Safety And Tolerance Of Epigenetic And Immunomodulating Drugs Combined With Chemotherapeutics In Patients Suffering From Advanced Pancreatic Cancer

Study Overview

Safety and Tolerance of Epigenetic and Immunomodulating Drugs Combined With Chemotherapeutics in Patients Suffering From Advanced Pancreatic Cancer

A multi-center, open-label phase I/II study to to determine the safety and tolerability of Azacitidine and/or Romidepsin in combination with nab-Paclitaxel/Gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDAC) (Part 1), followed by sequential immune targeting with programmed death-ligand (PD-L)1 blockade in combination with low-dose Lenalidomide (Part 2) in patients with controlled disease after 3 cycles (Part 1).

The first part of the study will employ a standard 3 + 3 design to test safety and tolerability of histone deacetylase (HDAC) inhibition with Romidepsin (Arm A), DNA methyltransferase (DNMT) inhibition with Azacitidine (Arm B) or both agents (Arm C), in each arm in combination with nab-Paclitaxel/Gemcitabine (Part 1a). Study treatment is given until intolerable toxicity as defined in the protocol. Treatment will escalate until the recommended dose for RDE is identified. For the expansion part (Part 1b) of the study, one of the treatment arms (Arm C over B over A) will be continued using a Simon Two-stage design to a maximum of 35 patients. All patients from Part 1a and 1b will be treated for a total of three cycles and will then enter the second part of the study in case of disease control with still measurable disease (PR, SD). In the second part (Part 2) of the study (consolidation therapy), all patients from Part 1 (dose escalation and expansion cohorts from experimental arms and standard arm) who have not progressed after three cycles of nab-Paclitaxel/Gemcitabine with or without additional epigenetic treatment (= at least SD by RECIST 1.1 after 3 cycles) receive sequential immune targeting with PD-L1 blockade (standard fixed dose Durvalumab 1500 mg q4w iv) in combination with low-dose Lenalidomide (10 mg d1-21 q4w po) until documented disease progression.

Pancreas Cancer
Pancreatic Adenocarcinoma
Pancreatic Ductal Adenocarcinoma

DRUG: Romidepsin
DRUG: Azacitidine
DRUG: nab-Paclitaxel
DRUG: Gemcitabine
DRUG: Durvalumab
DRUG: Lenalidomide capsule

SEPION
AX-CL-PANC-PI-008619 (OTHER Identifier) (OTHER: Financier)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2020-01-29	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2023-04-28
First Submitted that Met QC Criteria 2020-02-03	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2023-05-01
First Posted (ACTUAL) 2020-02-06	Results First Posted N/A	Last Verified 2023-04

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Non Randomized

Interventional Model:
Sequential

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Romidepsin/nab-Paclitaxel/Gemcitabine (Arm A) Part 1a: Romidepsin (2 mg/m² or 3.3 mg/m² or 7 mg/m²) will be administered in combination with nab-Paclitaxel (125 mg/m²)/Gemcitabine (1000 mg/m²) on Day 1, Day 8 and Day 15 (every 28 days) of each treatment cycle. Study treatment is given until intolerab	DRUG: Romidepsin Powder and solvent for solution for infusion; Intravenous use DRUG: nab-Paclitaxel Powder for suspension for injection; Intravenous use DRUG: Gemcitabine Powder for solution for infusion; Intravenous use
EXPERIMENTAL: Azacitidine/nab-Paclitaxel/Gemcitabine (Arm B) Part 1a: Azacitidine (20 mg/m² or 30 mg/m² or 40 mg/m²) will be administered on Days -7 to Day -3 of each treatment cycle. Additionally nab-Paclitaxel (125 mg/m²)/Gemcitabine (1000 mg/m²) will be given on Day 1, Day 8 and Day 15 (every 28 days) of each tr	DRUG: Azacitidine Powder for suspension for injection; Subcutaneous use DRUG: nab-Paclitaxel Powder for suspension for injection; Intravenous use DRUG: Gemcitabine Powder for solution for infusion; Intravenous use
EXPERIMENTAL: Romidepin/Azacitidine/nab-Paclitaxel/Gemcitabine (Arm C) Part 1a: The intervention to be administered depends on the determined dose in Arm A and Arm B. Additionally nab-Paclitaxel (125 mg/m²)/Gemcitabine (1000 mg/m²) will be given on Day 1, Day 8 and Day 15 (every 28 days) of each treatment cycle. Study treatm	DRUG: Romidepsin Powder and solvent for solution for infusion; Intravenous use DRUG: Azacitidine Powder for suspension for injection; Subcutaneous use DRUG: nab-Paclitaxel Powder for suspension for injection; Intravenous use DRUG: Gemcitabine Powder for solution for infusion; Intravenous use
ACTIVE_COMPARATOR: nab-Paclitaxel/Gemcitabine (Standard Arm) nab-Paclitaxel (125 mg/m²)/Gemcitabine (1000 mg/m²) will be administered on Day 1, Day 8 and Day 15 (every 28 days) of each treatment cycle.	DRUG: nab-Paclitaxel Powder for suspension for injection; Intravenous use DRUG: Gemcitabine Powder for solution for infusion; Intravenous use
EXPERIMENTAL: Arm C or B or A In Part 1b (expansion part) of the study, one of the treatment arms (Arm C over Arm B over Arm A) will be continued. Treatment will only be performed with the study drug that were tolerable in Part 1a (dose escalation).	DRUG: Romidepsin Powder and solvent for solution for infusion; Intravenous use DRUG: Azacitidine Powder for suspension for injection; Subcutaneous use DRUG: nab-Paclitaxel Powder for suspension for injection; Intravenous use DRUG: Gemcitabine Powder for solution for infusion; Intravenous use
EXPERIMENTAL: Durvalumab/Lenalidomide Part 2: All patients from Part 1 who have not progressed after three cycles receive standard fixed dose Durvalumab (1500 mg) on Day 1 of each 28-day treatment cycle by IV infusion in combination with orally administered low-dose Lenalidomide (10 mg) on Da	DRUG: Durvalumab Concentrate for solution for infusion; Intravenous use DRUG: Lenalidomide capsule Hard capsule for oral use

Primary Outcome Measures	Measure Description	Time Frame
Safety and tolerability of Azacitidine and/or Romidepsin in combination with nab-Paclitaxel/Gemcitabine	Dose limiting toxicities occurring during treatment cycle 1 of a respective dose level and regarded to be related to the studied drug combination. Common terminology criteria for adverse events (CTCAE) 5.0 will be used to assess toxicities.	at Days -7, -4, 1, 8, 15, 22 at cycle 1 (each cycle is 28 days)
Immune targeting with Durvalumab in combination with low-dose Lenalidomide	The efficacy and safety of this experimental (immune) consolidation therapy during this clinical trial will be monitored by imaging changes every 8 weeks.	up to 13 cycles (each cycle is 28 days)
Immune targeting with Durvalumab in combination with low-dose Lenalidomide	The efficacy and safety of this experimental (immune) consolidation therapy during this clinical trial will be monitored closely by tumor marker changes on Day 1 of each cycle.	up to 13 cycles (each cycle is 28 days)
Recommended dose for expansion (RDE)	Identification of the recommended dose for expansion of Azacitidine and/or Romidepsin in combination with nab-Paclitaxel/Gemcitabine.	at the end of cycle 3 (each cycle is 28 days)

Secondary Outcome Measures	Measure Description	Time Frame
Overall response rate (ORR)	Part 1: ORR according to RECIST version 1.1 (complete response [CR] and partial response [PR]) after respective treatment) every 6 weeks Part 2: ORR according to immune related RECIST 1.1 (irRECIST1.1) (CR and PR) after/during treatment with Lenalidomide and Durvalumab every 8 weeks	up to 16 months
Carbohydrate Antigen 19-9 (CA19-9) Response	Part 1: CA19-9 Response: CA19 -9 change after treatment compared to baseline level Part 2: 2nd CA19-9 Response: CA19 -9 change after treatment compared to last level determined in Part 1	at Day 1 of each treatment cycle (each cycle is 28 days), up to 16 month
Disease-control rate (DCR)	Part 1: DCR at 3-month according to RECIST version 1.1 (CR and PR and stable disease [SD] after respective treatment Part 2: 2nd DCR at 3-month and 6-month according to irRECIST1.1 (CR and PR and stable disease [SD] after respective treatment)	at the end of cycle 3 and 6 (each cycle is 28 days)
Overall survival (OS)	Time from Day 1 of the first cycle of chemotherapy to date of death from any cause. The rate of patients who are still alive after one year will be assessed.	at Day 1 of cycle 1 (each cycle is 28 days) until death or up to 4 years
Progression free survival (PFS)	Time from Day 1 of the first cycle of chemotherapy to date of objective disease progression or to death of any cause.	D1 of the first cycle (each cycle is 28 days), up to 16 month

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

Patients must have histologically confirmed PDAC
Patients must have metastatic disease (stage IV) and not received prior chemotherapy for stage IV disease
Patients must not have received the following drugs before: Azacitidine, Romidepsin, any checkpoint-inhibitor or immunomodulating agents such as Immunomodulatory imide drugs (IMiDs)
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
Male or female, age ≥ 18 years
Body weight > 30 kg for inclusion into Part 2
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Patients must have normal organ and marrow function
Patients must be recovered from the effects of any prior surgery
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
All subjects must agree to refrain from donating blood while on study drug and for 90 days after discontinuation from this study treatment
All subjects must have a life expectancy of at least 12 weeks
Females of childbearing potential (FCBP) must 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, and for at least 90 days after study treatment discontinuation
Males must agree to use a latex condom during any sexual contact with FCBP or a pregnant female, refrain from donating semen or sperm and not to father a child

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
Patients receiving any other investigational agents.
Patients who have previously received Romidepsin, Azacitidine, Lenalidomide or Durvalumab or any programmed cell death-1 (PD1) or programmed cell death ligand 1 (PD-L1) inhibitor or participate currently on another clinical trial
Patients with untreated or uncontrolled brain metastases or leptomeningeal disease
Presence of other active illnesses
Any known cardiac abnormalities such as: congenital long QT syndrome; corrected QT interval (QTc interval) ≥ 470 milliseconds. Calculated from 3 ECGs using Fridericia's Correction
Myocardial infarction within 6 months prior to cycle 1, day 1 (C1D1).
Other significant ECG abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min)
Symptomatic coronary artery disease (CAD)
Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to IV definitions and/or known ejection fraction <40% by multiple gated acquisition scan (MUGA) or <50% by echocardiogram and/or MRI
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)
Concomitant use of any drug known to prolong QT interval
Concomitant use of strong CYP3A4 inhibitors
Lactating, pregnant or breast feeding
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
Diagnosis of immunodeficiency or any condition that requires systemic steroid therapy or other forms of immunosuppressive therapy
Prior thromboembolic events
History of other malignancies
Any uncontrolled active systemic infection
Major surgery within 4 weeks prior to first dose of study drug
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.
History of stroke or intracranial hemorrhage within 6 months prior to enrollment
History of interstitial lung disease, idiopathic pulmonary fibrosis, or pulmonary hypersensitivity pneumonitis
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
Concomitant use of warfarin or other Vitamin K antagonists
Known allergy or hypersensitivity to any study drug or any of the study drug excipients
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 (ICF) and authorization to use protected health information.
Current or prior use of immunosuppressive medication within 14 days before the first dose of Durvalumab.
Active or prior documented autoimmune or inflammatory disorders
Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy
History of allogenic organ transplantation
Active infection including tuberculosis
Receipt of live attenuated vaccine within 30 days prior to the first dose of Investigational medicinal product (IMP)
Subject is an employee of the sponsor

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Celgene
AstraZeneca

Investigators

PRINCIPAL_INVESTIGATOR: Jens Siveke, Prof. Dr., Institute for Developmental Cancer Therapeutics

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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