| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced pancreatic cancer, non-resectable or borderline resectable, or metastatic pancreatic cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Locally advanced pancreatic cancer or metastatic pancreatic cancer |
| lokalavanceret kræft i bugspytkirtlen, hvor operation ikke er muligt/indikeret, eller kræft i bugspytkirtlen, der har spredt sig |
|
| 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 | 10033606 |
| E.1.2 | Term | Pancreatic cancer non-resectable |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| 1. To evaluate the safety and toxicity profile of nivolumab with ipilimumab in combination with standard chemotherapy and followed by nivolumab in combination with gemcitabine and nab-paclitaxel and MRI- and/or CT-guided adaptive stereotactic body radiotherapy (SBRT) for the treatment of BRPC, LAPC or mPC |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate PFS and PFS rate of nivolumab with ipilimumab combined with standard chemotherapy followed by nivolumab combined with gemcitabine/nab-paclitaxel and MRI- and/or CT-guided adaptive SBRT for the treatment of BRPC, LAPC or mPC
2. To evaluate OS and OS rate of nivolumab with ipilimumab combined with standard chemotherapy followed by nivolumab combined with gemcitabine/nab-paclitaxel and MRI- and/or CT-guided adaptive SBRT for the treatment of BRPC, LAPC or mPC
3. To evaluate anti-tumor activity of nnivolumab with ipilimumab combined with standard chemotherapy followed by nivolumab combined with gemcitabine/nab-paclitaxel and MRI- and/or CT-guided adaptive SBRT for the treatment of BRPC, LAPC or mPC
4. To determine rate of downstaging to surgical resection of nivolumab with ipilimumab in combination with standard chemotherapy followed by nivolumab in combination with gemcitabine and nab-paclitaxel and MRI- and/or CT-guided adaptive SBRT for the treatment of BRPC and LAPC |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Signed informed consent:
-Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care
-Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study
• Histological or cytological confirmation of borderline resectable, locally advanced or metastatic pancreatic carcinoma prior to entering this study
• No prior chemotherapy regimens received for PC.
• Age 18 years or older
• Life expectancy greater than 6 months
• ECOG/WHO Performance Status (PS) 0-1
• All participants will be required to undergo mandatory pre- and on-treatment biopsies at acceptable clinical risk as judged by the investigator. An archival pre-treatment sample is acceptable.
• Patients must have normal organ and marrow function as defined below:
-Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L
-Platelet count ≥ 100 x 10⁹/L
-Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) (patients with Gilbert's Syndrome must have a total bilirubin ≤ 50 mmol/L)
-Aspartate transaminase (AST)/Alanine transaminase (ALT) ≤ 5 x ULN
-Serum creatinine ≤ 1.5 x ULN or CrCl ≥ 40 mL/min (using the Cockcroft-Gault formula)
• Women of childbearing potential (WOCBP) must use method(s) of contraception as indicated in Appendix 3. For a teratogenic study drug and/or when there is insufficient information to assess teratogenicity (preclinical studies have not been done), a highly effective method(s) of contraception (failure rate of less than 1% per year) is required. The individual methods of contraception and duration should be determined in consultation with the investigator. WOCBP must follow instructions for birth control when the half-life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 30 days plus the time required for the investigational drug to undergo five half-lives. The half-life of nivolumab and ipilimumab is up to 25 days and 18 days, respectively. WOCBP should therefore use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug
• Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. The investigator shall review contraception methods and the time period that contraception must be followed. Men that are sexually active with WOCBP must follow instructions for birth control when the half-life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 90 days plus the time required for the investigational drug to undergo five half-lives. The half-life of nivolumab is up to 25 days. Men who are sexually active with WOCBP must continue contraception for 31 weeks (90 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug. Women who are not of childbearing potential (ie. who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception
• Subjects must have signed and dated a BIOPAC approved written informed consent form in accordance with regulatory and institutional guidelines.
|
|
| E.4 | Principal exclusion criteria |
• Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
• Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results
• Participants with active, known or suspected autoimmune disease. Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Participants with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Allergies and Adverse Drug Reaction:
-History of allergy to study drug components
-History of severe hypersensitivity reaction to any monoclonal antibody
• WOCBP who are pregnant or breastfeeding
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Incidence of treatment-related adverse events (AEs), severe adverse events (SAEs), AEs leading to discontinuation, death, and laboratory abnormalities. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Safety is evaluated continuously until 100 days after last treatment within trial |
|
| E.5.2 | Secondary end point(s) |
1. Median PFS and PFS rate at 6, 9, and 12 months using RECIST v1.1
2. Median OS and OSR at 6 months, 1 year, and 2 years
3. Objective response rate per RECIST v1.1 and median duration of response
4. Rate of downstaging to surgical resection
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| final analysis 2 years after inclusion of last patient |
|
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| New combinational therapy (each IMP has MA) |
|
| 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) | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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