Pembrolizumab With Olaparib as Combined Therapy in Metastatic Pancreatic Cancer

Study Overview
=================
Brief Summary
-----------------
A phase II study combining pembrolizumab with olaparib in metastatic pancreatic adenocarcinoma patients with high tumour mutation burden

Detailed Description
-----------------
This is a phase II single arm, open label, prospective trial investigating the efficacy of pembrolizumab plus olaparib in metastatic pancreatic adenocarcinoma patients exhibiting high tumour mutation burden (defined as ≥4 mutations/Mb, including tumours with Mismatch Repair Deficient (MMRD) /Microsatellite Instability (MSI) high).

Official Title
-----------------
A Phase II Study Combining Pembrolizumab With Olaparib in Metastatic Pancreatic Adenocarcinoma (PDA) Patients With High Tumour Mutation Burden

Conditions
-----------------
Pancreatic Cancer

Intervention / Treatment
-----------------
* Drug: Pembrolizumab
* Drug: Olaparib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Aged ≥ 16 years old Written informed consent Histologically or cytologically confirmed PDA High TMB (>4 mutations/Mb) identified by molecular profiling via the Precision-Panc master protocol, an NHS England Genomic Laboratory Hub, or by another validated molecular profiling platform (such as Foundation Medicine). Patients whose tumours have confirmed MMRD or MSI-H immunohistochemistry are also eligible. Radiologically confirmed stage 4 mPDA, with measurable disease Up to 1 prior systemic therapy regimen for unresectable (stage 3 or 4) PDA is allowed Prior radiotherapy is allowed as long as there is measurable disease which has not been irradiated. Karnofsky performance status ≥70% Life expectancy >12 weeks from the date of screening assessment Adequate bone marrow function: Absolute neutrophil count (ANC) ≥1.5 x 109 /L Haemoglobin (Hb) ≥ 90 g/L Platelets ≥100 x 109 /L Adequate liver function: Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤2.5 x upper limit of normal range (ULN), or <5 x ULN in the presence of liver metastases Total bilirubin <1.5 x ULN Received no more than 1 prior systemic therapy for metastatic disease Adequate renal function defined as a calculated creatinine clearance by Cockcroft- Gault of ≥51 mL/min Women of childbearing potential, male patients and their partners are required, and must adhere to the contraception requirement from informed consent until the last dose of the trial treatment and for 120 days after the last dose of trial treatment. (see section 11.11). Exclusion Criteria: Patients with resectable or locally advanced PDA Other invasive malignancies diagnosed within the last 2 years which have not been treated with curative intent Prior immune checkpoint inhibitors or PARP inhibitors Requirement for non-physiological dose of daily oral steroids, or regular use of any other immunosuppressive agents; prednisolone dose of < 10mg (or equivalent steroid dose) is allowed. Use of inhaled or topical steroids is allowed. Significant acute or chronic medical or psychiatric condition, disease or laboratory abnormality, which in the judgment of the investigator would place the patient at undue risk or interfere with the trial. Examples include, but are not limited to: A history of chronic obstructive pulmonary disease, interstitial lung disease, sarcoidosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis, cystic fibrosis or bronchiectasis affecting pulmonary function, causing breathlessness at rest Uncontrolled ischaemic heart or other cardiovascular event (myocardial infarction, new angina, stroke transient ischaemic attack, or new congestive cardiac failure) within the last 2 months Stable but significant cardiovascular disease defined by heart failure (New York Heart Association Functional Classification III or IV) or frequent angina Presence of active infection Cirrhotic liver disease, known HIV, chronic active or acute hepatitis B, or hepatitis C History of severe allergy or hypersensitivity reactions Autoimmune disease requiring chronic use of immunosuppressive agents. Replacement therapy using physiological doses for adrenal or pituitary insufficiency is allowed. Women who are pregnant, or plan to become pregnant or are lactating. Women of child-bearing potential and male patients who are unwilling to adhere to the contraception requirement from informed consent until the last dose of the trial treatment and for 120 days after the last dose of trial treatment. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the trial medication. Concomitant use of known potent CYP3A4 inhibitors and inducers. Restrictions relating to concomitant medications are described in section 10.9. Please consider wash-out periods. Judgment by the Investigator that the patient should not participate in the trial.

Ages Eligible for Study
-----------------
Minimum Age: 16 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab and olaparib<br>Pembrolizumab will be given as a fixed dose of 200mg standard dose on Day 1 (+/-3 days) of every 3 weeks cycle , administered intravenously as a  30 minute infusion, as per standard clinical practice. Patients continuing beyond 27 weeks can switch to pembrolizumab 400mg every 6 weeks (as per standard clinical practice). Olaparib dose is 300mg given orally, twice daily, from Day 1 to Day 21 continuously of each 3-week cycle. Dosing will start on day 1 of each cycle. | Drug: Pembrolizumab<br>* Pembrolizumab is a highly selective immunoglobulin G4-kappa humanised monoclonal antibody against Programmed cell death protein 1 (PD-1) receptor. It was generated by grafting the variable sequences of a very high-affinity mouse antihuman PD-1 antibody onto a human IgG4-kappa isotype with the containing a stabilizing Serine 228 to Proline Fc mutation.<br>* Other names: Keytruda;Drug: Olaparib<br>* Olaparib is a potent inhibitor of polyadenosine 5'diphosphoribose polymerase (PARP) developed as a monotherapy as well as for combination with chemotherapy, ionising radiation and other anti-cancer agents including novel agents and immunotherapy.<br>* Other names: KU-0059436;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR assessed by (RECIST) version 1.1 and CT scanning every 9 weeks for the first 9 cycles (27 weeks), then 12 weekly, or as clinically indicated | Through study completion, an average of 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (Safety and toxicity) | Safety and toxicity using NCI CTCAE version 5.0 | Through study completion, an average of 2 years | 
| Duration of Response (DOR) | DOR: the time (in days) from the first documentation of objective response (complete response or partial response, confirmed or unconfirmed, whichever status was recorded first, using RECIST criteria) until the first documented disease progression, or death (if before progression | Through study completion, an average of 2 years | 
| Progression Free Survival (PSF) | PFS: the time from registration to disease progression, or death, whichever occurs first, assessed by the treating investigators. Patients who remained alive without disease progression at the time of data analyses are censored at their last date of clinical follow-up for progression. Median, 1 year and 2 year PFS rates will be measured | through study completion, a maximum of 2 years | 
| Overall survival (OS) | OS: the time from registration to death. Patients who remain alive are censored at their last contact date for OS. Median, 1 year and 2 year OS rates will be measured. | through study completion, a maximum of 2 year | 
| European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients questionnaire (EORTC QLQC30) | EORTC QLQC30 quality of life questionnaire. Min score 28, maximum score 112. Higher scores equal worse outcome. (Extra 2 questions: min score 1, max score 7 each. Higher scores equals better outcomes.) | Every 9 weeks during the first 27 weeks and then every 12 weeks until death or maximum of 2 years | 
| European Organisation for Research and Treatment of Cancer Pancreatic Cancer Quality of Life Questionnaire (EORTC PAN26) | EORTC PAN26 quality of life questionnaire. Min score 26, maximum score 104. Higher scores equals worse outcomes. | Every 9 weeks during the first 27 weeks and then every 12 weeks until death or maximum of 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
High tumour burden, molecular profiling, confirmed MMRD or MSI-H IHC