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Determination Safety and Tolerability of Epigenetic and Immunomodulating Drugs in Combination With Chemotherapeutics in Patients Suffering From Advanced Pancreatic Cancer. (SEPION)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04257448
Recruitment Status : Recruiting
First Posted : February 6, 2020
Last Update Posted : September 17, 2020
Sponsor:
Collaborators:
Celgene
AstraZeneca
Information provided by (Responsible Party):
GWT-TUD GmbH

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Pancreas Cancer Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Drug: Romidepsin Drug: Azacitidine Drug: nab-Paclitaxel Drug: Gemcitabine Drug: Durvalumab Drug: Lenalidomide capsule Phase 1 Phase 2

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 75 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter, Phase I/II Study of Sequential Epigenetic and Immune Targeting in Combination With Nab-Paclitaxel/Gemcitabine in Patients With Advanced Pancreatic Ductal Adenocarcinoma.
Actual Study Start Date : May 25, 2020
Estimated Primary Completion Date : March 2024
Estimated Study Completion Date : June 2026

Resource links provided by the National Library of Medicine


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 intolerable toxicity or will escalate until the recommended dose for expansion for a maximum of 3 cycles.
Drug: Romidepsin
Powder and solvent for solution for infusion; Intravenous use
Other Name: Istodax

Drug: nab-Paclitaxel
Powder for suspension for injection; Intravenous use
Other Name: Abraxane

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 treatment cycle. Study treatment is given until intolerable toxicity or will escalate until the recommended dose for expansion for a maximum of 3 cycles.
Drug: Azacitidine
Powder for suspension for injection; Subcutaneous use
Other Name: Vidaza

Drug: nab-Paclitaxel
Powder for suspension for injection; Intravenous use
Other Name: Abraxane

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 treatment is given until intolerable toxicity or will escalate until the recommended dose for expansion for a maximum of 3 cycles.
Drug: Romidepsin
Powder and solvent for solution for infusion; Intravenous use
Other Name: Istodax

Drug: Azacitidine
Powder for suspension for injection; Subcutaneous use
Other Name: Vidaza

Drug: nab-Paclitaxel
Powder for suspension for injection; Intravenous use
Other Name: Abraxane

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
Other Name: Abraxane

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
Other Name: Istodax

Drug: Azacitidine
Powder for suspension for injection; Subcutaneous use
Other Name: Vidaza

Drug: nab-Paclitaxel
Powder for suspension for injection; Intravenous use
Other Name: Abraxane

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 Days 1 to 21 until documented disease progression. Study treatment is given for a maximum of 13 cycles.
Drug: Durvalumab
Concentrate for solution for infusion; Intravenous use
Other Name: Imfinzi

Drug: Lenalidomide capsule
Hard capsule for oral use
Other Name: Revlimid




Primary Outcome Measures :
  1. Safety and tolerability of Azacitidine and/or Romidepsin in combination with nab-Paclitaxel/Gemcitabine [ Time Frame: at Days -7, -4, 1, 8, 15, 22 at cycle 1 (each cycle is 28 days) ]
    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.

  2. Immune targeting with Durvalumab in combination with low-dose Lenalidomide [ Time Frame: up to 13 cycles (each cycle is 28 days) ]
    The efficacy and safety of this experimental (immune) consolidation therapy during this clinical trial will be monitored by imaging changes every 8 weeks.

  3. Immune targeting with Durvalumab in combination with low-dose Lenalidomide [ Time Frame: up to 13 cycles (each cycle is 28 days) ]
    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.

  4. Recommended dose for expansion (RDE) [ Time Frame: at the end of cycle 3 (each cycle is 28 days) ]
    Identification of the recommended dose for expansion of Azacitidine and/or Romidepsin in combination with nab-Paclitaxel/Gemcitabine.


Secondary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: up to 16 months ]
    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

  2. Carbohydrate Antigen 19-9 (CA19-9) Response [ Time Frame: at Day 1 of each treatment cycle (each cycle is 28 days), up to 16 month ]
    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

  3. Disease-control rate (DCR) [ Time Frame: at the end of cycle 3 and 6 (each cycle is 28 days) ]
    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)

  4. Overall survival (OS) [ Time Frame: at Day 1 of cycle 1 (each cycle is 28 days) until death or up to 4 years ]
    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.

  5. Progression free survival (PFS) [ Time Frame: D1 of the first cycle (each cycle is 28 days), up to 16 month ]
    Time from Day 1 of the first cycle of chemotherapy to date of objective disease progression or to death of any cause.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 of 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 of 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04257448


Contacts
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Contact: Medical Consutling +49 351 25933 ext 100 medical.consulting@gwtonline.de
Contact: Carsta Köhler, Dr. carsta.koehler@gwtonline.de

Locations
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Germany
Universitätsklinikum Essen Recruiting
Essen, Germany, 45147
Universitätsklinikum Frankfurt Recruiting
Frankfurt, Germany, 60590
Universitätsmedizin Göttingen Not yet recruiting
Göttingen, Germany, 37075
Universitätsklinikum Hamburg-Eppendorf Recruiting
Hamburg, Germany, 20251
Uniklinik Köln Recruiting
Köln, Germany, 50937
Ludwig-Maximilians-Universität München Not yet recruiting
München, Germany, 81377
Klinikum Nürnberg Recruiting
Nürnberg, Germany, 90419
Universitätsklinikum Ulm Recruiting
Ulm, Germany, 89081
Universitätsklinikum Würzburg Recruiting
Würzburg, Germany, 97080
Sponsors and Collaborators
GWT-TUD GmbH
Celgene
AstraZeneca
Investigators
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Principal Investigator: Jens Siveke, Prof. Dr. Institute for Developmental Cancer Therapeutics
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Responsible Party: GWT-TUD GmbH
ClinicalTrials.gov Identifier: NCT04257448    
Other Study ID Numbers: SEPION
AX-CL-PANC-PI-008619 ( Other Identifier: Financier )
First Posted: February 6, 2020    Key Record Dates
Last Update Posted: September 17, 2020
Last Verified: September 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Adenocarcinoma
Pancreatic Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Gemcitabine
Paclitaxel
Lenalidomide
Azacitidine
Durvalumab
Romidepsin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents