Prospective Comparative Study for Patients With Biochemical Recurrence Prostate Cancer Detecting by 18F-JK-PSMA-7

Investigational Product:

The investigational product in this study is 18F-JK-PSMA-7, a fluorine-18 labelled ligand binding specifically to prostate specific membrane antigen (PSMA).

The investigational product 18F-JK-PSMA-7 is a diagnostic radiopharmaceutical for use with positron emission tomography (PET).

The active substance of the diagnostic radiopharmaceutical product is 18F-JK-PSMA-7.

Fluorine (F) decays to stable oxygen (O) with a half-life of 110 minutes by emitting a positronic radiation of maximum energy of 634 keV, followed by photonic annihilation radiations of 511 keV.

The investigational product 18F-JK-PSMA-7 is a newly developed F-labelled PET tracer for functional imaging of PSMA expression.

PSMA is a transmembrane glycoprotein that is expressed in a variety of cells and is characterized by its overexpression in Prostate Cancer. The overexpression of PSMA has been observed both in primary Prostate Cancer as well as in metastatic lesions.

The active substance of Comparator is 18F-Fluorocholine. The Comparator will be a 18F-Fluorocholine with a Marketing Authorization in Italy that will be used in compliance with its Summary of Product Characteristics (SmPC).

18F-Fluorocholine is administrated as direct intravenous injection. One single administration of 18F-Fluorocholine is scheduled in each patient included in this study.

The analysis of images obtained with IMP (18F-JK-PSMA-7) and with Comparator (18F-fluorocholine) will be performed by two independent off site experts blinded to any patient´s clinical data, using the defined grid. Discrepancies between results of the two observers will be recorded by the clinical manager and a consensus reading with third expert will be organized. This reading will be used for determination of imaging performances.

Study duration.

• The study starts with a screening visit (-1), in which the medical history is collected, then a PET/TC examination (T0) is performed. The first examination will be performed with IMP.
• Whitin one month, a second PET-TC is performed using the Comparator, the other radiotracer (T1). Only for IMP are requested additional test of the tolerability (blood pressure, heart rate and inspection of injection site). The result of PET is analyzed by onsite reader, then by two blind out-site readers (blind to any clinical patient's data). A maximum wash-out period of 1 month is requested between the first and second reading performed by blind readers, in order to avoid that the reading can be affected by the knowledge of the first PET/TC examination.
• After 3 (T2) and 6 (T3) months from the last PET/TC examination (T1) a follow up visit will be performed in order to collect all the information related to procedures (treatments and/or examinations) performed by the patient according to clinical practices.
• After last visit and last patient (LVLP) of each site, the Assessment of Standard of Truth (SOT is established by a panel of expert blinded to result of PET/CT examination on the base of clinical data available in eCRF) and Performance evaluation will be performed (the Performance evaluation is an automatic determination); the estimated time for these activities is 6 months.
• In conclusion, each patient will be involved in the study about 7 months.

Two PET-TC will perform within one month of distance according to the following order: first the IMP than the Comparator.

This sequence of administration is established in advance as the organizational model, linked to the availability and management of the radiopharmaceutical, not allow to perform a randomization.

Risk and Benefits. The potential benefit from performing 18F-JK-PSMA-7 PET/CT in addition to PET/CT with Comparator in patients with biochemical recurrence of Prostate Cancer after primary treatment with curative intent consists from expected earlier and more sensitive localization of sites of recurrent disease than with 18F-Fluorocholine PET/CT which is currently the only one diagnostic radiopharmaceutical for use with PET approved for localization of lesions of recurrent Prostate Cancer. The early recognition of the disease resumption can allow the use of targeted treatments that can postpone the use of hormone therapy or, in case of metastatic disease, the use of systemic treatment.

In conclusion, the benefit / risk ratio for the patients involved is widely considered positive.

Primary objective. To show in an independent assessment by two readers blinded to clinical data the superiority of 18F-JK-PSMA-7 over 18F-Fluorocholine in patient-based detection rate of recurrent Prostate Cancer in patients with confirmed biochemical recurrence after treatment with curative intention.

Based on available bibliographic data we hypothesize that the detection rate of 18F-JKPSMA-7 is at least 20% higher than that of 18F-Fluorocholine.

Secondary objective.

• To evaluate the site-based sensitivity and specificity of 18F-JK-PSMA-7 and of 18F-Fluorocholine PET/CT for recurrent Prostate Cancer;
• To evaluate the frequency of change of actual therapeutic management motivated by result of 18F-JK-PSMA-7 and by 18F-Fluorocholine PET/CT in comparison with initially scheduled therapeutic management;
• To evaluate the discordance rate in 18F-JK-PSMA-7 and in 18F-Fluorocholine PET/CT reading among two blinded readers;
• To evaluate the safety profile of 18F-JK-PSMA-7 and of 18F-Fluorocholine.

Primary endpoints

• The patient-based detection rate of 18F-JK-PSMA-7 and of 18F-Fluorocholine PET/CT as a result of consensus of blind reading using an expert panel as a SOT. The eventual major discordance of results of blind readings will be solved by third reader blinded to results of previous blind readings. In particular, the study hypohesizes a 20% diagnostic superiority of 18F-JK-PSMA-7 versus 18F- Fluorocholine. The primary objective of the study is the identification of the possible best diagnostic rate of 18F-JK-PSMA-7 versus 18F- Fluorocholine in identiofying the reccurance of prostatic disesase in patients previusly subjected to prostectomy. Furthemore, the aim of the study is to evaluate the diagnostic accuracy of 18F-JK-PSMA-7 versus 18F- Fluorocholine even for low PSA levels, where the 18F- Fluorocholine is considered to be insensitive in these conditions..

Secondary endpoints

• The site-based sensitivity and specificity of 18F-JK-PSMA-7 and of 18F-Fluorocholine PET/CT of foci of recurrent Prostate Cancer;
• The change of actual therapeutic management motivated by result of 18F-JK-PSMA-7 and of 18F-Fluorocholine PET/CT in comparison with initially scheduled therapeutic management;
• The discordance rate in 18F-JK-PSMA-7 and in 18F-Fluorocholine PET/CT reading among two blinded readers;
• The adverse events or reactions related with use of 18F-JK-PSMA-7 and with use of 18F-fluorocholine

Statistical analysis The usual descriptive statistics, sample size (n), mean, standard deviation, median and range will be provided for the quantitative variables as well as the actual and percentage for each category of the qualitative variables.

Proportions comparisons: Chi-square test (X2), or Fisher test (F) when appropriated, are the tests of choice. If tests corrections are performed, estimations for both the corrected and the non-corrected tests will be provided.

To evaluate the study hypothesis, the 95% confidence interval (CI) of the difference between the 18F-JK-PSMA-7 and 18F-Fluorocholine positive results will be evaluated as follows:

1. the proportion of positives of the two tests will be said to be different if the CI of the difference does not include the number zero and consequently considered different at 5% statistical significance level;
2. the extent in which the two tests differ will be reported using the width of the CI;
3. the difference will be said to be clinically significant if the lower bound of the CI does not include the value 20% (the superiority hypothesis).

Sample Size The sample size was calculated on the basis of the diagnostic performances of the 18F-Fluorocholine PET/CT present in the literature. Three subgroups were identified.

Groups are identified by PSA ng/mL level. A sample size calculation was performed for each subgroup, considering the performance of the PET-18F-Fluorocholine and of the PET-18F-JK-PSMA-7 in that subgroup and computing the sample size adequate for testing the one-side hypothesis H0: pPSMA = pPSMA - superiority margin versus H1: pPSMA > pPSMA - superiority margin where: pPSMA is supposed to be 0.8 in the first subgroup of PSA, 0.95 in the second subgroup and 0.98 in the third one; the superiority margin is equal to 0.2 in the first two subgroup of PSA and 0.15 in the third one.

So, with an α=0.05 and a power (1-β) = 0.80:

• in the subgroup A, 33 patients are needed in order to test H0: pPSMA=0.6 (0.8-0.2) vs H1: pPSMA>0.6;
• in the subgroup B, 21 patients are needed in order to test H0: pPSMA=0.75 (0.95-0.2) vs H1: pPSMA>0.75;
• in the subgroup C, 25 patients are needed in order to test H0: pPSMA=0.83 (0.98-0.15) vs H1: pPSMA>0.83.

The resulting sample size is 79 patients. These resulting was incremented considering a dropout rate of 25%, obtaining 79/0.75 = 106 patients to be enrolled.

The sponsor is responsible for implementing and maintaining quality assurance and quality control systems to ensure that trials are conducted, and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirements.

The Sponsor is responsible for securing agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, and reports for the purpose of monitoring and auditing by the Sponsor, and inspection by domestic and foreign regulatory authorities.

Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly.

Agreements, made by the Sponsor with the investigator/institution and any other parties involved with the clinical trial, should be in writing, in protocol or in a separate agreement.

This study will be performed in accordance with the principles stated in the Declaration of Helsinki and subsequent amendments and in accordance with the Good Clinical Practice Guideline (CPMP/ICH/135/95).