The primary objective is progression-free survival (PFS); defined as the time from randomization to the date of the first documented tumor progression; determined using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria or death due…
ID
Source
Brief title
Condition
- Malignant and unspecified neoplasms gastrointestinal NEC
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective is progression-free survival (PFS); defined as the time
from randomization to the date of the first documented tumor progression;
determined using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
criteria or death due to any cause. We hypothesize that sunitinib will result
in a clinically relevant increase in PFS (from 2 months with TAS-102 arm to 5
months with).
Secondary outcome
Secondary objectives include;
- Overall Survival (OS), defined as the time from randomization to the date of
death.
- Comparison of QoL parameters between the two study arms. We will use the
validated European Organization for Research and treatment of Cancer Quality of
Life questionnaires (EORTC QoL), to assess patient reported outcomes during
treatment.
- Safety, as reported through the detailed incidence of deaths, adverse events
(AE), serious AE, AE leading to discontinuation or dose delay and specific
laboratory abnormalities in each treatment arm. Toxicities will be graded using
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse
Events (CTCAE) version 4.03, in combination with patient reported AE*s using
the recently developed pro-CTCAE questionnaires.
- Identification of biomarkers that will enable prognosis prediction for the
individual patient, pre-treatment classification and response prediction and
therapy response monitoring, based on blood diagnostics. This sub aim employs
three of the most promising liquid biopsy technologies based on our efforts to
develop microRNA, plasma DNA and platelet RNA biomarkers for which preliminary
proof of concept has been achieved.
- Health cost analyses.
- Evaluation of protein phosphorylation profiling with phosphoproteomics
techniques, as a potential clinical diagnostic tool, to predict for tumor
response to targeted therapy in tumor biopsies from metastasis.
Background summary
Despite the advance in treatment of mCRC, overall survival remains limited and
novel, effective approaches are actively pursued. Based on earlier experience
that demonstrated encouraging activity and manageable toxicity, this trial
proposes the repositioning of an already approved drug, for several tumor
types, from a daily lower dose to a higher dose, intermittent scheduling, in
patients with mCRC. Angiogenesis plays a crucial role in colorectal cancer
growth, proliferation, and metastasizing and it has been investigated as a
target for mCRC treatment. Novel drugs blocking the angiogenic pathway, as
TAS102, have shown minor significant benefit and has been recently approved for
mCRC treatment. Sunitinib has been
previously assessed in patients with mCRC, where it did not demonstrate a
meaningful response rate. However, its antiangiogenic mechanism of action makes
it plausible, that optimization of the drug itself, namely the scheduling,
might result in improved efficacy. Recent trials suggest that intermittent
dosing does not compromise the efficacy of sunitinib, while escalation of the
dose at the time of disease progression has been deemed safe and effective.
These, taken along with our earlier observations, underscore the scientific
validity of our approach. Our alternative treatment strategy with high-dose
sunitinib should be interpreted as a chemotherapy-like strategy with a
multikinase-inhibitor, shutting off the tumor cell machinery and thereby
inducing tumor cell death. If positive, this trial will result in direct
clinical implementation, since the aim in benefit is set at 3 months, while a
QoL analysis has been integrated in the study protocol according to standard
Dutch guidelines (PASKWIL-criteria). The design of this study addresses not
only the question whether this new treatment is active but will also determine
the position in the line of treatments, as it will establish a new drug of
choice. This addition in the lines of treatments could ultimately translate in
improved overall survival for the patients, while it offers more space for
customized planning of the therapeutic strategy for each individual patient.
Simultaneously this trial addresses one
of the current challenges in the treatment of mCRC, the population selection
via identification of biomarkers, by including an extensive reverse
translational approach as a secondary aim. The dedicated tumor and blood sample
collection and imaging aims in the identification of new predictive biomarkers
and the deciphering of molecular pathways underlining the biology of the
disease and the mechanism of action of sunitinib and TAS-102.
Study objective
The primary objective is progression-free survival (PFS); defined as the time
from randomization to the date of the first documented tumor progression;
determined using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
criteria or death due to any cause. We hypothesize that sunitinib will result
in a clinically relevant increase in PFS (from 2 months with TAS-102 arm to 5
months with).
Secondary objectives include;
- Overall Survival (OS), defined as the time from randomization to the date of
death.
- Comparison of QoL parameters between the two study arms. We will use the
validated European Organization for Research and treatment of Cancer Quality of
Life questionnaires (EORTC QoL), to assess patient reported outcomes during
treatment.
- Safety, as reported through the detailed incidence of deaths, adverse events
(AE), serious AE, AE leading to discontinuation or dose delay and specific
laboratory abnormalities in each treatment arm. Toxicities will be graded using
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse
Events (CTCAE) version 4.03, in combination with patient reported AE*s using
the recently developed pro-CTCAE questionnaires.
- Identification of biomarkers that will enable prognosis prediction for the
individual patient, pre-treatment classification and response prediction and
therapy response monitoring, based on blood diagnostics. This sub aim employs
three of the most promising liquid biopsy technologies based on our efforts to
develop microRNA, plasma DNA and platelet RNA biomarkers for which preliminary
proof of concept has been achieved.
- Health cost analyses.
- Evaluation of protein phosphorylation profiling with phosphoproteomics
techniques, as a potential clinical diagnostic tool, to predict for tumor
response to targeted therapy in a subgroup of patients willing to undergo an
extra tumor biopsy from a metastasis (mandatory for trial participation from
01-2021 onwards).
Study design
Randomized, open label, controlled, intervention phase II/III trial
Intervention
After study inclusion, patients will be randomized (1:1) via a centralized
randomization system to receive either oral sunitinib (700 mg once every 2
weeks) or TAS-102 (35 mg per square meter, twice daily, 5 days a week, with 2
days of rest, for 2 weeks, followed by a 14-day rest period). Patients will
receive treatment until disease progression or discontinuation due to
unacceptable toxic effects, withdrawal of consent, or other reason.
During the conduct of the trial an error was observed in the randomization
settings (by accident stratification per institute was enabled), causing an
imbalance in the treatments groups mainly regarding the stratification factor
time. To improve the balance between the groups we made the following changes
in consultation with the statistician and the METC:
1. The sample size will be increased with 10 patients (from N = 60 to N = 70)
2. The rest of the patients will be randomized 2:1 in favor of sunitinib
3. Patients will only be stratified for 1 stratification factor:
- time since diagnosis of first metastasis and inclusion (< 18 months versus
> 18 months)
Study burden and risks
Adverse effects of TAS-102 monotherapy, considered as a standard treatment in
mCRC patients, may occur. Patients randomized for the sunitinib arm may
experience physical discomfort or adverse effects. Response to therapy will be
measured by CT every 8 weeks (with the possibility to extend with 1 week).
Follow-up during therapy will include laboratory analyses together with
regularly visits to the outpatient clinic. Additional research blood samples
will be taken during regular visits to the outpatient clinic, together with
standard safety lab. Patients will be asked to complete quality of life (QoL)
forms. Follow-up after therapy, in case of disease progression or
discontinuation due to unacceptable toxic effects, withdrawal of consent, or
other reason will be every 12 weeks (to check for Adverse Events and survival).
Geert Grooteplein Zuid 8
Nijmegen 6525GA
NL
Geert Grooteplein Zuid 8
Nijmegen 6525GA
NL
Listed location countries
Age
Inclusion criteria
To be eligible for this trial, patients will need to meet all of the following
inclusion criteria. Screening must be performed no more than 14 days prior to
the first study drug dose., 1: Signed (by the patient or legally acceptable
representative) and dated Informed Consent Form (ICF). , 2: Histological or
cytological confirmed, documentation of incurable locally advanced or
metastatic, colorectal adenocarcinoma, not amenable for potentially curative
treatment (i.e. inoperable).
3: Indication for treatment with TAS-102; progressive on (or intolerant to)
therapy including fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy
and anti-EGFR therapy (for tumours with wild-type RAS, BRAF and a left sided
tumour)). , 4: Evaluable disease by RECIST version 1.1 criteria (see appendix
III)., 5: Age >= 18 years. , 6: Eastern Cooperative Oncology Group (ECOG)
Performance Status of 0-2., 7: Normal 12-lead ECG (clinically insignificant
abnormalities permitted)., 8: No signs of clinical thyroid abnormalities
(suppletion or blocking drugs permitted)., 9: Adequate bone marrow function;
hemoglobin > 5.6 mmol/l, absolute neutrophil count (ANC) > 1,5 x 10*9/l,
Platelet count *> 100 x 10*9/l, , 10: Adequate liver function; total bilirubin<
1.5 times the upper limit of normal (ULN), ALT and AST < 2.5 x ULN (In case of
liver metastases: <; 5 x ULN)., 11: Albumin higher than 25 g/L, 12: Serum
creatinine <;1.5 x ULN or creatinine clearance * 50 ml/min/1.73m2 (based on
MDRD)., 13: Pregnant or breast-feeding subjects: Women of childbearing
potential must have a negative pregnancy test performed within 7 days of the
start of treatment. For fertile men or women of childbearing potential:
documented willingness to use a highly effective means of contraception (e.g.,
hormonal methods [implants, injectables, or combined oral contraceptives],
intrauterine devices, sexual abstinence, or vasectomized or surgically
sterilized partner). Contraception is necessary for at least 6 months after
receiving the study medication.
Exclusion criteria
The following criteria exclude the patient from enrollment in this trial, 1:
Previous treatment with sunitinib and/or TAS-102 for mCRC., 2: Evidence of
significant uncontrolled concomitant disease, such as cardiovascular disease
(including stroke, New York Heart Association Class III or IV cardiac disease
or myocardial infarction within 6 months prior to screening, unstable
arrhythmia, clinically significant valvular heart disease and unstable angina);
pulmonary disease (including obstructive pulmonary disease > GOLD 2 and
inadequately treated symptomatic bronchospasm), and uncontrolled central
nervous system, renal, hepatic, endocrine, or gastrointestinal disorders; or a
serious non-healing wound or fracture., 3: Extensive prior radiotherapy in the
rectum, pelvis or in more than 3 vertebrae in the spine (less than 3 vertebrae
are considered a small radiation field and eligibility will be decided on an
individual basis from the PI)., 4: Poorly controlled hypertension despite
adequate blood pressure medication. Blood pressure must be <=160/95 mmHg at the
time of screening on a stable antihypertensive regimen. Blood pressure must be
stable on at least 2 separate measurements., 5: Instable seizure disorders
requiring anticonvulsant therapy., 6: Major surgery, other than diagnostic
surgery, within 4 weeks prior to day 1, without complete recovery., 7:
Uncontrolled bleeding disorders, and/or active bleeding., 8: Known active
bacterial, viral, fungal, mycobacterial, or other infection. (including HIV and
atypical mycobacterial disease, but excluding fungal infection of the nail
beds.), 9: Known hypersensitivity to sunitinib, TAS-102, or to its excipients.,
10: Presence of any significant psychiatric disorder(s) that would interfere
with the patient*s compliance., 11: Chemotherapy, radiotherapy, or other
anti-cancer therapy within the previous 4 weeks; no nitrosoureas or mitomycin C
within the previous 6 weeks; no investigational agents within the previous 4
weeks., 12: Clinically significant history of liver disease, including viral or
other hepatitis, current alcohol abuse, or cirrhosis., 13: Untreated or active
central nervous system (CNS) metastases., 14: Predisposing colonic or small
bowel disorders in which the symptoms are uncontrolled as indicated by baseline
of >3 loose stools daily despite medication., 15: Unresolved bowel obstruction,
16: Any evidence of a disease or condition that might affect compliance with
the protocol or interpretation of the study results or render the patient at
high risk from treatment complications.
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 | EUCTR2017-000364-15-NL |
| CCMO | NL60716.029.18 |