E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
CUP, Cancer of Unknown Primary |
|
E.1.1.1 | Medical condition in easily understood language |
Cancer which place of tumour origin is not clear |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 |
What is the overall survival(OS) & Progression Free Survival (PFS) for the 1st cohort
What is the overall response rates (OS) & Progression Free Survival (PFS)in a first-line setting for the 2nd cohort
|
|
E.2.2 | Secondary objectives of the trial |
• Incidence of adverse events up to 8 weeks after the last dose of Pembrolizumab in the second line setting
• Incidence of adverse events up to 8 weeks after the last dose of Pembrolizumab in Performance Status 2 (PS2) patients in any setting
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Be willing and able to provide written informed consent/assent for the trial. 2. Be 18 years of age on day of signing informed consent. 3. Have measurable disease based on RECIST 1.1. 4. Be willing to provide consent for archival tumour (in the form of formalin fixed paraffin embedded (FFPE) block) or fresh tumour material (if judged technically feasible by radiologist is mandatory for diagnosis and biomarker analysis. 5. Have a performance status of 0 to 2 on the ECOG Performance Scale. 6. Cohort 1 - have had at least one prior line / regimen of chemotherapy appropriate for CUP, have not had a RECIST response to first-line chemotherapy, or are progressing after an initial response, or are treatment intolerant to first-line chemotherapy, due to unacceptable toxicity. Cohort 2 - be chemo-naïve for CUP (Previous chemotherapy for other cancers is allowed) 7. Adequate organ and bone marrow function - Absolute neutrophil count (ANC) ≥ 1.5 x 109/L - Platelets ≥ 100 x 109/L - Haemoglobin ≥ 9 g/dL (≥90 g/L) without transfusion or EPO dependency - Serum creatinine ≤ 1.5 x Upper Limit of Normal (ULN) or Creatinine clearance ≥ 60 mL/min for patients with creatinine levels > 1.5 x ULN - Serum total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN for patients with total bilirubin levels >1.5 ULN - Aspartate aminotransferase [AST] ≤ 2.5 x ULN (< 5 x ULN if liver metastases are present) - Alanine aminotransferase [ALT]) ≤ 2.5 x ULN (< 5 x ULN if liver metastases are present) - Albumin ≥ 2.5g/dL - International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN - Activated Partial Thromboplastin Time (APTT) ≤1.5 X ULN (unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants)
8. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 9. Female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in Section 6.9.2 – Contraception, for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. 10. Male subjects of childbearing potential must agree to use an adequate method of contraception as outlined in Section 6.9.2 - Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
|
|
E.4 | Principal exclusion criteria |
Patients who meet any of the following exclusion criteria will not be eligible for this study: 1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment. 2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 3. Has a known history of active TB (Bacillus Tuberculosis) 4. Hypersensitivity to pembrolizumab or any of its excipients. 5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. 6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. - Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. - Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. 7. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. 8. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. 9. 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. 10. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. 11. Has an active infection requiring systemic therapy. 12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. 13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 14. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. 15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). 18. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary Objectives and Hypothesis
Objectives: In the context of the two sequential cohorts:- • Overall response rates by immune-related (irRECIST) and RECIST criteria in a second-line setting o Overall Survival (OS) & Progression Free Survival (PFS)
• Overall response rates by immune-related (irRECIST) and RECIST criteria in a first-line setting o OS & PFS
Hypothesis: Pembrolizumab has Efficacy in CUP • as a first-line treatment in terms of Response which translates into improved PFS and OS
• as a second-line treatment in terms Response which translates into improved PFS and OS
• and treatment leads to rapid improvement in quality of life (QOL) in high metastatic disease burden (in any line of therapy)
|
|
E.5.2 | Secondary end point(s) |
Secondary Objectives and Hypothesises Objective: • Incidence of adverse events up to 8 weeks after the last dose of Pembrolizumab in the second line setting
• Incidence of adverse events up to 8 weeks after the last dose of Pembrolizumab in Performance Status 2 (PS2) patients in any setting
Hypothesis: • Pembrolizumab is much better tolerated than conventional chemotherapy in CUP patients and PS2 patients may also benefit.
Exploratory Objective:
• Identification of genomic biomarkers predictive of immune response to Pembrolizumab
Hypotheses: • CUP patients have identifiable biomarkers predictive for Pembrolizumab efficacy
• CUP patients have high mutational loads and this correlates with increased efficacy with Pembrolizumab
|
|
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 | 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 | No |
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 | 3 |
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 | 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
|
The end of the trial is defined as the last data capture for the last patient on study; this will be 6 months after the last patient stops study treatment or up to 12 months after the last patient is entered whichever is sooner |
|
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 | 11 |
E.8.9.1 | In the Member State concerned days | 30 |
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 | 11 |
E.8.9.2 | In all countries concerned by the trial days | 30 |