| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pancreatic Ductal Adenocarcinoma (PDAC) |
| duktales Pankreaskarzinom |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pancreatic cancer |
| Bauchspeicheldrüsenkrebs |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033604 |
| E.1.2 | Term | Pancreatic cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10051971 |
| E.1.2 | Term | Pancreatic adenocarcinoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033599 |
| E.1.2 | Term | Pancreatic adenocarcinoma metastatic |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033605 |
| E.1.2 | Term | Pancreatic cancer metastatic |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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.
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| E.2.2 | Secondary objectives of the trial |
- 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 |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
- Exploratory analyses on tumor biopsy samples may include but will not be limited to: Genetic, epigenetic and expression profiling of tumor cells and immune phenotyping before and after therapy initiation including next generation sequencing (NGS)-based DNA/RNA-seq, genome-wide methylation profiling, immune cells infiltrate characterization (e.g. CD8, CD4, Treg, Macrophages and DC), immune phenotyping (e.g. interferon-stimulating genes such as IFI16, IFI27, IFI44, IFI44L, MX1 and OASL; induction of endogenous retroviral sequences (=ERVs) such as Syncytin-1-3, ERV-3, env-K, env-H and env-Fc1-2) by epigenetic treatment.
- An exploratory objective of this study is to evaluate biomarkers in liquid biopsies, including but not limited to tracking oncogenic mutations such as KRAS in cell free DNA (ctDNA analysis), cytokines, chemokines, circulating receptors or ligands, other immune-related biomarkers (e.g. interleukin 2, interferon-γ) and immuno-phenotyping (e.g. CD8, CD4, Treg, Macrophages).
- Fecal samples will be evaluated to identify biomarkers in the gut microbiome that are predictive of response to study drug, can aid in understanding the mechanisms of action of the treatment combinations, or can suggest novel therapeutic combinations.
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| E.3 | Principal 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 or a FCBP
• Agree to use a latex condom during any sexual contact with FCBP or a pregnant female while participating in the study and for 90 days following discontinuation from this study, even if he has undergone a successful vasectomy. For treatment with Gemcitabine and nab-Paclitaxel men must avoid fathering a child/ use a condom up to 6 months after their last dose. Depending on duration of Lenalidomide/Durvalumab treatment this period can be longer than 90 days after study discontinuation
• Agree to refrain from donating semen or sperm while on the study drugs and for 90 days after discontinuation from this study treatment. For treatment with nab-Paclitaxel and Gemcitabine male subjects must agree not to father a child or donate semen for at least 6 month afterlast intake of medication
• Agree not to father a child during the course of the trial and for at least 90 days after last administration of study drugs. For Gemcitabine and nab-Paclitaxel treatment up to 6 month after last drug intake.
16. Females of non-childbearing potential:
• Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrhea for at least 24 consecutive months without an alternative medical cause |
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| E.4 | Principal 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 purpose and risks of the study and to provide a signed and dated informed consent form and authorization to use protected health information
28. Current or prior use of immunosuppressive medication within 14 days (use 28 days if combining Durvalumab with a novel agent) before the first dose of Durvalumab
29. Active or prior documented autoimmune or inflammatory disorders
30. Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria .
• Patients with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with Durvalumab may be included only after consultation with the Study Physician.
31. History of allogenic organ transplantation
32. Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus
33. Receipt of live attenuated vaccine within 30 days prior to the first dose of IMP
34. Subject is an employee of GWT-TUD GmbH |
|
| E.5 End points |
| E.5.1 | 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, hematology, urinalysis)
• Performance status according to Eastern Cooperation Oncology Group (ECOG)
• Recording of AEs and concomitant medication
• Physical examination
• ECG
• ECHO (Echocardiography) or MUGA (Multiple-Gated-Acquisition-(MUGA)-Radionuclide-Imaging)
• Vital signs (pulse, blood pressure, body temparature)
Moreover, in the dose escalating part of the study (Part 1a/Phase I), the recommended dose for expansion (RDE) and dose limiting toxicity (DLT) of Azacitidine and/or Romidepsin in combination with nab-Paclitaxel/Gemcitabine will be identified after completion of 3 treatment cycles.
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
after completion of 3 treatment cycles
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| E.5.2 | 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) |
|
| E.5.2.1 | 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
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|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| combined epigenetic and chemotherapeutic targeting |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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