| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced pancreatic cancer. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced pancreatic cancer. |
|
| 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 |
|
| 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 | 10033606 |
| E.1.2 | Term | Pancreatic cancer non-resectable |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 | 10033607 |
| E.1.2 | Term | Pancreatic cancer recurrent |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 evaluate the anti-tumour efficacy of paricalcitol in combination with gemcitabine and nab-paclitaxel in patients with advanced pancreatic cancer who have received no prior systemic chemotherapy in the metastatic or recurrent setting. |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the overall survival (OS) times, time to treatment failure (TTF), confirmed tumour response rate and duration of response in patients treated with this regimen.
2. To assess the safety and tolerability of this regimen in these patients.
3. To assess the incidence of hypercalcaemia in patients treated with this regimen. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Translational Research Sub-Study as part of the main trial protocol.
1. To examine the correlation between molecular biomarkers and benefit from therapy.
2. To examine correlation between histopathology, desmoplastic reaction, morphometric evaluation of fibrosis (Masson’s trichrome staining) versus immunohistochemistry profiling
and benefit from therapy.
3. To determine if biophysical subtypes of PDAC cells and stromal components identified on CTs predict later outcome |
|
| E.3 | Principal inclusion criteria |
1. Written informed consent obtained prior to any study-related procedures.
2. Incurable recurrent, locally advanced or metastatic pancreatic adenocarcinoma.
3. Histologically or cytologically confirmed pancreatic adenocarcinoma.
4. No prior chemotherapy for incurable, locally advanced unresectable or metastatic pancreatic cancer. Patients may have received prior chemotherapy in the neo adjuvant or adjuvant setting provided they have a minimum treatment-free interval of 3 months.
5. At least one measurable lesion according to RECIST criteria (Version 1.1). Patients with bone only disease are not eligible.
6. Aged 18 years or older
7. ECOG performance status 0 – 2
8. Adequate haematological, renal and hepatic function measured within 28 days prior to commencing study:
- Total bilirubin ≤ ULN (or ≤ 3 x ULN (≤ grade 2) for patients with liver involvement)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (≤ grade 1) (≤ 5 x ULN for patients with liver involvement by pancreatic cancer).
- Glomerular filtration rate (GFR) ≥ 30mL/min/1.73 m2 (≤ grade 2) for patients with serum creatinine levels above or below the institutional normal range. If using creatinine clearance, actual body weight should be used for calculating creatinine clearance (e.g., using the Cockroft-Gault formula). For patients with a Body Mass Index (BMI) >30 kg/m2, lean body weight should be used instead.
- Platelet count ≥ 100 x 10^9/L.
- Haemoglobin (Hb) ≥ 8 g/dL (≤ grade 2)
- Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (≤ grade 1)
- Corrected serum calcium of ≤ 2.9 mmol/L (≤ grade 1).
9. Life expectancy of at least 12 weeks.
10. Women of childbearing potential and sexually active males must agree to use highly effective contraceptive measures. This applies from starting treatment until at least 6 months after the last study drug administration. The investigator or a designated associate is required to advise the patient how to achieve an adequate birth control. Highly effective contraception is defined in the study as methods that achieve a failure rate of less than 1% per year when used consistently and correctly. Such methods include:
i. Combined (oestrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation (oral, intravaginal, transdermal).
ii. Progestogen-only hormonal contraception associated with inhibition of
ovulation (oral, injectable and implantable).
iii. Intrauterine device (IUD).
iv. Intrauterine hormone-releasing system (IUS).
v. Bilateral tubal occlusion.
vi. Successfully vasectomised partner.
vii. Sexual abstinence. |
|
| E.4 | Principal exclusion criteria |
1. Treated with other investigational drugs within 28 days or 5.5 half-lives of treatment start; in addition, concurrent alternative (complementary) medications are excluded within 28 days of treatment start.
2. Known brain metastases, unless previously treated and well-controlled for at least 2 months.
3. Dementia, altered mental status, or any other psychiatric condition that would interfere with the patient's safety or informed consent
4. History of other malignancy other than pancreatic cancer. However, patients who have been disease free from another malignancy for at least 5 years, or patients with a history of resected non-melanoma skin cancer or successfully treated in situ cancer and superficial bladder tumours (Ta, Tis, T1) are eligible.
5. Known history of hypercalcaemia.
6. Presence or history of symptomatic kidney stones in the last 5 years.
7. Active, clinically serious infections > grade 2 (CTCAE v5.0).
8. Greater than or equal to grade 2 sensory or motor neuropathy
9. Uncontrolled intercurrent illness, including, but not limited to uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or social situation that would affect compliance with the requirements of this study.
10. GI tract disease resulting in an inability to take oral medications, malabsorption syndrome, where previous surgical procedures affect absorption and uncontrolled inflammatory bowel disease.
11. History of diseases known to be associated with calcium disorders, including: ongoing hyperparathyroidism and Sarcoidosis.
12. Hypersensitivity to any of the excipients of gemcitabine, Nab-paclitaxel or Paricalcitol.
13. Known vitamin D toxicity
14. Undergoing treatment with the following therapies and medications:
a) Concurrent use of drugs known to influence serum calcium such as thiazide diuretics, teriparatide (recombinant parathyroid hormone), calcitonin and multivitamin supplements containing > 400 IU of vitamin D or calcium.
b) Current use of drugs which could influence bioavailability of paricalcitol (such as magnesium-containing antacids, bile-resin binders).
c) Current use of strong inhibitors of CYP3A4 or CYP2C8 (see protocol Table 13)
d) Current use of inducers of CYP3A4 or CYP2C8 (see protocol Table 13)
e) Phosphate related medicinal products
Note:
Zoledronate or denosumab for patients with bone metastasis is allowed.
Calcium intake is not restricted, but calcium supplementation is not permitted.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
> Primary Endpoints
Anti-tumour efficacy of treatment with paricalcitol will be primarily measured as progression free survival (PFS): that is, the percentage of patients free of progression at 24 weeks from registration into the study as determined by radiographic disease assessments per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.
> Primary Safety Endpoints
To evaluate the safety and tolerability of this regimen as measured by incidence of adverse events reported and toxicity evaluation as per the NCI CTCAE version 5.0.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Planned efficacy assessments will occur by CT TAP every 12 weeks (+/- 14 days) until radiographically confirmed disease progression or consent withdrawal.
An interim analysis to be performed after the first 15 patients have been recruited.
Final analysis will be performed after the study has been completed, the data cleaned, and the database closed out, according to the trial Statistical Analysis Plan.
The study will be reviewed on a regular basis by the Cancer Trials Ireland Safety Monitoring Committee while patients are on treatment or in the immediate follow-up period, 30 days after the last dose. |
|
| E.5.2 | Secondary end point(s) |
> Secondary Efficacy Endpoints
The secondary efficacy endpoints of this study are the evaluation of the following parameters in patients treated with this regimen:
- Overall Survival (OS).
- Time to Treatment Failure (TTF) is defined as time from registration to discontinuation of therapy or add-on of new anti-cancer therapy for any reason (including death, progression and toxicity).
- Confirmed tumour response rate as assessed by RECIST criteria version 1.1.
- Duration of response (DR) as assessed by RECIST criteria version 1.1.
> Secondary Safety Endpoints
To assess the incidence of hypercalcaemia in patients treated with this regimen.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Planned efficacy assessments will occur by CT TAP every 12 weeks (+/- 14 days) until radiographically confirmed disease progression or consent withdrawal.
An interim analysis to be performed after the first 15 patients have been recruited.
Final analysis will be performed after the study has been completed, the data cleaned, and the database closed out, according to the trial Statistical Analysis Plan.
The study will be reviewed on a regular basis by the Cancer Trials Ireland Safety Monitoring Committee while patients are on treatment or in the immediate follow-up period, 30 days after the last dose. |
|
| 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 | Yes |
| 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 | 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 5 |
| 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
|
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
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