| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Stage IV pancreatic adenocarcinoma |
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| E.1.1.1 | Medical condition in easily understood language |
| Metastatic pancreatic cancer |
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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 |
| To determine the clinical benefit of adding paricalcitol to the regimen of paclitaxel protein bound plus cisplatin plus gemcitabine for patients with progressive metastatic PDA. |
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| E.2.2 | Secondary objectives of the trial |
• Evaluate the mechanisms of disease progression of patients with metastatic PDAC to paclitaxel protein bound plus cisplatin plus gemcitabine
• To assess the pharmacodynamics effect of paricalcitol for patients with metastatic PDA
• Evaluate the safety of cisplatin plus paclitaxel protein bound plus gemcitabine plus paricalcitol.
Tertiary/Exploratory
The results of any exploratory analysis will not be included in the clinical study report and may be reported separately from the main study results:
• To evaluate the pharmacodynamic effects of paricalcitol on PDA on core biopsies collected at baseline prior to the addition of paricalcitol and after 2 cycles of the triplet regimen plus paricalcitol (6 weeks): Stromal content (collagen and hyaluronan), CD31 staining, PD-1/ PDl-1 staining and expression, IHC evaluation of key immune cell populations (cytotoxic T Cells, TAMs, MDSCs, and Tregs), Clonality of intra-tumoural T cells by TSR sequencing (a measure of intratumoural response) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Willing and able to provide written informed consent.
2. Ability to comply with the protocol.
3. Aged ≥ 18 years; male or female.
4. Histologically or cytologically confirmed metastatic (stage IV) pancreatic ductal adenocarcinoma.
5. Karnofsky performance status ≥70.
6. At least one lesion that can be measured accurately at baseline as ≥10mm in the longest diameter (except lymph nodes which must have a short axis ≥15mm) with CT/MRI and which is suitable for repeated measurements per RECIST v1.1
7. Adequate haematological and end-organ function, as per the local institutions reference ranges, within 72 hrs prior to day 1 of cycle 1 of treatment defined by the following:
a. Haematology: ANC >1.5 x 109/L (>1500 cells / mm3); Platelet count > 100 x 109/L (>100,000 cells/mm3); haematocrit level >27% for females or >30% for males
b. Coagulation: INR and aPTT ≤1.5 x ULN.
c. Biochemistry: serum creatinine < 1.5mg/dl, bilirubin < 1.5 x ULN; AST / ALT ≤ 2.5 x ULN (or ≤ 5 x ULN in the presence of liver metastasis) calculated creatinine clearance ≥ 50ml/min (as measured by Cockcroft & Gault), calcium (corrected for calcium) ≤ 1 x ULN
8. Life expectancy ≥ 12 weeks.
9. Women of childbearing potential must agree not to become pregnant (e.g. post-menopausal for at least 1 year, surgically sterile, or practising adequate birth control methods) for the duration of the study and for 1 month after last dose of study treatment. Women of child bearing potential must have a negative serum or urine pregnancy test within 14 days of Cycle 1 Day 1 (preferably as close to the study treatment day as possible). Both male and female patients of reproductive potential must agree to use a reliable method of birth control from 2 weeks before the start of study treatment and until 1 month (female participants) or 6 months (male participants) after completion of treatment.
10. Tumour sites amenable to repeated biopsies.
11. Willingness to undergo paired tumour biopsies during the trial.
Optional: For patients who are entering the trial at the stage of starting Paricalcitol only:
12. A patient must have received paclitaxel protein bound and gemcitabine as first line chemotherapy for metastatic disease in exactly the same way as mandated in the current trial, to be enrolled directly to the add on paricalcitol component of the trial. The patient must have previously received the following minimum doses: abraxane 75 mg/m2 and gemcitabine 600 mg/m2. If lower than these doses then the patient will be ineligible for enrolment into the PINBALL trial.
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| E.4 | Principal exclusion criteria |
1. Patients must have received no previous radiotherapy, surgery, chemotherapy or investigational therapy for the treatment of metastatic disease. Prior treatments in the adjuvant setting with gemcitabine and/or 5-FU or gemcitabine administered as a radiation sensitizer are allowed, provided at least 6 months have elapsed since completion of the last dose and no lingering toxicities are present. If a patient has received paclitaxel protein bound and gemcitabine as first line chemotherapy for metastatic disease in the same way as mandated in the current trial, they can be considered eligible to be enrolled directly to the add on paricalcitol component of the trial. Unless the patient meets inclusion criteria 12.
2. Palliative surgery and/or radiation treatment less than 4 weeks prior to initiation of study treatment.
3. Exposure to any investigational agent within 4 weeks prior to initiation of study treatment.
4. Evidence of central nervous system (CNS) metastasis (negative imaging study, if clinically indicated, within 28 days of Cycle 1 Day 1).
5. 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.
6. Pre-existing hypercalcaemia, defined as baseline serum calcium (corrected for albumin) above the institutional ULN.
7. Current, serious, clinically significant cardiac arrhythmias as determined by the investigator.
8. History of HIV infection.
9. Active, clinically significant serious infection requiring treatment with antibiotics, antivirals or anti-fungals (see Section 6.10).
10. History of symptomatic genitourinary stones (e.g. kidney stones) within 12months of Cycle 1 Day 1.
11. Pre-existing, clinically significant peripheral neuropathy ≥ G2
12. Hypersensitivity to the active study drug substance or to any of its excipients as listed in section 6 of the SmPC of each study drug.
13. Patient is on prohibited concurrent medication (see Section 6.10). In particular, vitamin D and calcium supplements must be stopped at the time of enrolment and for the duration of study treatment.
14. Any other disease, metabolic dysfunction, physical examination finding or clinical laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of study treatment, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent.
15. Female patients who are pregnant or nursing.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| To evaluate the response after the administration of Paricalcitol to those with PDA who have progressed on paclitaxel protein bound plus cisplatin plus gemcitabine by using RECIST 1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| On disease progression after the addition of paricalcitol. |
|
| E.5.2 | Secondary end point(s) |
- To evaluate the treatment-related toxicities in this patient population.
- To evaluate the change in CA 19-9 (or CA 125, or CEA if not expressers of CA 19-9) in this patient population.
- To evaluate the change in parathyroid hormone (PTH) in individuals treated with paricalcitol
- To monitor and measure the serum levels of Vitamin D 25-OH with every 3 cycles of therapy
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- From consent to safety visit
- Every 3 weeks while on study treatment
- Every 3 weeks while on study treatment
- Every 3 weeks while on study treatment |
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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 | 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) | 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 | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| 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 visit (LPLV) and is expected to occur around 18 months after the last patient is enrolled in the study. All translational research is expected to be completed within 1 year of the LPLV. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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