| Eligibility |
Major Inclusion Criteria:
1. Signed written informed consent.
2. At least 18 years of age at the time of signing the ICF.
3. Histological or cytological confirmation of a solid, malignant tumor that is
refractory to standard therapies or for which no standard therapies exist.
Measurable or non-measurable disease according to RECIST version 1.1.
4. Eastern Cooperative Oncology Group/World Health Organization (ECOG/WHO) performance
status of 0 to 1 with no deterioration between screening and the first dose of the
study treatment, and a minimum life expectancy of 12 weeks
5. Body weight >30 kg and no cancer-associated cachexia (e.g., common terminology
criteria for adverse events [CTCAE] Grade 2 or worse weight loss over the past 3
months).
Major Exclusion Criteria:
1. History of another primary malignancy except for:
- Malignancy treated with curative intent and with no known active disease =2 years
before the first dose of the study drug and of low potential risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease
- Adequately treated carcinoma in situ without evidence of disease
2. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of
starting the study treatment, with the exception of alopecia and chemotherapy-related
peripheral neuropathy.
3. Presence of life-threatening metastatic visceral disease, as judged by the
investigator, uncontrolled central nervous system (CNS) metastatic disease. Patients
with spinal cord compression and/or brain metastases may be enrolled if definitively
treated (e.g., surgery or radiotherapy) and stable off steroids for at least 4 weeks
prior to start of the study treatment.
4. Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and tuberculosis testing in
line with local practice), hepatitis B (known positive hepatitis B virus [HBV],
surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus
(positive HIV 1/2 antibodies).
Patients with a past or resolved HBV infection (defined as the presence of hepatitis B
core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for
hepatitis C (HCV) antibody are eligible only if the polymerase chain reaction is
negative for HCV RNA.
5. Diagnosis of ataxia telangiectasia.
6. Refractory nausea and vomiting, chronic gastrointestinal diseases, or previous
significant stomach/bowel resection, with clinically significant sequelae that would
preclude adequate dissolution/absorption of ceralasertib. Partial gastrectomy with
preservation of gastric pyloric function and partial resection of the large intestine
can be eligible, but inclusion of patients with gastric pylorus resection or patients
with duodenum, jejunum or ileum resection requires discussion with the sponsor.
7. Past medical history of interstitial lung disease (ILD) / pneumonitis requiring
steroid treatment or any evidence of clinically active ILD / pneumonitis or potential
ILD / pneumonitis which is not excluded by the screening test.
8. Treatment with any of the following:
1. Any investigational medicinal product or other systemic anticancer treatment
within 4 weeks prior to the first dose of the study treatment, except for
immunotherapy or antibody therapy which has five-fold half-life >4 weeks is
within 8 weeks.
Note: androgen-deprivation therapy is permitted for patients with prostate cancer
2. The potent inducers or inhibitors of CYP3A within 2 weeks of the first dose of
the study treatment; except for St. John's wort, which is 3 weeks.
3. Prior exposure to an ATR inhibitor.
4. Major surgery (excluding placement of vascular access) within 4 weeks of the
first dose of the study treatment
5. Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a
limited field of radiation for palliation within 2 weeks of the first dose of the
study treatment.
9. Participation in any clinical research study involving treatment with any
investigational drug, radiotherapy or surgery, except for the non-treatment phases of
these studies, e.g., follow-up phase.
10. History of hypersensitivity to active or inactive excipients of ceralasertib or drugs
with a similar chemical structure or class to ceralasertib.
11. Patient has any of the following cardiac criteria:
1. Mean QT interval corrected by Fridericia's formula (QTcF) for heart rate =470 ms
calculated from ECGs.
2. Any clinically important abnormalities in rhythm, conduction, or morphology of
resting ECG, e.g., complete left bundle branch block, third degree heart block,
second degree heart block, first degree heart block.
3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalaemia, congenital long QT syndrome, family
history of long QT syndrome, or unexplained sudden death under 40 years of age or
any concomitant medication known to prolong the QT interval.
4. Patients with uncontrolled hypertension-blood pressure (BP) =150/95 mmHg despite
medical therapy.
5. Patients with relative hypotension (BP<100/60 mmHg) or clinically relevant
orthostatic hypotension, including a fall in blood pressure of >20 mmHg.
6. Unstable atrial fibrillation or unstable cardiac arrhythmia with a ventricular
rate >100 bpm on an ECG at rest.
7. Symptomatic heart failure-New York Heart Association Grade II to Grade IV.
8. Prior or current cardiomyopathy.
9. Severe valvular heart disease.
10. Uncontrolled angina (Canadian Cardiovascular Society Grade II to Grade IV despite
medical therapy) or acute coronary syndrome within 6 months prior to screening.
11. Patients at risk of brain perfusion problems, e.g., carotid stenosis. Stroke or
transient ischemic attack in the last 6 months prior to screening.
12. Inadequate bone marrow reserve or organ function as demonstrated by any of the
following laboratory values. Note that growth factor or blood transfusion support to
solely meet the criteria is prohibited for 14 days prior to the screening test unless
otherwise noted:
1. Absolute neutrophil count [ANC] <1.5 × 109/L.
2. Platelet count <100 × 109/L.
3. Haemoglobin <9 g/dL with no blood transfusions (packed red blood cells) in the
past 28 days.
4. Persisting (>4 weeks) severe pancytopenia due to previous therapy rather than
disease (ANC <1.5 × 109/L or platelets <100 × 109/L).
5. Alanine aminotransferase (ALT) >2.5 × the upper limit of normal (ULN).
6. Aspartate aminotransferase (AST) >2.5 × ULN.
7. Total bilirubin (TBL) >1.5 × ULN or >3 × ULN in the presence of documented
Gilbert's syndrome (unconjugated hyperbilirubinemia).
8. Alkaline phosphatase (ALP) >2.5 × ULN (and liver disease unrelated to the tumor).
Patients with elevated ALP due to tumor related bone metastases or liver
metastases will be eligible.
9. Creatinine clearance <45 mL/min calculated by Cockcroft-Gault equation
10. Haematuria: +++ on microscopy or dipstick.
11. INR =1.5 or other evidence of impaired hepatic synthesis function.
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