| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Histologically verified, locally advanced (nonresectable Stage II/III) or metastatic (Stage IV) adenocarcinoma of the pancreas. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pancreatic cancer. Only patients with inoperable disease will be included, meaning patients who's cancer has grown too much to operate, or spread to other parts of the body. |
|
| 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.1.3 | 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 efficacy of the combined Gemcitabine/ Nab-Paclitaxel or FOLFIRINOX, and Sonazoid under ultrasound treatment, compared to Gemcitabine/ Nab-Paclitaxel or FOLFIRINOX treatment alone. |
|
| E.2.2 | Secondary objectives of the trial |
1. To further evaluate efficacy of the combined Gemcitabine/ Nab-Paclitaxel or FOLFIRINOX, and Sonazoid under ultrasound treatment, compared to Gemcitabine/ Nab-Paclitaxel or FOLFIRINOX treatment alone.
2. To evaluate the effect of sonoporation on local disease progression using CT and ultrasound.
3. To evaluate the effect of sonoporation on tumour volume using clinical diagnostic CT protocols.
4. To evaluate if sonoporation impacts surgical operability, by comparing the frequencies of patients who becom surgically operable during the course of treatment.
5. To evaluate the safety of the combined Gemcitabine/ Nab-Paclitaxel or FOLFIRINOX, and Sonazoid under ultrasound treatment, compared to Gemcitabine/ Nab-Paclitaxel or FOLFIRINOX treatment alone.
Exploratory endpoints are described in the protocol. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients, who meet all the following inclusion criteria, are eligible for the study entry:
• Patient must be ≥18 years old.
• Patient has a diagnosis of inoperable PDAC and are scheduled to undergo SoC chemotherapy
o (ICD-10 C25.0 Malignant neoplasm: Body of pancreas, C25.2 Malignant neoplasm: Tail of pancreas and C25.3 Malignant neoplasm: Pancreatic duct).
o Histologically verified, locally advanced (nonresectable Stage II/III) or metastatic (Stage IV) adenocarcinoma of the pancreas.
• The PDAC must be visible on ultrasound.
• Must be ambulatory with an ECOG performance status between 0 and 2.
• Female patients of child-bearing potential must have a negative urine pregnancy test and use (and agree to continue to use) an effective or highly effective birth control method. Contraception must be used from the Screening Visit, throughout the study period and for 6 months after the last exposure to the IMPs.
Effective birth control methods include:
o Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action
o Male or female condom with or without spermicide
o Cap, diaphragm or sponge with spermicide
Highly effective birth control methods include:
o Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal)
o Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
o Intrauterine device (IUD)
o Intrauterine hormone-releasing system (IUS)
o Bilateral tubal occlusion
o Vasectomised partner
o Sexual abstinence
A pregnancy test must be performed at inclusion, at end of study and at any timepoint if pregnancy is suspected during the study period.
[Definition: A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.]
• Male patients with a female partner who is considered of childbearing potential, must agree to use a condom throughout the study and for 6 months after last exposure to the IMPs.
• Must have lab values as the following: Hemoglobin >10 g/dL, neutrophils (polymorphonuclear leukocytes) >3.5 109/L, PLT >150 and Bilirubin <75 µmol/L.
• Signed informed consent and expected cooperation of the patients for the treatment and follow up must be obtained and documented according to ICH/GCP, and national/local regulations. |
|
| E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet any of the following criteria:
• Patient participated in an investigational study within 7 days prior to study entry (or, if longer, within five half-lives of the last dose of any investigational drug).
• Patient has severe chronic obstructive pulmonary disease,or pulmonary hypertension or unstable cardiopulmonary conditions.
• Patients who are medically unstable. For example:
o Patients on life support or in a critical care unit.
o Patients with unstable occlusive disease (e.g., crescendo angina)
o Patients with clinically unstable cardiac arrhythmias, such as recurrent ventricular tachycardia.
o Patients with uncontrolled congestive heart failure (NYHA Class IV)
o Patients with recent cerebral hemorrhage.
o Patients who have undergone surgery within 24 hours prior to the study sonographic examination.
• Patient with a history of any psychiatric disorder or cognitive impairment that would interfere with participation in the study.
• Patient has a known history of HIV infection or active Hepatitis B or Hepatitis C infection.
• Patient requires dialysis or has severely impaired renal function, defined as estimated Glomerular Filtration Rate (eGFR) >30 at the Screening Visit.
• Patient has severe impairment of liver function, defined as a serum albumin level ≤ 25 g/L and/or a Protrombin Time INR > 2.3 (or APTT > 6 seconds above the upper limit of normal) at the Screening Visit.
• Patients with baseline ANC of < 1.5 x 109/L or platelets < 100 x 109/L prior to each treatment cycle.
• Patients with a history of anaphylactic allergy to eggs or egg products, manifested by one or more of the following symptoms: generalized urticaria, difficulty in breathing, swelling of the mouth and throat, hypotension, or shock. (Subjects with nonanaphylactic allergies to eggs or egg products may be enrolled in the study, but must be watched carefully for 1 h following the administration of Sonazoid).
• Patients that are allergic to any other component of Sonazoid.
• Patient is allergic to or intolerant of any IMPs included in the chemotherapy regimen that the patient is scheduled for (Gemcitabine/Nab-Paclitaxel or FOLFIRINOX).
• Patient has any known contraindications to any of the IMPs that the patient is scheduled for. Contraindications are described in the SmPCs.
• Any reason why, in the opinion of the investigator, the patient should not participate.
• Patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment
• Patient is pregnant or is breast-feeding. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Efficacy will be evaluated using progression free survival based on the RECIST-criteria. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Efficacy: Progression free survival will be evaluated based on CT examinations using the RECIST criteria. CTs will be performed at screening, every 8th week during the treatment period, at the 12-weeks follow-up and every 3rd month after follow-up until progression is detected. |
|
| E.5.2 | Secondary end point(s) |
1) Secondary efficacy endpoints:
a. Overall survival
b. Time to treatment failure, defined as time from study day 1 to disease progression (RECIST-criteria from CT) and/or rapidly deteriorating ECOG performance status.
c. Number of completed chemotherapy cycles before treatment failure
2) Local efficacy endpoints:
a. Changes in local disease progression using RECIST-criteria (CT)
b. Changes in maximum tumour diameter (CT and ultrasound)
3) Changes in disease progression using primary tumour volume (CT and ultrasound)
4) Surgical operability (yes/no): Based on CT imaging, i.e. evaluation every eight week while receiving treatment.
5) Safety will be evaluated using the following endpoints:
a. Frequency of AEs, SAEs and SUSARs, to be registered at all study visits
b. Clinical laboratory tests including blood smear, see Attachment A for details.
c. Physical examinations
d. Sitting vital signs, body temperature and body weight
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Time to treatment failure and number of cycles before treatment failure will be evaluated by ECOG performance status (all visits) and disease progression (CT every eight week during the study period, at 12-w follow-up and every 3rd month after last follow-up until progression is detected).
2) Local efficacy endpoints: CT every eight week during the study period, at 12-w follow-up and every 3rd month after last follow-up until progression. Ultrasound at all visits. Patients in the control group will undergo US examinations at baseline, study day 29 and 59, and during follow-up.
3) CT and US timings as described above (secondary endpoint 2)
4) CT timings are described above (secondary endpoint 2).
5) Safety: all visits, including follow-up visits. |
|
| 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 | Yes |
| 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) | 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 | 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 | Yes |
| 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
| 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 | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 |
|
| 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
|
| End of study is defined as when the last overall survival data has been collected. |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 2 |
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