Chlorambucil in Metastatic PDAC Patients Bearing a Germ Line DNA Defects Repair Mutations (SALE Trial)

Inclusion Criteria: 1. Pathologically confirmed pancreatic adenocarcinoma 2. Age ≥ 18 years 3. ECOG PS 0-2 4. Stage IV disease 5. Identified genetic aberrations that are associated with homologous recombination deficiency (HRD) 1. Cohort A: Documented mutation in gBRCA1 or gBRCA2 that is predicted to be deleterious or suspected deleterious 2. Cohort B: BRCA1 or BRCA2 mutations that are considered to be of uncertain/unknown significance (VUS) 3. Cohort C: Patients with other identified genetic aberrations that are associated with HRD 6. Adequate PFS during previous platinum-based chemotherapy for at least 4 months before progression 7. Screening laboratory values: Leukocytes \> 3000/mmc Thrombocytes \> 150000/mmc Hemoglobin \> 10 g/dl Creatinine \<2.0 times upper normal limit (unless normal creatinine clearance). Total bilirubin \< 2.0 times upper normal limit (unless due to Gilbert's syndrome). Alanine aminotransferase (ALT) \< 3.0 times upper normal limit. 8. Able to take oral medication 9. Progression during or after platinum-based chemotherapy 10. Other prior chemotherapy apart from first-line treatment for pancreatic cancer, are allowed, including maintenance treatment with PARP inhibitors 11. More than 2 weeks since prior chemotherapy end 12. Signed written informed consent 13. QTc \<450 msec or QTc \<480 msec for patients with bundle branch block Exclusion Criteria: 1. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months prior to screening, congestive heart failure, and arrhythmia requiring therapy, with the exception of extra systoles or minor conduction abnormalities 2. Active and uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy 3. Vaccination with vaccines called "live", since this treatment causes a drop of immunity defenses and a serious infection could result fatal. 4. History of seizure, head trauma and treatment with anti-epileptogenic drugs 5. Hypersensitivity to chlorambucil or to any excipients, in particular lactose 6. Recent radiotherapy (at least 4 weeks) or previous treatment with other cytotoxic agents 7. BRCA-mutated advanced pancreatic cancer who did not undergo maintenance with olaparib after platinum-based chemotherapy 8. Mismatch repair (MMR)/high levels of microsatellite instability (MSI-H), or high levels of tumor mutational burden (TMB) pancreatic cancer who did not undergo immunotherapy with pembrolizumab monotherapy or any other anti-PD1 agent 9. Concomitant PARP inhibitors therapy 10. Life expectancy less than 3 months, in the opinion of the investigator 11. Other past or current malignancy. Subjects who have been free of malignancy for at least 5 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible 12. Symptomatic duodenal stenosis 13. CT contrast medium allergy and claustrophobia to RM investigation 14. Any significant medical condition laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study 15. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study 16. Any condition that confounds the ability to interpret data from the study 17. Any familiar, sociologic or geographic conditions that can potentially interfere with the adhesion to the protocol or to the follow-up 18. Pregnant or nursing. Adequate contraception is defined as oral hormonal birth control, intrauterine device, and male partner sterilization (if male partner is sole partner for that subject) and the double barrier method (condom or occlusive cap plus spermicidal agent). 19. Concurrent treatment with other experimental drugs