PDR001 Plus Imatinib for Metastatic or Unresectable GIST
- Registration Number
- NCT03609424
- Lead Sponsor
- Asan Medical Center
- Brief Summary
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 39
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description PDR001 plus Imatinib PDR001, Imatinib -
- Primary Outcome Measures
Name Time Method Disease control rate up to 12 weeks Disease control rate (DCR: objective response + stable disease) at 12 weeks Primary Outcome of phase 2 part(defined by RECIST v1.1)
Recommended dose for expansion up to 12 weeks Primary Outcome of phase Ib part
Maximum tolerated dose up to 12 weeks Primary Outcome of phase Ib part
- Secondary Outcome Measures
Name Time Method Toxicity profile Up to 2 years Toxicity profile by the NCI-CTCAE v4.03
Overall survival Up to 2 years OS is defined as the time from the date of the start of PDR001 plus Imatinibto the time of death due to any cause
Progression-free survival Up to 2 years 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
Correlation of efficacy with potential biomarkers Up to 2 years 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
Mutational analysis Up to 2 years 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).
Response rate Up to 2 years Response rate per the RECIST v1.1 and iRECIST Responses are assessed every 8 weeks (at fixed calendar time) until disease progression or death.
Trial Locations
- Locations (1)
Asan Medical Center
🇰🇷Seoul, Korea, Republic of