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.
Inclusion Criteria:
- 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
Exclusion Criteria:
- 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
