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A Randomised Trial of Imatinib Alternating With Regorafenib Compared to Imatinib Alone for the First Line Treatment of Advanced Gastrointestinal Stromal Tumour (GIST)

NCT02365441

Description:

An open label randomised trial for adults with histologically confirmed measurable metastatic GIST who have received no other treatment for metastatic disease. The study aims to determine if an alternating regimen of imatinib and regorafenib has sufficient activity and safety in comparison to imatinib alone to warrant further evaluation as a first line treatment for metastatic GIST.

Related Conditions:
  • Gastrointestinal Stromal Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Randomised Trial of Imatinib Alternating With Regorafenib Compared to Imatinib Alone for the First Line Treatment of Advanced Gastrointestinal Stromal Tumour (GIST)
  • Official Title: A Randomised Phase II Trial of Imatinib Alternating With Regorafenib Compared to Imatinib Alone for the First Line Treatment of Advanced Gastrointestinal Stromal Tumour (GIST)

Clinical Trial IDs

  • ORG STUDY ID: AG1013GST
  • SECONDARY ID: ACTRN12614000950662
  • NCT ID: NCT02365441

Conditions

  • Gastrointestinal Stromal Tumour

Interventions

DrugSynonymsArms
RegorafenibArm B
imatinibGlevecArm A

Purpose

An open label randomised trial for adults with histologically confirmed measurable metastatic GIST who have received no other treatment for metastatic disease. The study aims to determine if an alternating regimen of imatinib and regorafenib has sufficient activity and safety in comparison to imatinib alone to warrant further evaluation as a first line treatment for metastatic GIST.

Detailed Description

      PROTOCOL SYNOPSIS Background Despite highly active current treatment for metastatic
      gastrointestinal stromal tumour (GIST) with the use of imatinib, most people will ultimately
      relapse and die of multifocal metastatic disease. Using an alternating regimen of imatinib
      and regorafenib with brief drug free intervals may allow tumour stem cells to re-enter the
      cell cycle and become susceptible once more to drug therapy. Regorafenib, a multi-targeted
      tyrosine kinase inhibitor (TKI) with activity against angiogenic, stromal and oncogenic
      receptor tyrosine kinases, has demonstrated activity in the treatment of GIST and is FDA
      approved for third line therapy of advanced GIST.

      General aim To determine if an alternating regimen of imatinib and regorafenib has sufficient
      activity and safety to warrant further evaluation as a first line treatment for metastatic
      GIST.

      Design Prospective, randomised, open label phase II trial, stratified by participating site,
      previous adjuvant therapy (prior vs none), and previous imatinib for metastatic disease for
      less than 21 days.

      Population The target population is adults with histologically confirmed, measurable
      metastatic GIST, who have received no prior treatment for metastatic disease. Patients who
      are currently taking, and have had up to 21 days of uninterrupted treatment with 400mg daily
      of imatinib are eligible to participate in this study.

      Study treatments

      Patients will be randomised to receive either:

      Arm A - imatinib 400mg orally daily continuously (control arm); or Arm B - alternating 28-day
      periods of imatinib 400mg orally daily for 21 to 25 days followed by a washout (drug free)
      period of 3 to 7 days, then regorafenib 160mg orally daily for 3 weeks followed by a 7 day
      washout (drug free) period.

      Treatment will continue until disease progression or prohibitive adverse events as detailed
      in the protocol.

      Statistical considerations In order to demonstrate a relative increase in progression free
      survival at 24 months from the date of randomisation from an expected 78% to 88%, with 80%
      power and 95% confidence based on A'Hern's adjustment to Fleming's design, approximately 110
      evaluable participants will be required in each arm. Thus, it is proposed to enrol 240
      participants into the trial, allowing for approximately a 10% drop-out rate. Currently 80% of
      participants are expected to achieve a clinical benefit at 24 months (CBR - rate of complete
      or partial response, or stable disease). A secondary outcome would be to determine whether a
      minimum 25% relative increase of the CBR (from 80% to 85%) in the experimental cohort can be
      attained. The study will be open to recruitment for 36 months while follow-up will continue
      until the last enrolled participant has been followed for a minimum of 24 months timed from
      the date of commencement of treatment.
    

Trial Arms

NameTypeDescriptionInterventions
Arm AActive Comparatorimatinib 400mg orally daily continuously
  • imatinib
Arm BExperimentalalternating 28-day periods of imatinib 400mg orally daily for 21 to 25 days followed by a washout (drug free) period of 3 to 7 days, then regorafenib 160mg orally daily for 3 weeks followed by a 7 day washout (drug free) period.
  • Regorafenib
  • imatinib

Eligibility Criteria

        Inclusion Criteria:

          -  Adults (over 18 yrs) with histologically confirmed GIST. In CD-117-negative cases
             DOG-1 must be positive or a KIT/PDGFRA mutation must be present.

          -  Unresectable, metastatic disease.

          -  No prior TKI for metastatic disease, with the exception of those patients who have had
             up to 21 days of uninterrupted treatment on 400mg daily of imatinib.

          -  Imatinib therapy given as an adjuvant treatment and completed at least 3 months prior
             to entry into this trial is permitted. Patients who have progression of GIST while on
             adjuvant therapy are not eligible for this trial.

          -  ECOG performance status 0-2

          -  Measurable disease by RECIST version 1.1. (Note: Participants with only peritoneal
             disease will be eligible only if they have lesions measurable in two dimensions and
             have at least 1 lesion which is ≥ 2 cm in size).

          -  Adequate bone marrow function (Haemoglobin ≥ 9.0g/dL, platelet count ≥ 100 x 109/L,
             and absolute neutrophil count ≥ 1.5 x 109/L).

          -  Adequate liver function (Serum total bilirubin ≤1.5 x ULN, INR ≤ 1.5, and ALT, AST,
             ALP ≤2.5 x ULN (≤ 5 x ULN for participants with liver metastases). Lipase level must
             be ≤ 1.5 x ULN.

          -  Adequate renal function (Creatinine clearance > 50ml/min) based on either the
             Cockcroft Gault formula, 24 hour urine or Glomerular Filtration Rate (GFR scan); and
             serum creatinine ≤ 1.5 x ULN.

          -  Tumour tissue available for central review.

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

          -  Study treatment both planned and able to start within 14 days of randomisation.

          -  Signed, written informed consent.

        Exclusion Criteria:

          -  Concurrent GI illness which may prevent absorption of imatinib or regorafenib - please
             note that prior gastrectomy or bowel resection does not exclude patients from this
             study.

          -  Use of other investigational drugs within 4 weeks prior to enrolment.

          -  Known sensitivity to any of the study drugs, study drug classes, or excipients in the
             formulation.

          -  Participants receiving therapeutic doses of warfarin.

          -  Presence of brain metastases.

          -  The presence of PDGFR D842V mutation or other mutation known to cause imatinib
             resistance.

          -  Inability to swallow tablets.

          -  Arterial thrombotic or ischaemic events, such as cerebrovascular accident or pulmonary
             embolism within 6 months prior to randomisation; or major venous thrombotic events
             requiring use of an anticoagulant such as warfarin within 6 months prior to
             randomisation.

          -  Poorly controlled hypertension (systolic blood pressure > 140 mmHg or diastolic
             pressure > 90 mmHg despite optimal medical management).

          -  Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             prior to randomisation, or non healing wound, ulcer or fracture.

          -  Congestive cardiac failure (NYHA ≥ grade 2), unstable angina or new onset angina
             within the previous 3 months, or AMI within the previous 6 months. Cardiac arrhythmias
             requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).

          -  Haemorrhage or bleeding event ≥ Grade 3 according to CTCAE v4.0 within 4 weeks prior
             to randomisation.

          -  Ongoing infection of > Grade 2 according to CTCAE v4.0.

          -  Active hepatitis B or C or HIV, or chronic hepatitis B or C requiring treatment with
             antiviral therapy. Testing for these is not mandatory unless clinically indicated.

          -  Interstitial lung disease with ongoing signs and symptoms.

          -  Persistent proteinuria of ≥ Grade 3 (>3.5g/24 hours) according to CTCAE v4.0

          -  Other significant medical or psychiatric condition judged by the investigator to
             interfere with protocol requirements.

          -  Use of biological response modifiers such as granulocyte colony stimulating factor
             (G-CSF), within 3 weeks prior to randomisation.

          -  Patients taking strong cytochrome P (CYP) CYP3A4 inhibitors (eg clarithromycin,
             indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole,
             ritonavir, saquinovir, telithromycin, voriconazole) or strong CYP3A4 inducers (eg
             carbamazepine, phenobarbitol, phenytoin, rifampicin, St John's wort).

          -  History of another malignancy within 5 years prior to registration. 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. Patients with a history of other malignancies are
             eligible if they have been continuously disease free for at least 5 years after
             definitive primary treatment.

          -  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. Women of
             childbearing potential and men must agree to use adequate contraception before
             entering the trial until at least 8 weeks after the last study drug administration.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival at 24 months (disease progression or death)
Time Frame:24 Months
Safety Issue:
Description:PFS at 24 months as calculated from the time from either (i) randomization if patients have not yet commenced treatment) or (ii) commencement of therapy (if patients are randomized during the first cycle of imatinib) to the date of progression as determined by RECIST v1.1

Secondary Outcome Measures

Measure:Objective tumour response rate at 16 weeks
Time Frame:16 weeks
Safety Issue:
Description:Objective tumour response rate following 2 cycles of treatment
Measure:Clinical benefit rate at 16 weeks
Time Frame:16 weeks
Safety Issue:
Description:Clinical benefit rate (SD + PR + CR) following 2 cycles of treatment
Measure:Complete response rate
Time Frame:5 years
Safety Issue:
Description:complete response rate will be calculated by summing the number of participants assessed as having a complete response and dividing this by the total number of participants evaluable for response (according to RECIST Version 1.1).
Measure:Time to treatment failure
Time Frame:5 years
Safety Issue:
Description:Time to treatment failure is defined as the time from either (i) randomization (if patients have not yet commenced treatment) or (ii) commencement of therapy (if patients are randomized during the first cycle of imatinib) to treatment discontinuation for any reason, including disease progression, treatment toxicity, patient preference, or death.
Measure:Adverse Events
Time Frame:5 years
Safety Issue:
Description:Safety/toxicity/tolerability
Measure:Overall survival
Time Frame:5 years
Safety Issue:
Description:Overall survival is defined as the interval from either (i) randomization (if patients have not yet commenced treatment) or (ii) commencement of therapy (if patients are randomized during the first cycle of imatinib) to date of death from any cause, or the date of last known follow-up alive.

Details

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

Trial Keywords

  • GIST
  • Advanced

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