| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Locally advanced or metastatic solid tumour.
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| E.1.1.1 | Medical condition in easily understood language |
| Solid tumour cancer (any type of cancer apart from leukaemia or lymphoma) which has spread. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065143 |
| E.1.2 | Term | Malignant solid tumour |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049280 |
| E.1.2 | Term | Solid tumour |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the safety and tolerability of combined administration of ATR inhibitor AZD6738 and gemcitabine chemotherapy in increasing doses, and determine the recommended phase 2 dose (RP2D) combination(s). |
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives:
• To evaluate preliminary evidence of the anti-tumour effect of this strategy.
Exploratory objectives:
• To obtain a preliminary assessment of AZD6738 activity in the tumour by evaluation of pharmacodynamic (PDy) biomarker changes which may include (but are not limited to) functional ATR inhibition.
• To explore potential biomarkers of response and acquired resistance to AZD6738 that may be observed in plasma circulating tumour DNA (ctDNA) and tumour samples from participants treated with AZD6738 in combination with gemcitabine.
• To characterise the pharmacokinetic (PK) variability of AZD6738 when given orally in combination with gemcitabine.
• To measure the concentrations and distribution of intra-tumoral gemcitabine and its metabolites, compared to plasma gemcitabine concentration.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To be included in the trial the participant must meet all of the following criteria:
• Written informed consent to participate.
• Aged 18 years and over.
• ECOG performance status of 0 or 1.
• Dose escalation phase only: Patients with inoperable/unresectable, histologically proven, locally advanced or metastatic solid tumour that has progressed on standard therapy, or patients unwilling to receive standard therapy.
• Treatment expansion phase only: Patients with inoperable, histologically proven, locally advanced or metastatic pancreatic adenocarcinoma that has progressed on conventional chemotherapy, or patients unwilling to receive standard therapy.
• Documented evidence of progression (radiological or clinical) prior to trial entry.
• Estimated life expectancy of ≥12 weeks.
• Measurable tumour lesions that can be accurately assessed at baseline by computed tomography (CT) and are suitable for repeated assessment as per RECIST 1.1 and considered accessible for core biopsy.
• Women of childbearing potential, male participants and their partners are required, and must be willing, to use 2 highly effective forms of contraception for the duration of the trial and for six (6) months after the completion of the trial treatment. Women of non-childbearing potential must meet one of the following:
• Documented postmenopausal (defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments).
• Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy with last menses >1 year ago (excluding tubal ligation, radiation-induced oophorectomy).
• Documented amenorrhoeic for 12 months (defined as women under the age of 50 years with serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and plasma oestradiol levels in the postmenopausal range for the institution).
• Patient is willing and able to comply with the protocol for the duration of the trial.
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| E.4 | Principal exclusion criteria |
• Diagnosis of ataxia-telangiectasia syndrome.
• Women who are pregnant or breast-feeding.
• Women of child-bearing potential and male participants who are unwilling to use 2 highly effective forms of contraception during the trial and for 6 months after the completion of the trial treatment.
• Cytotoxic chemotherapy within 21 days of start of treatment (greater than five half-lives is allowed for washout in patients treated with non-cytotoxic drugs). Exposure to a small molecule IMP within 30 days or 5 half-lives (whichever is longer) prior to the start of treatment.
• Palliative radiotherapy within 21 days of start of treatment.
• Immunotherapy within 42 days of start of treatment.
• New treatment with bisphosphonates or denosumab for bone metastases within 5 days of start of treatment (patients can receive a stable dose of bisphosphonates or denosumab for bone metastases before and during the trial as long as these were started at least 5 days prior to start of treatment).
• Major surgery within 2 weeks of start of treatment (patients must have recovered from any effects of major surgery).
• Current treatment with steroids (doses of >10mg of prednisone or equivalent) or other immunosuppressive drugs within 14 days of start of treatment.
• Any other malignancy which has been active or treated within the past three years (with the exception of cervical intra-epithelial neoplasia, non-melanoma skin cancer, ductal carcinoma in situ, stage 1 grade 1 endometrial carcinoma, or other solid tumours curatively treated with no evidence of disease for ≥5 years prior).
• Current treatments with known potent cytochrome P (CYP) 3A inhibitors, potent CYP3A inducers, CYP3A4 and/or CYP2B6 substrates with a narrow therapeutic index or Pgp modulators (wash out period of five half-lives, but three weeks for St. John’s Wort, see Appendix 5). The use of herbal supplements or ‘folk remedies’ is not permitted.
• Impaired hepatic or renal function defined as:
o AST or ALT >2.5 x ULN (or 5 times if liver metastasis).
o Total bilirubin >1.5 x ULN.
o Glomerular filtration rate (GFR) (calculated by Cockcroft-Gault) of <41 ml/min.
• Inadequate bone marrow reserve or organ function defined as:
o Absolute neutrophil count <1.5 x 10*9/L.
o Platelet count <100 x 10*9/L with no blood transfusions in the past 28 days.
o Haemoglobin <90 g/L with no platelet transfusions in the past 28 days.
• INR ≥1.25 above the normal range.
• Haematuria +++.
• Known history of cardiac dysfunction within the last 6 months defined as:
o Myocardial infarction
o NYHA Class II/III/IV heart failure
o Unstable angina pectoris
o Unstable cardiac arrhythmias not controlled with a pacemaker or medication (e.g. complete left bundle branch block or third degree heart block).
• Any of the following cardiac criteria:
o Mean resting corrected QT interval (QTc) >470 msec for women, and >450 msec for men obtained from 3 electrocardiograms (ECGs) 2-5 minutes apart using the Fredericia formula.
o Patients with relative hypotension (<90/60 mm Hg) or clinically relevant orthostatic hypotension, including a fall in blood pressure of > 20 mmHg.
o Patients with known reduced LVEF < 55%.
o Patients at risk of brain perfusion problems (e.g. medical history of carotid stenosis, pre-syncope, syncope episodes or a history of transient ischaemic attack).
o Uncontrolled hypertension (grade 2 or above) requiring clinical intervention.
• Patients unable to swallow orally administered medication and with gastrointestinal disorders likely to interfere with absorption of AZD6738.
• Any other concurrent severe and/or uncontrolled medical condition that places the patient at unacceptable risk of toxicity or non-compliance (examples include, but are not limited to, active bleeding diatheses, renal transplant, uncontrolled major seizure disorder, severe COPD, superior vena cava syndrome, extensive bilateral lung disease on high resolution CT scan, severe Parkinson’s disease, active inflammatory bowel disease, psychiatric condition, or active infection (including any patient known to have hepatitis B, hepatitis C, human immunodeficiency virus (HIV) or requiring systemic antibiotics, antifungals or antiviral drugs)). Screening for chronic conditions is not required.
• Prior exposure to an ATR inhibitor.
• A known hypersensitivity to AZD6738 or gemcitabine (e.g. excessive myelosuppression), any excipient of the products, or any contraindication to the combination of anti-cancer agents.
• Any unresolved toxicities from prior therapy of CTCAE grade >1 (with the exception of alopecia and CTCAE grade 2 neuropathy).
• Spinal cord compression (unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of treatment).
•Brain metastases.
• Judgment by the Investigator that the patient should not participate in the trial.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Dose limiting toxicity (DLT) rate for the combination of AZD6738 and gemcitabine. A target probability of 25% of experiencing a DLT will be used in the model to determine the recommended phase 2 dose (RP2D) and schedule for the combination. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| DLT rate will be assessed throughout the study from Day 1 to Day 28 of treatment Cycle 1. DLT rates will be used for dose escalation decisions. |
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| E.5.2 | Secondary end point(s) |
Secondary end points:
• Tumour response using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, and duration of response.
• progression-free survival (PFS).
Exploratory outcome measures
• Changes in proliferation and apoptosis markers (e.g. Ki67/Mib1), and replication stress markers in tumour samples.
• Monitoring of ctDNA levels throughout drug administration.
• Assessment of potential baseline biomarkers in tumour samples (e.g. ATM status, p53 status).
• Measurement of trough AZD6738 concentrations in plasma.
• Measurement of intra-tumoral gemcitabine and its metabolites, compared to plasma gemcitabine concentration.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Tumour response will be assessed throughout the trial at baseline, every 8 weeks during treatment, and every 12 weeks during follow-up (if applicable).
Progression free survival will be assessed from initial start of treatment to date of progression, date of death or end of trial follow-up.
Exploratory endpoints will be assessed throughout the trial. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Dose escalation and scheduling study. |
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| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of trial will be one year post last patient first treatment to allow participant’s to be followed up in line with the protocol schedule. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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