| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033605 |
| E.1.2 | Term | Pancreatic cancer metastatic |
| 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 |
The study aim is to identify sub-groups of patient's based on their cancer biomarkers and associated drugs which produce a partial or complete response to treatment.
The primary endpoint of the study is response rate (complete or partial) to treatment based on CT scan results using the RECIST V1.1 criteria, this is also known as objective response rate (ORR). |
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| E.2.2 | Secondary objectives of the trial |
The secondary aim is efficacy of the experimental drugs and associated target biomarkers in terms of progression free survival and overall survival and safety and tolerability of the experimental drugs.
The exploratory aim is to identify the hypothesized patient's biomarkers that correlate with ORR, progression free survival, overall survival and therapeutic responsiveness |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
As this is a platform study there is a core criteria that all patients who enter the PRIMUS 004 platform study need to meet and there are also appendix specific criteria that relate specifically to the patient group entering that treatment appendix. This is due to the different treatment offered within each appendix and the sub-groups of patients within each appendix.
Core Inclusion Criteria:
Patient has been enrolled in the Precision Panc-Master Protocol and their tissue taken post first line treatment progression has been deemed suitable for NGS analysis
Patient has provided signed informed consent for the appropriate PRIMUS-004 Appendix
Age ≥ 16 years
Histologically confirmed metastatic pancreatic ductal adenocarcinoma and its variants, with measurable disease as per RECIST 1.1
Patient must have received only one previous chemotherapy regimen, which was given for a minimum period of 12 weeks. Eligible patients could have received their 12 weeks of first line treatment for advanced or metastatic disease or in the (neo-)adjuvant setting when distant metastasis have developed during or within 6 months of completing chemotherapy treatment.
ECOG performance status 0-1
Life expectancy of no less than 12 weeks
Adequate organ and bone marrow function as defined below (also refer to adequate organ function as defined in relevant drug-specific appendix):
a. Haemoglobin ≥ 9.0 gdL
b. Absolute neutrophil count ≥ 1.5 x109/L
c. Platelet count ≥ 100 x109/L
d. Total bilirubin ≤ 1.5 x ULN, unless the patient has documented Gilbert’s syndrome
e. AST and/or ALT ≤ 2.5 x ULN, or ≤ 5 x ULN if the patient has liver metastases
f. GFR ≥ 51 ml/min as assessed using the Cockroft Gault equation, or Wright formula or measured by EDTA clearance
Negative serum HCG test for females with child-bearing potential. Postmenopausal women must have been amenorrhoeic for at least 12 months to be considered of non-childbearing potential
Woman of child-bearing potential, and men with female partners of child bearing potential, must agree to use adequate contraceptive measures (see section 4.1.8.1) for the duration of the study and for up to 6 months after the completion of study treatment. Men with pregnant or lactating partners should be advised to use barrier method contraception to prevent exposure to the foetus or neonate
Compliant, and can be followed up regularly
Appendix I Specific Inclusion Criteria:
Patient has the ability to provide written informed consent to participate in the trial and be compliant with the protocol requirements.
Patient must have measurable disease (pre- and post-platinum chemotherapy) as per RECIST V1.1.
ECOG Performance status 0-1.
Life expectancy of at least 12 weeks.
Haemoglobin ≥ 10.0 g/dL, with no blood transfusion in the past 28 days.
Patient must have completed at least 16 weeks of platinum chemotherapy as first line treatment for advanced pancreatic cancer.
Patients must have achieved at least stable disease as a response to platinum by RECIST V1.1 and this must be confirmed by repeat assessment at a minimum of 4 weeks from previous scan.
Archival tissue sample taken prior to platinum chemotherapy is available and suitable for Next Generation Sequencing analysis.
Ability to swallow study medication and no gastrointestinal disorders likely to cause malabsorption of study drug(s).
Known HRRm status from pre-first line treatment biopsy.
(The following inclusion criteria will only be used after the HRR assay has been validated and can be performed within NHS GGC Molecular Genetics).
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| E.4 | Principal exclusion criteria |
Core Exclusion Criteria:
Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period (no longer receiving experimental treatment) of an interventional study unless that study primary endpoint has been met
Patients weighing less than 30 kg
Receipt of last dose of anti-cancer therapy (chemotherapy, targeted therapy, immunotherapy, etc.) within 21 days of Cycle 1 Day 1. A duration of five half lives is allowed for patients treated with non-cytotoxic drugs. If sufficient wash-out time has not occurred within 21 days due to the schedule or pharmacokinetics properties of an agent, a longer wash-out period will be required as agreed by the Investigator.
Palliative radiotherapy must have been completed 21 or more days before Cycle 1 Day 1. The patient can receive a stable dose of bisphosphonates or denosumab for bone metastases, if appropriate, before and during the study as long as these were started at least 5 days prior to the study treatment
Major surgery (as defined by the investigator) within 2 weeks of starting study treatment: patients must have recovered from any effects of any major surgery
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 ≥ 3 years prior to study entry
With the exception of alopecia and Common Terminology Criteria for Adverse Events (CTCAE) grade 2 neuropathy, any unresolved toxicities from prior therapy ≥ grade 2
History of myocardial ischemia (MI), unstable angina, stroke, or transient ischemia within previous 6 months
As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases that places the patient at unacceptable risk of toxicity or non-compliance.
Patients with symptomatic uncontrolled brain metastases. Patients with a history of treated central nervous system (CNS) metastases are eligible, provided they meet all of the following criteria: disease outside the CNS is present, no clinical evidence of progression since completion of CNS-directed therapy, minimum 3 weeks between completion of radiotherapy and Cycle 1 Day 1 and recovery from significant (Grade ≥ 3) acute toxicity with no ongoing requirement for >10 mg of prednisolone per day or an equivalent dose of other corticosteroid. If on corticosteroids, the patient should be receiving a stable dose of corticosteroids, started at least 4 weeks prior to treatment
Women who are breast feeding
Appendix I Specific Exclusion Criteria:
Previous treatment with a PARP inhibitor (including olaparib) or other ATR inhibitor (unless treatment was for less than 3 weeks duration and at least 12 months have elapsed between the last dose and randomisation.
Patients with myelodysplastic syndrome (MDS)/Acute myeloid leukaemia (AML) or with features suggestive of MDS/AML.
Mean resting corrected QT interval (QTc) >470 msec for females and >450 for men, obtained from 3 electrocardiograms (ECGs).
Patients at risk of brain perfusion problems
Patients with relative hypotension(<90/60 mm Hg) or clinically relevant orthostatic hypotension, including a fall in systolic blood pressure of > 20 mm Hg
A known hypersensitivity to olaparib, AZD6738 or any excipient of the product, or any contraindication to the combination anti-cancer agent, as per local prescribing information.
Immunocompromised patients e.g. known to be serologically positive for human immunodeficiency virus (HIV) or patients with known active hepatitis (Hepatitis B or C). Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
Whole blood transfusions in the last 120 days prior to entry to the study
Involvement in the planning and/or conduct of PRIMUS-004.
Previously treated in the PRIMUS-004 study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome is to identify biomarker sub-groups and associated experimental drugs which result in a partial or complete response to treatment measured by objective response rate to treatment (complete or partial response) assessed using CT or MRI scans reported to RECIST V1.1. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Each appendix may have slightly different time-points of when this will be evaluated.
These are listed below.
Appendix 1:
CT or MRI scans will be performed every 8 weeks and reported to RECIST V1.1. These will continue until disease progression. |
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| E.5.2 | Secondary end point(s) |
1. Progression free survival and OS based on RECIST V1.1
2. Disease control rate (Complete or Partial response, or Stable disease) based on RECIST V1.1
3. Safety profile based on CTCAE V5.0
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Each appendix may have slightly different time-points of when this will be evaluated.
These are listed below.
Appendix I:
1 & 2. CT or MRI scans performed every 8 weeks until disease progression
3. Day 1 of each cycle, follow up visits |
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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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| 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 | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 20 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| 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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For the purpose of complying with UK Clinical Trial Regulations the trial will be considered ‘closed’ when the
endpoint for the primary analysis of the final experimental arm has been reached. |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 30 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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