Trial of Pembrolizumab in Metastatic Castration Resistant Prostate Cancer

PERSEUS1 is an open-label, single arm, phase II trial evaluating the efficacy of Pembrolizumab in metastatic castration resistant prostate cancer (mCRPC) patients (Part A) with a biomarker enrichment stage (Part B) if efficacy is shown in part A.

Open-label, single arm, phase II trial initially pursuing a two-stage Simon Minimax design. The null hypothesis Po will be 0.20; the alternative hypothesis Pa will be 0.40 (type 1 error will be 0.05 and type 2 error will be 0.10).

Patients with metastatic CRPC tumours characterised by high mutational load, high microsatellite instability as established, for example, by the Promega MSI 1.2 analysis system, or a DNA repair defect including loss of MMR, identified on archival or fresh tissue biopsy specimens (through a TMG approved sequencing study e.g. the MAESTRO study) who have either exhausted established active anticancer drugs, or preferred not to have established agents, will be offered entry into the PERSEUS1 study.

Part A: Part A is an open-label, single arm, two-stage Simon Minimax design phase II trial.

Stage 1: Patients will continue their LHRH analogue therapy. This cohort will include 24 patients as the first stage of a two-stage Phase II. If more than 5 responses in these first 24 patients are reported then the study will proceed to stage 2. Anti-tumour activity will be assessed (measured by response rates) by PSA, imaging assessments (CT \& bone scans or when indicated whole body MRI) and CTC count measures. Whole Body MRI (WB-MRI) will be performed instead of CT in patients with contraindications to CT contrast), or instead of bone scan in patients with widespread bone disease at baseline thought to be non-evaluable by PCWG criteria due to inability to reliably identify two new lesions.

Stage 2: This will enrol a further 21 patients to a total of 45 patients. Ineffectiveness will be concluded if ≤5 and ≤13 responses are seen in the stage 1 and stage 2 respectively and the null hypothesis will be rejected (i.e. further research would be warranted) if \>13 responses are reported from the first 45 patients.

With this Simon Minimax design the probability of early termination of this trial when the true response probability (P0) is \<0.20 is 0.66.

Part B: Biomarker enrichment stage: If the null hypothesis is rejected (and with Sponsor approval and confirmation of sufficient funding) the study will continue with stratified recruitment into biomarker defined cohorts in order to increase the precision with which the response rate can be estimated within mCRPC molecular subgroups of interest. It is anticipated that approximately 55 patients will be included in Part B, which will make a total of 100 mCRPC patients in part A and B together, including ≥9 patients for each of:

A) MMR defective mCRPC; B) High mutational load mCRPC without MMR defects; C) mCRPC with deleterious homologous recombination (HR) DNA repair aberrations (BRCA2, ATM, BRCA1, PALB2, others); D) mCRPC with deleterious nucleotide excision repair (NER) aberrations; E) mCRPC with deleterious base excision repair (BER) aberrations; F) mCRPC with deleterious aberrations in non-homologous end-joining (NHEJ).

Eligibility for more than one cohort is anticipated to be uncommon; where this occurs "allocation" to a cohort will be determined in discussion with the CI based on initial sequencing results and with priority given to driver (rather than sub-clonal) mutations. Patients recruited in Part A will be retrospectively "allocated" to a cohort on the basis of their initial sequencing data (reported prior to trial entry) prior to any response assessments, for the purposes of analysis. Within each biomarker subgroup (A-F) this will allow us to reject the probability of a \>30% response rate if we see no responses in 9-patients, with a 5% false negative risk (Gehan design). If ≥1 responses are seen in 9 patients in a subtype, recruitment will continue to that subtype with a further 20-25 patients such that the final estimate of the response rate has a standard error of 10%. Response rates with confidence intervals will be reported for each subtype.

In the absence of any safety concerns from the IDMC, recruitment will continue seamlessly from Part A stage 1 to Part A stage 2 and from Part A stage 2 to the Part B biomarker enrichment cohorts. It is possible that at the time of the Part A stage 1 and 2 overall analysis (based on 45 patients), the graduation of some of the more common subgroups to the enrichment phase will be known (e.g. if more than 1 response from 9 patients recruited to a biomarker subgroup that cohort would continue to at least 20 patients). Conversely, if no successes have been seen in 9 patients of a particular subtype, recruitment to that subtype would not proceed to the enrichment stage.

The biomarker defined cohorts may accrue at different rates related to genomic prevalence. At each stop/go decision point (end of enrichment stage 1 in a particular cohort) overall progress of all the ongoing enrichment cohorts will be reviewed by the IDMC/TSC. They will be asked to advise on the value of continued accrual to the cohorts particularly in light of slow recruitment.

Eligibility Criteria:
Inclusion Criteria:

1. Male, aged 18 years or older.
2. Histologically confirmed metastatic castrate resistant adenocarcinoma of the prostate. 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. Identified high mutational load (defined as 11 or more mutations per targeted panel - see Section 5.5 below) on next generation sequencing and/or a DNA repair defect that can increase mutation load including MMR deficiency and/or high MSI by next generation sequencing.
4. Patients with no measurable disease and only widespread bone disease must have a CTC count \>5.
5. Willing and able to comply with the follow-up schedule and the requirements of the biomarker studies including the paired fresh tumour biopsies.
6. Written informed consent.
7. Prior treatment with at least one of the approved treatments for mCRPC (i.e. Abiraterone, Enzalutamide, Docetaxel, Cabazitaxel, Radium 223).
8. 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.
9. 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. The PSA value at the Screening visit should be ≥ 2 µg/L (2 ng/ml) if there is no measurable disease; 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.

   • Radiographic progression of soft tissue disease by iRECIST criteria or of bone metastases by PCWG3 criteria with two or more confirmed new bone lesions on a bone scan/wb-MRI with or without PSA progression.
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 appendix A3 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:

Haemoglobin (Hb) ≥ 9.0 g/dL Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L Platelet count ≥ 100 x 10\^9/L International normalised ratio (INR) ≤ 1.5x upper limit of normal (ULN) Or: Prothrombin time ≤ 1.5x upper limit of normal (ULN) Serum bilirubin (for patients with total bilirubin \>1.5x ULN) Or: Direct bilirubin ≤ 1.5x ULN ≤1.5x ULN Alanine aminotransferase (ALT) and aspartate aminotransferase (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: creatinine clearance = (((140 - age) x mass (kg)) x 1.23) / serum creatinine (µ mol⁄L)

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 the expected start or after any dose of pembrolizumab. Examples include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, seasonal flu, H1N1 flu, rabies, BCG, and typhoid vaccine.

  4. Patients receiving growth factors including, but not limited to, granulocyte colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (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 (New York Heart Association 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 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.

  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 chronic respiratory disease. 13. 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). 14. History of any autoimmune disease: patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], systemic lupus erythematosus, autoimmune vasculitis \[e.g., Wegener's Granulomatosis\]); CNS or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis, multiple sclerosis). Patients with controlled Graves' disease will be allowed.

    15. Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 16. Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected).

    17. History of congenital platelet function defect (e.g., Bernard-Soulier syndrome, Chediak-Higashi syndrome, Glanzmann thrombasthenia, storage pool defect).

    18. Patients with history of (non-infectious) pneumonitis that required steroids or current pneumonitis.

    19. 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.

    20. 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.