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JOURNAL ONKOLOGIE – STUDIE

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

Rekrutierend

NCT-Nummer:
NCT04257448

Studienbeginn:
Mai 2020

Letztes Update:
17.09.2020

Wirkstoff:
Romidepsin, azacitidine, Nab-Paclitaxel, Gemcitabine, Durvalumab, Lenalidomide capsule

Indikation (Clinical Trials):
Adenocarcinoma, Pancreatic Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
-

Sponsor:
GWT-TUD GmbH

Collaborator:
Celgene, AstraZeneca,

Studienleiter

Jens Siveke, Prof. Dr.
Principal Investigator
Institute for Developmental Cancer Therapeutics

Kontakt

Medical Consutling
Kontakt:
Phone: +49 351 25933
Phone (ext.): 100
E-Mail: medical.consulting@gwtonline.de
» Kontaktdaten anzeigen

Studienlocations (3 von 9)

Kinderonkologisches Zentrum Universitätsklinikum Essen
Hufelandstraße 55
45147 Essen
DeutschlandRekrutierend» Google-Maps
Universitätsklinikum Frankfurt
60590 Frankfurt
(Hessen)
GermanyRekrutierend» Google-Maps
Brustzentrum der Universitätsmedizin Göttingen
Robert-Koch-Straße 40
37075 Göttingen
DeutschlandNoch nicht rekrutierend» Google-Maps
Brustzentrum am Universitätsklinikum Hamburg-Eppendorf
Martinistraße 52
20251 Hamburg
DeutschlandRekrutierend» Google-Maps
Lungenkrebszentrum Uniklinik Köln / Solingen
Kerpener Straße 62
50937 Köln
DeutschlandRekrutierend» Google-Maps
Ludwig-Maximilians-Universität München
81377 München
(Bayern)
GermanyNoch nicht rekrutierend» Google-Maps
Interdisziplinäres Brustzentrum Klinikum Nürnberg
Prof.-Ernst-Nathan-Straße 1
90419 Nürnberg
(Bayern)
DeutschlandRekrutierend» Google-Maps
Leberkrebszentrum Universitätsklinikum Ulm
Albert-Einstein-Allee 23
89081 Ulm
DeutschlandRekrutierend» Google-Maps
Onkologisches Zentrum Universitätsklinikum Würzburg
Josef-Schneider-Straße 6
97080 Würzburg
DeutschlandRekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

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.

Ein-/Ausschlusskriterien

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

Studien-Rationale

Primary outcome:

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:

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.

Studien-Arme

  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.

Geprüfte Regime

  • Romidepsin (Istodax):
    Powder and solvent for solution for infusion; Intravenous use
  • Azacitidine (Vidaza):
    Powder for suspension for injection; Subcutaneous use
  • nab-Paclitaxel (Abraxane):
    Powder for suspension for injection; Intravenous use
  • Gemcitabine:
    Powder for solution for infusion; Intravenous use
  • Durvalumab (Imfinzi):
    Concentrate for solution for infusion; Intravenous use
  • Lenalidomide capsule (Revlimid):
    Hard capsule for oral use

Quelle: ClinicalTrials.gov


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