Clinical Trials /

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

NCT04257448

Description:

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).

Related Conditions:
  • Pancreatic Ductal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Determination Safety and Tolerability of Epigenetic and Immunomodulating Drugs in Combination With Chemotherapeutics in Patients Suffering From Advanced Pancreatic Cancer.
  • 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.

Clinical Trial IDs

  • ORG STUDY ID: SEPION
  • SECONDARY ID: AX-CL-PANC-PI-008619
  • NCT ID: NCT04257448

Conditions

  • Pancreas Cancer
  • Pancreatic Adenocarcinoma
  • Pancreatic Ductal Adenocarcinoma

Interventions

DrugSynonymsArms
RomidepsinIstodaxArm C or B or A
AzacitidineVidazaArm C or B or A
nab-PaclitaxelAbraxaneArm C or B or A
GemcitabineArm C or B or A
DurvalumabImfinziDurvalumab/Lenalidomide
Lenalidomide capsuleRevlimidDurvalumab/Lenalidomide

Purpose

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).

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.
    

Trial Arms

NameTypeDescriptionInterventions
Romidepsin/nab-Paclitaxel/Gemcitabine (Arm A)ExperimentalPart 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.
  • Romidepsin
  • nab-Paclitaxel
  • Gemcitabine
Azacitidine/nab-Paclitaxel/Gemcitabine (Arm B)ExperimentalPart 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.
  • Azacitidine
  • nab-Paclitaxel
  • Gemcitabine
Romidepin/Azacitidine/nab-Paclitaxel/Gemcitabine (Arm C)ExperimentalPart 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.
  • Romidepsin
  • Azacitidine
  • nab-Paclitaxel
  • Gemcitabine
nab-Paclitaxel/Gemcitabine (Standard Arm)Active Comparatornab-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.
  • nab-Paclitaxel
  • Gemcitabine
Arm C or B or AExperimentalIn 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).
  • Romidepsin
  • Azacitidine
  • nab-Paclitaxel
  • Gemcitabine
Durvalumab/LenalidomideExperimentalPart 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.
  • Durvalumab
  • Lenalidomide capsule

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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)
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:up to 16 months
Safety Issue:
Description: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
Measure: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
Safety Issue:
Description: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
Measure:Disease-control rate (DCR)
Time Frame:at the end of cycle 3 and 6 (each cycle is 28 days)
Safety Issue:
Description: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)
Measure:Overall survival (OS)
Time Frame:at Day 1 of cycle 1 (each cycle is 28 days) until death or up to 4 years
Safety Issue:
Description: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.
Measure:Progression free survival (PFS)
Time Frame:D1 of the first cycle (each cycle is 28 days), up to 16 month
Safety Issue:
Description:Time from Day 1 of the first cycle of chemotherapy to date of objective disease progression or to death of any cause.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:GWT-TUD GmbH

Last Updated

March 30, 2021