01.12.2017 | Study protocol | Ausgabe 1/2017 Open Access

A phase II randomized trial of Observation versus stereotactic ablative RadiatIon for OLigometastatic prostate CancEr (ORIOLE)
- Zeitschrift:
- BMC Cancer > Ausgabe 1/2017
Background
Methods/design
Objectives
Secondary endpoints
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To describe the toxicity of SBRT/SABR delivered for the population enrolled using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
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To determine local control at 6-months after SABR in patients with oligometastatic disease.
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To assess progression free survival (PFS) and ADT-free survival (ADT-FS) after randomization defined as the time interval between the day of randomization and progression.
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To assess quality of life in the SBRT/SABR arm using the Brief Pain Inventory form [ 34].
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To estimate the proportion of 18F-DCFPyL-PET/MRI or –PET/CT positive sites that are positive for new or progressive metastatic disease by bone scan/CT at baseline and 6 months following SABR and vice versa.
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To enumerate CTCs using EPIC HD-CTC platforms at baseline and day 180 from randomization.
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To enumerate circulating tumor DNA (ctDNA) using Cancer Personalized Profiling by deep sequencing (CAPP-Seq) at baseline, day 90 and day 180 from randomization for control and SABR arms.
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To quantitatively sequence T-cell receptor (TCR) repertoires using peripheral blood monocytes and the ImmunoSEQ platform at baseline and day 90 from randomization.
Inclusion criteria
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Patient must have 1-3 asypmtomatic metastatic tumor(s) of the bone or soft tissue developed within the past 6-months that are ≤ 5.0 cm or < 250 cm 3.
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Patient must have had their primary tumor treated with surgery and/or radiation and salvage radiation to the prostate bed or pelvis is allowed.
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Histologic confirmation of malignancy (primary or metastatic tumor).
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Prostate specific antigen (PSA) ≥ 0.5 ng/mL but ≤ 50 ng/mL and Testosterone ≥ 125 ng/dL.
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PSA doubling time (PSADT) < 15 months. PSADT will be calculated using as many PSA values that are available from time of relapse (PSA > 0.2 ng/dL).
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Patient may have had prior systemic therapy and/or ADT associated with treatment of their primary prostate cancer. Patient may have had ADT associated with salvage radiation therapy.
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Patient must be ≥ 18 years of age, have the ability to understand, and the willingness to sign, a written informed consent document.
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Patient must have an Eastern Cooperative Oncology Group performance status ≤ 2.
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Patient must have normal organ and marrow function as defined as:
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Leukocytes >2,000/μL, absolute neutrophil count >1,000/μL, platelets >50,000/μL
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Exclusion criteria
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No more than 3 years of ADT is allowed, with the most recent ADT treatment having occurred greater than 6 months prior to enrollment.
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18F-DCFPyL-PET/MRI or 18F-DCFPyL-PET/CT scan within the past 6 months with results that demonstrate lesions not seen on baseline CT or bone scan
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Castration-resistant prostate cancer (CRPC).
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Spinal cord compression or impending spinal cord compression.
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Suspected pulmonary and/or liver metastases (greater > 10 mm in largest axis).
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Receipt of any other investigational agents or participation in a concurrent treatment protocol.
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Serum creatinine and total bilirubin > 3 times the upper limit of normal
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Liver Transaminases > 5-times the upper limit of normal.
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Inability to lie flat during or tolerate PET/CT, PET/MRI or SABR.
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Refusal to sign informed consent.
Evaluation of randomization and blinding
Interventions
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Standard blood tests [complete blood count with differential (CBC w/Diff), lactate dehydrogenase (LDH), serum chemistry, and PSA evaluation]
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Research laboratory tests: CAPP-Seq, rectal swab, and Color Test
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Physician examination, medical history, medication review, performance status, quality of life (QoL) and adverse event (AE) evaluations
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Standard blood tests (CBC w/Diff, LDH, serum chemistry, testosterone, and PSA evaluation)
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Research blood tests: CAPP-Seq
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Physician examination, medical history, medication review, performance status, QoL and AE evaluations
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Standard blood tests (CBC w/Diff, LDH, serum chemistry, testosterone and PSA evaluation),
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Research blood tests: CAPP-Seq
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Imaging: bone scan and CT/MRI
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Standard blood tests (CBC w/Diff, LDH, serum chemistry, and PSA evaluation)Research laboratory tests: EPIC HD-CTC, ImmunoSEQ, CAPP-Seq, rectal swab, and Color Test
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Imaging: 18F-DCFPyL PET/CT or PET/MRI
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Physician examination, medical history, medication review, performance status, QoL and AE evaluations
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Standard blood tests (CBC w/Diff, LDH, serum chemistry, testosterone, and PSA evaluation)
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Research blood tests: ImmunoSEQ, CAPP-Seq
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Physician examination, medical history, medication review, performance status, QoL and AE evaluations
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Standard blood tests (CBC w/Diff, LDH, serum chemistry, testosterone, and PSA evaluation)
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Research blood tests: EPIC HD-CTC, CAPP-Seq
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Imaging: Bone scan and 8F-DCFPyL PET/CT or PET/MRI
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CT- and/or MRI-simulation will be performed with fabrication of a radiation therapy immobilization device custom-made for each patient. The treating radiation oncologist will identify the location of the tumor. Gross tumor volume (GTV) delineation will be performed with a diagnostic radiologist on sequential axial computed tomography images. A radiosurgical treatment plan will then be developed based on tumor geometry and location. The clinical tumor volume (CTV) will equal the GTV. The dose will be prescribed to the minimal isodose line that completely covers the planning target volume (PTV), defined as CTV plus a variable (up to 5 mm) margin. Adjacent normal structures, including but not limited to the heart, esophagus, aorta, spinal cord, kidneys, rectum, bowel, liver, and stomach, within 5 cm of the CTV will be identified for the purpose of limiting incidental radiation to these structures.
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In addition, prior to treatment delivery, a four-dimensional cone beam CT study will be performed on individual patients to assess respiration and determine targeting accuracy for tumors that may be subject to respiratory motion such as those in the bones of the thorax. If tumor motion is greater than 5 mm, the PTV will be expanded accordingly.
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SABR will be delivered in 1 to 5 fractions, and the dose and fractionation schedule will depend on the size and location of the lesion and the surrounding normal tissue constraints in accordance with AAPM Task Group 101 recommendations [ 36].
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Within three weeks of the initial treatment planning imaging study, SABR will be administered using image-guidance. During treatment, real time cone beam CT images of the patient’s body site of interest will be obtained. Cone beam CT will be obtained immediately prior to treatment and will be repeated until the treatment shift, required to align the planning CT and the cone beam CT performed on the day of treatment, is within tolerance for the body site.
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Site-specific grade 4/5 toxicity will be monitored in the SABR arm. If it becomes evident that the proportion of grade 4/5 toxicity at specific sites convincingly exceeds 20%, the study will be halted for a safety consultation. Specifically, we will apply a Bayesian toxicity monitoring rule that suspends the enrollment for a posterior probability ≥ 75% of toxicity being larger than 20%. The monitoring rule uses Beta (0.5, 5.5) as prior distribution, meaning our prior guess of the proportion of toxicity is 8.3% with a 90% chance that this proportion is 0.04%-30.6%.
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Patients will be followed from Day 1 to Day 180.
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All AEs and serious adverse events (SAEs) are recorded on source documents. The investigator will follow up on all AEs and SAEs until the events have subsided, returned to baseline or, in case of permanent impairment, until the condition stabilizes.
Stastical analysis
Sample size and accrual
Data analysis
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A minimization approach [ 35] will be applied to ensure balanced assignment to each treatment arm by: 1) Initial treatment with surgery vs. radiation therapy; 2) Prior hormonal therapy vs. no prior hormonal therapy; and 3) PSADT <6 mos vs. 6-14.9 mos. Baseline PSA level is defined as that measured Day 1 following randomization.
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The primary clinical outcome will be the proportion of patients who have progressed after 6 months from randomization. For each arm, we will calculate the proportion of patients who have progressed and extract 95% confidence intervals. If a patient has withdrawn from the study before 6 months, they will be considered to have progressed.
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Progression will be a composite endpoint defined from the Prostate Cancer Working Group 2 (PCWG2) criteria for mCRPC [ 38] and our previous trials in a population of men with biochemical failure without metastases [ 37– 39]. Progression will be defined as either: 1) a ≥ 25% increase in PSA from nadir (and by ≥ 2 ng/mL), requiring confirmation ≥ 4 weeks later (PCWG2 criteria); and/or, 2) clinical/radiographic-progression defined as symptomatic progression (worsening disease-related symptoms or new cancer-related complications), or radiologic progression (on CT scan: ≥ 20% enlargement in sum diameter of soft-tissue target lesions [RECIST 1.1 criteria]; on bone scan: ≥ 1 new bone lesions), initiation of ADT or death due to any cause, whichever occurs first. Death is considered a severe adverse event here.
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We will compare the proportion of patients who have progressed in the observation and SABR arms using Fisher’s exact test. The analysis population includes all randomized subjects based on intention-to-treat.
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For safety analysis, adverse events will be summarized by type and grade.
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Hazard rate estimates and 95% confidence intervals as well as Kaplan-Meier (KM) estimates will be calculated for PFS, ADT-FS, TTLP and TTDP. The median PFS, ADT-FS, TTLP and TTDP will be reported.
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Each metastatic lesion will be considered a target lesion and independently evaluated for response using RECIST 1.1 or bone scan evaluation criteria below. The lesion will be coded as locally controlled if it is considered stable radiographic disease or if there is evidence of a partial or complete response. Local control assessment will start at three months following randomization and continuous assessment will be pursued during the follow-up period. The proportion of locally controlled lesions will be estimated using generalized estimating equations.
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QoL will be assessed using the Brief Pain Inventory form. An overall score will be calculated pre-treatment and at the time of the 2 nd radiologic reassessment. The change in score will be evaluated by paired t-test.
Response criteria
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Complete Response (CR): Disappearance of all target lesions and PSA below baseline
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Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum OR at least 1/3 of lesions are stable or resolved by bone scan AND PSA below baseline
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Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since treatment initiation OR the appearance of >1 new lesion(s) by bone scan OR PSA ≥25% above nadir or > 50 ng/ml.
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Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since treatment initiation OR PSA > baseline but not ≥25% above nadir and <50 ng/ml.
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Complete Response (CR): Disappearance of all target lesions and PSA below baseline
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Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum OR at least 1/3 of lesions are stable or resolved by bone scan AND PSA below baseline
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Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since treatment initiation OR the appearance of >1 new lesion(s) by bone scan OR PSA ≥25% above nadir or > 50 ng/ml.
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Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since treatment initiation OR PSA > baseline but not ≥25% above nadir and <50 ng/ml.
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Duration of CR or PR: The duration of CR or PR will be recorded from the date criteria for CR or PR are first met until the first date current or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since treatment initiation).
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Duration of Stable Disease: Stable disease will be recorded until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started.