PDR001 Plus Imatinib for Metastatic or Unresectable GIST
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|ClinicalTrials.gov Identifier: NCT03609424|
Recruitment Status : Not yet recruiting
First Posted : August 1, 2018
Last Update Posted : October 19, 2018
|Condition or disease||Intervention/treatment||Phase|
|Gastrointestinal Stromal Tumors||Drug: PDR001, Imatinib||Phase 1 Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||41 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase Ib/II Study of PDR001 Plus Imatinib for Metastatic or Unresectable GIST With Prior Failure of Imatinib, Sunitinib and Regorafenib|
|Estimated Study Start Date :||December 30, 2018|
|Estimated Primary Completion Date :||August 30, 2020|
|Estimated Study Completion Date :||August 30, 2020|
|Experimental: PDR001 plus Imatinib||
Drug: PDR001, Imatinib
-Phase Ib part
: The standard 3+3 dose escalation scheme will be applied. DLTs will be evaluated during the first cycle (4 weeks).
PDR001 400mg, every 4 weeks, IV
Imatinib dose level -1 : 200mg, PO, QD Imatinib dose level 1 : 300mg, PO, QD Imatinib dose level 2 : 400mg, PO, QD
-Phase II part
- Maximum tolerated dose [ Time Frame: up to 12 weeks ]Primary Outcome of phase Ib part
- Recommended dose for expansion [ Time Frame: up to 12 weeks ]Primary Outcome of phase Ib part
- Disease control rate [ Time Frame: 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)
- Progression-free survival [ Time Frame: 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
- Overall survival [ Time Frame: 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
- Response rate [ Time Frame: 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.
- Toxicity profile [ Time Frame: Up to 2 years ]Toxicity profile by the NCI-CTCAE v4.03
- Correlation of efficacy with potential biomarkers [ Time Frame: 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 [ Time Frame: 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).
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03609424
|Contact: Yoon-Koo Kang, MD, PhDfirstname.lastname@example.org|
|Contact: Min-Hee Ryu, MD, PhDemail@example.com|
|Principal Investigator:||Yoon-Koo Kang, MD, PhD||Asan Medical Center|