Gastrointestinal Stromal TumorsNCT05464875
A Multicenter Study of Avapritinib Efficacy and Safety of Metastatic or Unresectable Gastrointestinal Stromal Tumors
An observational study of Gastrointestinal Stromal Tumors and Unresectable Solid Tumor, run by Xinhua Zhang, MD at 1 site in China.
Trial summary
This is a prospective, multicenter, observational real-world study to explore the therapy patterns and clinical outcomes of Avapritinib in patients with metastatic or unresectable gastrointestinal stromal tumors. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Gastrointestinal Stromal Tumors, Unresectable Solid Tumor, Recurrent Metastatic Malignant Neoplasm
- How many people
- 74 participants
- Where
- 1 siteChina
- Study dates
- 9 Jul 2022to 31 Dec 2025
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Approximately 74 patients with metastatic or unresectable advanced gastrointestinal stromal tumors from tier-3 hospitals who meet the criteria will be enrolled in the study.
Who may be able to join
- Patients who are aged ≥ 18 years.
- Gastrointestinal stromal tumors confirmed by histopathological examination, and CD- and/or DOG-1-positive by immunohistochemistry.
- Presence of mRECIST v1.1-compliant lesions with at least one measurable lesion (non-lymphadenopathy ≥1.0 cm or ≥2-fold scan slice thickness).
- Treatment with Avapritinib.
- Patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2 at screening.
- Patient informed consent and signed written consent form.
- The patient was compliant and voluntarily scheduled for follow-up, treatment, laboratory tests, and other study procedures.
Who cannot join
- KIT or PDGFRA wild type.
- Failure to complete continuous atorvastatin for at least 15 days due to intolerability or disease progression.
- Other serious acute or chronic physical or mental problems, or laboratory abnormalities, may increase the risk associated with participation in the study or use of drugs, or interfere with the judgment of the study results and, in the judgment of the investigator, are not considered appropriate for participation in the investigator.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
China1 site, 1 recruiting
- Recruiting
The First Affiliated Hospital, Sun Yat-sen University
Guangzhou, 510080
Xinhua Zhang, +8613828463644, zhangxinhua@mail.sysu.edu.cn
About this study
This is a prospective, multicenter, observational real-world study to explore the therapy patterns and clinical outcomes of Avapritinib in patients with metastatic or unresectable gastrointestinal stromal tumors.
Read the detailed description
INTRODUCTION AND RATIONALE Gastrointestinal stromal tumors (GIST) are thought to develop from the interstitial cells of Cajal or their stem cell precursors. They are the most common mesenchymal tumors occurring in the gastrointestinal (GI) tract. The annual incidence of GIST is about 1/100,000 ~ 2/100,000 globally. Biological behavior can range from benign to malignant, and immunohistochemical staining is usually positive for CDs 117 and DOG-1, showing Cajal cell differentiation. Eighty-five percent of GISTs is caused by activating mutations in the receptor tyrosine kinase KIT or platelet-derived growth factor receptor alpha (PDGFRA) gene. Targeted therapy for KIT and PDGFRA alters metastatic or unresectable GISTs without effective drug therapy, allowing tumor control and significantly prolonging patient survival. Imatinib, a first-line drug, has been shown to control in 80% of patients, whereas 50% of patients develop tumor progression after twenty-four months of treatment, with an estimated ten-year progression-free survival (PFS) rate of approximately 9 %. The most significant cause of progression was secondary mutations in the ATP binding domain or activation ring of KIT results in resistance to imatinib. Sunitinib, the second-line standard of care, and regorafenib, the third-line standard of care, inhibit some of the secondary mutations, with median PFSs of about 5.6 months for sunitinib and 4.8 months for regorafenib. However, imatinib and other targeted drugs that have been approved for the treatment of GISTs are naturally resistant to the activated ring exon 18 D842V mutation of PDGFRA, which accounts for 5 %-6 %[10% of the primary mutations in GISTs. Avapritinib was approved for marketing in January 2020 for the treatment of PDGFRA D842V mutant GISTs, thus making this type of GISTs medically acceptable.
Avapritinib is a type I tyrosine kinase inhibitor (TKI) that has significant inhibitory effects on KIT or PDGFRA in activated configurations, such as mutations in the KIT or PDGFRA activated loop. Preclinical studies have found broad-spectrum inhibition of KIT or PDGFRA, including mutations in exons 11,17,18 of KIT, and mutations in exon 18 of PDGFRA, with a 24 hr, concentration-dependent inhibitory effect. Weak affinity for wild-type KIT and PDGFRA, PDGFRB, CSF1R, and FLT3. In the Phase 1 clinical study in patients with metastatic or unresectable PDGFRA D842V-mutated GISTs, the objective response rate (ORR) for avapritinib was 91%, with a complete response rate of 13%, a median duration of efficacy (DOR) of 27.6 m (95% CI 17.6-N%), and a median PFS of 34 m (95% CI 22.9-N%) estimated to be 61% at 36months. The daily 30-600 mg of Avapritinib showed an initial anti-tumor effect, but the time to effect at the high dose was significantly shorter than at the low dose. Both the US and the European Medicines Agency (FDA and EMA) have approved the use of Avapritinib in GISTs with PDGFRA exon 18 mutations due to its significant therapeutic effect on PDGFRA D842V mutations. In patients with KIT or non-D842V PDGFRA mutations treated more than three lines, the ORRs of atorvastatin were 17%, all were partial responses (PRs), the median DORs were 10.2 m (95% CI 7.% -10.2), the clinical benefit rate (CBRs) was 38%, the median PFSs were 3.7 m (95% CI 2.% -4.6), the median OSs were 11.6 m (95% CI 9.% -12.6), and there was no difference in efficacy between the 300 mg and 400 mg daily dose groups. The above studies showed that Avapritinib was effective in the treatment of PDGFRA D842V mutant GISTs, and some patients with KIT or non-D842V PDGFRA mutations were able to obtain tumor control from the treatment of Avapritinib, with a dose effect on the anti-tumor efficacy, but no significant difference in the high dose 300 mg or 400 mg efficacy.
With respect to the safety of avapritinib, patients with >99% reported at least one adverse event (Adverse events, AEs), with common AEs including nausea (59%), fatigue (50%), periorbital edema (42%), anemia (39%), diarrhea (36%), and vomiting (33%). The incidence of grade ≥3 AEs was 72% and higher in the 400 mg dose group than in the 300 mg dose group, 84% and 73%, respectively. Common AEs included anemia (30%), fatigue (8%), abdominal pain (6%) and hypophosphatemia (6%). The incidence and severity of AEs in elderly patients (≥65 y) was slightly higher than that in younger patients. The incidence of treatment-related adverse events leading to discontinuation of Avapritinib was 11.2%, the most common were cognitive effects (4.1%), intracranial hemorrhage (1.2%), fatigue (<1%), and vomiting (<1%), which were higher in the 400 mg group than in the 300 mg group. The incidence of downtitration of Avapritinib was (32%), and the incidence of AEs of each grade and grade ≥3 was significantly lower after downtitration than before downtitration.
Preclinical studies with avapritinib suggest that the drug can penetrate the blood-brain barrier with a brain-to-plasma concentration ratio of 0.7 -1.0 3, leading to edema of the choroid plexus in dogs and intracranial hemorrhage at high doses. Therefore, central nervous system AEs, including cognitive effects and intracranial haemorrhage [14], are of particular interest in clinical studies. In the Phase I/II clinical study of Avapritinib (Navigator), the incidence of cognitive effects in patients receiving Avapritinib was 42% (104/250) and 40% in the 300 mg group, which was lower than that in the 400 mg dose group (50%). Memory impairment was the most common manifestation of cognitive effects, with an incidence of 27% in the 300 mg group and 40% in the 400 mg group, with a higher incidence in elderly patients (age ≥65 y). The cognitive effects were mostly Grade 1-2 in the Avapritinib 300 mg group and 7.5% in the Avapritinib 300 mg group. The cognitive effects were improved in most patients by discontinuation or dose adjustment, with a median adjusted dose of 233 mg. The incidence of intracranial hemorrhage was 2.4% in the Avapritinib 300 mg dose group, one case of grade 1 subdural hematoma, three cases of grade 1, 2 and 4 intracranial hemorrhage, and one case of grade 3 intracranial hemorrhage. Intracranial hemorrhage was improved by discontinuation or dose adjustment, and no patient died due to intracranial hemorrhage. Median PFSs were 11.4 m (95 %CI 8.% -20.3) in dose-reduced patients and 7.2 m (95 %CI 5.% -24.0) in dose-unadjusted patients, with similar trends for both non-D842V 4 + line therapy and D842V mutations. These studies indicate that the overall safety of Avapritinib is adequate, but special attention needs to be paid to central nervous system AEs, including cognitive abnormalities and cerebral haemorrhage, which have a dose effect, the incidence of high-dose cognitive abnormalities of Avapritinib is higher, the incidence of high-dose cognitive abnormalities of Avapritinib is higher after dose reduction, whether D842V mutations or non-D842V mutations, dose adjustment does not affect survival, and PFSs are longer in appropriately reduced-dose patients.
Avapritinib is a small molecule oral TKI with a dose-proportional increase in Cmax and AUC over the 30-400 mg qd range with a mean accumulation rate of 2. -8.9 2 after repeat dosing. Protein binding was 98.8%, mainly metabolized by CYP3A in vivo, 70% excreted in feces, major metabolite, and plasma elimination half-life was 32-57 h. Pharmacokinetic inter-individual differences were large, with in vivo exposure varying up to 8-10-fold in the 300 mg qd dose group. Approximately 50% or more of the patients who started 300 mg qd had high drug exposures, and the incidence of cognitive abnormalities was associated with cumulative exposure to Avapritinib, i.e., there were large individual pharmacokinetic differences, with a tendency to increase the incidence of Grade III or IV AEs as patients' in vivo concentrations of Avapritinib increased. However, there are no lowest effective exposures and highest toxic exposures leading to central nervous AEs in the benefit populations of atorvastatin for the treatment of PDGFRA D842V mutations and PDGFRA mutations with KIT or non-D842V.
Therefore, it is necessary to conduct a multicenter observational study on the pharmacokinetics, efficacy, and safety of Avapritinib in patients with metastatic or unresectable GIST, to explore the influencing factors on the pharmacokinetics of Avapritinib, to identify the treatment window of Avapritinib, so that the dose can be adjusted according to the in vivo exposure of Avapritinib, to reduce the risk or severity of AEs, to improve the treatment effect, and to conduct individualized administration.
- Conditions
- Gastrointestinal Stromal Tumors, Unresectable Solid Tumor, Recurrent Metastatic Malignant Neoplasm
- Keywords
- Avapritinib, Genetic testing
- Medical subject headings
- Gastrointestinal Stromal Tumors, Neoplasm Metastasis
What is being measured
The primary outcome is the main question the study is designed to answer.
Objective Response Rate
To evaluate objective response rate (ORR,CR+PR) determined by radiology assessment per mRECIST(Response Evaluation Criteriain Solid Tumours), version 1.1 in patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.Complete response is the disappearance of all lesions with nodes measuring < 10 mm and normal tumour markers.A decrease in the sum of target disease of ≥ 30% represents partial response.
Measured: 2 years
Clinical Benefit Rate
To evaluate clinical benefit rate(CBR,CR+PR+>16 weeks continuation SD) determined by radiology assessment per mRECIST, version 1.1 in patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.Complete response is the disappearance of all lesions with nodes measuring < 10 mm and normal tumour markers.A decrease in the sum of target disease of ≥ 30% represents partial response.Stable disease lies between partial response and progressive disease.
Measured: 2 years
Duration Of Response
To evaluate duration of response (DOR) determined by radiology assessment per mRECIST, version 1.1 in patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.Complete response is the disappearance of all lesions with nodes measuring < 10 mm and normal tumour markers.A decrease in the sum of target disease of ≥ 30% represents partial response.Stable disease lies between partial response and progressive disease.If a lesion reappears after disappearing in a patient with complete response, progressive disease is declared. However, if such a lesion behaves in this manner in a patient with stable disease or partial response, it is the change in sum of target disease that defines the response or progression.
Measured: 2 years
Secondary outcomes (13)
Progression-free survival
To evaluate PFS determined by radiology assessment per mRECIST, version 1.1 in patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.Complete response is the disappearance of all lesions with nodes measuring < 10 mm and normal tumour markers.A decrease in the sum of target disease of ≥ 30% represents partial response.Stable disease lies between partial response and progressive disease.If a lesion reappears after disappearing in a patient with complete response, progressive disease is declared. However, if such a lesion behaves in this manner in a patient with stable disease or partial response, it is the change in sum of target disease that defines the response or progression.
Measured: 2 years
overall survival
To evaluate OS determined in patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.Complete response is the disappearance of all lesions with nodes measuring < 10 mm and normal tumour markers.A decrease in the sum of target disease of ≥ 30% represents partial response.Stable disease lies between partial response and progressive disease.If a lesion reappears after disappearing in a patient with complete response, progressive disease is declared. However, if such a lesion behaves in this manner in a patient with stable disease or partial response, it is the change in sum of target disease that defines the response or progression.
Measured: 2 years
Treatment-emergent adverse events
To evaluate treatment-emergent adverse events determined in patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.
Measured: 2 years
adverse events of special interest
To evaluate adverse events of special interest determined in patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.
Measured: 2 years
serious adverse events
To evaluate serious adverse events determined in patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.
Measured: 2 years
t1/2
To evaluate t1/2 determined in patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.t1/2:The half-life of a drug is the time it takes to metabolize half of a drug.
Measured: 2 years
Cmin(minimum concentration)
To evaluate minimum concentration determined in patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.
Measured: 2 years
Cmax(Peak Concentration)
To evaluate Peak Concentration determined in patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.
Measured: 2 years
Css,avg（Mean blood drug concentration）
To evaluate Mean blood drug concentration determined in patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.
Measured: 2 years
Tmax（peak time）
To evaluate peak time determined in patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.
Measured: 2 years
AUC（area under the curve）
To evaluate area under the curve determined in patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.
Measured: 2 years
CL（clearance rate）
To evaluate clearance rate determined in patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.
Measured: 2 years
Vd（volume of distribution）
To evaluate volume of distribution determined in patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Jul 2022
- Study start9 Jul 2022
- Primary completion31 Dec 2025 (estimated)
- Study completion31 Dec 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (19)Papers the sponsor has linked to this study.
- Other trials for Gastrointestinal Stromal TumorsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case only
- Time perspective
- Prospective
- Enrolment
- 74 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Xinhua Zhang, MD
- Sponsor type
- University, hospital or other
- Collaborators
- Peking University Cancer Hospital & Institute, Fudan University, Peking University People's Hospital, Chinese PLA General Hospital, Xiangya Hospital of Central South University, Peking University Shenzhen Hospital, Nanfang Hospital, Southern Medical University, West China Hospital, Jiangsu Cancer Institute & Hospital, Shanghai Zhongshan Hospital, Sun Yat-Sen University Cancer Center, Xijing Hospital, Shengjing Hospital, Shanghai Jiao Tong University School of Medicine, Liaoning Cancer Hospital & Institute, Sixth Affiliated Hospital, Sun Yat-sen University, Fujian Medical University Union Hospital, Cancer Hospital of Guangxi Medical University, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, First Affiliated Hospital of Chongqing Medical University, Chongqing University Cancer Hospital
- Responsible party
- Sponsor-investigator, Xinhua Zhang, MD, First Affiliated Hospital, Sun Yat-Sen University
- Investigators
- Xinhua Zhang, PhD, Principal investigator, First affiliated hosptial,Sun Yat-sen university
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05464875
- Sponsor's protocol ID
- No.[2022]106
- Status last verified
- Feb 2025
- First submitted
- 9 Jul 2022
- Last updated
- 26 Feb 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, Miettinen M, O'Leary TJ, Remotti H, Rubin BP, Shmookler B, Sobin LH, Weiss SW. Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol. 2002 May;33(5):459-65. doi: 10.1053/hupa.2002.123545.
PubMed 12094370von Mehren M, Joensuu H. Gastrointestinal Stromal Tumors. J Clin Oncol. 2018 Jan 10;36(2):136-143. doi: 10.1200/JCO.2017.74.9705. Epub 2017 Dec 8.
PubMed 29220298China Society of Clinical Oncology Gastrointestinal Stromal Tumors Expert Committee. Chinese Consensus on Diagnosis and Treatment of Gastrointestinal Stromal Tumors (2017 Edition). Electronic Journal of Comprehensive Cancer Therapy. 2018;4(1): 31-42.
Ducimetiere F, Lurkin A, Ranchere-Vince D, Decouvelaere AV, Peoc'h M, Istier L, Chalabreysse P, Muller C, Alberti L, Bringuier PP, Scoazec JY, Schott AM, Bergeron C, Cellier D, Blay JY, Ray-Coquard I. Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study with central pathology review and molecular testing. PLoS One. 2011;6(8):e20294. doi: 10.1371/journal.pone.0020294. Epub 2011 Aug 3.
PubMed 21826194Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen CJ, Van den Abbeele AD, Druker BJ, Kiese B, Eisenberg B, Roberts PJ, Singer S, Fletcher CD, Silberman S, Dimitrijevic S, Fletcher JA. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003 Dec 1;21(23):4342-9. doi: 10.1200/JCO.2003.04.190.
PubMed 14645423Casali PG, Zalcberg J, Le Cesne A, Reichardt P, Blay JY, Lindner LH, Judson IR, Schoffski P, Leyvraz S, Italiano A, Grunwald V, Pousa AL, Kotasek D, Sleijfer S, Kerst JM, Rutkowski P, Fumagalli E, Hogendoorn P, Litiere S, Marreaud S, van der Graaf W, Gronchi A, Verweij J; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group, Italian Sarcoma Group, and Australasian Gastrointestinal Trials Group. Ten-Year Progression-Free and Overall Survival in Patients With Unresectable or Metastatic GI Stromal Tumors: Long-Term Analysis of the European Organisation for Research and Treatment of Cancer, Italian Sarcoma Group, and Australasian Gastrointestinal Trials Group Intergroup Phase III Randomized Trial on Imatinib at Two Dose Levels. J Clin Oncol. 2017 May 20;35(15):1713-1720. doi: 10.1200/JCO.2016.71.0228. Epub 2017 Mar 31.
PubMed 28362562Wardelmann E, Merkelbach-Bruse S, Pauls K, Thomas N, Schildhaus HU, Heinicke T, Speidel N, Pietsch T, Buettner R, Pink D, Reichardt P, Hohenberger P. Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res. 2006 Mar 15;12(6):1743-9. doi: 10.1158/1078-0432.CCR-05-1211.
PubMed 16551858Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, Desai J, Fletcher CD, George S, Bello CL, Huang X, Baum CM, Casali PG. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006 Oct 14;368(9544):1329-38. doi: 10.1016/S0140-6736(06)69446-4.
PubMed 17046465Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, Hohenberger P, Leahy M, von Mehren M, Joensuu H, Badalamenti G, Blackstein M, Le Cesne A, Schoffski P, Maki RG, Bauer S, Nguyen BB, Xu J, Nishida T, Chung J, Kappeler C, Kuss I, Laurent D, Casali PG; GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):295-302. doi: 10.1016/S0140-6736(12)61857-1. Epub 2012 Nov 22.
PubMed 23177515Corless CL, Schroeder A, Griffith D, Town A, McGreevey L, Harrell P, Shiraga S, Bainbridge T, Morich J, Heinrich MC. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol. 2005 Aug 10;23(23):5357-64. doi: 10.1200/JCO.2005.14.068. Epub 2005 May 31.
PubMed 15928335Klug LR, Kent JD, Heinrich MC. Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases. Pharmacol Ther. 2018 Nov;191:123-134. doi: 10.1016/j.pharmthera.2018.06.016. Epub 2018 Jun 30.
PubMed 29964125Evans EK, Gardino AK, Kim JL, Hodous BL, Shutes A, Davis A, Zhu XJ, Schmidt-Kittler O, Wilson D, Wilson K, DiPietro L, Zhang Y, Brooijmans N, LaBranche TP, Wozniak A, Gebreyohannes YK, Schoffski P, Heinrich MC, DeAngelo DJ, Miller S, Wolf B, Kohl N, Guzi T, Lydon N, Boral A, Lengauer C. A precision therapy against cancers driven by KIT/PDGFRA mutations. Sci Transl Med. 2017 Nov 1;9(414):eaao1690. doi: 10.1126/scitranslmed.aao1690.
PubMed 29093181Gebreyohannes YK, Wozniak A, Zhai ME, Wellens J, Cornillie J, Vanleeuw U, Evans E, Gardino AK, Lengauer C, Debiec-Rychter M, Sciot R, Schoffski P. Robust Activity of Avapritinib, Potent and Highly Selective Inhibitor of Mutated KIT, in Patient-derived Xenograft Models of Gastrointestinal Stromal Tumors. Clin Cancer Res. 2019 Jan 15;25(2):609-618. doi: 10.1158/1078-0432.CCR-18-1858. Epub 2018 Oct 1.
PubMed 30274985Heinrich MC, Jones RL, von Mehren M, Schoffski P, Serrano C, Kang YK, Cassier PA, Mir O, Eskens F, Tap WD, Rutkowski P, Chawla SP, Trent J, Tugnait M, Evans EK, Lauz T, Zhou T, Roche M, Wolf BB, Bauer S, George S. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol. 2020 Jul;21(7):935-946. doi: 10.1016/S1470-2045(20)30269-2.
PubMed 32615108Jones RL, Serrano C, von Mehren M, George S, Heinrich MC, Kang YK, Schoffski P, Cassier PA, Mir O, Chawla SP, Eskens FALM, Rutkowski P, Tap WD, Zhou T, Roche M, Bauer S. Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: Long-term efficacy and safety data from the NAVIGATOR phase I trial. Eur J Cancer. 2021 Mar;145:132-142. doi: 10.1016/j.ejca.2020.12.008. Epub 2021 Jan 16.
PubMed 33465704
Study at a glance
From the registry record, last updated by the sponsor on 26 Feb 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Multicenter Study of Avapritinib Efficacy and Safety of Metastatic or Unresectable Gastrointestinal Stromal Tumors
- ClinicalTrials.gov ID
- NCT05464875
- Acronym / sponsor ID
- No.[2022]106
- Conditions
- Gastrointestinal Stromal Tumors, Unresectable Solid Tumor, Recurrent Metastatic Malignant Neoplasm
- Keywords
- Avapritinib, Genetic testing
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 74 participants (estimated)
- Lead sponsor
- Xinhua Zhang, MDUniversity, hospital or other
- Collaborators
- Peking University Cancer Hospital & Institute, Fudan University, Peking University People's Hospital, Chinese PLA General Hospital, Xiangya Hospital of Central South University, Peking University Shenzhen Hospital, Nanfang Hospital, Southern Medical University, West China Hospital, Jiangsu Cancer Institute & Hospital, Shanghai Zhongshan Hospital, Sun Yat-Sen University Cancer Center, Xijing Hospital, Shengjing Hospital, Shanghai Jiao Tong University School of Medicine, Liaoning Cancer Hospital & Institute, Sixth Affiliated Hospital, Sun Yat-sen University, Fujian Medical University Union Hospital, Cancer Hospital of Guangxi Medical University, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, First Affiliated Hospital of Chongqing Medical University, Chongqing University Cancer Hospital
- Study start
- 9 Jul 2022 (actual)
- Primary completion
- 31 Dec 2025 (estimated)
- Study completion
- 31 Dec 2025 (estimated)
- First posted
- 19 Jul 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a prospective, multicenter, observational real-world study to explore the therapy patterns and clinical outcomes of Avapritinib in patients with metastatic or unresectable gastrointestinal stromal tumors.
Detailed description
INTRODUCTION AND RATIONALE Gastrointestinal stromal tumors (GIST) are thought to develop from the interstitial cells of Cajal or their stem cell precursors. They are the most common mesenchymal tumors occurring in the gastrointestinal (GI) tract. The annual incidence of GIST is about 1/100,000 ~ 2/100,000 globally. Biological behavior can range from benign to malignant, and immunohistochemical staining is usually positive for CDs 117 and DOG-1, showing Cajal cell differentiation. Eighty-five percent of GISTs is caused by activating mutations in the receptor tyrosine kinase KIT or platelet-derived growth factor receptor alpha (PDGFRA) gene. Targeted therapy for KIT and PDGFRA alters metastatic or unresectable GISTs without effective drug therapy, allowing tumor control and significantly prolonging patient survival. Imatinib, a first-line drug, has been shown to control in 80% of patients, whereas 50% of patients develop tumor progression after twenty-four months of treatment, with an estimated ten-year progression-free survival (PFS) rate of approximately 9 %. The most significant cause of progression was secondary mutations in the ATP binding domain or activation ring of KIT results in resistance to imatinib. Sunitinib, the second-line standard of care, and regorafenib, the third-line standard of care, inhibit some of the secondary mutations, with median PFSs of about 5.6 months for sunitinib and 4.8 months for regorafenib. However, imatinib and other targeted drugs that have been approved for the treatment of GISTs are naturally resistant to the activated ring exon 18 D842V mutation of PDGFRA, which accounts for 5 %-6 %[10% of the primary mutations in GISTs. Avapritinib was approved for marketing in January 2020 for the treatment of PDGFRA D842V mutant GISTs, thus making this type of GISTs medically acceptable.
Avapritinib is a type I tyrosine kinase inhibitor (TKI) that has significant inhibitory effects on KIT or PDGFRA in activated configurations, such as mutations in the KIT or PDGFRA activated loop. Preclinical studies have found broad-spectrum inhibition of KIT or PDGFRA, including mutations in exons 11,17,18 of KIT, and mutations in exon 18 of PDGFRA, with a 24 hr, concentration-dependent inhibitory effect. Weak affinity for wild-type KIT and PDGFRA, PDGFRB, CSF1R, and FLT3. In the Phase 1 clinical study in patients with metastatic or unresectable PDGFRA D842V-mutated GISTs, the objective response rate (ORR) for avapritinib was 91%, with a complete response rate of 13%, a median duration of efficacy (DOR) of 27.6 m (95% CI 17.6-N%), and a median PFS of 34 m (95% CI 22.9-N%) estimated to be 61% at 36months. The daily 30-600 mg of Avapritinib showed an initial anti-tumor effect, but the time to effect at the high dose was significantly shorter than at the low dose. Both the US and the European Medicines Agency (FDA and EMA) have approved the use of Avapritinib in GISTs with PDGFRA exon 18 mutations due to its significant therapeutic effect on PDGFRA D842V mutations. In patients with KIT or non-D842V PDGFRA mutations treated more than three lines, the ORRs of atorvastatin were 17%, all were partial responses (PRs), the median DORs were 10.2 m (95% CI 7.% -10.2), the clinical benefit rate (CBRs) was 38%, the median PFSs were 3.7 m (95% CI 2.% -4.6), the median OSs were 11.6 m (95% CI 9.% -12.6), and there was no difference in efficacy between the 300 mg and 400 mg daily dose groups. The above studies showed that Avapritinib was effective in the treatment of PDGFRA D842V mutant GISTs, and some patients with KIT or non-D842V PDGFRA mutations were able to obtain tumor control from the treatment of Avapritinib, with a dose effect on the anti-tumor efficacy, but no significant difference in the high dose 300 mg or 400 mg efficacy.
With respect to the safety of avapritinib, patients with >99% reported at least one adverse event (Adverse events, AEs), with common AEs including nausea (59%), fatigue (50%), periorbital edema (42%), anemia (39%), diarrhea (36%), and vomiting (33%). The incidence of grade ≥3 AEs was 72% and higher in the 400 mg dose group than in the 300 mg dose group, 84% and 73%, respectively. Common AEs included anemia (30%), fatigue (8%), abdominal pain (6%) and hypophosphatemia (6%). The incidence and severity of AEs in elderly patients (≥65 y) was slightly higher than that in younger patients. The incidence of treatment-related adverse events leading to discontinuation of Avapritinib was 11.2%, the most common were cognitive effects (4.1%), intracranial hemorrhage (1.2%), fatigue (<1%), and vomiting (<1%), which were higher in the 400 mg group than in the 300 mg group. The incidence of downtitration of Avapritinib was (32%), and the incidence of AEs of each grade and grade ≥3 was significantly lower after downtitration than before downtitration.
Preclinical studies with avapritinib suggest that the drug can penetrate the blood-brain barrier with a brain-to-plasma concentration ratio of 0.7 -1.0 3, leading to edema of the choroid plexus in dogs and intracranial hemorrhage at high doses. Therefore, central nervous system AEs, including cognitive effects and intracranial haemorrhage [14], are of particular interest in clinical studies. In the Phase I/II clinical study of Avapritinib (Navigator), the incidence of cognitive effects in patients receiving Avapritinib was 42% (104/250) and 40% in the 300 mg group, which was lower than that in the 400 mg dose group (50%). Memory impairment was the most common manifestation of cognitive effects, with an incidence of 27% in the 300 mg group and 40% in the 400 mg group, with a higher incidence in elderly patients (age ≥65 y). The cognitive effects were mostly Grade 1-2 in the Avapritinib 300 mg group and 7.5% in the Avapritinib 300 mg group. The cognitive effects were improved in most patients by discontinuation or dose adjustment, with a median adjusted dose of 233 mg. The incidence of intracranial hemorrhage was 2.4% in the Avapritinib 300 mg dose group, one case of grade 1 subdural hematoma, three cases of grade 1, 2 and 4 intracranial hemorrhage, and one case of grade 3 intracranial hemorrhage. Intracranial hemorrhage was improved by discontinuation or dose adjustment, and no patient died due to intracranial hemorrhage. Median PFSs were 11.4 m (95 %CI 8.% -20.3) in dose-reduced patients and 7.2 m (95 %CI 5.% -24.0) in dose-unadjusted patients, with similar trends for both non-D842V 4 + line therapy and D842V mutations. These studies indicate that the overall safety of Avapritinib is adequate, but special attention needs to be paid to central nervous system AEs, including cognitive abnormalities and cerebral haemorrhage, which have a dose effect, the incidence of high-dose cognitive abnormalities of Avapritinib is higher, the incidence of high-dose cognitive abnormalities of Avapritinib is higher after dose reduction, whether D842V mutations or non-D842V mutations, dose adjustment does not affect survival, and PFSs are longer in appropriately reduced-dose patients.
Avapritinib is a small molecule oral TKI with a dose-proportional increase in Cmax and AUC over the 30-400 mg qd range with a mean accumulation rate of 2. -8.9 2 after repeat dosing. Protein binding was 98.8%, mainly metabolized by CYP3A in vivo, 70% excreted in feces, major metabolite, and plasma elimination half-life was 32-57 h. Pharmacokinetic inter-individual differences were large, with in vivo exposure varying up to 8-10-fold in the 300 mg qd dose group. Approximately 50% or more of the patients who started 300 mg qd had high drug exposures, and the incidence of cognitive abnormalities was associated with cumulative exposure to Avapritinib, i.e., there were large individual pharmacokinetic differences, with a tendency to increase the incidence of Grade III or IV AEs as patients' in vivo concentrations of Avapritinib increased. However, there are no lowest effective exposures and highest toxic exposures leading to central nervous AEs in the benefit populations of atorvastatin for the treatment of PDGFRA D842V mutations and PDGFRA mutations with KIT or non-D842V.
Therefore, it is necessary to conduct a multicenter observational study on the pharmacokinetics, efficacy, and safety of Avapritinib in patients with metastatic or unresectable GIST, to explore the influencing factors on the pharmacokinetics of Avapritinib, to identify the treatment window of Avapritinib, so that the dose can be adjusted according to the in vivo exposure of Avapritinib, to reduce the risk or severity of AEs, to improve the treatment effect, and to conduct individualized administration.
Study design
- Observational model
- Case only
- Time perspective
- Prospective
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Approximately 74 patients with metastatic or unresectable advanced gastrointestinal stromal tumors from tier-3 hospitals who meet the criteria will be enrolled in the study.
Key inclusion criteria (7 listed)
- Patients who are aged ≥ 18 years.
- Gastrointestinal stromal tumors confirmed by histopathological examination, and CD- and/or DOG-1-positive by immunohistochemistry.
- Presence of mRECIST v1.1-compliant lesions with at least one measurable lesion (non-lymphadenopathy ≥1.0 cm or ≥2-fold scan slice thickness).
- Treatment with Avapritinib.
- Patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2 at screening.
Key exclusion criteria (3 listed)
- KIT or PDGFRA wild type.
- Failure to complete continuous atorvastatin for at least 15 days due to intolerability or disease progression.
- Other serious acute or chronic physical or mental problems, or laboratory abnormalities, may increase the risk associated with participation in the study or use of drugs, or interfere with the judgment of the study results and, in the judgment of the investigator, are not considered appropriate for participation in the investigator.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Objective Response Rate
Time frame: 2 years
To evaluate objective response rate (ORR,CR+PR) determined by radiology assessment per mRECIST(Response Evaluation Criteriain Solid Tumours), version 1.1 in patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.Complete response is the disappearance of all lesions with nodes measuring < 10 mm and normal tumour markers.A decrease in the sum of target disease of ≥ 30% represents partial response.
Clinical Benefit Rate
Time frame: 2 years
To evaluate clinical benefit rate(CBR,CR+PR+>16 weeks continuation SD) determined by radiology assessment per mRECIST, version 1.1 in patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.Complete response is the disappearance of all lesions with nodes measuring < 10 mm and normal tumour markers.A decrease in the sum of target disease of ≥ 30% represents partial response.Stable disease lies between partial response and progressive disease.
Duration Of Response
Time frame: 2 years
To evaluate duration of response (DOR) determined by radiology assessment per mRECIST, version 1.1 in patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.Complete response is the disappearance of all lesions with nodes measuring < 10 mm and normal tumour markers.A decrease in the sum of target disease of ≥ 30% represents partial response.Stable disease lies between partial response and progressive disease.If a lesion reappears after disappearing in a patient with complete response, progressive disease is declared. However, if such a lesion behaves in this manner in a patient with stable disease or partial response, it is the change in sum of target disease that defines the response or progression.
13 secondary outcomes
Progression-free survival
Time frame: 2 years
overall survival
Time frame: 2 years
Treatment-emergent adverse events
Time frame: 2 years
adverse events of special interest
Time frame: 2 years
serious adverse events
Time frame: 2 years
t1/2
Time frame: 2 years
Cmin(minimum concentration)
Time frame: 2 years
Cmax(Peak Concentration)
Time frame: 2 years
Css,avg（Mean blood drug concentration）
Time frame: 2 years
Tmax（peak time）
Time frame: 2 years
AUC（area under the curve）
Time frame: 2 years
CL（clearance rate）
Time frame: 2 years
Vd（volume of distribution）
Time frame: 2 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Feb 2025.
- Results publication: PubMed 12094370Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, Miettinen M, O'Leary TJ, Remotti H, Rubin BP, Shmookler B, Sobin LH, Weiss SW. Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol. 2002 May;33(5):459-65. doi: 10.1053/hupa.2002.123545.
- Results publication: PubMed 29220298von Mehren M, Joensuu H. Gastrointestinal Stromal Tumors. J Clin Oncol. 2018 Jan 10;36(2):136-143. doi: 10.1200/JCO.2017.74.9705. Epub 2017 Dec 8.
- Results publicationChina Society of Clinical Oncology Gastrointestinal Stromal Tumors Expert Committee. Chinese Consensus on Diagnosis and Treatment of Gastrointestinal Stromal Tumors (2017 Edition). Electronic Journal of Comprehensive Cancer Therapy. 2018;4(1): 31-42.
- Results publication: PubMed 21826194Ducimetiere F, Lurkin A, Ranchere-Vince D, Decouvelaere AV, Peoc'h M, Istier L, Chalabreysse P, Muller C, Alberti L, Bringuier PP, Scoazec JY, Schott AM, Bergeron C, Cellier D, Blay JY, Ray-Coquard I. Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study with central pathology review and molecular testing. PLoS One. 2011;6(8):e20294. doi: 10.1371/journal.pone.0020294. Epub 2011 Aug 3.
- Results publication: PubMed 14645423Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen CJ, Van den Abbeele AD, Druker BJ, Kiese B, Eisenberg B, Roberts PJ, Singer S, Fletcher CD, Silberman S, Dimitrijevic S, Fletcher JA. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003 Dec 1;21(23):4342-9. doi: 10.1200/JCO.2003.04.190.
- Results publication: PubMed 28362562Casali PG, Zalcberg J, Le Cesne A, Reichardt P, Blay JY, Lindner LH, Judson IR, Schoffski P, Leyvraz S, Italiano A, Grunwald V, Pousa AL, Kotasek D, Sleijfer S, Kerst JM, Rutkowski P, Fumagalli E, Hogendoorn P, Litiere S, Marreaud S, van der Graaf W, Gronchi A, Verweij J; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group, Italian Sarcoma Group, and Australasian Gastrointestinal Trials Group. Ten-Year Progression-Free and Overall Survival in Patients With Unresectable or Metastatic GI Stromal Tumors: Long-Term Analysis of the European Organisation for Research and Treatment of Cancer, Italian Sarcoma Group, and Australasian Gastrointestinal Trials Group Intergroup Phase III Randomized Trial on Imatinib at Two Dose Levels. J Clin Oncol. 2017 May 20;35(15):1713-1720. doi: 10.1200/JCO.2016.71.0228. Epub 2017 Mar 31.
- Results publication: PubMed 16551858Wardelmann E, Merkelbach-Bruse S, Pauls K, Thomas N, Schildhaus HU, Heinicke T, Speidel N, Pietsch T, Buettner R, Pink D, Reichardt P, Hohenberger P. Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res. 2006 Mar 15;12(6):1743-9. doi: 10.1158/1078-0432.CCR-05-1211.
- Results publication: PubMed 17046465Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, Desai J, Fletcher CD, George S, Bello CL, Huang X, Baum CM, Casali PG. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006 Oct 14;368(9544):1329-38. doi: 10.1016/S0140-6736(06)69446-4.
- Results publication: PubMed 23177515Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, Hohenberger P, Leahy M, von Mehren M, Joensuu H, Badalamenti G, Blackstein M, Le Cesne A, Schoffski P, Maki RG, Bauer S, Nguyen BB, Xu J, Nishida T, Chung J, Kappeler C, Kuss I, Laurent D, Casali PG; GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):295-302. doi: 10.1016/S0140-6736(12)61857-1. Epub 2012 Nov 22.
- Results publication: PubMed 15928335Corless CL, Schroeder A, Griffith D, Town A, McGreevey L, Harrell P, Shiraga S, Bainbridge T, Morich J, Heinrich MC. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol. 2005 Aug 10;23(23):5357-64. doi: 10.1200/JCO.2005.14.068. Epub 2005 May 31.
- Results publication: PubMed 29964125Klug LR, Kent JD, Heinrich MC. Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases. Pharmacol Ther. 2018 Nov;191:123-134. doi: 10.1016/j.pharmthera.2018.06.016. Epub 2018 Jun 30.
- Results publication: PubMed 29093181Evans EK, Gardino AK, Kim JL, Hodous BL, Shutes A, Davis A, Zhu XJ, Schmidt-Kittler O, Wilson D, Wilson K, DiPietro L, Zhang Y, Brooijmans N, LaBranche TP, Wozniak A, Gebreyohannes YK, Schoffski P, Heinrich MC, DeAngelo DJ, Miller S, Wolf B, Kohl N, Guzi T, Lydon N, Boral A, Lengauer C. A precision therapy against cancers driven by KIT/PDGFRA mutations. Sci Transl Med. 2017 Nov 1;9(414):eaao1690. doi: 10.1126/scitranslmed.aao1690.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Xinhua Zhang, PhD principal investigator
First affiliated hosptial,Sun Yat-sen university
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Gastrointestinal Stromal Tumors and Unresectable Solid Tumor, run by Xinhua Zhang, MD at 1 site in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 26 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Xinhua Zhang, PhD (+8620-87332200, zhangxinhua@mail.sysu.edu.cn), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Objective Response Rate (time frame: 2 years). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05464875, which also lists 19 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Feb 2025.