| Eligibility |
Inclusion Criteria:
1. Signed and dated informed consent,
2. Age =18 years
3. Body weight >30 kg,
4. Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up,
5. Life expectancy of at least 4 months,
6. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1,
7. Pathologically confirmed pancreatic adenocarcinoma with distant metastases (stage IV
disease),
8. No prior therapy for metastatic disease other than mFOLFIRINOX (in case of previous
adjuvant therapy, the interval between the end of adjuvant chemotherapy and relapse
must be >6 months),
9. Stability or tumor response (Response evaluation criteria in solid tumors [RECIST]
1.1) after 4 months of mFOLFIRINOX (8 cycles) for metastatic disease,
10. Have tissue from archival tissue sample from surgery or biopsy identified and
confirmed as available for study
11. Availability of tumor somatic genetic analyses data, performed during the first 4
months of mFOLFIRINOX (specific informed consent),
12. In case of germinal BRCA gene mutation identified before inclusion the patient can be
included until olaparib receives a marketing authorization for the treatment
indication of the patients in the study and the treatment is available in the retail
pharmacy; it will be prescribed according to the summary product characteristics
(SmPC),
13. At least one measurable or evaluable lesion as assessed by CT-scan or MRI according to
RECIST 1.1 and feasibility of repeated radiological assessments,
14. Normal organ and bone marrow function prior to administration of study treatment as
defined below:
- Hemoglobin = 10.0 g/dL with no blood transfusion in the past 28 days,
- Absolute neutrophil count (ANC) = 1.5 x 109/L,
- Platelet count = 100 x 109/L,
- Total bilirubin = 1.5 x institutional upper limit of normal (ULN),
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) = 2.5 x
institutional ULN unless liver metastases are present in which case
= 5x ULN,
- Creatinine clearance (CrCl) = 50 mL/min estimated using the Cockcroft-Gault
equation, Estimated CrCl =(140-age [years]) x weight (kg) (x F)a serum creatinine
(mg/dL) x 72 a F=0.85 for females and F=1 for males.
15. Absence of known dihydropyrimidine dehydrogenase (DPD) deficiency,
16. Female patients must be surgically sterile, or be post-menopausal, or have negative
serum pregnancy test if pre-menopausal at inclusion and must commit to using reliable
and appropriate methods of contraception during the study and during at least 6 months
after the end of studytreatment (when applicable).
Women will be considered post-menopausal if they have been amenorrhoeic for 12 months
without an alternative medical cause. The following age-specific requirements apply:
- Women < 50 years of age would be considered post-menopausal if they have been
amenorrhoeic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone (LH) and follicle-stimulating
hormone (FSH) levels in the postmenopausal range for the institution or underwent
surgical sterilization (bilateral oophorectomy or hysterectomy).
- Women = 50 years of age would be considered post-menopausal if they have been
amenorrhoeic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses > 1 year ago, had
chemotherapy-induced menopause with last menses > 1 year ago, or underwent
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
hysterectomy). All female patients with reproductive potential must have a
negative pregnancy test (beta human chorionic gonadotropin [ß-HCG]) within 72
hours prior to starting the protocol treatment. Breastfeeding is not allowed.
Male patients must agree to use effective contraception in addition to having
their partner use a contraceptive method as well during the trial and during at
least 6 months after the end of the study treatment. Men and women with childhood
potential are required to use adequate birth control during the study,
17. Registration in a national health care system (PUMa; Couverture Maladie Universelle
included).
Exclusion Criteria:
1. Histology other than PDAC
2. Toxicities after mFOLFIRINOX treatment not resolved to = grade 1 prior to maintenance
treatment, except for oxaliplatin induced neuropathy, alopecia, or grade = 2 are
permitted
3. Patients with known brain metastases at inclusion,
4. Enrollment in another therapeutic trial
5. Evidence of interstitial lung disease, any active non-infectious pneumonitis, or known
active infection including active tuberculosis
6. Hepatitis B virus (HBV; known positive HBV surface antigen (HbsAg) result), hepatitis
C virus (HCV), or human immunodeficiency virus (positive HIV ½ antibodies).
7. Active uncontrolled infection, current unstable, or uncompensated respiratory or
cardiac conditions, or active digestive hemorrhages less than 3 months,
8. Patient has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the study,
9. Live vaccine administration within 30 days prior to the first dose of study treatment,
10. Treatment with any other investigational medicinal product within 28 days prior to
study entry,
11. Other malignancy unless curatively treated with no evidence of disease for = 5 years
except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer
of the cervix, ductal carcinoma in situ (DCIS), and stage 1, grade 1 endometrial
carcinoma,
12. Uncontrolled intercurrent illness, including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, acute
coronary syndrome within 6 months prior to starting treatment, prior or current
cardiomyopathy, unstable angina pectoris, cardiac arrhythmia, interstitial lung
disease, serious chronic gastrointestinal conditions associated with diarrhea, or
psychiatric illness/social situations that would limit compliance with study
requirement, substantially increase risk of incurring AEs or compromise the ability of
the patient to give written informed consent,
13. Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible
cardiac conditions, as judged by the Investigator or patients with congenital long QT
syndrome. Mean corrected QT interval (QTc) for heart rate using the QTcF formula =
must be <470 ms,
14. Pregnancy/lactation,
15. Uncontrolled massive pleural effusion or massive ascites,
16. Tutelage or guardianship.
Arm A: Specific exclusion criteria for patients with the BRCAness profile in order to
receive olaparib
1. Myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of
myelodysplastic syndrome (MDS)/ DS)/acute myeloid leukemia (AML),
2. Unable to swallow orally administered medication and gastrointestinal disorders likely
to interfere with absorption of the study medication,
3. Any previous treatment with PARP inhibitor, including olaparib,
4. Concomitant use of known strong cytochrome P450, family 3, subfamily A (CYP3A)
inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors
boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir,
telaprevir) or moderate CYP3A inhibitors. The required washout period prior to
starting olaparib is 2 weeks,
5. Concomitant use of known strong or moderate CYP3A inducers.
6. Major surgery within 2 weeks of starting study treatment and patients must have
recovered from any effects of any major surgery.
7. Previous allogenic bone marrow transplant or double umbilical cord blood
transplantation (dUCBT),
8. Whole blood transfusions in the last 120 days prior to entry to the study (packed red
blood cells and platelet transfusions are acceptable outside of 28 days prior to study
treatment,
9. Known hypersensitivity to the excipients of the olaparib
Arm B/C: Specific criteria for patients without the BRCAness profile and with KRAS mutation
in order to receive durvalumab:
1. Prior treatment with any of the following immune checkpoint inhibitor:
anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-cytotoxic T lymphocyte antigen 4 (CTLA-4)
antibody,
2. Active autoimmune disease that has required systemic treatment in the past 2 years;
replacement therapy is considered a form of systemic treatment and is not a criterion
of exclusion,
3. Any systemic steroid therapy whatever the duration of this corticotherapy,
4. Active or prior documented autoimmune or inflammatory disorders
Arm B/C: Specific exclusion criteria for patients without BRCAness profile and with
KRAS-mutated tumors in order to receive selumetinib:
1. Cardiac conditions
2. Documented antecedent history of retinopathy or retinal disorders as known
ophthalmologic conditions
3. Patients with any other significant abnormality on ophthalmic examination (performed
by an ophthalmologist) should be discussed for potential ineligibility
4. The last palliative radiotherapy seance within 7 days of the first dose of study
treatment
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