Clinical Trials /

PDR001 Plus Imatinib for Metastatic or Unresectable GIST

NCT03609424

Description:

Assuming that PDR001, an anti-PD-1 antibody, with imatinib might be effective in advanced GIST after failure of standard TKI therapies including imatinib, sunitinib, and regorafenib. In this phase I/II study of PDR001 plus imatinib, it is aimed to evaluate the safety and efficacy of this regimen as 4th line of treatment in advanced GIST.

Related Conditions:
  • Gastrointestinal Stromal Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: PDR001 Plus Imatinib for Metastatic or Unresectable GIST
  • Official Title: A Phase Ib/II Study of PDR001 Plus Imatinib for Metastatic or Unresectable GIST With Prior Failure of Imatinib, Sunitinib and Regorafenib

Clinical Trial IDs

  • ORG STUDY ID: AMC1802
  • NCT ID: NCT03609424

Conditions

  • Gastrointestinal Stromal Tumors

Interventions

DrugSynonymsArms
PDR001, ImatinibPDR001 plus Imatinib

Purpose

Assuming that PDR001, an anti-PD-1 antibody, with imatinib might be effective in advanced GIST after failure of standard TKI therapies including imatinib, sunitinib, and regorafenib. In this phase I/II study of PDR001 plus imatinib, it is aimed to evaluate the safety and efficacy of this regimen as 4th line of treatment in advanced GIST.

Detailed Description

      Immunotherapy may be the novel strategy to enhance the outcomes of TKI-refractory GIST.
      Although current understanding of the immune response in GIST remains limited compared to
      other cancer types, several data suggest that the immunotherapy may be the way to overcome
      the mutation-related primary and secondary TKI resistance, and the exploration is needed.

      The PD-1-PD-L1 pathway is the one of key targets for immune checkpoint inhibitor, and
      anti-PD-1 antibodies including pembrolizumab, nivolumab has already shown a remarkable
      efficacy in several cancer types including melanoma, lung cancer, and gastric cancer with
      approval by FDA in melanoma and lung cancer. PDR001 is a novel anti-PD-1 inhibitor under
      investigation for the treatment of multiple tumor types, and the available safety data from
      on-going clinical trials indicate that PDR001 monotherapy is generally well tolerated and the
      safety profile appears to be similar across different tumor types.

      Recent phase II study reported that pembrolizumab, an anti-PD-1 inhibitor, demonstrated only
      modest anti-tumor efficacy in advanced GISTs. However, the sample size was small with only 10
      GIST tumors in the study, and high proportion of GIST tumors were prominently infiltrated by
      IDO positive M2 macrophage, which plays important role in immune suppression. Thus, further
      strategies are warranted to assess the combination of immune checkpoint inhibitor with an
      agent which can inhibit the IDO pathway in advanced GIST.

      PD-L1 expression has been regarded as a promising biomarker to predict the efficacy of
      anti-PD-1 or PD-L1 monoclonal antibodies, although negative PD-L1 expression do not preclude
      the efficacy of anti-PD-1 or PD-L1 antibodies. Although the data in regards to the PD-L1
      expression in metastatic GISTs are limited, a recent study showed that the PD-L1 expression
      is observed in the subset of localized GIST tissue samples and its expression is correlated
      with prognosis. Further translational research of immune milieu using GIST tissues are
      necessary to establish the role of immunotherapy in metastatic GISTs, and concurrent
      prospective studies using immune check point inhibitors may enhance the speed of this work.

      The relevance of continuous KIT inhibition in tyrosine kinase inhibitor (TKI) refractory
      GISTs was proven in previous phase III RIGHT study which compared imatinib rechallenge and
      placebo after failure of at least first line imatinib and second line sunitinib. In this
      study, the inhibition of KIT by imatinib was significantly associated with prolonged PFS
      (median PFS of 1.8 months) compared to placebo (median 0.9 month; HR 0.46, 95% CI 0.27-0.78;
      p=0.005). Disease control rate at 12 weeks was also improved with imatinib rechallenge than
      placebo (32% vs 5%, p=0.003).

      Immune cells such as T cells (Treg), natural killer (NK) cells, and macrophages are present
      in GIST tissue samples, and their presence or activation were related with prognosis or
      response to imatinib. Imatinib indirectly have an impact on NK cells and CD8+ T cells, and
      concurrent use of CTLA-4 blockade with imatinib augments the efficacy of imatinib in mouse
      GIST by increasing IFN-r producing CD8+ T cells. Moreover, previous study showed that
      imatinib potentiates antitumor T-cell responses in GISTs through the inhibition of IDO. This
      may suggest that concurrent use of imatinib and immune checkpoint inhibitors may enhance the
      efficacy of immune checkpoint inhibitors.

      Based on this background, we assume that PDR001, an anti-PD-1 antibody, with imatinib might
      be effective in advanced GIST after failure of standard TKI therapies including imatinib,
      sunitinib, and regorafenib. In this phase I/II study of PDR001 plus imatinib, It is aimed to
      evaluate the safety and efficacy of this regimen as 4th line of treatment in advanced GIST.
    

Trial Arms

NameTypeDescriptionInterventions
PDR001 plus ImatinibExperimental
  • PDR001, Imatinib

Eligibility Criteria

        1. Age 18 years or older, at the time of acquisition of informed consent

          2. Histologically confirmed metastatic or unresectable GIST with CD117(+), DOG-1(+), or
             mutation in KIT or PDGFRαgene

          3. Disease control (response or stabilization for at least 6 months) with first-line
             imatinib and failure (progression) to imatinib, sunitinib, and regorafenib. Disease
             progression is defined as (1) size increase ≥ 20% by RECIST version 1.1, (2)
             appearance of a definite new lesion (excluding small cystic new lesions in the liver
             within 6 months of starting TKIs), (3) new solid nodule ≥ at least 2 cm in size within
             a cystic mass, or (4) increase of the size ( ≥ 20%) of previously existing solid
             nodule ≥ at least 2 cm in size within a cystic mass.

          4. ECOG performance status of 0-2

          5. Resolution of all toxic effects of prior treatments to grade 0 or 1 by NCI-CTCAE
             version 4.0

          6. At least one measurable lesion by RECIST version 1.1.

          7. Adequate bone marrow, hepatic, renal, and other organ functions

               -  Neutrophil ≥ 1,500/mm3

               -  Platelet ≥ 75,000/mm3

               -  Hemoglobin ≥ 8.0 g/dL

               -  Total bilirubin ≤ 1.5 x upper limit of normal (ULN)

               -  AST/ALT ≤ 3 x ULN without liver metastases or AST/ALT ≤ 5 x ULN with liver
                  metastases

               -  Creatinine≤ 1.5 x ULN

          8. Women with reproductive potential must have a negative serum or urine pregnancy test

          9. Washout period of previous TKIs or chemotherapy for more than 4 times the half-life
             (Seven days of washout period is enough for imatinib, sunitinib, and regorafenib).

         10. No prior use of PDR001 or other immune check point inhibitors

         11. Provision of a signed written informed consent

        Exclusion criteria

          1. Patients who are intolerant to imatinib

          2. Women of child-bearing potential who are pregnant or breast feeding or adults of
             reproductive potential not employing an effective method of birth control.

          3. Impaired cardiac function or clinically significant cardiac disease, including any of
             the following:

             Clinically significant and/or uncontrolled heart disease such as congestive heart
             failure (CHF) requiring treatment (NYHA grade ≥ 2), uncontrolled hypertension or
             clinically significant arrhythmia

               -  Congenital long QT syndrome

               -  QTc> 470 msec on screening ECG

               -  Unstable angina pectoris ≤ 3 months prior to starting study drug

               -  Acute Myocardial Infarction ≤ 3 months prior to starting study drug

          4. Uncontrolled infection

          5. History of severe hypersensitivity reactions to other monoclonal antibodies

          6. Active autoimmune disease or a documented history of autoimmune disease, or any
             condition that requires systemic steroids, except vitiligo or resolved asthma/atopy
             that is treated with broncho-dilators (e.g., albuterol).

          7. Other severe, acute, or chronic medical or psychiatric condition or laboratory
             abnormality that may increase the risk associated with study participation or study
             drug administration or may interfere with the interpretation of study results and, in
             the judgment of the investigator, would make the subject inappropriate for this study

          8. Major surgery ≤ 28 days prior to starting study drug or who have not recovered from
             side effects of such therapy

          9. Known diagnosis of HIV infection (HIV testing is not mandatory)

         10. History of another primary malignancy that is currently clinically significant or
             currently requires active intervention

         11. Patients with brain metastases as assessed by radiologic imaging (e.g. CT, MRI) due to
             symptoms clinically suspected of brain metastases

         12. Alcohol or substance abuse disorder

         13. Active HBV and HCV infections requiring therapy: patients with undetectable HBV DNA
             level under the anti-viral agents are allowed to be enrolled.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose
Time Frame:up to 12 weeks
Safety Issue:
Description:Primary Outcome of phase Ib part

Secondary Outcome Measures

Measure:Progression-free survival
Time Frame:Up to 2 years
Safety Issue:
Description:Progression-free survival (PFS) per the RECIST v1.1 and iRECIST PFS is defined as the time from the date of first dosing of PDR001 plus Imatinib to the date of progression or death due to any cause
Measure:Overall survival
Time Frame:Up to 2 years
Safety Issue:
Description:OS is defined as the time from the date of the start of PDR001 plus Imatinibto the time of death due to any cause
Measure:Response rate
Time Frame:Up to 2 years
Safety Issue:
Description:Response rate per the RECIST v1.1 and iRECIST Responses are assessed every 8 weeks (at fixed calendar time) until disease progression or death.
Measure:Toxicity profile
Time Frame:Up to 2 years
Safety Issue:
Description:Toxicity profile by the NCI-CTCAE v4.03
Measure:Correlation of efficacy with potential biomarkers
Time Frame:Up to 2 years
Safety Issue:
Description:Correlation of efficacy (DCR, ORR, PFS, and OS) with potential biomarkers including CD3, CD8, PD-1, PD-L1, LAG3, TIM3, CD204 (M2 macrophage), CD169 (M1 macrophage) using multiplex IHC
Measure:Mutational analysis
Time Frame:Up to 2 years
Safety Issue:
Description:Mutational analysis of KIT exons 9, 11, 13, and 17, and PDGFRα exons 12, 14, and 18 with direct sequencing using DNA extracted from archival tissues, newly obtained tissues at baseline, and/or at 4 weeks after the start of the study medication (biopsies at baseline and 4 weeks after study treatment are optional).

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Asan Medical Center

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