| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Adenocarcinoma of the Pancreas |
| adenocarcinoma pancreatico metastatico |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pancreatic Cancer |
| Cancro al pancreas |
|
| 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.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- To determine efficacy of devimistat plus modified FOLFIRINOX (mFFX) compared to standard care FOLFIRINOX (FFX) in terms of Objective Response Rate (ORR). ORR is defined as Complete Response (CR) plus Partial Response (PR)
- To evaluate Progression-Free Survival (PFS) and Objective Response Rate (ORR) [Complete Response (CR) + Partial Response (PR)] of CPI-613® (devimistat) plus mFFX versus FFX (control arm) by independent, blinded, central review by RECIST guideline version 1.1 |
- Determinare l'efficacia di devimistat più FOLFIRINOX modificato (mFFX) rispetto a FOLFIRINOX (FFX) per cure standard in termini di tasso di risposta obiettiva (ORR). ORR è definito come risposta completa (CR) più risposta parziale (PR)
- Valutare la sopravvivenza libera da progressione (Progression-Free Survival, PFS) e il tasso di risposta oggettiva (Objective Response Rate, ORR) [CR (risposta completa) + PR (risposta parziale)] di CPI-613® (devimistat) più mFFX rispetto a FFX (braccio di controllo) mediante esame centrale, indipendente, in cieco, con linee guida RECIST versione 1.1 |
|
| E.2.2 | Secondary objectives of the trial |
• To determine efficacy of devimistat plus mFFX compared to standard care FFX in terms of Overall Survival (OS) at both Final Analysis and Follow-up Analysis.
• To evaluate Duration of Response (DOR)
• Safety Analysis: The assessment of safety will be based mainly on the frequency of adverse events based on the Common Terminology Criteria for Adverse Events (CTCAE version 4) grade. Adverse events will be coded according to MedDRA. The safety outcomes will include the occurrence of at least one serious adverse event, of at least onegrade 3/4 adverse event, and of at least one adverse event requiring the discontinuation of study treatment. QTc intervals will be also evaluated as part of safety analysis.
• To assess PK of devimistat.
• To evaluate Patient-Reported Outcomes (PRO) for devimistat plus mFFX compared to standard care FFX. |
Per determinare l'efficacia di devimistat più mFFX rispetto a FFX in terapia standard in termini di Sopravvivenza globale (OS) sia nell'analisi finale che nell'analisi di follow-up.
• Valutare la durata della risposta (DOR)
• Analisi di sicurezza: la valutazione della sicurezza si baserà principalmente sulla frequenza degli eventi avversi in base al criterio di terminologia comune per gli eventi avversi (versione 4 CTCAE). Gli eventi avversi saranno codificati secondo MedDRA. I risultati di sicurezza includeranno il verificarsi di almeno un evento avverso grave, di almeno un evento avverso di grado 3/4 e di almeno un evento avverso che richiede l'interruzione del trattamento in studio. Gli intervalli QTc saranno anche valutati come parte dell'analisi di sicurezza.
• Valutare PK di devimistat
• Valutare i risultati riportati dal paziente (PRO) per devimistat più mFFX rispetto alla FFX per cure standard. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
5.1.1 Histologically or cytologically confirmed metastatic adenocarcinoma stage IV of the pancreas with relationship with to the primary tumor only.
5.1.2 No prior treatments for stage IV pancreatic adenocarcinoma (prior adjuvant or neoadjuvant treatment is allowed provided completed > 6 months prior to disease recurrence)
5.1.3 Eastern Cooperative Oncology Group (ECOG) performance status 0 – 1
5.1.4 Male and female patients 18 – 75 years of age
5.1.5 Measurable disease determined using guidelines of Response Evaluation Criteria In Solid Tumors (RECIST version 1.1)
5.1.6 Expected survival >3 months
5.1.7 Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must use accepted highly effective contraceptive methods (abstinence, intrauterine device [IUD], oral contraceptive(s), intrauterine hormone releasing system (IUS), bilateral tubal occlusion or vasectomized partner) during and for 6 months after last study dose and must have a negative serum or urine pregnancy test within 1 week prior to treatment initiation, at monthly interval and, at the end of systemic exposure, and at 30 days after the systemic exposure
5.1.8 Males with Females partners of child bearing potential must agree to use double barrier contraceptive measure, oral contraception or avoidance of intercourse during the study and for 6 months after last study dose is received.
5.1.9 At least 2 weeks must have elapsed from any prior surgery with resolution of any sequela for randomization
5.1.10 Laboratory values =2 weeks prior to randomization must be:
- Adequate hematologic values
• Platelet count =100,000 cells/mm3 or =100 bil/L;
• Absolute neutrophil count [ANC] =1,500 cells/mm3 or =1.5 bil/L;
• Hemoglobin =9 g/dL or =90 g/L)
- Adequate hepatic function
• Aspartate aminotransferase [AST/SGOT] =3x upper normal limit [UNL]
• Alanine aminotransferase [ALT/SGPT] =3x UNL (=5x UNL if liver metastases present)
• Bilirubin (=1.5x UNL); bilirubin = 2.5 x ULN for subjects with Gilbert’s syndrome
• Serum albumin > 3.0 g/dL
- Adequate renal function
• serum creatinine clearance CLcr > 30 mL/min. (Cocroft-Gault Formula should be used for CrCl calculation)
- Adequate coagulation function
• International Normalized Ratio or INR must be <1.5 unless on therapeutic blood thinners)
5.1.11 No evidence of active infection and no serious infection within the past 30 days.
5.1.12 Mentally competent, ability to understand and willingness to sign the informed consent form |
5.1.1 Histologically or cytologically confirmed metastatic stage IV adenocarcinoma of the pancreas with relationship with to the primary tumor only.
5.1.2 No prior treatments for stage IV pancreatic adenocarcinoma (prior adjuvant or neoadjuvant treatment is allowed provided completed > 6 months prior to disease recurrence)
5.1.3 Eastern Cooperative Oncology Group (ECOG) performance status 0 – 1
5.1.4 Male and female patients 18 – 75 years of age
5.1.5 Measurable disease determined using guidelines of Response Evaluation Criteria In Solid Tumors (RECIST version 1.1)
5.1.6 Expected survival >3 months
5.1.7 Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must use accepted highly effective contraceptive methods (abstinence, intrauterine device [IUD], oral contraceptive(s), intrauterine hormone releasing system (IUS), bilateral tubal occlusion or vasectomized partner) during and for 6 months after last study dose and must have a negative serum or urine pregnancy test within 1 week prior to treatment initiation, at monthly interval and, at the end of systemic exposure, and at 30 days after the systemic exposure
5.1.8 Males with Females partners of child bearing potential must agree to use double barrier contraceptive measure, oral contraception or avoidance of intercourse during the study and for 6 months after last study dose is received.
5.1.9 At least 2 weeks must have elapsed from any prior surgery with resolution of any sequela for randomization
5.1.10 Laboratory values =2 weeks prior to randomization must be:
- Adequate hematologic values
• Platelet count =100,000 cells/mm3 or =100 bil/L;
• Absolute neutrophil count [ANC] =1,500 cells/mm3 or =1.5 bil/L;
• Hemoglobin =9 g/dL or =90 g/L)
- Adequate hepatic function
• Aspartate aminotransferase [AST/SGOT] =3x upper normal limit [UNL]
• Alanine aminotransferase [ALT/SGPT] =3x UNL (=5x UNL if liver metastases present)
• Bilirubin (=1.5x UNL); bilirubin = 2.5 x ULN for subjects with Gilbert’s syndrome
• Serum albumin > 3.0 g/dL
- Adequate renal function
• serum creatinine clearance CLcr > 30 mL/min. (Cocroft-Gault Formula should be used for CrCl calculation)
- Adequate coagulation function
• International Normalized Ratio or INR must be <1.5 unless on therapeutic blood thinners)
5.1.11 No evidence of active infection and no serious infection within the past 30 days.
5.1.12 Mentally competent, ability to understand and willingness to sign the informed consent form |
|
| E.4 | Principal exclusion criteria |
5.2.1 Endocrine or acinar pancreatic carcinoma
5.2.2 Known cerebral metastases, central nervous system (CNS), or epidural tumor
5.2.3 Prior treatment with any chemotherapy for metastatic adenocarcinoma of the pancreas
5.2.4 Completion of a gemcitabine-based adjuvant chemotherapy regimen within less than 6 months at the time of screening.
5.2.5 Receipt of neoadjuvant or adjuvant FOLFIRINOX therapy if <6 months prior to disease recurrence
5.2.6 Patients with hypersensitivity to devimistat, FFX treatment or any of their excipients
5.2.7 Presence of clinically significant abdominal ascites
5.2.8 Patients receiving any other standard or investigational treatment for their cancer, or any other investigational agent for any indication within the past 2 weeks prior to initiation of devimistat treatment
5.2.9 Serious medical illness that would potentially increase patients’ risk for toxicity
5.2.10 Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g., active peptic ulcer disease)
5.2.11 Female patients who are pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 6 months after the last dose of study treatment
5.2.12 Female patients of childbearing potential with a positive pregnancy test assessed by a serum pregnancy test at screening
5.2.13 Female patients of childbearing potential unwilling to use 1 highly effective method of contraception during treatment and for 6 months after the last dose of study treatment
5.2.14 Male patients with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for 6 months after completion of study treatment
5.2.15 Male patients unwilling to abstain from donating sperm during treatment and for 6 months after completion of study treatment
5.2.16 Life expectancy less than 3 months
5.2.17 Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of patients
5.2.18 Unwilling or unable to follow protocol requirements
5.2.19 Active heart disease including but not limited to symptomatic congestive heart failure (NYHA class 3 or 4), symptomatic coronary artery disease, symptomatic angina pectoris, or symptomatic myocardial infarction
5.2.20 Patients with a history of myocardial infarction that is <3 months prior to registration
5.2.21 Evidence of active infection, or serious infection within the past 30 days.
5.2.22 Patients with known HIV infection
5.2.23 Patients who have received cancer immunotherapy of any type within the past 2 weeks prior to initiation of devimistat treatment (steroids given for supportive care or in response to allergic reactions are allowed at any time)
5.2.24 Requirement for immediate palliative surgery, radiation or chemotherapy of any kind. Stenting for bile duct obstruction and need for pain medications are allowed provided all other inclusion criteria are met
5.2.25 Prior malignancy except for the following: adequately treated basal or squamous cell skin cancer, in situ cervical cancer, adequately treated cancer from which the patient has been disease-free for at least 3 years prior to screening
5.2.26 Unwilling or unable to avoid the concomitant use of strong CYP3A4 inducers or inhibitors during treatment with irinotecan
5.2.27 A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval > 480 milliseconds (ms) (CTCAE grade 1) using Fredericia’s QT correction formula (i.e. QTcF)
5.2.28 A history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family history of long QT syndrome)
5.2.29 The use of concomitant medications that prolong the QT/QTc intervals
5.2.30 Contraindications to any of the FFX treatment as detailed in the Protocol "Exclusion Criteria" Section. |
5.2.1 Endocrine or acinar pancreatic carcinoma
5.2.2 Known cerebral metastases, central nervous system (CNS), or epidural tumor
5.2.3 Prior treatment with any chemotherapy for metastatic adenocarcinoma of the pancreas
5.2.4 Completion of a gemcitabine-based adjuvant chemotherapy regimen within less than 6 months at the time of screening.
5.2.5 Receipt of neoadjuvant or adjuvant FOLFIRINOX therapy if <6 months prior to disease recurrence
5.2.6 Patients with hypersensitivity to devimistat, FFX treatment or any of their excipients
5.2.7 Presence of clinically significant abdominal ascites
5.2.8 Patients receiving any other standard or investigational treatment for their cancer, or any other investigational agent for any indication within the past 2 weeks prior to initiation of devimistat treatment
5.2.9 Serious medical illness that would potentially increase patients’ risk for toxicity
5.2.10 Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g., active peptic ulcer disease)
5.2.11 Female patients who are pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 6 months after the last dose of study treatment
5.2.12 Female patients of childbearing potential with a positive pregnancy test assessed by a serum pregnancy test at screening
5.2.13 Female patients of childbearing potential unwilling to use 1 highly effective method of contraception during treatment and for 6 months after the last dose of study treatment
5.2.14 Male patients with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for 6 months after completion of study treatment
5.2.15 Male patients unwilling to abstain from donating sperm during treatment and for 6 months after completion of study treatment
5.2.16 Life expectancy less than 3 months
5.2.17 Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of patients
5.2.18 Unwilling or unable to follow protocol requirements
5.2.19 Active heart disease including but not limited to symptomatic congestive heart failure (NYHA class 3 or 4), symptomatic coronary artery disease, symptomatic angina pectoris, or symptomatic myocardial infarction
5.2.20 Patients with a history of myocardial infarction that is <3 months prior to registration
5.2.21 Evidence of active infection, or serious infection within the past 30 days.
5.2.22 Patients with known HIV infection
5.2.23 Patients who have received cancer immunotherapy of any type within the past 2 weeks prior to initiation of devimistat treatment (steroids given for supportive care or in response to allergic reactions are allowed at any time)
5.2.24 Requirement for immediate palliative surgery, radiation or chemotherapy of any kind. Stenting for bile duct obstruction and need for pain medications are allowed provided all other inclusion criteria are met
5.2.25 Prior malignancy except for the following: adequately treated basal or squamous cell skin cancer, in situ cervical cancer, adequately treated cancer from which the patient has been disease-free for at least 3 years prior to screening
5.2.26 Unwilling or unable to avoid the concomitant use of strong CYP3A4 inducers or inhibitors during treatment with irinotecan
5.2.27 A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval > 480 milliseconds (ms) (CTCAE grade 1) using Fredericia’s QT correction formula (i.e. QTcF)
5.2.28 A history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family history of long QT syndrome)
5.2.29 The use of concomitant medications that prolong the QT/QTc intervals
5.2.30 Contraindications to any of the FFX treatment as detailed in the Protocol "Exclusion Criteria" Section. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Overall Response Rate (ORR)
2. Progression-Free Survival (PFS) |
1) tasso di risposta oggettiva (ORR)
2) sopravvivenza libera da progressione (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Patient’s best response within the first 12 cycles
2. Date of randomization to the date of progressive disease or death from any cause |
1. La migliore risposta del paziente entro i primi 12 cicli
2. Data di randomizzazione alla data di malattia progressiva o morte per qualsiasi causa |
|
| E.5.2 | Secondary end point(s) |
1. Overall Survival (OS)
2. Duration of Response (DOR)
3. Safety: AEs, SAEs, QTc.
4. Pharmacokinetics
5. Patient-Reported Outcomes (PRO) |
1. Overall Survival (OS)
2. Duration of Response (DOR)
3. Safety: AEs, SAEs, QTc.
4. Pharmacokinetics
5. Patient-Reported Outcomes (PRO) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Date of randomization to the date of death from any cause
2. Date of initial documented response (CR or PR) to the first documented date of disease progression or death
3. Throughout the study
4. Day 1&3 of cycles 1&2, day 3 of subsequent cycles
5. Baseline and day 1 of every even numbered cycle |
1. Date of randomization to the date of death from any cause
2. Date of initial documented response (CR or PR) to the first documented date of disease progression or death
3. Throughout the study
4. Day 1&3 of cycles 1&2, day 3 of subsequent cycles
5. Baseline and day 1 of every even numbered cycle |
|
| 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 | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 44 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Israel |
| Korea, Republic of |
| United States |
| Belgium |
| France |
| Germany |
| Hungary |
| Italy |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| 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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