Pancreatic cancer Cancer Malignant neoplasm of pancreas
Conditions
Interventions
This open-label, multi-centre phase IB study has two parts:
Part 1 is the dose-escalation stage which will test different doses of the combination of ATRA, gemcitabine and nab-paclita
however, the dose of ATRA given to patients may be altered to make sure they have the required levels of Vitamin A in their blood.
Study timelines:
Recruitment for par
Sponsors
Barts Health NHS Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Each patient must meet all of the following inclusion criteria to be enrolled in the study: 1. Written informed consent prior to admission to this study 2. Age =18 years. No upper age limit 3. WHO performance status 0 or 1 4. Life expectancy =12 weeks 5. Histologically proven Pancreatic ductal adenocarcinoma (PDAC). Formalin-fixed, paraffin-embedded tumour sample from the primary cancer must be available for central testing. If not available or sufficient patients will be asked to undergo a US or CT guided biopsy prior to study entry to satisfy this eligibility criterion. 6. Locally advanced or metastatic disease which is measurable according to the Response Evaluation Criteria in Solid Tumours (RECIST v1.1) 7. Received no prior systemic therapy for metastatic or locally advanced disease. Prior adjuvant chemotherapy (with gemcitabine or any other drug/s) is allowed if completed at least 6 months previously. 8. Adequate hematologic and end-organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment: 8.1. Absolute Neutrophil Count =1.5 x 109/l (without granulocyte colony-stimulating factor support within 2 weeks prior to the first study treatment) 8.2. Platelet count =100 x 109/l (without transfusion within 2 weeks prior to the first study treatment) 8.3. Haemoglobin =10 g/dl (transfusion permitted to establish target haemoglobin levels prior to the first study treatment) 8.4. Calculated creatinine clearance (e.g. Cockcroft-Gault) =50 ml/min 8.5. 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 8.6. AST or ALT <2.5 x ULN or <5 x ULN in the presence of liver metastases 8.7. Alkaline phosphatase (ALP) <2.5 x ULN or <5 x ULN in the presence of liver and/or bone metastases 8.8. 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 or urine 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
Exclusion criteria
Exclusion criteria: A patient will not be eligible for inclusion in this study if any of the following criteria apply: 1. Patient has known brain 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, as per the Investigator’s assessment 3. Patients with pre-existing sensory neuropathy >grade 1 4. History of malignancy in the last 5 years; with the exception of: 4.1. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible 4.2. Patients with other malignancies are eligible if they were cured by surgery alone or surgery plus radiotherapy and have been continuously disease-free for at least 5 years 5. Patient has active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy 6. Patient has HIV, or active hepatitis B or C infection 7. Patient has undergone major surgery, other than diagnostic surgery (i.e., surgery 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 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 STARPAC 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 breastfeeding 17. Patient has received a live vaccine within 4 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part 1: Dose Limiting Toxicities (DLT) attributed as possibly, probably or definitely related to the study treatment measured using adverse events recorded within the first 28 days of treatment Part 2: Determination of optimal biological dose (OBD) based on serum Vitamin A levels measured using blood sample analysis at the end of each treatment cycle - up to 6 cycles of treatment (1 cycle = 28 days) | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Maximum concentration observed (Cmax) determined using ATRA PK measured using blood sample analysis pre-dose and post-dose up to 5 hours on day 1 of cycles 1-3 2. Time of maximum concentration observed (Tmax) determined using ATRA PK measured using blood sample analysis pre-dose and post-dose up to 5 hours on day 1 of cycles 1-3 3. Area under the curve (AUC) determined using ATRA PK measured using blood sample analysis pre-dose and post-dose up to 5 hours on day 1 of cycles 1-3 4. Serum Vitamin A levels measured using blood sample analysis at baseline and at the end of cycles 1 and 2 5. Incidence of AE (graded by NCI CTCAE v4.03) from the time of consent until end of treatment, an average of 8 months 6. Objective response rate (ORR), defined as the percentage of patients with measurable disease at baseline who have at least one visit response of CR or PR prior to any evidence of progression assessed by the site radiologist using CT scans (RECIST v1.1) 8 weekly until progression or death for a maximum of 12 months 7. Progression-free survival (PFS), defined as the time from the date of registration to the date of first documented tumour progression (as assessed by the site radiologist and/or investigator, using RECIST v1.1) or death from any cause, whichever occurs first - assessed 8 weekly until progression or death for up to 12 months 8. Overall survival (OS), defined as the time from registration to death from any cause or 12 months follow up, whichever occurs first | — |
Countries
England, United Kingdom
Outcome results
None listed