| Eligibility |
Inclusion Criteria:
- Willing and able to provide written informed consent
- Aged at least 18 years.
- Karnofsky Performance Score (KPS) of =60.
- Histologically confirmed diagnosis of cancer with clear evidence of metastasis on
imaging. Confirmation of metastasis by biopsy is preferred but not required.
- Candidates for SBRT delivered as 6Gy x 5 daily fractions to 2 sites of disease. The
radiation plan should meet departmental guidelines. Patients can have more than 2
sites of disease. If patient requires RT to other sites of disease this can be done
after completion of DLT period.
- Adequate organ system functions, as outlined below:
- Absolute neutrophil count (ANC) =1.0 x 109/L
- Platelets =75 x 109/L
- Hemoglobin =8 g/dL
- Total bilirubin =1.5 times the ULN
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =2.5 times
the ULN if no liver involvement or =5 times the ULN with liver involvement with
metastatic disease.
- Creatinine <1.5 times ULN concurrent with creatinine clearance >50 mL/min
(measured or calculated by Cockcroft and Gault equation); confirmation of
creatinine clearance is only required when creatinine is >1.5 times ULN.
- Lipase within normal limits (WNL)
- Creatine kinase (CK) =5 times ULN
- Females of childbearing potential must have a negative pregnancy test during screening
and must not be breastfeeding or intending to become pregnant during the study. Male
patients with female partners of child-bearing potential must be willing to use two
forms of acceptable contraception, including one barrier method, during their
participation in this study and for 16 weeks following the last dose of the study
drug.
- Ability to swallow and retain oral medication.
Exclusion Criteria:
- Prior radiotherapy to the same region within the last 3 months.
- Ongoing treatment for brain metastases. Patients with brain metastases may participate
in this trial however, treatment for brain metastases will have to be completed prior
to study enrollment. Treatments can begin or resume two weeks after completing
protocol therapy.
- History of epilectic disorder.
- For Arm B patients with cancers involving the spinal cord, the length of the spinal
cord lesion requiring palliative treatment is greater than 10 cm.
- Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation
pneumonitis which required steroid treatment, or any evidence of clinically active
interstitial lung disease.
- Evidence of established ILD on screening CT scan.
- Evidence of severe pulmonary infections, as judged by the investigator, based on
clinical findings and investigations.
- Concurrent severe and/or uncontrolled medical condition (e.g., severe COPD).
- Cardiac dysfunction defined as: Myocardial infarction within six months of study
entry, NYHA Class II/III/IV heart failure, unstable angina or unstable cardiac
arrhythmias.
- Any of the following cardiac criteria:
- Mean resting corrected QT interval (QTcF) > 470 msec obtained from 3
electrocardiograms (ECGs) (QTc interval will be calculated using Fridericia's
formula).
- Any clinically important abnormalities in rhythm, conduction or morphology of
resting ECG, e.g., complete left bundle branch block, third degree heart block.
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalemia, congenital long QT syndrome, family
history of long QT syndrome or unexplained sudden death under 40 years-of-age.
Patients stable on concomitant medications known to prolong the QT interval may
be allowed to participate in the study provided that their mean resting corrected
QT interval \(QTcF) is < 470 msec at baseline.
- History or presence of myopathy or raised CK >5 x ULN on 2 occasions at screening.
- Anticancer therapy within 7 days of first SBRT. These treatments should also be held
for 7 days after last dose of SBRT. Patients who have received an immune checkpoint
inhibitor within 28 days of first administration of study therapy will be excluded.
- History of hypersensitivity to AZD1390 and excipients or drugs with a similar chemical
structure or class to AZD1390.
- Patients receiving treatment with strong inhibitors or inducers of CYP3A4 within 2
weeks before the first dose of AZD1390.
- Patients who require sensitive substrates of BCRP, OATP1B1, MATE1, MATE2K and P-gp
such as prazosin, cimetidine, simvastatin, dofetilide, metformin, dabigatran, digoxin
and fexofenadine should be avoided while on study.
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