| Eligibility |
Inclusion Criteria:
1. Written informed consent obtained from the patient prior to performing any
protocol-related procedures, including screening evaluations.
2. Willing and able to comply with the protocol for the duration of the study including
undergoing treatment and scheduled visits and examinations including follow up.
3. Histologically or cytologically proven BTC (extrahepatic CCA, intrahepatic CCA, or
gallbladder carcinoma).
4. Failure (documented progression or toxicity) of previous platinum-based (cisplatin or
oxaliplatin) therapy (e.g. GEMCIS, GEMOX, FOLFIRINOX) Note: a maximum of 1 previous
chemotherapy line is allowed; maintenance therapy with chemotherapy or targeted agent,
except immunotherapy, will be permitted.
5. Age = 18 years at the time of study entry.
6. ECOG PS 0-1.
7. Recurrent or advanced disease not amenable to surgery, radiation, or combined modality
therapy with curative intent (previous resection of primary tumor allowed).
8. Measurable or evaluable (radiologically detectable disease which does not fulfill
RECIST criteria for measurable disease) lesions according to RECIST v1.1 criteria
(CT-scan < 3 weeks).
9. Have tissue from an archival tissue sample that has been identified and confirmed as
available for study, or newly obtained core or excisional biopsy of a tumor lesion.
10. Adequate organ function, as defined by the following:
- Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) <
3 x upper limit of normal (ULN)
- Total serum bilirubin < 1.5 ULN
- Prothrombin ratio > 70%
- Serum albumin = 28 g/L
- Hemoglobin = 9.0 g/dl
- White blood cell count (WBC) = 3,000/µL
- Absolute neutrophil count (ANC) = 1,500/µL
- Platelets = 100,000/µL
- Serum creatinine = 1.5 ULN or creatinine clearance > 50 mL/min (MDRD).
11. Body weight > 40 kg.
12. Any other prior therapy directed at the malignant tumor, including chemotherapy,
chemoembolization therapy, molecular targeted therapy (including antiangiogenics), and
radiotherapy, must be discontinued at least 2 weeks prior to registration and at least
3 weeks before day 1 on trial.
13. Life expectancy = 3 months.
14. Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. Women will be considered post-menopausal if they have
been amenorrheic for 12 months without an alternative medical cause. The following
age-specific requirements apply:
Women < 50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal treatments
and if they have luteinizing hormone and follicle-stimulating hormone levels in the
post-menopausal range for the institution or underwent surgical sterilization
(bilateral oophorectomy or hysterectomy).
Women = 50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses > 1 year ago, had
chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
Women participants of childbearing potential must have a negative serum pregnancy test
within the 7 days prior to the first treatment administration. Both women participants
of childbearing potential and men participants who are sexually active with women of
childbearing potential must agree to use a reliable method of birth control (i.e.
pregnancy rate < 1% per year); women of childbearing potential will be instructed to
adhere to contraception for a period of 180 days after the last dose of durvalumab and
tremelimumab or 90 days after the last dose of durvalumab monotherapy or 6 months
after the last dose of paclitaxel. Men participants who are sexually active with women
of childbearing potential will be instructed to adhere to contraception and must
refrain from sperm donation for a period of 180 days after the last dose of durvalumab
and tremelimumab or 90 days after the last dose of durvalumab monotherapy or 6 months
after the last dose of paclitaxel.
15. Registration in a national health care system (PUMA included).
Exclusion Criteria:
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site).
2. Concurrent enrolment in another clinical study, unless it is an observational
(non-interventional) or supportive care clinical study or during the follow-up period
of an interventional study.
3. Receipt of the last dose of anticancer therapy (investigational product, chemotherapy,
targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) = 21
days prior to the first dose of study drug. If sufficient wash-out time has not
occurred due to the schedule or pharmacokinetics properties of an agent, a longer
wash-out period will be required, as agreed by AstraZeneca/MedImmune and the
investigator.
4. Mixed histology (hepatocholangiocarcinoma).
5. Extensive tumor massively replacing both entire lobes.
6. Obstructive jaundice (bilirubin > 1.5 ULN) without adequate biliary drainage.
7. 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
- Patients with Grade = 2 neuropathy will be excluded
- Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with durvalumab or tremelimumab may be included only after consultation
with the Study Physician.
8. History of allogenic organ transplantation.
9. Any systemic steroid therapy (> 10 mg daily dose of prednisone or equivalent) whatever
the duration of this corticotherapy
Note: The following are exceptions to this criterion:
- Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
articular injection)
- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent
- Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication).
10. Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and TB testing in line with
local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),
hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies) Note:
Patients with past HBV infection or resolved HBV infection (defined as having a
negative HBsAg test and a positive hepatitis B core antigen [HBc] antibody test) are
eligible.
Note: Patients positive for HCV antibody are eligible only if polymerase chain
reaction testing is negative for HCV ribonucleic acid (RNA).
11. Diagnosis of any second malignancy within the last 5 years, except for adequately
treated basal cell or squamous cell skin cancer, or in situ carcinoma of the cervix
uteri.
12. Prior treatment with taxane or any immune ICI, including durvalumab and tremelimumab
or any other anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody.
13. Known active central nervous system metastases and/or carcinomatous meningitis;
patients with previously treated brain metastases may participate provided they are
stable (without evidence of progression by imaging for at least 4 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 > 10
mg/day of prednisone or equivalent for at least 14 days prior to trial treatment.
14. Uncontrolled massive pleural effusion or massive ascites.
15. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc]), that has required systemic treatment (i.e.
with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
Note: Patients with vitiligo, alopecia, or any chronic skin condition that does not
require systemic therapy are exception to this criterion.
Note: History of autoimmune-related hypothyroidism on a stable dose of thyroid
replacement hormone may be eligible.
Note: Controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible.
16. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
situations that would limit compliance with study requirement, substantially increase
risk of incurring AEs or compromise the ability of the patient to give written
informed consent.
17. Live vaccine administration within 30 days prior to the first dose of study treatment
Note: Patients, if enrolled, should not receive live vaccine whilst receiving
investigational product and up to 30 days after the last dose of investigational
product.
18. Known or suspected allergy or hypersensitivity to any of the study drugs or any of the
study drug excipients (taxane, durvalumab, or tremelimumab).
19. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) = 470 ms.
20. History or current evidence of any condition, therapy, or laboratory abnormality that
might confound the results of the trial, interfere with participation for the full
duration of the trial, or is not in the best interest of the participant, in the
opinion of the treating investigator.
21. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of
radiation within 4 weeks of the first dose of study drug.
22. Major surgical procedure (as defined by the Investigator) within 28 days prior to the
first dose of investigational product Note: Local surgery of isolated lesions for
palliative intent is acceptable.
23. Pregnancy/lactation.
24. Tutelage or guardianship.
|
