005
November 18, 2014
October 2004
August 2017   (final data collection date for primary outcome measure)
Prostate cancer-specific mortality. [ Time Frame: Two main endpoint analyses are planned when 6.5 and 10 years have elapsed from randomisation of the last participant ] [ Designated as safety issue: No ]
  • Biochemical Failure
  • Survival
Complete list of historical versions of study NCT00193856 on ClinicalTrials.gov Archive Site
  • Cumulative incidence of PSA progression [ Time Frame: Two main endpoint analyses are planned when 6.5 and 10 years have elapsed from randomisation of the last participant ] [ Designated as safety issue: No ]
  • Cumulative incidence of local, distant and bony progression and associated patterns of clinical progression [ Time Frame: Two main endpoint analyses are planned when 6.5 and 10 years have elapsed from randomisation of the last participant ] [ Designated as safety issue: No ]
  • All-cause mortality [ Time Frame: Two main endpoint analyses are planned when 6.5 and 10 years have elapsed from randomisation of the last participant ] [ Designated as safety issue: No ]
  • Changes in bone mineral density and osteopenic fracture [ Time Frame: One endpoint analysis is planned when 4.5 years have elapsed from randomisation of the last participant ] [ Designated as safety issue: Yes ]
  • Quality of life assessment [ Time Frame: One endpoint analysis is planned when 3 years have elapsed from randomisation of the last participant ] [ Designated as safety issue: No ]
  • Treatment related morbidity [ Time Frame: One endpoint analysis is planned when 4 years have elapsed from randomisation of the last participant ] [ Designated as safety issue: Yes ]
  • Cumulative incidence of secondary therapeutic intervention [ Time Frame: Two main endpoint analyses are planned when 6.5 and 10 years have elapsed from randomization of the last participant ] [ Designated as safety issue: No ]
  • Patterns of failure
  • Treatment related toxicity
  • Quality of life
  • Bone density changes
  • Influence of histopathology
  • Influence of radiation dose
Not Provided
Not Provided
 
RADAR Trial - Randomised Androgen Deprivation and Radiotherapy
A Randomised Trial Investigating the Effect on Biochemical (PSA) Control and Survival of Different Durations of Adjuvant Androgen Deprivation in Association With Definitive Radiation Treatment for Localised Carcinoma of the Prostate.

The principal objectives of the RADAR trial is to address the hypotheses; 1) that 18 months androgen deprivation in conjunction with radiotherapy is superior to 6 months androgen deprivation prior to and during radiotherapy; 2) that 18 months Bisphosphonate therapy will prevent bone loss caused by androgen deprivation therapy and further reduce relapse risk by impeding the development of bony metastases.

Traditionally androgen deprivation (by orchidectomy, or more recently by medication) has been reserved for the palliative treatment of men with advanced, incurable prostate cancer. However, evidence from large scale trials is beginning to suggest that androgen deprivation (AD) may be helpful in preventing relapse in patients with more localised disease who are treated surgically or by radiotherapy. Of the 8000 patients per annum who are treated with curative intent, one half (4000) have cancers where 'adjuvant' AD may be prescribed according to interpretation of the registered indications. There are, however, enormous variations in prescribing practices which reflect uncertainty as to the appropriate indications. An important issue is osteopenia.

The increasing use of AD in men with earlier stages of cancer, whose life expectancies exceed 3 years, has exposed many unwanted metabolic sequelae of prolonged AD, the most important being osteopenia. In 1996, with the funding support of the NHMRC and the pharmaceutical industry, TROG therefore launched a large randomised three-arm trial. Two of the arms repeated the two arms of the US Radiation Therapy Oncology Group (RTOG) 86.01 trial which, at the time, was showing early indications of benefit for the addition of two months maximal androgen deprivation (MAD), using Goserelin (Zoladex) and Flutamide, before radiation therapy and one month during. Since work from Canada had indicated that continued AD for periods longer than three months produced additional shrinkage of the prostatic tumour, the TROG 96.01 trial incorporated a third arm: six months MAD prior to and during radiotherapy. The trial completed its recruitment target of 800 eligible patients in early 2000. Although in August 2001 the median follow up time was still very short, a preliminary analysis indicated that significant increases in time to biochemical relapse had been produced by AD. In fact, the benefits of AD were independent of stage, tumour grade and initial PSA value which were confirmed also to predict time to biochemical failure. The hazard of relapse reduced to 0.75 (0.55 - 0.97, 95% confidence intervals) with 3 months AD, and still further to 0.6 (0.45 - 0.82) with six months AD.

Subsequent international developments in this area of research encouraged the design of a 'follow on' trial. A European Organisation for Research and Treatment of Cancer (EORTC) trial reported that 3 years of adjuvant ('post hoc') AD (using Goserelin alone), administered after radiotherapy, reduced relapse and improved survival in patients with locally advanced prostate cancer. The US Radiation Therapy Oncology Group (RTOG) 85.31 trial indicated that indefinite Goserelin administration after radiotherapy reduced treatment failure rates at all sites when compared with radiotherapy alone. The RTOG 92.02 trial showed that 24 months of adjuvant Goserelin also reduced failure rates in patients treated with 4 months of MAD prior to and during radiotherapy. Subset analyses of the RTOG trials, suggested that patients who gain most from prolonged AD in terms of survival are those with high grade cancers.

It was therefore logical for TROG to propose a second trial with the intention of finding out whether an additional 12 months of AD administered after radiotherapy (aka 'intermediate term' AD [ITAD]) would reduce relapse and mortality in patients treated with six months of AD prior to and during radiotherapy (aka 'short term' AD [STAD]) as in the 'best' arm of its first (96.01) trial. The availability of the potent bisphosphonate, zoledronic acid, also made it possible to find out whether or not osteopenia induced in the two arms of the proposed second trial would be prevented by a second random assignment to 18 months' bisphosphonate therapy (BP).

This is a randomised phase III multicentre clinical trial.

After informed consent is given and eligibility is checked patients will be randomised to one of four trial arms:

  1. 6 months of androgen blockade with an LH-RH analogue (5 months before start of radiotherapy) (STAD),
  2. 18 months of androgen blockade with an LH-RH analogue (starting 5 months before start of radiotherapy) (ITAD),
  3. 18 months of therapy with zoledronic acid 4 mg by intravenous infusion every 3 months for 18 months beginning concurrently with STAD
  4. 18 months of therapy with zoledronic acid beginning concurrently with ITAD.

Stratification will be according to the following criteria:

T2 / T3, 4 Gleason score 2 - 6 / 7+ Presenting PSA <10 / 10 - 20 / >20 Treatment centre

Radiation Treatment will be delivered using a conventional technique, unless the treatment centre of the participating clinician demonstrates an ability to deliver the treatment using a CRT, IMRT, or HDRB technique verified by the trial TACT.

Drug Treatment:

LH-RH analogue (LH-RHa) (Leuprorelin acetate 22.5 mg) will be delivered as a depot injection every 3 months. This will be administered as an Intramuscular injection (IMI).

Zoledronic acid 4 mg will be delivered as an intravenous infusion over 15 minutes once every 3 months for 18 months, in patients randomised to this therapy. No placebo therapy will be given to patients randomised to 'no bisphosphonate therapy' treatment arm.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Open Label
Primary Purpose: Treatment
Prostate Cancer
  • Drug: Leuprorelin Acetate
    LH-RH analogue (LH-RHa) (Leuprorelin acetate 22.5 mg) will be delivered as a depot injection every 3 months. This will be administered as an intramuscular injection (IMI).
  • Drug: Zoledronic Acid
    Zoledronic acid 4 mg will be delivered as an intravenous infusion over 15 minutes once every 3 months for 18 months, in patients randomised to bisphosphonate therapy.
  • Radiation: Conventional external beam therapy
    The prescribed dose will be 66 Gy in 33 fractions of 2 Gy to the ICRU 50 point utilising a minimum of three fields with >= 6 MV photons.
  • Active Comparator: A
    LH-RH analogue for 5 months prior to and during first month of radiation treatment (total 6 mths)
    Interventions:
    • Drug: Leuprorelin Acetate
    • Radiation: Conventional external beam therapy
  • Active Comparator: B
    LH-RH analogue for 5 months prior to and during first month of radiation treatment (total 6 months) + bisphosphonate therapy.
    Interventions:
    • Drug: Leuprorelin Acetate
    • Drug: Zoledronic Acid
    • Radiation: Conventional external beam therapy
  • Experimental: C
    LH-RH analogue as for arm A, but continued for further 12 months (total 18 months)
    Interventions:
    • Drug: Leuprorelin Acetate
    • Radiation: Conventional external beam therapy
  • Experimental: D
    LH-RH analogue as for arm A, but continued for further 12 months (total 18 months) + bisphosphonate therapy.
    Interventions:
    • Drug: Leuprorelin Acetate
    • Drug: Zoledronic Acid
    • Radiation: Conventional external beam therapy

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
1000
August 2018
August 2017   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Histological confirmation of adenocarcinoma of the prostate in the three months prior to randomisation
  • Gleason primary and secondary pattern reported. If the volume of tumour in biopsies is too small for the pathologist to allocate a secondary pattern, the primary pattern alone is sufficient.
  • Primary tumour stage T2b - 4 (UICC 2002), or T2a providing biopsies demonstrate Gleason score 7 or more, and presenting PSA 10 or more
  • PSA value obtained within one month of randomisation
  • No evidence of lymphatic or haematogenous metastases, as determined by negative chest x-ray, CT scan of abdomen and pelvis, and bone scan in the 3 months prior to randomisation
  • ECOG performance status 0 - 1
  • No concurrent medical conditions likely to significantly reduce prospects of 5 year survival
  • Patient accessible to follow up at intervals specified in protocol
  • Written informed consent given (signed by both patient and investigator prior to randomisation)

Exclusion Criteria:

  • Previous or concurrent malignancy within previous 5 years except for non-melanomatous skin cancer
  • Prostatectomy
  • Prior pelvic radiotherapy
  • Prior hormone treatment for prostate cancer
  • Inability to complete self administered QOL questionnaire
  • Prior bisphosphonate therapy
  • Serum creatinine > 2 x ULN
  • Osteoporosis resulting in >30% loss in vertebral height in one or more thoraco-lumbar vertebrae
  • Liver disease resulting in ALT or AST levels >3 x ULN
  • Prolonged continuous glucocorticoid therapy > 10 mg/day of prednisone equivalent (>6 months)
  • Current treatment with bisphosphonate
  • Inability to attend for follow-up at the Investigator's clinic
Male
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
Australia,   New Zealand
 
NCT00193856
TROG 03.04, ACTRN12607000097448
Yes
Trans-Tasman Radiation Oncology Group (TROG)
Trans-Tasman Radiation Oncology Group (TROG)
  • National Health and Medical Research Council, Australia
  • Hunter Medical Research Institute (HMRI)
  • Health Research Council, New Zealand
  • Abbott
  • Novartis Pharmaceuticals
  • Cancer Society of New Zealand
  • University of Newcastle, Australia
  • Radiation Oncology, Calvary Mater Newcastle, Australia
Study Chair: Jim Denham, FRANZCR University of Newcastle, Australia
Trans-Tasman Radiation Oncology Group (TROG)
November 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP