| Eligibility |
Inclusion Criteria:
1. Fully-informed written consent and locally required authorization (European Union [EU]
Data Privacy Directive in the EU) obtained from the patient/legal representative prior
to performing any protocol-related procedures, including screening evaluations.
2. Age = 18 years.
3. Histologically documented diagnosis of cholangiocarcinoma or gall bladder carcinoma
and available tumor tissue (block or at least 4 slides) for translational research.
4. Performance status (PS) = 1(ECOG scale).
5. At least one measurable site of disease as defined by RECISTv1.1 criteria.
6. Adequate bone marrow and renal function including the following: Hemoglobin
= 9.0 g/dL; absolute neutrophil count = 1.5 x 10^9/L; platelets = 100 x 10^9 /L;
Creatinine = 1.5 x upper normal limit.
7. Calculated creatinine clearance =40 mL/min as determined by the Cockcroft- Gault
equation (using actual body weight)
8. Adequate hepatic function (with stenting for any obstruction, if required) including
the following: Total bilirubin = 2x upper normal limit; AST (SGOT), ALT (SGPT) = 5 x
upper normal limit; prothrombin time = 60%; albumin = 30 g/L.
9. Female patients with reproductive potential must have a negative urine or serum
pregnancy test within 7 days prior to start of trial.
10. Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. Women will be considered postmenopausal 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).
11. The patient is willing and able to comply with the protocol for the duration of the
study, including hospital visits for treatment and scheduled follow-up visits and
examinations.
Exclusion Criteria:
1. Concurrent enrolment in another clinical study, unless it is an observational
(non-interventional) clinical study, or during the follow-up period of an
interventional study
2. Participation in another clinical study with an investigational product within 21 days
prior to the first dose of the study treatment.
3. Prior immunotherapy or use of other investigational agents, including prior treatment
with an anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1
(PD-L1), anti-PD-L2, or anti-cytotoxic T-lymphocyte associated antigen-4 (anti-CTLA-4)
antibody, therapeutic cancer vaccines.
4. Prior chemotherapy with gemcitabine, Cisplatin and/or capecitabine (exception:
gemcitabine, cisplatind and/or capecitabine in the adjuvant setting, last infusion has
to be = 6 months prior randomization).
5. 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 evaluated on a case-by-case basis after
consultation with the Study Physician.
- 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.
6. Any concurrent chemotherapy, IMP, biologic, or hormonal therapy for cancer treatment.
Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone
replacement therapy) is acceptable. Note: Local treatment of isolated lesions for
palliative intent is acceptable (eg, local radiotherapy).
7. 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 drugs.
8. Major surgery (as defined by the Investigator) within 4 weeks prior to the first dose
of the investigational product (IMP) of starting the study and patients must have
recovered from effects of major surgery. Note: Local non-major surgery for palliative
intent (eg, surgery of isolated lesions, per-cutaneous biliary drainage or biliary
stenting) is acceptable.
9. History of allogenic organ transplantation.
10. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the
exception of diverticulosis], celiac disease, systemic lupus erythematosus,
Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves'
disease, rheumatoid arthritis, hypophysitis, uveitis, etc]).
The following are exceptions to this criterion:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone
replacement
- Any chronic skin condition that does not require systemic therapy
- Patients without active disease in the last 5 years may be included but only
after consultation with the study physician
11. 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
12. History of another primary malignancy except for:
- Malignancy treated with curative intent and with no known active disease =5 years
before the first dose of IMP and of low potential risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease
- Adequately treated carcinoma in situ without evidence of disease
13. History of leptomeningeal carcinomatosis
14. Brain metastases or spinal cord compression. Patients with suspected brain metastases
at screening should have a CT/ MRI of the brain prior to study entry.
15. History of active primary immunodeficiency
16. 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). Patients
with a past or resolved HBV infection (defined as the presence of hepatitis B core
antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative
for HCV RNA.
17. Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab or tremelimumab. The following are exceptions to this criterion:
- Intranasal, inhaled, topical steroids, or local steroid injections (eg, 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 (eg, CT scan
premedication) Receipt of live attenuated vaccine within 30 days prior to the
first dose of IMP.
Note: Patients, if enrolled, should not receive live vaccine whilst receiving IMP and up to
30 days after the last dose of IMP. 19. Body weight =30 kg. 20. Female patients who are
pregnant or breastfeeding or male or female patients of reproductive potential who are not
willing to employ effective birth control from screening to 90 days after the last dose of
tremelimumab monotherapy or 180 days after the last dose of durvalumab + tremelimumab
combination therapy. 21. Known allergy or hypersensitivity to any of the IMPs or any of the
constituents of the product. 22. Prior randomisation or treatment in a previous durvalumab
and/or tremelimumab clinical study regardless of treatment arm assignment. 23. Any
co-existing medical condition that in the investigator's judgement will substantially
increase the risk associated with the patient's participation in the study. Patient who has
been incarcerated or involuntarily institutionalized by court order or by the authorities §
40 Abs. 1 S. 3 Nr. 4 AMG. 25. Patients who are unable to consent because they do not
understand the nature, significance and implications of the clinical trial and therefore
cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].
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