E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic or Advanced Adenocarcinoma of the Pancreas Expressing Guanylyl Cyclase C (GCC) |
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E.1.1.1 | Medical condition in easily understood language |
Previously treated tumors consisting of cells from the gastro-intestinal tract located in the pancreas which is advanced or has spread. |
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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 | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10033599 |
E.1.2 | Term | Pancreatic adenocarcinoma metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10051971 |
E.1.2 | Term | Pancreatic adenocarcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052747 |
E.1.2 | Term | Adenocarcinoma pancreas |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 evaluate the overall response rate (ORR) of patients with advanced or metastatic GCC-positive adenocarcinoma of the pancreas treated with MLN0264 |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety profile of MLN0264
To evaluate PFS
To evaluate duration of response (DOR)
To evaluate disease control rate (DCR)
To evaluate OS
To examine the pharmacokinetic (PK) profile
To evaluate tumor size reduction
To investigate the association between GCC expression level and antitumor effects of MLN0264
To assess immunogenicity of MLN0264 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Each patient must meet all the following inclusion criteria to be enrolled in the study:
1. Male or female patients 18 years of age or older when written informed consent is obtained.
2. Histologically confirmed metastatic or advanced inoperable adenocarcinoma of the pancreas with IHC evidence of GCC expression indicated by an H-score of 10 or greater.
3. Treatment with 1 or more prior chemotherapies for advanced or metastatic adenocarcinoma of the pancreas.
4. Measurable disease as defined by RECIST version 1.1 guidelines.
5. ECOG performance status of 0 or 1 within 14 days before enrollment.
6. Female patients who:
- Are postmenopausal for at least 1 year before the screening visit, OR
- Are surgically sterile, OR
- If they are of childbearing potential, agree to practice 2 effective methods ofcontraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study drug, or
- Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:
- Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or
- Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.)
7. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
8. Adequate organ and hematological function as evidenced by the following laboratory values within 14 days before enrollment:
- Absolute neutrophil count (ANC) ≥ 1.5 x109/L
- Platelet count ≥ 100 x 109/L
- Hemoglobin ≥ 9 g/dL
- Activated partial thromboplastin time (aPTT) ≤ 1.5 x the upper limit of the normal range (ULN) per institutional laboratory normal range
- International normalized ratio (INR) ≤ 1.5 x ULN
- Serum creatinine ≤ 1.5 x ULN
- Total bilirubin ≤ 1.5 x ULN
- Albumin ≥ 3g/dL
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN
- Serum lipase ≥ 3 x ULN and serum amylase within the normal range
9. Resolution of all toxic effects of prior treatments except alopecia to Grade 0 or 1 by NCI CTCAE version 4.03.
10. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures. |
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E.4 | Principal exclusion criteria |
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Radiotherapy within 4 weeks before enrollment
2. Concurrent treatment or treatment within 4 weeks of study entry with any other investigational agent or chemotherapy
3. Female patients who are lactating and breastfeeding or have a positive pregnancy test during the Screening period
4. Uncontrolled, clinically significant, symptomatic cardiovascular disease within 6 months before enrollment, including myocardial infarction, unstable angina, Grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or arrhythmias not controlled by outpatient
medication
5. Treatment with any medication that has a clinically relevant potential risk of prolonging the QT interval or inducing torsades de pointes that cannot be discontinued or switched to a different medication before starting study drug
6. Patients with ECG abnormalities considered by the investigator to be clinically significant, or repeated baseline prolongation of the rate-corrected QT interval (QTc)
7. Ongoing or clinically significant active infection as judged by the investigator
8. Signs of PN ≥ NCI CTCAE Grade 2
9. Concomitant chemotherapy, hormonal therapy, immunotherapy, or any other form of cancer treatment
10. Use of strong cytochrome P450 (CYP) 3A4 inhibitors within 2 weeks before the first dose of study drug
11. Any preexisting medical condition of sufficient severity to prevent full compliance with the study
12. History of or current neoplasm other than pancreatic adenocarcinoma, except for curatively treated nonmelanoma skin cancer or in situ carcinoma of the cervix uteri
13. Known diagnosis of human immunodeficiency virus (HIV) infection
14. Symptomatic brain metastases
15. Ongoing anticoagulant therapy (eg, aspirin, coumadin, heparin) |
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E.5 End points |
E.5.1 | Primary end point(s) |
ORR (complete response [CR] + PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Screening, Day 21 of every other cycle starting with Cycle 2 (ie, Cycles 2, 4, 6, etc.), at EOT, and during Progression Free Survival Follow-up (PFSFU). |
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E.5.2 | Secondary end point(s) |
-AEs, serious adverse events (SAEs), clinical laboratory values, and vital sign measurements
- Efficacy Endpoints: PFS, DOR, DCR, including CR + PR + SD with minimum 12 weeks duration, OS, Tumor size reduction
- PK parameters
- - GCC H-score assessed by immunohistochemistry (IHC)
- Assessment of antitherapeutic antibodies (ATA) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
AEs: From the first dose of study drug to 30 days after the last
dose.
SAEs: From the signing of the ICF to 30 days after the last dose
Clinical laboratory values: Day 1, Day 15 Cycle 1&2; Day 1 Cycle 3+; EoT.
Vital sign measurements: Screening; Day 1 at 5 and 15 minutes after the start of infusion and upon completion of the infusion for all cycles; EoT.
Efficacy Endpoints: Screening; Day 21 of every other cycle starting with Cycle 2 (ie, Cycles 2, 4, 6, etc.); EOT, and during PFSFU.
PK parameters: Specified timepoints on Day 1 all cycles; Day 3, Day 4, Day 8 & Day 15 Cycles 1 to 3; Day 4 & Day 8 Cycle 6; EoT.
GCC H-score assessed by immunohistochemistry (IHC): pre-screening.
Assessment of antitherapeutic antibodies (ATA): day 1 pre-dose; EoT. |
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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 | No |
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 | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
biomarkers and immunogenicity |
|
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) | 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
| 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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
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 |
Belgium |
Brazil |
Italy |
Peru |
Spain |
United Kingdom |
United States |
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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
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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 | 4 |
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 | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |