Primary Objective:* The primary objective is to demonstrate the efficacy of avapritinib based on progression-free survival (PFS) determined by central radiological assessment per modified Response Evaluation Criteria in Solid Tumors (mRECIST),…
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Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is PFS, based on central radiological assessment per
mRECIST, version 1.1, in patients with advanced GIST. Progression-free survival
is defined as time from randomization to disease progression, or death due to
any cause, whichever occurs first.
Secondary outcome
The key secondary endpoints are:
* Objective response rate defined as the percentage of patients whose best
response is CR or PR as assessed by central radiology using mRECIST, version
1.1.
* Overall survival defined as the time from date of randomization to death due
to any cause.
Background summary
Approximately 90% of patients with GIST have a tumor that is dependent on a
mutation in either V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene
homolog (KIT) (75%-80%) or the highly related protein platelet-derived growth
factor receptor alpha (PDGFR*) (10%-15%). On a molecular level, the most common
sites for oncogenic mutations at the time of diagnosis are in the juxtamembrane
domain (exon 11 [60%-70%]) and extracellular domain (exon 9 [5%-15%]) for KIT
and in the activation loop (Exon 18) for PDGFR* where the most common
activation loop mutation is D842V. The current treatment paradigm for advanced
GIST involves successive use of tyrosine kinase inhibitors (TKIs) that target
KIT or PDGFR*.
Avapritinib (formerly BLU-285), a highly potent and selective oral kinase
inhibitor, was designed to treat imatinib-resistant GIST by targeting
KIT/PDGFR* activation loop mutants. Avapritinib has potent activity on the KIT
and PDGFR* activation loop mutants (exon 17/18), including the D842V mutation,
with biochemical half-maximal inhibitory concentration (IC50) against all
activation loop mutants of less than 2 nM. In addition, avapritinib has
demonstrated considerable potency across a wide array of disease-relevant KIT
mutants found in patients with GIST including those that appear as secondary
mutants after imatinib treatment and those found as primary mutants in
imatinib-naïve GIST.
No currently approved TKI selectively and potently inhibits activation loop
mutations of KIT and PDGFR*. Thus, GISTs linked to either of these mutations
represent an important medical need especially in patients who did not respond
to imatinib and 1 other TKI and who have not been treated with regorafenib.
Study objective
Primary Objective:
* The primary objective is to demonstrate the efficacy of avapritinib based on
progression-free survival (PFS) determined by central radiological assessment
per modified Response Evaluation Criteria in Solid Tumors (mRECIST), version
1.1 in patients with advanced GIST following 2 or 3 prior TKI therapies,
including imatinib, compared to patients treated with regorafenib.
The key secondary objectives are:
* To evaluate objective response rate (ORR) determined by central radiology
assessment per mRECIST, version 1.1 in patients with advanced GIST treated with
avapritinib compared to patients treated with regorafenib.
* To evaluate overall survival (OS) in patients with advanced GIST treated with
avapritinib compared to patients treated with regorafenib.
Study design
This is an open-label, randomized, Phase 3 study in patients with locally
advanced unresectable or metastatic GIST (advanced GIST) of avapritinib versus
regorafenib in patients previously treated with imatinib and 1 or 2 other TKIs.
All study visits are intended to be conducted on an outpatient basis. After
provision of written informed consent, patients will be evaluated for study
eligibility during the screening period within 4 weeks (28 days) before study
drug administration on Cycle 1 Day 1 (C1D1). During the screening period,
eligibility will be confirmed; management of baseline concomitant conditions
will be recorded and stabilized; and baseline symptoms will be assessed.
Hematology, blood chemistry, mutation status, brain imaging (computed
tomography [CT] scan or magnetic resonance imaging [MRI]), and baseline tumor
assessments (CT scan or MRI) will be performed within 28 days of C1D1.
Patients will be randomly assigned, in a 1:1 ratio, to 1 of 2 treatment arms:
Arm A (avapritinib) or Arm B (regorafenib) stratified by treatment regimen
(third vs. fourth), geographic region (Asia vs. rest of the world), and
mutation status measured in ctDNA or a tumor sample (PDGFR* D842V mutation
present vs. absent). Patients randomized to Arm A will receive avapritinib 300
mg orally (PO) once daily (QD). Patients who experience disease progression on
avapritinib, based on central review, will be offered the opportunity to
continue taking treatment with avapritinib if there is no clinical evidence of
disease progression (including worsening of laboratory values); the patient is
not experiencing rapid progression of disease or a progressive tumor requiring
urgent alternative medical intervention at critical anatomical sites (eg,
spinal cord compression); and there has been no decline in Eastern Cooperative
Oncology Group Performance Status (ECOG PS). Patients randomized to ArmA must
consent to continue avapritinib treatment after disease progression.
Patients randomized to Arm B will receive regorafenib 160 mg PO QD for 3 weeks
out of every 4 weeks (28 days) cycle (ie, 3 weeks on/1 week off). Patients who
experience disease progression on regorafenib (Arm B), as confirmed by central
radiology review, may be offered the opportunity to cross over to the
avapritinib treatment arm (Arm A) after an evaluation of their disease
progression and a washout period of 7 to 28 days after their last dose of
regorafenib.
At least 60% of the patients enrolled should be receiving the study drug as
their third treatment regimen for GIST, ie, no more than 40% of patients should
be receiving the study drug as their fourth treatment regimen for GIST. In
addition, patients will receive best supportive care, excluding any additional
anticancer therapy such as any systemic antineoplastic therapy (including
kinase inhibitors and chemotherapy), radiation therapy, or surgery.
All patients will present to the study center on C1D1 for the first dose of
study drug, vital sign measurements, safety monitoring, quality-of-life (QoL)
assessment, PRO assessments, electrocardiogram (ECG) assessment, and AE
recording. On Cycle 2 Day 1 (C2D1) and Cycle 3 Day 1 (C3D1), patients will
present to study centers for physical examination, laboratory assessments, QoL
assessments, PRO assessments, and AE/concomitant medication recording. For all
subsequent cycles, all patients will attend study center visits every other
cycle on Day 1 of odd cycles (ie, C5D1, C7D1 etc.) for safety monitoring
including ECG, hematology, blood chemistry, QoL assessments, PRO assessments,
and AE recording. At any point in time between treatment cycles patients should
attend or contact the study center for AE reporting, evaluation, and medical
intervention.
Tumor assessments will be performed at Baseline and then every 8 weeks (± 1
week), regardless of the scheduled treatment cycles, ie, if study treatment is
interrupted or discontinued for any reason, tumor imaging should continue
according to an 8-week schedule until tumor progression is confirmed by central
radiology review. Computed tomography with intravenous contrast is the
preferred imaging modality, unless a site of disease is better evaluated by MRI.
All patients will attend an End-of-Treatment (EOT) visit within 14 (±7) days
after the last dose of study drug. A safety Follow-up visit for resolution of
any ongoing AE will be made on Day 30 (±7 days) after the last dose of study
drug, or at the time the patient initiates another antineoplastic therapy.
Patients who discontinue study treatment before disease progression will
undergo tumor assessments every 8 weeks until disease progression, death, or
patient withdrawal of consent. After documentation of disease progression by
central radiology review, patients are to be followed for subsequent
antineoplastic therapy and survival approximately every 2 months until death,
withdrawal of consent or closure of the study by the Sponsor.
Intervention
Patients will be randomly assigned, in a 1:1 ratio, to 1 of 2 treatment arms:
Arm A (avapritinib) or Arm B (regorafenib) stratified by treatment regimen
(third vs. fourth), geographic region (Asia vs. rest of the world), and
mutation status measured in ctDNA or a tumor sample (PDGFR* D842V mutation
present vs. absent).
Group A: avapritinib 300 mg orally (PO) once daily (QD), dose escalation to 400
mg PO QD is permitted
Group B: regorafenib 160 mg PO QD for 3 weeks out of every 4 weeks (28 days)
cycle (ie, 3 weeks on/1 week off).
It is anticipated that patients will receive at least 1 cycle of avapritinib if
randomized to Arm A and regorafenib if randomized to Arm B; no maximum
treatment duration has been set. After C1, patients may continue to receive
study drug until precluded by toxicity, noncompliance, pregnancy, withdrawal of
consent, physician decision, progressive disease (PD), death, or closure of the
study by the sponsor.
Study burden and risks
No currently approved TKI effectively inhibits exon 17 mutant KIT or D842V
mutant PDGFRa. Thus, GIST dependent on either of these mutations represents an
unmet medical need. Similarly, the D816V mutation in KIT, which is in exon 17,
is an important driver in SM. Preclinical data suggest that avapriti nib
(formerly BLU-285), a selective and potent inhibitor of exon 17 mutant KIT and
D842 mutant PDGFRa, may be active in these clinical settings.
Preliminary review of efficacy data in the GIST study appears positive for both
PDGFRa D842- driven GIST and treatment-resistant KIT-driven GIST.
Following review of the cumulative safety information obtained thus far in
ongoing clinical trials, the benefit/risk ratio of avapritinib remains
favorable for continuation of the development program.
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Listed location countries
Age
Inclusion criteria
1. Patients who are * 18 years of age.
2. Patients who have GIST, which is histologically confirmed metastatic and/or
unresectable (confirmed to be unresectable by a qualified surgeon).
3. Patients who received imatinib and 1 or 2 other TKIs for the treatment of
GIST, including TKIs used for adjuvant therapy. Each different TKI is counted
once regardless of how often it was used, and if two different TKIs are used in
combination, both TKIs are counted. Patients must have disease progression
prior to enrollment. Prior use of other systemic and local therapies is not
restricted.
4. Patients who have an ECOG PS of 0 to 1.
5. Patients, or legal guardian if permitted by local regulatory authorities,
who provides informed consent to participate in the study.
Exclusion criteria
1. Patients who have received prior treatment with avapritinib or regorafenib.
2. Patients who have received more than 3 different TKIs for the treatment of
GIST, including TKIs used for adjuvant therapy. Each different TKI is counted
once regardless of how often it was used, and if two different TKIs are used in
combination, both TKIs are counted.
3. Patients who are known to be both KIT and PDGRF* wild type.
4. Patients who received any systemic anticancer therapy within 1 week before
the first dose of study drug. Prior radiotherapy (including stereotactic
radiotherapy) to major organs within 2 weeks of the first dose of study drug,
or focal radiotherapy, (including stereotactic radiotherapy), such as to
bones, limbs, or other areas not involving major organs, within 3 days.
5. Patients who have clinically significant, uncontrolled, cardiovascular
disease, including congestive heart failure Grades II, III or IV according to
the New York Heart Association classification, myocardial infarction or
unstable angina within the previous 6 months, or uncontrolled
hypertension.
6. Patients who have experienced arterial thrombotic or embolic events such as
cerebrovascular accident within 6 months before the first dose of study drug,
or venous thrombotic events such as pulmonary embolism within the 14 days
before the first dose of study drug or deep vein thrombosis within 14 days
before the first dose of study drug. Patients with venous thrombotic events
such as pulmonary embolism or deep vein thrombosis * 14 days before the first
dose of study drug are not excluded provided they are on stabel dosis of
anticoagulation, or have completed the planned coagulation regimen.
7. Patients who have experienced any hemorrhage or bleeding event NCI CTCAE
version 5.0 Grade 3 or higher within 4 weeks before the first dose of study
drug.
8. Patients who have a known risk of intracranial bleeding, such as a brain
aneurysm that has not been removed or repaired, or history of intracranial
bleeding within one year prior to randomization.
9. Patients who have a symptomatic non-healing wound, ulcer, gastrointestinal
perforation, or bone fracture.
10. Patients who have poor organ function as defined by one or more laboratory
parameters, as described in the protocol.
11. Patients who have received neutrophil growth factor support within 14 days
of the first dose of study drug.
12. Patients who require therapy with a concomitant medication that is a strong
inhibitor or strong or moderate inducer of CYP3A4.
13. Patients who have had a major surgical procedure within 14 days of the
first dose of study drug. Patient has significant traumatic injury within 28
days before the first dose of study drug.
14. Patients who have a history of another primary malignancy that has been
diagnosed or required therapy within 3 years before the first dose of study
drug. The following prior malignancies are not exclusionary: completely
resected basal cell and squamous cell skin cancer, curatively treated localized
prostate cancer, and completely resected carcinoma in situ of any site.
Patients with a prior or concurrent malignancy whose natural history or
treatment does not have the potential to interfere with the safety or efficacy
assessment of the investigational agent may be included after approval by
medical monitor.
15. Patients who have a history of a seizure disorder requiring antiseizure
medication.
16. Patients who have metastases to the brain.
17. Patients who are unwilling or unable to comply with scheduled visits, drug
administration plan, laboratory tests, or other study procedures and study
restrictions.
18. Patients who have a QT interval corrected using Fridericia's formula (QTcF)
of > 450 msec
19. Women who are unwilling, if not postmenopausal or surgically sterile, to
abstain from sexual intercourse or employ highly effective contraception from
the time of the first dose of study drug and for at least 60 days after the
last dose of study drug. Men who are unwilling, if not surgically sterile, to
abstain from sexual intercourse or employ highly effective contraception from
the time of the first dose of study drug and for at least 90 days after the
last dose of study drug.
20. Women who are pregnant, as documented by a serum beta human chorionic
gonadotropin (*hCG ) pregnancy test consistent with pregnancy, obtained within
7 days before the first dose of study drug.
21. Women who are breastfeeding.
22. Patients who have prior or ongoing clinically significant illness, medical
condition, surgical history, physical finding, or laboratory abnormality that,
in the Investigator's opinion, could put the patient at an unacceptable high
risk for toxicities, or alter the absorption, distribution, metabolism, or
excretion of the study drug; or impair the assessment of study results.
23. Patients with a known hypersensitivity to avapritinib, regorafenib, or the
excipients in either study drug.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-003497-14-NL |
| ClinicalTrials.gov | NCT03465722 |
| CCMO | NL65030.091.18 |