| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| advanced biliary tract cancer (BTC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| advanced biliary tract cancer (BTC) |
|
| 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 | PT |
| E.1.2 | Classification code | 10008593 |
| E.1.2 | Term | Cholangiocarcinoma |
| 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 evaluate the efficacy of the combination of mFOLFOX6, bevacizumab
and atezolizumab in advanced-stage BTC measured by radiographic
tumor response |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of the combination of mFOLFOX6,
bevacizumab and atezolizumab in BTC by measuring disease control,
progression-free survival (PFS) and overall survival (OS)
• To evaluate safety and tolerability of the combination of mFOLFOX6,
bevacizumab and atezolizumab in patients with BTC |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must fulfill all of the following criteria for study entry:
1. Signed informed consent form
2. Age ≥ 18 years by the time of inclusion in the study
3. Ability to comply with the study protocol, in the investigator’s judgment
4. Histologically confirmed advanced BTC
5. Patient must have received at least one prior line of systemic therapy in advanced-stage BTC
6. Adjuvant or neoadjuvant chemotherapy is allowed, provided it is completed at least 6 months before start of study treatment.
7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 (see Appendix VI)
8. Life expectancy > 12 weeks
9. Measurable disease, according to RECIST v1.1. Lesions intended to be biopsied should not be defined as target lesions.
10. Tumor must be accessible for biopsies and patient willing to provide tissue from a newly obtained biopsy of a tumor lesion. In exceptional cases, if a pre-treatment biopsy is not deemed feasible by the investigator, archival biopsies can be used after Sponsor approval has been obtained, as long as they were collected no more than 6 months prior to enrollment.
11. Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment:
WBC ≥ 2.5 x 109/L
ANC ≥ 1.5 x 109/L without granulocyte colony-stimulating factor support
Platelet count ≥ 100 x 109/L without transfusion
Hemoglobin ≥ 9 g/dL. Patients may be transfused to meet this criterion.
Albumin ≥ 2.5 g/dL
Serum total bilirubin ≤ 3 ULN; patients with known Gilbert’s disease may have a total bilirubin ≤ 3.0 x ULN
Patients not receiving therapeutic anticoagulation must have an INR < 1.5 ULN and PTT < 1.5 ULN . The use of full dose oral or parenteral anticoagulants is allowed as long as the INR or PTT is within therapeutic limits (according to the medical standard of the enrolling institution) and the patient has been on a stable dose of anticoagulants for at least three weeks at the time of initiation of study treatment. Prophylactic use of anticoagulants is allowed.
Amylase and lipase ≤ 1.5 x ULN
AST, ALT and ALP ≤ 3 x ULN with the following exceptions:
o Patients with documented liver metastases: AST and/or ALT ≤ 5 x ULN
o Patients with documented liver or bone metastases: ALP ≤ 5 x ULN
Serum creatinine ≤ 1.5 ULN or Creatinine clearance ≥ 30 mL/min (calculated using the Cockcroft-Gault formula)
12. For women of childbearing potential: Negative serum pregnancy test within 21 days prior to C1D1. Agreement to remain abstinent (refrain from heterosexual intercourse) or use of contraceptive methods that result in a failure rate of ≤ 1% per year during the treatment period and for at least 180 days after the last study treatment.
A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of ≤ 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
13. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 180 days after the last dose of study treatment. Men must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. |
|
| E.4 | Principal exclusion criteria |
1. Malignancies other than BTC within 3 years prior to C1D1 with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year overall survival > 90%) treated with expected curative outcome
2. Patients with known microsatellite instability high (MSI-H) status. Patients with unknown MSI status are eligible and the MSI status will be analyzed retrospectively. Patients who are then determined to be MSI high will be allowed to continue the study treatment, but will be replaced by microsatellite-stable (MSS) or MSI-low tumors.
3. Untreated CNS metastases. Treatment of brain metastases, either by surgical or radiation techniques must have been completed at least 4 weeks prior to initiation of study treatment.
4. Radiation therapy within 21 days prior to C1D1 and/or persistence of radiation-related adverse effects
5. Prior allogeneic bone marrow transplantation or solid organ transplant for another malignancy in the past
6. Spinal cord compression not definitively treated with surgery and/or radiation
7. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
8. Uncontrolled tumor pain.
9. Treatment with any investigational agent or approved therapy within 14 days or two investigational agent half-lives (whichever is longer) prior to C1D1
10. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-PD-1 and anti-PD-L1 or VEGF/VEGFR inhibitors
11. Known dihydropyrimidine dehydrogenase deficiency or thymidylate synthase gene polymorphism predisposing the patient for 5-FU toxicity
12. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
13. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any components of atezolizumab or bevacizumab formulations
14. Current or recent (within 10 days of study enrollment) use of acetylsalicylic acid (> 325 mg/day), clopidogrel (> 75 mg/day) or thrombolytic agents for therapeutic purposes
15. History of clinically significant cardiac or pulmonary dysfunction
16. History of idiopathic pulmonary fibrosis, organizing pneumonia
17. Major surgical procedure within 4 weeks prior to C1D1 or anticipation of need for a major surgical procedure during the course of the study
18. Evidence of tumor invading or abutting major blood vessels
19. Serious non-healing wound, active ulcer or untreated bone fracture
20. History of abdominal fistula or gastrointestinal perforation within 6 months prior to C1D1
21. History of hemoptysis (≥ ½ teaspoon of bright red blood per episode), or any other serious hemorrhage, or at risk of bleeding
22. INR > 1.5 and aPTT > 1.5 x ULN within 14 daysprior to C1D1 (excluding patients on prophylactic or therapeutic anticoagulation)
23. History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding
24. Proteinuria at screening as demonstrated by urine dipstick ≥ 2+ or 24-hour proteinuria > 1.0 g
25. Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment.
26. Systemic immunostimulatory agents (including, but not limited to, interferons and IL-2) are prohibited within 4 weeks or five half-lives of the drug (whichever is longer) prior to C1D1.
27. Autoimmune conditions with exceptions
28. Infectious diseases
Severe infection within 4 weeks prior to initiation of C1D1, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
Patients with active hepatitis B
Patients with past HBV infection or resolved HBV infection are eligible. HBV DNA test must be performed in these patients prior to C1D1.
Patients with active hepatitis C. Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA
Positive HIV test at screening or at any time prior to screening. Patients without a prior positive HIV test result will undergo an HIV test at screening, unless not permitted per local regulations
Known active tuberculosis
Patients must not receive any kind of living, attenuated vaccine (e.g., Fluenz® Tetra) within 4 weeks prior to C1D1 or at any time during the study and for at least 5 months after the last dose of study drug.
29. Pregnant or lactating, or intending to become pregnant during the study or within 5 months after final dose for atezolizumab or 6 months for bevacizumab.
30. Uncontrolled serious medical or psychiatric illness |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
ORR defined as the proportion of patients with a complete response (CR)
or partial
response (PR), determined by the investigator (INV) following RECIST
v1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| ORR will be assessed after 12 weeks of treatment |
|
| E.5.2 | Secondary end point(s) |
• Disease control rate (DCR) at weeks 12 and 18
• Duration of response (DOR)
• Best objective response rate (BORR)
• Progression-free survival (PFS)
• Time to treatment failure (TTF)
• Best percentage change from baseline in tumor size
All secondary endpoints above will be based on investigator assessment
both by INV-RECIST v1.1 and (also ORR) by modified criteria for immunotherapies iRECIST
• ORR by independent radiological review per RECIST v1.1 and by
modified criteria for immunotherapies iRECIST
• Overall survival (OS)
• Safety: incidence and severity of adverse events (AEs) (with severity
determined according to NCI CTCAE v5.0), vital signs and clinical
laboratory test results |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Weeks 12 and 18 for the Disease control rate (DCR) |
|
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| 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 study will end if either a criterion for futility or efficacy addressed
in the interim analyses is not fulfilled or if the maximum enrolled
number of patients has been followed until death, withdrawal of
consent, lost to follow-up, or the Sponsor decides to end the trial,
whichever occurs first. |
|
| 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 | 10 |
| 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 | 10 |
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