| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pancreatic cancer - locally advanced |
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| E.1.1.1 | Medical condition in easily understood language |
| Pancreatic cancer - locally advanced |
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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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033604 |
| E.1.2 | Term | Pancreatic cancer |
| 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 primary objective of the trial is:
To assess the efficacy of ATRA when given in combination with gemcitabine and nab-paclitaxel based on progression-free survival (PFS). |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the trial are:
- To assess the efficacy of ATRA when given in combination with gemcitabine and nab-paclitaxel based on objective response rate (ORR)
- To assess the efficacy of ATRA when given in combination with gemcitabine and nab-paclitaxel based on overall survival (OS)
- To assess the safety and tolerability of ATRA when given in combination with gemcitabine and nab-paclitaxel over the first 6 cycles
- To assess the surgical resection rate of ATRA when given in combination with gemcitabine and nab-paclitaxel
- To assess the resection margin negative (R0) surgical resection rate of ATRA when given in combination with gemcitabine and nab-paclitaxel
- To assess quality of life (QOL) of patients receiving ATRA in combination with Gemcitabine and Nab-Paclitaxel. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent prior to admission to this study
2. Age ≥16 years. No upper age limit.
3. ECOG performance status 0 or 1
4. Histologically proven pancreatic ductal adenocarcinoma (PDAC) as part of the Precision-Panc Master Protocol, or for patients who have gone exploratory laparotomy and found to have locally, unresectable advanced disease.
5. Locally advanced disease which is measurable according to the Response Evaluation Criteria in Solid Tumours (RECIST v1.1). See section 3.2 for definition of laPDAC.
6. CT chest abdomen and pelvis as well as PET-CT within 28 days of day 1 of treatment (MRI Liver only if indeterminate liver lesions) to confirm absence of metastatic disease.
7. Received no prior systemic therapy for metastatic or locally advanced disease.
8. Adequate haematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment:
a. Absolute Neutrophil Count > 1.5 x 109/l (without granulocyte colony-stimulating factor support within 2 weeks prior to the first study treatment)
b. Platelet count > 100 x 109/l (without transfusion within 2 weeks prior to the first study treatment)
c. Haemoglobin > 10 g/dl (transfusion permitted to establish target haemoglobin levels prior to the first study treatment)
d. Calculated creatinine clearance (e.g. Cockcroft-Gault) > 50 ml/min
e. Bilirubin level ≤ 1.5 ULN (patients with known Gilbert disease who have bilirubin levels ≤ 3 x ULN may be enrolled). Patients must be able to undergo biliary stenting if required before or, if required, during the trial
f. AST or ALT <2.5 x ULN or <5 x ULN
g. Alkaline phosphatase (ALP) <2.5 x ULN
h. INR and aPTT ≤1.5 x ULN; this applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose.
9. Female patients of child-bearing potential are eligible, provided they have a negative serum pregnancy test within 7 days prior to the first dose of study treatment, preferably as close to the first dose as possible. All patients with reproductive potential must agree to use a medically acceptable method of contraception throughout the treatment period and for 1 month after discontinuation of ATRA and / or gemcitabine/nab-paclitaxel (whichever is the latest) and for 6 months after discontinuation for male patients. Acceptable methods of contraception include IUD, oral contraceptive, sub-dermal implant and double barrier (condom with a contraceptive sponge or contraceptive pessary). Micro-dosed progesterone preparations (“mini-pill”) are an inadequate method of contraception during treatment with ATRA. If patients are taking this pill they should be instructed to stop and another form of contraceptive should be prescribed instead.
10. Able to follow protocol requirements as assessed by the Principal Investigator.
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| E.4 | Principal exclusion criteria |
1. Patient has known distant metastases.
2. Patient has experienced a significant reduction in performance status between the screening/ baseline visit and within 72 hours prior to commencement of treatment as per trial protocol, such that the ECOG PS is ≥ 2 and as per the Investigator’s assessment.
3. Patients with pre-existing sensory neuropathy >grade 1
4. History of other malignancies (except cured basal or squamous cell carcinoma, superficial bladder cancer, prostate cancer in active surveillance, or carcinoma in situ of the cervix) unless documented free of cancer for ≥2 years
5. Patient has active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy.
6. Patient has known active, uncontrolled HIV, or active, uncontrolled hepatitis B or C infection.Patients with undetectable viral load are eligible.
7. Patient has undergone major surgery, other than diagnostic surgery (i.e., surgery done to obtain a biopsy for diagnosis without removal of an organ), within 4 weeks prior to Day 1 of treatment in this study.
8. Patient has a history of allergy (including soya bean or peanut allergies) or hypersensitivity to any of the study drugs or any of their excipients, or the patient exhibits any of the events outlined in the Contraindications or Special Warnings and Precautions sections of the products or comparator SmPC or Prescribing Information.
9. History of connective tissue disorders (e.g., lupus, scleroderma, arteritis nodosa).
10. Patient with a history of interstitial lung disease, history of slowly progressive dyspnoea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis or multiple allergies.
11. Patient with high cardiovascular risk, including, but not limited to, recent coronary stenting or myocardial infarction in the past year. A high cardiovascular risk is defined as person having recent (within last 12 months) coronary stenting or myocardial infarction or unstable angina which in the opinion of Principal Investigator, with or without a cardiologist opinion, is deemed to have an absolute risk for cardiovascular death of ≥ 5% over next 10 years (ESC/ESH guidelines).
12. History of Peripheral Artery Disease (e.g., claudication, Leo-Buerger's disease).
13. Patient has serious medical risk factors involving any of the major organ systems, or serious psychiatric disorders, which could compromise the patient's safety or the study data integrity.
14. Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug ≤30 days prior to study entry depending on the half-life of the investigational drug and/or guidance issued by the IMP manufacturer. Please contact the STAR-PAC2 coordinating team for further information.
15. Patient is taking any prohibited concurrent medication, including vitamin A supplements, and is unwilling to stop use prior to and during the trial.
16. Patient is pregnant, planning to become pregnant or breast feeding.
17. Patient has received a live vaccine within four weeks prior to receiving their first dose of study treatment.
18. Patient is unwilling or unable to comply with study procedures, as assessed by the Principal Investigator.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival (PFS) defined as the time from the date of randomisation to the date of first documented tumour progression (response evaluation criteria in solid tumours [RECIST] v1.1) or death from any cause, whichever occurs first. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Objective response rate (ORR) defined as the number of patients with an objective response (OR) divided by the number of patients analysed. OR is defined as the number of patients with at least one confirmed response of complete response (CR) or partial response (PR). OR will be calculated in patients with measurable disease at baseline.
- Overall survival (OS) is defined as the time from the date of randomisation to death from any cause. All deaths will be included, whether they occur on study or following treatment discontinuation. For patients who have not died, OS will be censored at the date of last contact.
- Safety and tolerability as assessed by AEs (CTCAE v5.0).
- Surgical resection rate defined as patients undergoing complete resection of known pancreatic primary and associated lymph nodes at any point after enrolment, in each arm.
- Patient reported outcomes as measured by questionnaire EQ-5D_5L.
- Resection margin negative (R0) surgical resection rate defined as histologically confirmed complete resection of known pancreatic primary from those resected.
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| 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 |
| Determination of MTD (part 1) and OBD (part 2) |
|
| 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 | Yes |
| 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 16 |
| 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
|
| The end of study is defined as last patient last data collection, which for the primary and secondary analysis is expected to occur within approximately 12 months after the last patient last visit. |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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