PASSION (olaParib mAintenance in chemotherapy-Sensitive metaStatic pancreatIc adenOcarciNoma - mPDAC): a phase II, proof of principle, study

Prior treatment

• History of another primary malignancy except for malignancy treated with curative intent with no known active disease for ≥ 5 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the skin that has undergone potentially curative therapy, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), and Stage 1, grade 1 endometrial carcinoma. Patients with a history of localised triple negative breast cancer may be eligible, provided they completed their adjuvant chemotherapy more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease.
• Exposure to an investigational product within 30 days or five half-lives (whichever is the longer) prior to enrolment.
• Any previous treatment with PARP inhibitor, including Olaparib.
• Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment.
• Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) within 2 weeks prior to first dose of study intervention. The required washout period prior to starting Olaparib is 2 weeks.
• Concomitant use of known strong ( eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort ) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
• Major surgery (excluding local surgery of isolated lesions for palliative treatment or diagnostic staging) within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery or an anticipated need for major surgery during the study.
• Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
• Participation in another clinical study with an investigational product administered in the last 6 months.
• Previous enrolment in the present study.
• Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days.

Other illness

• Gemcitabine monotherapy as I-line treatment for metastatic disease.
• Patients with a known hypersensitivity to olaparib or any of the excipients of the product.
• Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade 2) caused by previous cancer therapy, excluding alopecia.
• Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of MDS/AML.
• Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
• Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
• Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
• Patients with known active hepatitis (i.e. Hepatitis B or C): Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

Lab values

• Whole blood transfusions within 120 days prior to gBRCA testing sample collection (packed red blood cells and platelet transfusions are acceptable).
• Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.

Other

• Significant traumatic injury within 4 weeks of the first dose of study intervention.
• Involvement in the planning and/or conduct of the study.
• Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
• Breast feeding women.

• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
• Patients must have controlled disease after at least 16 weeks of standard first-line polychemotherapy (FOLFIRINOX, NALIRIFOX, PAXG, AG) for metastatic PDAC; previous neoadjuvant/adjuvant treatment +/- complementary RT before or after curative resection are admitted, provided that relapse has occurred >6 months after completion of the curative treatment.
• Disease progression per RECIST1.1 criteria must be excluded by at least two consecutive imaging assessments performed at least 4 weeks apart from each other, the most recent of which can be used as screening for this protocol, provided that it has been performed at least 16 weeks after first-line chemotherapy first administration.
• For patients with elevated serum CA19.9 at the beginning of first-line chemotherapy, absence of a >25% increase over nadir levels in two consistent (same laboratory, same detection methods, same normal ranges) measurements performed at least two weeks apart from each other must be documented for inclusion.
• Genetic evidence of BRCA/HR-related mutations: patients with documented pathogenic or likely pathogenic (class 4-5, according to ACMG/AMP guidelines) germline/somatic mutations in BRCA1/2 or other HR-related genes will be enrolled within cohort A (see attached study scheme); patients in whom pathogenic or likely pathogenic alterations are not documented or cannot be assessed will be considered for enrollment within cohort B (Figure 1).
• Female participants must be 1 year post-menopausal (no menstrual bleeding for at least 1 year prior to study enrolment and corresponding follicle-stimulating hormone and estradiol levels), surgically sterile, or using one highly effective form of birth control (a highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly; see APPENDIX C for a comprehensive list of acceptable birth control methods). Women of childbearing potential must agree to use one highly effective method of birth control. They should continue using their chosen method of birth control for a minimum of 6 months after the last dose. Additionally, non‑sterilised male partners of a woman of childbearing potential must use a male condom plus spermicide.
• Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below: Haemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days; Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L; Platelet count ≥ 100 x 10^9/L; Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN); Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be ≤ 5x ULN; Patients must have creatinine clearance estimated of ≥51 mL/min using the Cockcroft-Gault equation [estimated creatinine clearance = (140-age in years) x weight in kg x F/serum creatinine (mg/dL) x 72, where F=0.85 for females and F=1 for males] or based on a 24-hour urine test or another validated test as per local practice. Patients who do not meet eligibility criteria at screening, due to incomplete recovery from chemotherapy-related AEs or reversible concomitant conditions that do not qualify as exclusion criteria, can be rescreened, provided that olaparib treatment is started no more than 8 weeks after the last chemotherapy dose. At the time of starting protocol treatment, all previous chemotherapy treatment should be discontinued.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Table 7).
• Patients must have a life expectancy ≥ 16 weeks.
• Patients with measurable disease and/or non-measurable or no evidence of disease assessed at baseline by CT (or MRI where CT is contraindicated) will be entered in this study. RECIST 1.1 has been modified to allow the assessment of progression due to new lesions in patients with no evidence of disease at baseline.
• Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses.
• For inclusion in the biomarker research, patients must fulfil the following criteria: Provision of informed consent for biomarker research prior to collection of samples. Informed consent for biomarkers research will be administered at pre-screening and will allow for the analysis of the genetic/molecular data even in the event that the patient is not eligible for the treatment part of the protocol.
• Subjects aged at least 18 years at the time of signing the ICF are eligible for the study; there is no upper age limit, provided that all other eligibility criteria are fulfilled.
• Patients with histologically or cytologically confirmed metastatic PDAC are eligible for this study.