E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult patients (aged ≥18 years) with histologically or cytologically confirmed metastatic pancreatic ductal adenocarcinoma who are treatment naive or have tumor progression following prior standard first-line 5-FU-containing or gemcitabine-containing chemotherapy. |
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E.1.1.1 | Medical condition in easily understood language |
Pancreatic Ductal Adenocarcinoma |
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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 | 20.0 |
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 |
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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 |
1. Cohort 1: To assess the safety, tolerability of Medi4736 in combination with nab-paclitaxel + gemcitabine 2. Cohort 2: To assess the safety, tolerability and ORR of MEDI4736 + AZD5069 in combination. |
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E.2.2 | Secondary objectives of the trial |
1.To further assess the efficacy of MEDI4736 +AZD5069 in terms of DoR, DCR, PFS, PFS3, PFS6, OS, OS6, and OS12.
2.To investigate the relationship between PD-L1 expression by IHC and efficacy parameters
3.To investigate the immunogenicity of MEDI4736 in combination with AZD5069.
4.To assess the PK of MEDI4736 and the combination of MEDI4736 and AZD5069. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age ≥18 years at the time of screening. 2. Written informed consent and any locally required authorization obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations. 3. Histologically or cytologically confirmed metastatic PDAC, no more than 1 prior systemic chemotherapy regimen or treatment-naïve patients 4. Life expectancy ≥ 12 weeks. 5. Eastern Cooperative Oncology Group 0 or 1 6. At least 1 lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have short axis ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) scan and that is suitable for accurate repeated measurements -Patient should receive no more than 1 prior chemotherapy regimen or any other systemic therapy for recurrent/metastatic PDAC. 7. Adequate organ and bone marrow function as defined below: Hemoglobin ≥9 g/dL Albumin ≥3 g/dL Absolute neutrophil count ≥1500/mm3 Platelet count ≥100000/mm3 Serum bilirubin ≤1.5 × the upper limit of normal (ULN). ALT and AST ≤2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤5 × ULN Serum creatinine ≤1.5 mg/dL or calculated creatinine clearance ≥40 mL/min 8. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female premenopausal patients 9. Mandatory tumor biopsy at screening |
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E.4 | Principal exclusion criteria |
1. Any concurrent chemotherapy, investigational product , biologic, or hormonal therapy for cancer treatment. 2. Receipt of any investigational anticancer therapy within 28 days or 5 half-lives, whichever is shorter, prior to the first dose of study treatment. 3. Concurrent enrollment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study. 4. Receipt of last dose of an approved anticancer therapy within 21 days prior to the first dose of study treatment. 5. Major surgical procedure (as defined by the Investigator) within 21 days prior to the first dose of IP 6. Patients weighing less than 30 kg. 7. History of leptomeningeal carcinomatosis 8. Ascites requiring intervention 9. Brain metastases or spinal cord compression 10. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. 11. Current or prior use of immunosuppressive medication within 14 days before the first dose of MEDI4736. with exceptions that Intranasal, inhaled, or topical steroids; or local steroid injections; Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent; Steroids as premedication for hypersensitivity reactions and chemotherapy induced nausea and vomiting. 12.Current or prior use of immunosuppressive medication within 14 days before the first dose of MEDI4736 13. History of organ transplant that requires use of immunosuppressive agents. 14. Active autoimmune disorders , or prior documented severe autoimmune or inflammatory disorders requiring immunosuppressive treatment - Prior exposure to immune-mediated therapy - Has received any potent and moderate cytochrome P450 (CYP)3A4 inhibitors, potent and moderate CYP3A4 inducers, P-glycoprotein substrates (digoxin and dabigatran), breast cancer resistance protein substrates (topotecan), sensitive CYP2B6 substrates (bupropion and efavirenz), warfarin and coumarin derivatives, or herbal supplements within 14 days of the first dose of study treatment 15. Uncontrolled intercurrent illness 16. Other malignancy within 5 years except for noninvasive malignancies such as cervical carcinoma in situ, non-melanomatous carcinoma of the skin, prostate cancer or ductal carcinoma in situ of the breast that has/have been surgically cured 17. Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥470 ms calculated from 3 ECG reports 18. History of active primary immunodeficiency. 19. Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus. 20. Active infection including hepatitis B, hepatitis C, or human immunodeficiency virus (HIV). 21. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. 22. Female patients who are pregnant or breastfeeding, or male or female patients of reproductive potential who are not employing an effective method of birth control (see Section 3.8). 23. Known allergy or hypersensitivity to IP formulations or to other human monoclonal antibodies. 24. Any condition that, in the opinion of the Investigator, would interfere with evaluation of IP or interpretation of patient safety or study results. 25. Prior exposure to immune-mediated therapy or prior randomization or treament in previous MEDI4736 and/or tremelimumab clinical trials regardless of treatment arm assignment. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Objective response rate (Medi4736+AZD5069) 2. Calculation or derivation of safety variables |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Objective response rate: RECIST assessment will be every 6 weeks (q6w ±7 days) for the first 48 weeks relative to the date of the first infusion, and q12w ±7 days thereafter until confirmed objective disease progression
2. Data from all cycles of treatment will be combined in the presentation of the safety data |
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E.5.2 | Secondary end point(s) |
1.Duration of Response, Disease control rate, Progression-free survival (PFS), Proportion of patients alive and PFS at 3, 6 & 12 months 2. ORR, DoR, DCR, Os, and PFS across PD-L1 expression using Investigator assessments according to RECIST 1.1 3.Presence of ADAs for MEDI4736 4.Concentration of MEDI4736 & AZD5069 in blood and noncompartmental PK parameters |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-2 Objective response rate: RECIST assessment will be every 6 weeks (q6w ±7 days) for the first 48 weeks relative to the date of the first infusion, and q12w ±7 days thereafter until confirmed objective disease progression. Biopsy for PD-L1 expression analysis taken at screening and at Week 4
3.Samples for immunogenicity assessment for MEDI4736 taken on day 1 of Cycles 1, 2, 3, 4, 7 and 3&6 months after last dose of IP
4 PK (Serum/Blood - MEDI4736&AZD5069), taken on day 1 of Cycles 1, 2, 3, 4, 7. and 3 months after last dose of IP for MEDI4736 only |
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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 | 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 | Yes |
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) | Yes |
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 | 2 |
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 | 6 |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
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 |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 11 |