| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| metastatic or advanced inoperable Her-2 negative esophagogastric adenocarcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| metastatic advanced gastric cancer |
|
| 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 | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10062878 |
| E.1.2 | Term | Gastrooesophageal cancer |
| 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 |
| Assessment of overall survival (OS) at one year |
|
| E.2.2 | Secondary objectives of the trial |
Assessment of progression-free survival (PFS)
Assessment of Objective response rate (ORR)
Assessment of Best Overall Response (BOR)
Assessment of Time to tumor progression (TTP)
Assessment of Overall Survival (OS)
Assessment of Feasibility
Assessment of Safety and toxicity |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Metastatic or unresectable, histologically confirmed Her-2 negative (as assessed locally by a certified test) adenocarcinoma of the gastroesophageal junction (AEG I-III according to Sievert´s classification) or the stomach.
2. Adjuvant/neoadjuvant or perioperative chemotherapy or chemoradiotherapy must have been finished at least 6 months before start of the study intervention.
3. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
4. Ability for oral intake of the study drug.
5. Male/female* participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of esophagogastric adenocarcinoma will be enrolled in this study.
*There are no data that indicate special gender distribution. Therefore, patients will be enrolled in the study gender-independently.
6. Male participants: A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 6 months after the last dose of study intervention and refrain from donating sperm during this period.
7. Female participants: A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies:
a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3
OR
b. A WOCBP who agrees to follow the contraceptive guidance as given in Appendix 3 during the treatment period and for at least 6 months after the last dose of study intervention.
8. The participant provides written informed consent for the trial.
9. Have measurable or evaluable disease based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
10. Have provided archival tumor tissue sample. FFPE tissue blocks are preferred to slides.
11. Have adequate organ function as defined in protocol. Specimens must be collected within 14 days prior to the start of study intervention.
|
|
| E.4 | Principal exclusion criteria |
1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to start of study intervention. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) or with a PARP inhibitor, including Olaparib.
3. Has received prior systemic anti-cancer therapy for metastatic or locally advanced (irresectable) disease. A prior neoadjuvant or adjuvant chemotherapy is allowed
4. Persistent clinically relevant toxicities, CTCAE Grade > 2 caused by previous cancer treatment.
5. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.
6. Participant received colony-stimulating factors within 28 days prior to the first dose of study intervention
7. Participant is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption.
8. Major surgery within 2 weeks of starting study intervention and patients must have recovered from any effects of any major surgery.
9. Participant is currently receiving either strong or moderate inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 2 weeks.
10. Participant is currently receiving either strong or moderate inducers of CYP3A4 that cannot be discontinued for the duration of the study.
11. Concomitant use of drugs inhibiting DPD activity
12. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator, or patients with congenital long QT syndrome.
13. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed.
14. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.
15. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
16. Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ that have undergone potentially curative therapy are not excluded.
17. Participant has MDS/AML
18. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously completely resected brain metastases may participate if there is no sign of progression for at least 4 weeks by repeat imaging clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
19. Has severe hypersensitivity (≥ Grade 3) to FOLFOX or CAPOX-based chemotherapy, olaparib, pembrolizumab and/or any of its excipients.
20. Known DPD deficiency. Patients with a reduced DPD activity (CPIC activity score of 1.0-1.5) might participate in the study and receive a reduced dosage of 5-FU/capecitabine after discussion with the coordinating investigator and sponsor
21. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
22. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
23. Has an active infection requiring systemic therapy.
24. Has a known history of Human Immunodeficiency Virus (HIV) infection (known HIV1/HIV2 antibodies positive).
25. Has a known history of/active Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA is detected) infection.
26. Participant is considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection.
27. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 6 months after the last dose of study intervention.
28. Has had an allogenic tissue/solid organ transplant. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
PFS – time from enrollment to disease progression according to RECIST 1.1 and iRECIST or death due to any cause.
ORR – percentage of patients with complete response (CR) or partial response (PR) according to RECIST 1.1 and iRECIST
BOR – best response recorded from enrollment to treatment discontinuation for any reason
TTP - time from enrollment to disease progression according to RECIST 1.1 and iRECIST.
OS - time from enrollment to the date of death of any cause.
Feasibility rate - severe toxicity/withdrawal rate before the fourth cycle of pembrolizumab/olaparib has been completed
(Serious) Adverse Events - Recorded and graded according to NCI-CTC V5.0. Occurrence of (Serious) Adverse Events at any time during the study. Description by nature (Primary System Organ Class and Preferred Term), severity and causal relationship to drug administration |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
PFS, TTP, OS, toxicity: continuously
ORR, BOR: at week 12 and then every 9 weeks
Feasibility: after 4 cycles of pembrolizumab/olaparib |
|
| 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) | 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 11 |
| 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
|
Database closure is defined as the end of the trial: Sites need to collect survival data of patients and are involved in the data cleaning process actively (e.g. additional source data may be requested and additonal monitoring visits may be neccessary). Therefore, database closure is considered the end of the trial.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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