| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced neuroendocrine tumor (NET) of pancreatic, GI lung origin or poorly-differentiated gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC), that have progressed on prior treatment |
|
| E.1.1.1 | Medical condition in easily understood language |
Advanced neuroendocrine cancer of gastrointestinal or pancreatic or lung origin poorly-differentiated gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC)that have progressed on prior treatment
|
|
| 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 | PT |
| E.1.2 | Classification code | 10052399 |
| E.1.2 | Term | Neuroendocrine tumour |
| 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 |
To estimate the antitumor activity of PDR001 as a single agent in the well-differentiated NET and poorly-differentiated GEP-NEC groups.
|
|
| E.2.2 | Secondary objectives of the trial |
Key secondary (part 1 and part 2 for
expanded cohort(s))
-To estimate efficacy of PDR001
- To assess the safety and tolerability of PDR001
- To evaluate additional efficacy parameters
- To evaluate biochemical response to treatment (based on CgA and NSE) in the well-differentiated NET and poorly-differentiated GEP-NEC groups
- To characterize the pharmacokinetics of PDR001 with 400 mg flat dose Q4W in the well differentiated NET and poorly differentiated GEP-NEC groups
- To characterize patient's health related quality of life with PDR001 in the well-differentiated NET and poorly-differentiated GEP-NEC groups
- To evaluate the prevalence and incidence of immunogenicity in the well-differentiated NET and poorly differentiated GEP-NEC groups |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent must be obtained prior to any screening procedures
2. Adult males or females ≥ 18 years at screening.
3. Pathologically confirmed, advanced (unresectable or metastatic):
Well-differentiated (G1 or G2) based on local pathology report, nonfunctional neuroendocrine tumor of GI, pancreatic or thoracic (including lung and thymus) origin.
Poorly-differentiated GEP-NEC based on local pathology report
4. No active symptoms related to carcinoid syndrome during the last 3 months prior to start of study treatment.
5. Patients must have received prior treatment for advanced disease:
Well-differentiated NET group:
a. Thoracic (lung and thymus origin) cohort:
Thymus origin: at least one prior systemic therapy according to investigator's choice
Lung origin: at least one prior systemic therapy is required, which must include everolimus.
b. GI cohort: at least two prior systemic regimens, which must include everolimus. Prior systemic therapies may include: somatostatin analogs, PRRT, and/or chemotherapy.
c. pNET cohort: at least two prior systemic regimens, which must include everolimus and/or sunitinib. Prior systemic therapies may include: somatostatin analogs, PRRT and/or chemotherapy.
Note: For well-differentiated NET, Prior treatment with interferon alpha is allowed provided that it is not the last treatment received prior to study entry.
Poorly-differentiated GEP-NEC group: at least one prior chemotherapy regimen according to Investigator's choice.
6. Radiological documentation of disease progression:
Well-differentiated NET group: Disease progression while on/or after the last treatment, and this progression must have been observed within 6 months prior to start of study treatment (i.e. maximum of 24 weeks from documentation of progression until study entry). Disease must show evidence of radiological disease progression based on scans performed not more than 12 months apart.
Poorly-differentiated GEP-NEC group: Disease progression while on or after prior treatment.
7. At least one measurable lesion assessed by CT and/or MRI according to RECIST 1.1.
Note: Any lesions which have been subjected to percutaneous therapies or radiotherapy should not be considered measurable, unless the lesion has clearly progressed since the procedure.
8. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
9. Tumor biopsy material must be provided for all patients for the purpose of biomarker analysis:
Well-differentiated (G1/2) NET: Biopsy material must be provided following the diagnosis of metastatic disease. The tumor sample must be collected from a metastatic site not previously irradiated and should preferably be taken within 6 months but not more than 24 months prior to start of study treatment.
Poorly-differentiated GEP-NEC: Biopsy material must be collected from the primary tumor or from a metastatic site not previously irradiated, taken not more than 24 months prior to start of study treatment.
10. Women of childbearing potential must have had a negative serum pregnancy test within 72 hours prior to the start of study treatment. Highly effective contraception must be used while on study.
11. Patient is deemed by the investigator to have the ability and means to be compliant with the protocol (treatment and follow-up).
12. Patient must meet the following laboratory values at the screening visit:
Absolute Neutrophil Count ≥1.5 x 109/L
Platelets ≥75 x 109/L
Hemoglobin (Hgb) ≥9 g/dL
Serum creatinine <1.5 mg/dL
Total bilirubin ≤1.5 x ULN
Aspartate transaminase (AST) ≤3.0 x ULN, except for patients with liver metastasis, if AST ≤5.0 x ULN
Alanine transaminase (ALT) ≤3.0 x ULN, except for patients with liver metastasis, if ALT ≤5.0 x ULN |
|
| E.4 | Principal exclusion criteria |
1. Well-differentiated, grade 3 neuroendocrine tumors; poorly-differentiated neuroendocrine carcinoma of any origin (other than GEPNEC); including NEC of unknown origin, adenocarcinoid, and goblet cell carcinoid.
2. Pretreatment with interferon as last treatment prior to start of study treatment.
3. Prior treatment for study indication.
4. Systemic chronic steroid therapy (≥ 10mg/day prednisone or equivalent) or any immunosuppressive therapy 7 days prior to planned date for first dose of study treatment.
5. Any untreated central nervous system (CNS) lesion.
6. Malignant disease, other than that being treated in this study.
7. Major surgery, open biopsy, or significant traumatic injury within 2 weeks prior to start of study treatment.
8. Anticipation of the need for major surgical procedure during the course of the study.
9. Radiation therapy within 4 weeks prior to start of study treatment.
10. History of severe hypersensitivity reactions to other monoclonal antibodies.
11. Impaired cardiac function or clinically significant cardiac disease.
12. Autoimmune disease that has required systemic treatment. Stable and adequate controlled endocrinopathies requiring replacement therapy are not considered as systemic treatment and therefore are allowed.
13. Active infection requiring systemic antibiotic therapy.
14. Known history of testing positive for Human Immunodeficiency Virus (HIV) infection.
15. Patients with active Hepatitis B infection (HBsAg positive) will be excluded.
16. Patients with positive test for hepatitis C ribonucleic acid (HCV RNA).
17. Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results.
18. Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment.
19. Presence of ≥ CTCAE grade 2 toxicity (except alopecia, peripheral neuropathy, and ototoxicity, which are exclusion criteria if ≥ CTCAE grade 3) due to prior cancer therapy.
20. Not able to understand and to comply with study instructions and requirements.
21. Pregnant or nursing (lactating) women confirmed by a positive hCG laboratory test within 72 hours prior to initiating study treatment. Note:
Low levels of hCG may also be considered a tumor marker, therefore if low hCG levels are detected, another blood sample at least 4 days later must be taken to assess the kinetics of the increase and transvaginal
ultrasound must be performed to rule out pregnancy.
22. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 150 days
after stopping treatment with PDR001. Highly effective contraception methods include:
a. Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
b. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
c. Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that patient
d. Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable
efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception
Note: In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
23. Known history or current interstitial lung disease or non-infections pneumonitis.
24. Use of somatostatin analogs or any other medications administered to control active symptoms related to arcinoid syndrome during the last 3 months prior to start of study treatment |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
ORR (confirmed PR and CR)
according to blinded independent
review committee (BIRC) radiological
assessment by RECIST 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Imaging:
Treatment Period: Every 8 weeks counting from Cycle 1 Day 1 for the first 13 cycles and then every 12 weeks from Cycle 13 Day1 thereafter
EOT: If a scan was not conducted within 30 days prior to end of study treatment
Efficacy follow-up: Continue same schedule as during treatment period until BIRC confirmed irRECIST progression
|
|
| E.5.2 | Secondary end point(s) |
- DoR by RECIST 1.1 and as per BIRC
- Frequency and severity of adverse events. Other safety data as considered appropriate
- Disease Control Rate (DCR),
- Time to Response (TTR),
- PFS by RECIST 1.1 and as per BIRC
- Immune Response Criteria by irRECIST and as per BIRC (irORR, irDoR, irTTR, irDCR, irPFS)
- 1-year and 2-year overall survival (OS) rate
- ORR (confirmed PR and CR) and DoR by RECIST 1.1 and as per BIRC
- Changes from baseline in CgA and NSE
- PK parameters (e.g. Ctrough)
- Global health status/QOL score of the EORTC QLQ-C30 and the index score of the EQ-5D-5L
- Antidrug antibodies (ADA) prevalence at baseline and ADA incidence on-treatment |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Imaging:
Treatment Period: Every 8 weeks counting from C1 D1 for the first 13 cycles and then every 12 weeks from C13 D1 thereafter
EOT: If a scan was not conducted within 30 days prior to end of study treatment
Efficacy f/u: until BIRC confirmed irRECIST progression
PK/IG:
Treatment period:
At D1 of all cycles until C13 and D1 of every 6 cycles thereafter
EOT
30-Day safety f/u
Unscheduled:
At the time of PD based on RECIST 1.1
At the time of PD based on irRECIST
PRO:
Screening
Treatment: Every 8 weeks from C3 D1 for the first 13 cycles and every 12 weeks from C13 D1 thereafter EOT 30-day safety follow-up
Efficacy follow-up: Continue same schedule as during treatment period until BIRC confirmed irRECIST progression
CgA/NSE:
Screening
Treatment: D1 of each 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 | Yes |
| 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) | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Canada |
| France |
| Germany |
| Israel |
| Italy |
| Japan |
| Netherlands |
| Norway |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| United States |
|
| 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
|
| The study will end 2 years after LPFT once all patients complete a maximum of 2 year treatment or discontinue treatment and complete the safety follow-up evaluation period. If the primary endpoint is not met or results are inconclusive, the study ends after all patients discontinue treatment and complete the safety follow-up evaluation period after the primary analysis assessment has been performed 1 year after LPFT. Further details are described in protocol section 4.3 |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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