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Capecitabine ON Temozolomide Radionuclide Therapy Octreotate Lutetium-177 NeuroEndocrine Tumours Study

NCT02358356

Description:

Two parallel phase II randomized open label trials of Lutetium-177 Octreotate (177Lu‐Octreotate) peptide receptor radionuclide therapy (PRRT) and capecitabine (CAP)/temozolomide (TEM) chemotherapy (chemo): (i) versus CAPTEM alone in the treatment of low to intermediate grade pancreatic neuroendocrine tumours (pNETs); (ii) versus PRRT alone in the treatment of low to intermediate grade mid gut neuroendocrine tumours (mNETs).

Related Conditions:
  • Appendix Neuroendocrine Tumor
  • Pancreatic Neuroendocrine Tumor
  • Small Intestinal Neuroendocrine Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Capecitabine ON Temozolomide Radionuclide Therapy Octreotate Lutetium-177 NeuroEndocrine Tumours Study
  • Official Title: Capecitabine ON Temozolomide Radionuclide Therapy Octreotate Lutetium-177 NeuroEndocrine Tumours Study

Clinical Trial IDs

  • ORG STUDY ID: CTC0120 / AG0114NET
  • NCT ID: NCT02358356

Conditions

  • Midgut Neuroendocrine Tumours
  • Pancreatic Neuroendocrine Tumours

Interventions

DrugSynonymsArms
octreotatelutatePRRT
CapecitabineXelodaCAPTEM
TemozolomideCAPTEM

Purpose

Two parallel phase II randomized open label trials of Lutetium-177 Octreotate (177Lu‐Octreotate) peptide receptor radionuclide therapy (PRRT) and capecitabine (CAP)/temozolomide (TEM) chemotherapy (chemo): (i) versus CAPTEM alone in the treatment of low to intermediate grade pancreatic neuroendocrine tumours (pNETs); (ii) versus PRRT alone in the treatment of low to intermediate grade mid gut neuroendocrine tumours (mNETs).

Detailed Description

      PROTOCOL SYNOPSIS

      Background

      Neuroendocrine tumours (NETs) are a heterogeneous group of malignancies that can arise at any
      site in the gastrointestinal tract, that are known by their ability to over express
      somatostatin receptors. Originally called carcinoid tumours, these tumours are rising in
      incidence. In patients with incurable disease, several systemic options have demonstrated
      activity but few have been compared in prospective, randomised controlled trials (RCTs).
      177Lu-Octreotate peptide receptor radionuclide therapy (PRRT) and CAPTEM have shown promising
      activity in initial single arm trials. Prospective RCTs are needed to build on these early
      trials to determine the optimal role of these therapies in clinical practice.

      CONTROL NETs is a parallel group phase II randomised open label trial of Lutetium-177
      Octreotate (177Lu‐Octreotate (Lutate)) peptide receptor radionuclide therapy (PRRT) and
      capecitabine (CAP)/temozolomide (TEM) chemotherapy (chemotherapy): (i) versus CAPTEM alone in
      the treatment of low to intermediate grade pancreatic neuroendocrine tumours (pNETs); (ii)
      versus PRRT alone in the treatment of low to intermediate grade midgut neuroendocrine tumours
      (mNETs).

      General aim

      i) To determine the relative activity of CAPTEM/PRRT in biopsy-proven, low to intermediate
      grade, unresectable, metastatic 68Ga-octreotate PET-avid NETs in the following parallel phase
      II studies: Group A: pNETs and Group B: mNETs.

      ii) To inform future comparative phase III RCTs to determine the optimal therapies in pNETs
      and mNETs.

      Design

      Two parallel non-comparative group randomised, controlled, multi-centre phase II, 2 arm
      open‐label controlled trials with 2:1 allocation (experimental : control)

        1. Study A: pNETs: PRRT/CAPTEM vs. CAPTEM (control)

        2. Study B: mNETs: PRRT/CAPTEM vs. PRRT (control)

      Randomisation will be performed using the method of minimisation.

      Patients will be stratified by:

        -  Previous systemic therapy regimens (0,1 v 2)

        -  WHO tumour grade: Low Grade - G1 (Ki67<3% (mitotic count <2)) vs. Intermediate Grade -
           G2 (Ki67 3-20% (mitotic count 2-20))

        -  visceral only vs. visceral with bone metastases

        -  Treating institution

      Population

      The target population for this study is consenting adult patients with advanced, unresectable
      low or intermediate grade (Ki-67<20%) midgut neuroendocrine tumours (mNETs) or pancreatic
      neuroendocrine tumours (pNETs ), who have received ≤ 2 prior systemic therapies for advanced
      unresectable disease (including long acting somatostatin analogues).

      Assessments

        -  Patients will be assessed at each treatment cycle for toxicity

        -  CT including a 3 phase contrast CT of the liver will be undertaken at baseline, then
           every 2 months (pNET) or every 4 months (pNET) until radiologic progression by RECIST
           v1.1.

        -  68Ga-DOTATATE PET CT Scan will be undertaken at baseline, then every 4 months until
           radiologic progression by RECIST v1.1.

        -  18F-FDG PET Scan may be performed at the discretion of treating clinician at baseline,
           then every 2 months until radiologic progression by RECIST v1.1) for G2 NETS.

        -  24-h whole-body planar gamma imaging will be undertaken on the day after administration
           of PRRT (every 2 months).

        -  Serum biomarkers will be undertaken every 4 months until disease progression.

        -  Quality of life assessments will be undertaken at every 2 months until disease
           progression using QLC C30 and QLQ-GINET21.

        -  Health utilities will be evaluated with EQ-5D-5L every 2 months until completion of
           study follow up.

      Statistical considerations

      Both studies are based on a Simon's two-stage design and are randomised using a 2:1
      randomisation (Experimental: Control). A mix of approximately 30% G1 patients and 70% G2
      patients is expected.

      Study A, pNETs (n=90) will have 80% power with 95% confidence interval to exclude a 12 months
      PFS of 60% in favour of a more interesting rate of 77% in the experimental arm.

      For Study B, mNETs (n=75), the PFS at 24 months in the control arm is expected to be 52%.
      Thus study B will have 80% power with 95% confidence interval to demonstrate a PFS rate at 24
      months of 70% in experimental arm, a result that would warrant further investigation.

      A total sample size of 165 patients for the two studies will be accrued over 2 years.

      Patients will be followed up for a minimum of 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
PRRTActive Comparator7.8GBq 177Lu Octreotate (Lutate) given intravenously (IV) on day 1 every 8 weeks for 4 cycles.
  • octreotate
CAPTEMActive ComparatorOral capecitabine 750mg/m2 b.i.d. days 1-14 and temozolomide 75mg/m2 b.i.d. days 10-14 every 28 day cycle, up to 8 cycles.
  • Capecitabine
  • Temozolomide
PRRT/CAPTEMExperimental7.8GBq 177Lu Octreotate (Lutate) given intravenously (IV) on day 10 every 8 weeks for 4 cycles, with concurrent oral capecitabine 750mg/m2 b.i.d. days 1-14 and temozolomide 75mg/m2 b.i.d. days 10-14 up to 4 cycles.
  • octreotate
  • Capecitabine
  • Temozolomide

Eligibility Criteria

        Inclusion Criteria:

          -  Adults ≥18 years old with histologically proven, moderate to well‐differentiated G1/2
             pancreatic or midgut NETs with Ki‐67 < 20%;

          -  The presence of somatostatin receptor avidity suitable for PRRT demonstrated on
             68Ga‐octreotate PET scan;

          -  Progressive advanced/metastatic disease that has progressed during or after ≤ 2 prior
             systemic therapies;

          -  Unresectable disease, determined by an appropriately specialized surgeon or deemed not
             suitable for liver directed therapies where liver is the only site of disease;

          -  ECOG performance status 0‐2;

          -  Ability to swallow oral medication;

          -  Adequate renal function (measured creatinine clearance > 50 ml/min by DTPA or
             51CR-EDTA), bone marrow function (Hb > 9 g/d/L, ANC > 1.5 x109L, and platelets > 100 x
             10/L);

          -  Adequate liver function (serum total bilirubin ≤ 1.5 x ULN, and Alanine
             aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP) ≤
             2.5 x ULN (≤ 5 x ULN for patients with liver metastases)). INR ≤ 1.5 (or on a stable
             dose of LMW heparin for >2 weeks at time of enrolment .);

          -  Life expectancy of at least 9 months;

          -  Study treatment both planned and able to start within 28 days of randomisation; )

          -  Willing and able to comply with all study requirements, including treatment, timing
             and/or nature of required assessments;

          -  Signed, written informed consent.

        Exclusion Criteria:

          -  Primary NETs other than small bowel (midgut) or pancreatic NETs;

          -  Cytotoxic chemotherapy, targeted therapy, or biotherapy within the last four weeks;

          -  Prior intrahepatic 90Y microspheres, such as SIR-Spheres in the past six months;

          -  Prior Peptide Receptor Radionuclide Therapy;

          -  Major surgery/surgical therapy for any cause within one month;

          -  Surgical therapy of loco-regional metastases within the last three months prior to
             randomisation;

          -  Uncontrolled metastatic disease to the central nervous system. To be eligible, CNS
             metastases should have been treated with surgery and/or radiotherapy and the patient
             should have been receiving a stable dose of steroids for at least 2 weeks prior to
             randomisation, with no deterioration in neurological symptoms during this time;

          -  Poorly controlled concurrent medical illness. E.g. unstable diabetes (Note: optimal
             glycaemic control should be achieved before starting trial therapy); Symptomatic NYHA
             class III or IV congestive cardiac failure, myocardial infarction within 6 months of
             start of the study, serious uncontrolled cardiac arrhythmia, unstable angina, or any
             other clinically significant cardiac disease;

          -  History of other malignancies within 5 years except where treated with curative intent
             AND with no current evidence of disease AND considered not to be at risk of future
             recurrence Patients with a past history of adequately treated carcinoma-in-situ, basal
             cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial
             transitional cell carcinoma of the bladder are eligible;

          -  Any uncontrolled known active infection, including chronic active hepatitis B,
             hepatitis C, or HIV. Testing for these is not mandatory unless clinically indicated.
             Participants with known Hepatitis B/C infection will be allowed to participate
             providing evidence of viral suppression has been documented and the patient remains on
             appropriate anti-viral therapy;

          -  Impairment of gastrointestinal function or gastrointestinal disease that may
             significantly alter the absorption of capecitabine/temozolomide (e.g., ulcerative
             disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or
             substantial small bowel resection);

          -  Presence of any psychological, familial, sociological or geographical condition
             potentially hampering compliance with the study protocol and follow-up schedule,
             including alcohol dependence or drug abuse;

          -  Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal,
             infertile, or use a reliable means of contraception. Women of childbearing potential
             must have a negative pregnancy test done within 7 days prior to registration. Men must
             have been surgically sterilised or use a (double if required) barrier method of
             contraception .
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival
Time Frame:12 months for pNETs and 24 months for mNets
Safety Issue:
Description:To determine the rate of progression free survival (PFS) at 12 months in pNETs (Group A), and at 24 months in mNETs (Group B). (PFS defined from time of randomisation to disease progression as defined by RECIST criteria version 1.1).

Secondary Outcome Measures

Measure:Objective tumour response rate (partial or complete response) as per RECIST v1.1 criteria
Time Frame:12 months or 24 months as appropriate
Safety Issue:
Description:To determine objective tumour response rate (OTRR) (partial or complete response (PR/CR)).
Measure:Overall survival (death from any cause)
Time Frame:12 months or 24 months as appropriate
Safety Issue:
Description:To determine overall survival (OS) (death from any cause).
Measure:Safety (rates of adverse events worst grade according to NCI CTCAE v4.0)
Time Frame:12 months or 24 months as appropriate
Safety Issue:
Description:To determine safety (rates of adverse events).
Measure:Quality of life (QOL scores determined at beginning, during treatment and until disease progression)
Time Frame:12 months or 24 months as appropriate
Safety Issue:
Description:To determine Quality of Life (QoL) (QoL scores from EORTC QLQ C30 and QLQ-GINET21 questionnaires)
Measure:Resource utilisation (use of healthcare resources) and cost-effectiveness (Health utility score determined at beginning, during treatment and until end of follow up, correlated with MBS & PBS data)
Time Frame:12 months or 24 months as appropriate
Safety Issue:
Description:To determine resource utilization (costs associated with treatment regimen, MBS and PBS data, and health utilities scores from EQ-5D-5L).
Measure:Clinical Benefit
Time Frame:12 months or 24 months as appropriate
Safety Issue:
Description:To evaluate the proportion of patients who have experienced a clinical benefit of the regimen(s). (Clinical Benefit is defined as the proportion of patients who experience complete or partial response (using RECIST v1.1) or stable disease at 12 months or 24 months as appropriate).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Australasian Gastro-Intestinal Trials Group

Trial Keywords

  • midgut
  • pancreatic
  • neuroendocrine
  • advanced
  • unresectable low
  • intermediate grade
  • mNETs
  • pNETs

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