A two stage, open-label, phase II trial assessing the efficacy of a single oral agent AZD4547 in malignant mesothelioma.
Institute of Respiratory Health
55 participants
Apr 7, 2016
Interventional
Conditions
Summary
This primary purpose of this study is to evaluate the safety and efficacy of AZD4547 for the treatment of malignant mesothelioma which has progressed following first line chemotherapy. You may be eligible to participate in this study if you are aged 25 years or over, and have been diagnosed with mesothelioma which has progressed following first or second line chemotherapy with pemetrexed and cisplatin and/or carboplatin. Study details All participants in this study will receive two oral doses of the study drug, AZD4547 per day for 6 months, with appointments with study staff every 3 weeks throughout this period to monitor side effects and adherence to the medication. Researchers will examine disease progression and survival at 6 months, as well as side effect data from the three-weekly appointments to determine the efficacy and safety of the drug. Information from this study will then be used to inform researchers on whether continued study of this drug is both worthwhile and safe, in the hope that it may provide a safe and effective second line therapy for mesothelioma in patients whose disease has progressed following first line chemotherapy.
Eligibility
Inclusion Criteria13
- Histologically or cytologically malignant pleural mesothelioma
- Provision of signed and dated, written informed consent prior to any study specific procedures.
- Male or female aged 25 years or older.
- Histologically or cytologically confirmed diagnosis of mesothelioma.
- Progression after first line chemotherapy with pemetrexed and a platinum-based drug (cisplatin and/or carboplatin).
- Evidence of measurable disease. Measurable disease must be outside a previous radiotherapy field, unless it has been documented to progress after radiotherapy.
- ECOG performance status 0-1, minimum life expectancy of 12 weeks from proposed first dose date, no deterioration within 2 weeks of screening and first dose.
- Females should be using adequate contraceptive measures (see restrictions), should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential, or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:
- Post-menopausal defined as:
- a. Aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments.
- b. Aged under 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments and with LH and FSH levels in the postmenopausal range.
- Documentation of irreversible surgical sterilisation by hysterectomy, and/or bilateral oophorectomy and/or bilateral salpingectomy but excludes bilateral tubal ligation.
- Male patients should be willing to use barrier contraception, ie condoms.
Exclusion Criteria39
- Any prior chemotherapy other than pemetrexed and a platinum compound.
- Concurrent treatment with any experimental drugs or other anti-cancer therapy.
- Prior exposure to any of the following: Prior exposure to an FGFR inhibitor and/orPrior treatment in this or another AZD4547 study, or randomisation in a study in which AZD4547 is/was under investigation.
- AZD4547 in the present study (ie, dosing with AZD4547 previously initiated in this study).
- Potent inhibitors or inducers of CYP3A4, inhibitors of CYP2D6 or substrates of CYP3A4 within 2 weeks before the first dose of study treatment (3 weeks for St John’s Wort). Refer to Section 7.7 of this document for an example list of applicable drugs.
- Any chemotherapy, immunotherapy or anticancer agents within 3 weeks before the first dose of study treatment.
- Major surgery (excluding placement of vascular access) within 4 weeks before the first dose of study treatment.
- Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 2 weeks before the first dose of study treatment.
- Other concomitant anti-cancer therapy except corticosteroids.
- Any of the following ophthalmological criteria:
- Current evidence or previous history of RPED.
- Previous laser treatment or intra-ocular injection for treatment of macular degeneration.
- Current evidence or previous history of dry or wet age-related macular degeneration.
- Current evidence or previous history of retinal vein occlusion.
- Current evidence or previous history of retinal degenerative diseases (eg, hereditary).
- Current evidence or previous history of any other clinically relevant chorioretinal defect.
- Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD4547.
- With the exception of alopecia, any unresolved toxicities from prior therapy with a Common Terminology Criteria for Adverse Events (CTCAE) grade >1 at the time of starting study treatment.
- As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
- Any of the following cardiac criteria:
- Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 consecutive electrocardiograms (ECGs).
- 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, 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.
- Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
- Absolute neutrophil count < 1.5 x 109/L.
- Platelet count < 100 x 109/L.
- Haemoglobin < 90 g/L (can be transfused to meet inclusion criterion).
- Alanine aminotransferase > 2.5 times the upper limit of normal (ULN) if no demonstrable liver metastases/invasion or > 5 times ULN in the presence of liver metastases or liver invasion.
- Aspartate aminotransferase > 2.5 times ULN if no demonstrable liver metastases/liver invasion or > 5 times ULN in the presence of liver metastases or liver invasion.
- Total bilirubin > 1.5 times ULN.
- 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.
- Corrected total calcium > ULN (corrected for albumin using a standard formula that will be specified in the protocol).
- Total phosphate > ULN.
- Pregnant or breast-feeding women or women of childbearing potential with a positive pregnancy test prior to receiving study medication.
- History of hypersensitivity to active or inactive excipients of AZD4547 or other drugs formulated in Cremaphor EL (polyoxyethylated castor oil or other drugs with a similar chemical structure or class to AZD4547.
- Patients with a history of another primary malignancy within 5 years prior to starting study treatment, except adequately treated basal or squamous cell carcinoma of the skin, carcinoma of the cervix in situ and the disease under study.
- Known spinal cord compression, brain metastases or leptomeningeal disease (baseline CT brain or MRI is only required if there is clinical suspicion of central nervous system involvement).
- Serious medical or psychiatric conditions, which might prevent management according to the protocol.
- Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
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Interventions
In mesothelioma we have established that Fibroblast Growth Factor (FGF)-9 plays a key role in the pathobiology of the tumour and that targeting the downstream actions of FGF-9 significantly reduces tumour growth. AZD4547 is A FGF receptor inhibitor that will be used in patients with malignant mesothelioma that has progressed despite first or second line chemotherapy. The selected starting dose of AZD4547 to be used as monotherapy will be 80 mg twice daily in a continuous dosing schedule. This will be taken orally as a tablet. Participants may continue to receive AZD4547 as long as they are continuing to show clinical benefit, as judged by the investigators, and in the absence of discontinuation criteria such as: 1. Progressive disease (PD) is documented by a site investigator. 2. Unacceptable toxicity as determined by the patient or site investigator 3. Delay of day 1 treatment for 21 days due to toxicity. 4. The investigator determines that continuation of treatment is not in the patient’s best interest. 5. New occurrence of an exclusion criterion affecting patient safety, e.g. pregnancy or psychiatric illness. 6. Required use of a concomitant treatment that is not permitted. 7. Failure to comply with the protocol, e.g. repeatedly failing to attend scheduled assessments. If a patient has failed to attend scheduled assessments in the study, the Investigator must determine the reasons and document the circumstances as completely and accurately as possible in the medical records and CRF. 8. The patient declines further study treatment, or withdraws their consent to participate in the study. The use of AZD4547 will be a continuous schedule and as such there is no maximum duration of use unless there is evidence of disease progression as judged by the investigators. Participants will be followed up every 3 weeks by a medical specialist where adherance to the drug and adverse events related to the drug will be evaluated. Adverse events will be assessed by clinical history/examination, laboratory tests, vital signs, electrocardiogram, ophthalmological assessment and radiological investigations.
Locations(1)
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ACTRN12615001291572