Pancreatic Ductal Adenocarcinoma (PDAC) MedDRA version: 21.0 Level: LLT Classification code 10033604 Term: Pancreatic cancer System Organ Class: 100000004864 MedDRA version: 21.1 Level: LLT Classification code 10051971 Term: Pancreatic adenocarcinoma System Organ Class: 100000004864 MedDRA version: 21.0 Level: LLT Classification code 10033599 Term: Pancreatic adenocarcinoma metastatic System Organ Class: 100000004864 MedDRA version: 21.1 Level: LLT Classification code 10033605 Term: Pancreat
Conditions
Interventions
Trade Name: Vidaza®
Pharmaceutical Form: Powder for suspension for injection
INN or Proposed INN: AZACITIDINE
CAS Number: 320-67-2
Concentration unit: mg milligram(s)
Concentration type: equal
Concent
Sponsors
GWT-TUD GmbH
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patients must have histologically confirmed PDAC 2. Patients must have metastatic disease (stage IV) and not received prior chemotherapy for stage IV disease (adjuvant/additive chemotherapy is allowed if completed at least 6 months prior to study inclusion) 3. Patients must not have received the following drugs before: Azacitidine, Romidepsin, any checkpoint-inhibitor or immunomodulating agents such as IMiDs (Lenalidomide) 4. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension in accordance with RECIST criteria v. 1.1 5. Male or female, age = 18 years 6. Body weight > 30 kg for inclusion into Part 2 (according to Durvalumab treatment) 7. ECOG performance status 0 or 1 8. Patients must have normal organ and marrow function as defined below • Leukocytes = 2,5*10^9/L • Absolute neutrophil count = 1,5*10^9/L • Platelets = 100*10^9/L • Haemoglobin = 9 g/dL • Total bilirubin = 1.5 x upper limit of normal (ULN) This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician • Asparate aminotransferase/alanine aminotransferase (AST/ALT) (SGOT/SGPT) = 2.5 x ULN and = 5 in the case of liver metastasis • Measured creatinine clearance (CL) >60 mL/min or Calculated creatinine CL>60 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance 9. Patients must be recovered from the effects of any prior surgery 10. 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 11. All subjects must agree to refrain from donating blood while on study drug and for 90 days after discontinuation from this study treatment 12. All subjects must have a life expectancy of at least 12 weeks 13. All subjects must agree not to share medication. 14. Females of childbearing potential (FCBP) must • Understand the potential teratogenic risk to the unborn child • Understand the need and agree to utilize two reliable forms of contraception simultaneously without interruption for at least 28 days before starting study drug, while participating in the study (including dose interruptions), and for at least 90 days after study treatment discontinuation • Understand and agree to inform the investigator if a change or stop of method of contraception is needed • Be capable of complying with effective contraceptive measures • Be informed and understand the potential consequences of pregnancy and the need to notify her study doctor immediately if there is a risk of pregnancy • Understand the need to commence the study treatment as soon as study drug is dispensed following a negative pregnancy test • Understand the need and accept to undergo pregnancy testing based on the frequency outlined in this protocol • Acknowledges that she understands the hazards Lenalidomide can cause to an unborn fetus and the necessary precautions associated with the use of Lenalidomide • Females must agree to abstain from breastfeeding during study participation and for at least 90 days after study drug discontinuation 15. Males must • Understand the potential teratogenic risk if engaged in sexual activity with a pregnant female
Exclusion criteria
Exclusion criteria: 1. Patients who have had radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events from agents administered more than 4 weeks earlier 2. Patients receiving any other investigational agents 3. Patients who have previously received Romidepsin, Azacitidine, Lenalidomide or Durvalumab or any PD1 or PD-L1 inhibitor or participate currently on an other clinical trial, unless it is an observational clinical study or during the follow-up period of an interventional study 4. Patients with untreated or uncontrolled brain metastases or leptomeningeal disease 5. Presence of other active illnesses 6. Any known cardiac abnormalities such as: • Congenital long QT syndrome • QTc interval = 470 milliseconds. Calculated from 3 ECGs using Fridericias Correction 7. Myocardial infarction within 6 months of C1D1 8. Other significant ECG abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia 9. Symptomatic coronary artery disease, e.g., angina Canadian Class II-IV 10. Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to IV definitions and/or known ejection fraction <40% by MUGA or <50% by echocardiogram and/or MRI 11. A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter defibrillator (AICD) 12. Concomitant use of any drug known to prolong QT interval 13. Concomitant use of strong CYP3A4 inhibitors 14. Lactating, pregnant or breast feeding 15. Patients with any other medical or psychological condition deemed by the investigator to be likely to interfere with a patient’s ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results 16. Diagnosis of immunodeficiency or any condition that requires systemic steroid therapy or other forms of immunosuppressive therapy 17. Prior thromboembolic events 18. History of other malignancies, except: • Malignancy treated with curative intent and with no known active disease present for = 5 years before the first dose of study drug and felt to be at low risk for recurrence by investigator. • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease • Adequately treated carcinoma in situ without current evidence of disease 19. Any uncontrolled active systemic infection 20. Major surgery within 4 weeks of first dose of study drug 21. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk. 22. History of stroke or intracranial hemorrhage within 6 months prior to enrollment 23. History of interstitial lung disease, idiopathic pulmonary fibrosis, or pulmonary hypersensitivity pneumonitis 24. Unable to swallow oral medication or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction 25. Concomitant use of warfarin or other Vitamin K antagonists 26. Known allergy or hypersensitivity to any study drug or any of the study drug excipients 27. Unwilling or unable to participate in all required study evaluations and procedures. Unable to understand the
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of the study, including the dose escalating part (Part 1a), the dose expansion part (Part 1b) as well as the consolidation part (Part 2), is to determine the safety and tolerability of Azacitidine and/or Romidepsin in combination with nab-Paclitaxel/Gemcitabine, followed by sequential immune targeting with PD-L1 blockade in combination with low-dose Lenalidomide in patients with advanced PDAC (Part 1 and 2). Moreover, in the dose escalating part of the study (Part 1a), the recommended dose for expansion and dose-limiting toxicity of Azacitidine and/or Romidepsin in combination with nab-Paclitaxel/Gemcitabine will be identified. ;Secondary Objective: - to assess overall response rate (ORR) , CA 19-9 response and disease control rate (=1st DCR after 3 cycles), progression free survival (PFS), overall survival (OS), duration of objective response (DOR) and best objective response rate (BORR) in patients treated at the recommended dose and regimen of Azacitidine and/or Romidepsin in combination with nab-Paclitaxel/Gemcitabine (Part 1a and Part 1b) - to show a promising clinical activity of the selected epigenetic and chemotherapeutic targeting approach from Part 1a with regard to the disease control rate (Part 1b) - to assess 2nd ORR, 2nd CA 19-9 response and 2nd DCR (after start of Part 2), PFS, OS, DOR and BORR in patients treated with Durvalumab and Lenalidomide as consolidation treatment (Part 2) - to assess overall survival (OS) in all patients treated at the recommended dose and regimen;Primary end point(s): The primary endpoint is the safety and tolerability of Azacitidineand/or Romidepsin in combination with nab-Paclitaxel/Gemcitabine, followed by sequential immune targeting with programmed death-ligand (PD-L)1 blockade in combination with low-dose Lenalidomide in patients with advanced PDAC (Part 1 and 2). Safety and tolerability will be determined by the following parameters: •Clinical laboratory (clinical chemistry, hem | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary endpoints (after completion of 3 treatment cycles) are defined as: Part 1: • Overall response rate (ORR) according to RECIST version 1.1 (stable disease [SD] and complete response [CR] and partial response [PR]) after respective treatment) • CA19-9 Response: CA19 -9 change after treatment compared to baseline level • Disease-control rate (DCR) at 3-month according to RECIST version 1.1 (CR and PR and stable disease [SD] after respective treatment) • Overall survival (OS) • Progression free survival (PFS) • Duration of objective response (DOR) and best objective response rate (BORR) Part 2: • Overall response rate (ORR) according to irRECIST1.1 (Wolchok, 2009) (CR and PR and SD) after/during treatment with Lenalidomide and Durvalumab • 2nd CA19-9 Response: CA19 -9 change after treatment compared to last level determined in Part 1 • 2nd DCR at 3-month and 6-month according to irRECIST1.1 (CR and PR and stable disease [SD] after respective treatment) • Overall survival (OS) • Progression free survival (PFS) • Duration of objective response (DOR) and best objective response rate (BORR);Timepoint(s) of evaluation of this end point: Part 1: after completion of 3 treatment cycles Part 2: at 3-month and 6-month after start of treatment with Lenalidomide and Durvalumab | — |
Countries
Germany
Contacts
Public ContactMedical Consulting
GWT-TUD GmbH
Outcome results
None listed