| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Castration Resistant Prostate Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To determine the efficacy of Pembrolizumab 200 mg IV 3-weekly in patients suffering from mCRPC with putative phenotypes associated with immunotherapy sensitivity after progression on standard treatments.
Patients with these specific genetic aberrations will have previously been identified through a TMG approved sequencing programme e.g. the MAESTRO study. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives:
1. To determine radiological antitumour activity, against mCRPC of pembrolizumab 200mg IV 3-weekly after disease progression on standard treatments
2. To estimate the biochemical antitumour activity, against mCRPC, of pembrolizumab 200mg 3-weekly after disease progression on standard treatments.
3. To evaluate the duration of survival benefit in patients with mCRPC who receive pembrolizumab 200mg IV 3-weekly after progression on standard treatments.
4. To report the safety of Pembrolizumab 200mg IV 3-weekly against mCRPC after progression on standard treatments.
Exploratory objectives:
1. To explore the association of HIMUT, MSI, DNA repair defects including MMR-, PD-1, PD-L1 and PD-L2 positivity and tumour infiltrating lymphocytes with response.
2. To assess tumour tissue for other molecular determinants of response, progression and disease stability using next generation sequencing technology.
3. To assess the baseline clinical characteristics of the subjects |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Individual, aged 18 years or older.
2. Histologically confirmed adenocarcinoma of the prostate (tumours with neuroendocrine features are eligible). If the patient does not have a prior histological diagnosis then the planned baseline fresh biopsy may be used for both the purpose of confirming the histological diagnosis prior to trial entry and for subsequent biomarker analysis. All patients must be willing to have fresh biopsies to obtain tumour tissue for biomarker analysis.
3. mCRPC with one of the following:
• MMR defective disease by immunohistochemistry;
• Tumours with evidence of bi-allelic CDK12 loss;
• Tumours with high MSI-NGS with either:
o deleterious MMR gene mutation OR;
o high CD3 (≥70th centile) OR;
o HIMUT (≥11);
• Tumours with HIMUT with either high CD3 or a deleterious mutation in a DNA
repair gene;
• The presence of DNA repair defects (HR, NHEJ, NER) with high CD3 count;
4. Patients with:
• Measurable soft tissue disease as per iRECIST criteria (with or without bone disease), OR
• Non measurable soft tissue disease as per iIRECIST criteria (with or without bone disease), and a CTC count ≥>5 cells/7.5 ml and PSA value ≥ 2 µg/L (2 ng/ml)
5. Documented prostate cancer progression as assessed by the investigator with one of the following:
• PSA progression defined by a minimum of three rising PSA levels with an interval of ≥ 1-week between each determination. Patients on systemic glucocorticoids for control of symptoms must have documented PSA progression by PCWG3 while on the same dose of systemic glucocorticoids prior to commencing Cycle1 Day1 of treatment.
• Radiological progression of soft tissue disease by RECIST criteria or of bone metastases by PCWG3 criteria with two or more confirmed new bone lesions on a bone scan/WBMRI with or without PSA progression.
6. Willing and able to comply with the follow-up schedule and the requirements of the biomarker studies including the paired fresh tumour biopsies.
7. Written informed consent.
8. Prior treatment with at least one of the approved treatments for mCRPC (i.e. Abiraterone, Enzalutamide, Docetaxel, Cabazitaxel, Radium 223).
9. At least 28-days washout at trial entry since the completion of prior therapy, including major surgery, chemotherapy and other investigational agents. For hormonal treatment and radiotherapy refer to the guidelines below:
• At least 28-days since the completion of prior flutamide treatment. Patients whose PSA did not decline in response to antiandrogens given as a second line or later intervention will only require a 14-day washout prior to Cycle 1, Day 1.
• At least 42-days since the completion of prior bicalutamide (Casodex) and nilutamide (Nilandron) treatment. Patients whose PSA did not decline for at least 3-months in response to antiandrogens given as second line or later intervention will require only a 14-day washout period prior to Cycle 1 Day 1.
• At least 14-days from any radiotherapy with the exception of a single fraction of radiotherapy for the purposes of palliation (confined to one field) is permitted.
10. Surgically or medically castrated, with testosterone levels of <50 ng/dL (<2.0 nM). If the patient is being treated with LHRH agonists (patient who have not undergone orchiectomy), this therapy must have been initiated at least 4 weeks prior to Cycle 1 Day 1 and must be continued throughout the study.
11. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
12. Albumin ≥25 g/L.
13. Patient and the patient’s partner of reproductive potential who are sexually active, must agree to use adequate methods of contraception during the course of the study and for 120 days after the last dose of study drug (see protocol appendix 3 for accepted methods of contraception).
14. QT interval corrected for heart rate according to Fridericia’s formula (QTcF) <470 msec or <480 msec with bundle branch block.
15. Patients with primary hypothyroidism can be considered eligible if thyroid stimulating hormone (TSH) at the screening visit is within normal range while patient is under hormonal treatment.
16. Subjects must have adequate bone marrow, hepatic and renal function
documented within 7-days of trial entry defined as:
Hb≥ 9.0g/dL, ANC≥1.5x10^9/L, Platelet count≥100x10^9/L, INR or
Prothrombin time≤ 1.5xULN, Serum bilirubin or Direct bilirubin (for
patients with total bilirubin >1.5x ULN) ≤ 1.5x ULN
ALT and AST≤ 2.5x ULN (for patients with liver metastases ≤ 5x ULN is
permissible), Serum creatinine ≤1.5 x ULN or Calculated creatinine
clearance >40mL/min for patients with creatinine levels above institutional
normal. For GFR estimation, the Cockcroft and Gault equation should be used |
|
| E.4 | Principal exclusion criteria |
1. Patients with a history of prior treatment with anti-PD-1, anti-PD-L1,
anti-PD-L2, anti-CD137, anti-OX-40, anti-CD40, or anti-CTLA-4 antibodies.
2. Patients who have received any of the following concomitant therapies:
IL-2, interferon or other non-study immunotherapy regimens;
immunosuppressive agents; other investigational therapies; or chronic use
of systemic corticosteroids (used in the management of cancer or non-
cancer-related illnesses) within 1 week prior to first dose. A dose of
10mg of prednisolone or equivalent will be allowed if clinically
indicated.
3. Patients who have received any non-oncology vaccine therapy used for
prevention of infectious diseases including seasonal vaccinations for up
to 28-days prior to or after any dose of pembrolizumab.
4. Patients receiving growth factors including, but not limited to,
G-CSF, GM-CSF, erythropoietin, within 14-days of study drug administration.
Use of such agents while on study is also prohibited. Prior use of growth
factors should be documented in the patient’s medical history.
5. Uncontrolled intercurrent cardiovascular disease as symptomatic
congestive heart failure (NYHA Class III or IV heart disease), unstable
angina pectoris, cardiac arrhythmia, poorly controlled hypertension (defined
as systolic blood pressure of ≥150mmHg or diastolic blood pressure of >100
mmHg based on a mean of three measurements at approximately 2-minute
intervals).
6. Any psychiatric illness/social situations that would limit compliance
with study requirements.
7. Any acute toxicity due to prior chemotherapy and / or radiotherapy that
has not resolved to a NCI-CTCAE v4.0 grade ≤1 with the exception of
chemotherapy induced alopecia and grade 2 peripheral neuropathy.
8. Prior malignancy diagnosed within the previous 2-years with a >30%
probability of recurrence within 12-months, with the exception of non-
melanoma skin cancer, and in-situ or non-muscle invasive bladder cancer and
germline MMR defect associated cancers that have been completely resected.
9. Patients with myelodysplastic syndrome or acute myeloid leukaemia.
10. Patients with known active central nervous system (CNS) metastases and/or
carcinomatous meningitis. Subjects with previously treated brain
metastases may participate provided they are stable (without evidence of
progression by imaging for at least four weeks prior to the first dose of
trial treatment and any neurologic symptoms have returned to baseline),
have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment. This exception
does not include carcinomatous meningitis which is excluded regardless of
clinical stability.
11. Patients with symptomatic or impending cord compression unless
appropriately treated beforehand and clinically stable and asymptomatic.
12. Any immunological disorder requiring treatment with immunosuppressive
treatments:
• High dose of steroids (low dose of steroids as 10mg of prednisolone or
equivalent are allowed if the patient is not able to discontinue this
treatment; patient needs to be on a stable dose for at least 4-weeks
before the enrolment);
• Cytotoxic agents (such as alkylating agents or antimetabolites);
• Antibodies (polyclonal antibodies; monoclonal antibodies different from
pembrolizumab);
• Drugs acting on immunophilins (cyclosporin, tacrolimus, sirolimus);
• Other drugs (interferons, TNF binding proteins, mycophenolate).
13. History of any autoimmune disease: patients with a history of
inflammatory bowel disease are excluded from this study, as are patients
with a history of symptomatic disease, systemic lupus erythematosus,
autoimmune vasculitis; CNS or motor neuropathy considered of autoimmune
origin. Patients with controlled Graves’ disease will be allowed.
14. Known history of HIV
15. Known active Hepatitis B or C
16. History of congenital platelet function defect
17. Patients with history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
18. Initiating bisphosphonate therapy or adjusting bisphosphonate dose/regimen within 30 days prior to Cycle 1 Day 1. Patients on a stable bisphosphonate regimen are eligible and may continue.
19. Presence of a condition or situation, which, in the investigator’s opinion, may put the patient at significant risk, may confound the study results, or may interfere significantly with the patient's participation in the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
To evaluate composite tumour response by 24 weeks, defined as the best response observed within 24 weeks of treatment, and on the basis of the following outcomes; if any of these occur patients will be considered to have responded:
• Objective response by iRECIST
• CTC count conversion from >5 to <5 cells/7.5ml
• PSA decline of ≥50%
Radiological response has to be confirmed by a second scan four or more weeks after the first scan showing response. PSA and CTC responses will need confirmation by a second consecutive value obtained three or more weeks after the first value indicated a response. Response by PSA or CTC count conversion response needs to occur without evidence of radiological progression at the time of the response assessment. Evaluable patients with no confirmed response as defined above will be classified as non-responders.
The analysis of the primary outcome will use the evaluable-patient population with sensitivity analyses using the ITT and per protocol populations. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Response will be evaluated 24 weeks post trial entry. The last value of PSA, CTC count, CT scan/bone scan/WB-MRI on or up to 28 days before the date of first study treatment will be used as the baseline value for this assessment. |
|
| E.5.2 | Secondary end point(s) |
Secondary end points:
• Composite response rate while on treatment, defined as the best response while patient is on treatment and on the basis of objective response by iRECIST, and/or CTC count conversion and/or PSA decline of ≥50%, as defined above for the primary endpoint.
• Radiological endpoints:
o Radiological progression-free survival
o Time to radiological progression;
o Progression free survival (PFS).
o Bone disease objective response by WBMRI Criteria
• Biochemical endpoints:
o Time to PSA progression;
o Duration of PSA response (decline of ≥50%);
o Maximum PSA decline at any time during the trial treatment and PSA decline at 12
weeks
• Overall survival (OS)
• Safety and tolerability as defined by CTC-AE, V 4.0 criteria
Exploratory end points:
• Molecular endpoints
o PD-1, PDL-1 and PDL-2 expression
o Mutational load (number of mutations per MB of DNA sequenced)
o Presence of mismatch repair defect as determined by immunohistochemistry or
microsatellite instability (MSI).
o CD3, CD8, lymphocyte infiltration
o T-Reg infiltration (CD4+ CD25+ FoxP3+)
Both diagnostic archival FFPE tumour tissue (when available) and fresh mCRPC tumour tissue will be analysed.
• NGS data from tumour and circulating white blood cell (eg T-cell receptor
sequencing) DNA and RNA including analyses of neoepitopes by targeted panel
NGS and exome/transcriptome analyses when feasible.
• Immunophenotyping endpoint:
o WBC immunotyping
• Whole blood mRNA expression profiling
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary endpoints will be evaluated 24 weeks post trial entry. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Development of targeted therapies based on molecular profiling |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The trial end date is deemed to be the date of last data capture. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 8 |
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