| Eligibility |
Inclusion Criteria:
- a. Phase Ia (dose escalation only)
Histologically or cytologically confirmed, advanced unresectable or metastatic
gastrointestinal cancers of following histologies:
- Colorectal adenocarcinoma
- Gastric adenocarcinoma
- Esophageal adenocarcinoma
- Pancreatic adenocarcinoma
- Cholangiocarcinoma and gallbladder carcinoma
- Small intestine adenocarcinoma b. Phase Ib (expansion phase)
- Histologically or cytologically confirmed, advanced unresectable or metastatic
colorectal adenocarcinoma.
- Patient who has failed all available conventional therapies known to confer
clinical benefit for their disease based on local approved standards. For
patients with colorectal cancer, prior treatment with regorafenib or TAS-102 is
optional.
- Phase Ia (dose escalation) only: Patient with either measurable or
non-measurable/non-evaluable disease.
- Phase Ia (expanded cohort) and Phase Ib (expansion phase) only: At least one
target lesion that can be accurately measured per RECIST v.1.1
- Availability and willingness to provide an archived tumor tissue specimen and
undergo tumor biopsy before treatment. Pre-treatment fresh tumor biopsy
collections for biomarker analyses are considered optional in phase Ia and
mandatory in phase Ib. Only nonsignificant risk procedures per the investigator's
judgment will be used to obtain any biopsies specified in this study. In case a
fresh tumor biopsy cannot be obtained due to before mentioned reasons an archived
tumor tissue specimen obtained within =6 months of screening must be submitted.
In case the patient undergoes baseline tumor biopsy, an archived tumor tissue
specimen must be submitted regardless of the date of collection.
- Adequate hepatic, renal and bone marrow functions as defined by all of the below:
- Total bilirubin = 1.5 x institutional Upper Level of Normal (ULN) (= 3 x institutional
ULN for patient with Gilbert's syndrome)
- ALT and AST =2.5 x institutional ULN (=5 x institutional ULN for patients with known
liver metastases)
- Serum creatinine =1.5x institutional ULN. If creatinine is > 1.5 x ULN, patient is
eligible if concurrent creatinine clearance = 50 ml/min (>0.05 L/min) (measured or
calculated by CKD-EPI formula or Japanese version of CKD-EPI formula for Japanese
patients).
- ANC = 1.0x 10^9/L (= 1.0 x 10^3/µL, = 1,000/mm3)
- Platelets = 100x10^9/ L (= 100 x 10^3/µL, = 100 x 10^3/mm3)
- Hemoglobin (Hb) =8.5 g/dl, = 85 g/L, or = 5.3 mmol/L (without transfusion within
previous week)
- Serum lipase = 1.5 institutional ULN
- Recovery from any adverse events according to Common Terminology Criteria for
Adverse Events (CTCAE) v5.0 of previous anti-cancer therapies to baseline or
CTCAE grade 1, except for alopecia CTCAE grade 2, sensory peripheral neuropathy
CTCAE grade = 2 or considered not clinically significant.
- Eastern Cooperative Oncology Group (ECOG) performance status = 1
- Life expectancy = 3 months in the opinion of the investigator
- Of legal adult age (according to local legislation) at screening
- Signed and dated written informed consent in accordance with ICH-GCP and local
legislation prior to admission to the trial.
- Male or female patients. Women of childbearing potential (WOCBP) and men able to
father a child must be ready and able to use highly effective methods of birth
control per ICH M3 (R2) that result in a low failure rate of less than 1% per
year when used consistently and correctly.
Exclusion Criteria:
- Previous systemic anti-cancer therapy within the specified timeframe from the last
dose intake to the first dose of trial treatment as shown below:
- Any non-investigational drug, including anti-angiogenic antibodies (bevacizumab
or ramucirumab) and anti-EGFR antibodies (cetuximab or panitumumab), within 14
days.
- Any investigational drug or other antibodies including immune checkpoint
inhibitors, within 28 days.
- Radiation therapy within 4 weeks prior to start of treatment. However, palliative
radiotherapy for symptomatic metastasis is allowed if completed within 2 weeks prior
to start of treatment but must be discussed with the sponsor.
- Any serious concomitant disease or medical condition affecting compliance with Trial
requirements or which are considered relevant for the evaluation of the efficacy or
safety of the trial drug, such as neurologic, psychiatric, infectious disease or
active ulcers (gastro-intestinal (GI) tract, skin) or laboratory abnormality that may
increase the risk associated with trial participation or trial drug administration,
and in the judgment of the Investigator, would make the patient inappropriate for
entry into the trial. Any history of stroke or myocardial infarction within 6 months
prior to screening.
- Known pathological condition of GI tract, liver and pancreas, excluding the disease
under study, that may interfere with assessment of drug safety or may increase the
risk of toxicity:
- inflammatory bowel disease
- chronic pancreatitis
- other serious GI pathological conditions by judgment of the investigator e.g.
autoimmune disease with GI involvement, unexplained active diarrhea CTCAE grade
=2 according to CTCAE v5.0.
- Known history of human immunodeficiency virus infection.
- Any of the following laboratory evidence of hepatitis virus infection. Test results
obtained in routine diagnostics are acceptable if done within 14 days before the
informed consent date:
- Positive results of hepatitis B surface (HBs) antigen
- Presence of HBc antibody together with HBV-DNA
- Presence of hepatitis C RNA
- Active concomitant malignancies, other than the one treated in this trial.
- Chronic alcohol or drug abuse or any condition that, in the investigator's opinion,
makes the patient an unreliable trial participant or unlikely to comply with the
protocol requirements or not expected to complete the trial as scheduled.
- Women who are pregnant, nursing, or who plan to become pregnant while in the trial;
female patients who do not agree to the interruption of breast feeding from the start
of study treatment to within 30 days after the last study treatment.
- Presence of uncontrolled or symptomatic brain or subdural metastases. Inclusion of
patients with brain metastases who have completed local therapy and are considered
stable by the investigator, or with newly identified asymptomatic brain metastases at
screening will be allowed. Use of corticosteroids is allowed if the dose was stable
for at least 1 week before the baseline MRI.
- Patients who are under judicial protection and patients who are legally
institutionalized
- Major surgery (major according to the investigator's assessment) performed within 3
weeks prior to treatment start or planned within 3 months after screening, e.g. hip
replacement.
- Any of the following cardiac criteria:
- Resting corrected QT interval (QTc) >470 msec
- Any clinically important abnormalities (as assessed by the Investigator) in
rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle
branch block, third degree heart block
- Patients with an ejection fraction (EF) <50% or the lower limit of normal of the
institutional standard will be excluded. Only in cases where the Investigator (or
the treating physician or both) suspects cardiac disease with negative effect on
the EF, will the EF be measured during screening using an appropriate method
according to local standards to confirm eligibility (e.g., echocardiogram,
multi-gated acquisition scan). A historic measurement of EF no older than 6
months prior to first administration of study drug can be accepted provided that
there is clinical evidence that the EF value has not worsened since this
measurement in the opinion of the Investigator or of the treating physician or
both.
- Known hypersensitivity to the trial medication and/or its components i.e. polysorbate
20, sodium citrate, lysine hydrochloride, sucrose, citric acid.
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