Trial Title:
Rivoceranib Plus Paclitaxel in Patients With Gastrointestinal Stromal Tumor
NCT ID:
NCT05905887
Condition:
Gastrointestinal Stromal Tumors
Conditions: Official terms:
Gastrointestinal Stromal Tumors
Paclitaxel
Apatinib
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Rivoceranib Mesylate, Paclitaxel
Description:
Paclitaxel will be administered at 80mg/m2/day every four weeks at Day 1, Day 8 and Day
15 per cycle. One cycle consists of 4 weeks (28 days).
Rivoceranib 400 mg orally once a day.
Arm group label:
rivoceranib plus paclitaxel
Summary:
The purpose of this study is to evaluate the efficacy and safety of rivoceranib and
paclitaxel combination therapy in patients with P-glycoprotein overexpressing GIST who
failed standard treatment with imatinib, sunitinib, and regorafenib.
Detailed description:
With the development of KIT mutation and KIT tyrosine kinase inhibitor imatinib
(GlivecTM, Novartis), survival of patients with advanced and/or metastatic
gastrointestinal stromal tumor (GIST) has significantly improved. Recently, sunitinib
(SuteneTM, Pfizer) and regorafenib (StivargaTM, Bayer) have been proven to be effective
as second- and third-line treatment, respectively in GIST patients who failed to imatinib
treatment. However, almost all patients eventually experience disease progression due to
the development of drug resistance to first-line imatinib, second-line sunitinib
treatment, and third-line regorafenib. As a fourth-line treatment, ripretinib was proven
to prolong progression-free survival as compared to placebo with a median
progression-free survival of 6.3 months in the Phase 3 INVICTUS study. However,
ripretinib is not available in many regions including Korea, making it difficult to use.
Therefore, a new treatment options are needed in the clinical setting post-imatinib,
sunitinib and regorafenib.
Historic data suggest that GISTs do not respond to conventional cytotoxic chemotherapy,
but systematic unbiased screening has not been performed. A recent large-scaled
chemotherapy susceptibility screening with GIST cells showed that among a total of 89
chemotherapies, 37 have anti-cancer effect in at least one type of GIST cells. It was
suggested that of these agents, transcriptional inhibitors and chemotherapies such as
topoisomerase II, paclitaxel, and bortezomib would be effective. Based on these results,
our group has recently performed a phase II study for evaluating efficacy and safety of
paclitaxel in patients with advanced and/or metastatic GIST after failure of at least
imatinib and sunitinib. Although paclitaxel showed overall limited anti-tumor efficacy,
it was more effective in patients with low P-glycoprotein expression. Based on these
study results, it was hypothesized that paclitaxel would also be effective in GIST
patients, and a phase II study was conducted to evaluate the efficacy and safety of
paclitaxel in 25 patients with advanced and/or metastatic GIST who failed imatinib and
sunitinib treatment. At week 16, the disease control rate (DCR; response + stable lesion)
was 16.7%, showing a limited anticancer effect. However, in patients with a low level of
P-glycoprotein expression, the DCR was 25% at 16 weeks, suggesting that paclitaxel may be
efficacious in this clinical setting. Subsequently, a phase II clinical trial of
paclitaxel is currentl ongoing in patients with metastatic or progressive GIST with low
P-glycoprotein expression who have failed imatinib, sunitinib, and regorafenib treatment
in patients with a low P-glycoprotein expression level. However, data from Asan Medical
Center suggest that only about 20% of GISTs have a low P-glycoprotein expression level
(IHC score 3 points or less) in this clinical setting.
P-glycoprotein is a plasma membrane protein that acts as an efflux pump for drugs and is
implicated in multidrug resistance. In particular, hydrophobic chemotherapeutic agents
such as paclitaxel are known to be substrates of P-glycoprotein, supporting the concept
that GIST patients with high P-glycoprotein expression may be resistant to paclitaxel.
This raise the possibility that paclitaxel-based combination treatment may be considered
when the function of P-glycoprotein is inhibited.
Ricoveranib is a mutikinase inhibitor with anti-angiogenic activity. In a phase 3 study
conducted in China, rivoceranib improved overall survival compared to placebo as a
3rd-line treatment for metastatic gastric cancer. In addition, an improvement in
progression-free survival compared to placebo was confirmed in the multinational phase 3
ANGEL study. Recently, the combination therapy of rivoceranib and camrelizumab, an immune
checkpoint inhibitor, in unresectable liver cancer has been proven to improve survival
results compared to sorafenib. When it comes to the treatment of GIST, the
anti-angiogenic activity and inhibition of P-glycoprotein by rivoceranib suggest its
potential use in GIST patients. In particular, when used in combination with paclitaxel
in GIST whose P-glycoprotien expression level is high, rivoceranib is expected to have an
additional or synergistic anti-tumor activity. In a phase 1 clinical study of metastatic
gastric cancer, the combination therapy of rivoceranib and palclitaxel was confirmed to
be safe as well as showing clinical efficacy. The recommended dose for phase 2 study was
rivoceranib 400mg and paclitaxel 80mg/m2 (days 1,8 and 15, 4-week cycle).
The objective of this study is to evaluate the safety and efficacy of paclitaxel in
combination with rivoceranib in patients with metastatic or advanced GIST with a high
P-glycoprotein expression level after failure of at least imatinib, sunitinib and
regorafenib.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Age 20 years or older, at the time of acquisition of informed consent
- Histologically confirmed metastatic and/or advanced GIST with CD117(+), DOG-1(+), or
mutation in KIT or PDGFRα gene
- P-glycoprotin IHC score > 3 (Tumor tissue with disease progression after regorafenib
treatment)
- Failed (progressed and/or intolerable) after prior treatments for GIST, including at
least imatinib and sunitinib, regorafenib.
- Eastern Cooperative Oncology Group (ECOG) performance status 0 ~ 2
- Resolution of all toxic effects of prior treatments to grade 0 or 1 by NCI-CTCAE
version 5.0
- At least one measurable lesion as defined by RECIST version 1.1.
- Adequate bone marrow, hepatic, renal, and other organ functions Neutrophil
>1,500/mm3 Platelet > 100,000/mm3 Hemoglobin >8.0 g/dL Total bilirubin < 1.5 x upper
limit of normal (ULN) AST/ALT < 2.5 x ULN Creatinine <1.5 x ULN
- Life expectancy > 12 weeks
- Washout period of previous TKIs or chemotherapy for more than 4 times the half life
((Imitinib and regorafenib need 1 week and sunitinib need 2 weeks.)
- Provision of a signed written informed consent
Exclusion Criteria:
- Women of child-bearing potential who are pregnant or breast feeding
- Women or men who are not willing to use effective contraception entering the study
period or until at least 3 months after the last study drug administration.
- If any of the following applies within ≤ 6 months prior to starting study enrollment
: Myocardial Infarction, severe instable angina, coronary/peripheral bypass, NYHA
class III or IV congestive heart failure, stroke or transient ischemic attack,
treatment required severe arrhythmia.
- Uncontrolled infection
- Acute and chronic liver disease and all chronic liver impairment.(But Patients with
stable chronic hepatitis B are eligible)
- Uncontrolled gastrointestinal toxicities with toxicity greater than NCI CTCAE grade
2
- Acute, or chronic medical or psychiatric condition or laboratory abnormality such as
active uncontrolled infection that difficult to study participation in the judgment
of the investigator
- The patient experienced any bleeding episode considered life-threatening, or any
grade 3 or 4 bleedig event. (required transfusion or endoscopic or surgical
intervention)
- Currently clinically significant (within 7 days prior to screening) treatment of
anticoagulants or other thrombolytic agents. A maximum dose of 325 mg/day of aspirin
is allowed
- History of uncontrolled hypertension (blood pressure ≥140/90 mmHg and change in
antihypertensive medication within 7 days prior to screening) that is not well
managed by medication and the risk of which may be precipitated by a VEGF inhibitor
therapy.
- History of clinically serious opearation, bone fracture or non-healing wounds within
the last 3 weeks prior to screening
- History of other significant cardiovascular diseases or vascular diseases, within
the last 6 months prior to screening (e.g., hypertensive crisis, and hypertensive
encephalopathy or transient ischemic attack or significant peripheral vascular
diseases] that, in the investigator's opinion, may pose a risk to the patient on
VEGFR inhibitor therapy.
- History of clinically significant glomerulonephritis, biopsy-proven
tubulointerstitial nephritis, crystal nephropathy, or other renal insufficiencies
- Known diagnosis of HIV infection (HIV testing is not mandatory).
- History of another primary malignancy that is currently clinically significant or
currently requires active intervention.
- Patients with clinically suspected brain metastasis symptom, brain metastases as
assessed by radiologic imaging
- Alcohol or substance abuse disorder.
- Known hypersensitivity to rivoceranib or any component of its formulation or history
of severe hypersensitivity to including Cremophor R EL(polyoxyethylated castor oil)
drug
- Concomitant treatment with strong inhibitors or inducers of CYP3A4, CYP2C9 and
CYP2C19
- Active bacterial infections
Gender:
All
Minimum age:
20 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Asan Medical Center, University of Ulsan College of Medicine
Address:
City:
Seoul
Zip:
138-736
Country:
Korea, Republic of
Status:
Recruiting
Contact:
Last name:
Min-Hee Kang, MD, PhD
Phone:
+82-2-3010-5935
Email:
miniryu@amc.seoul.kr
Contact backup:
Last name:
Hyung-Don Kim, MD, PhD
Phone:
+82-2-3010-0236
Email:
kimhdmd@amc.seoul.kr
Start date:
September 6, 2023
Completion date:
December 31, 2026
Lead sponsor:
Agency:
Asan Medical Center
Agency class:
Other
Source:
Asan Medical Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05905887
