To evaluate the safety, tolerability, and anti-tumor activity of the combination of
durvalumab + tremelimumab or durvalumab alone in different solid tumors.
This is an open-label, multi-center, study to determine the short and long term safety of
fixed doses of durvalumab 1500 mg + tremelimumab 75 mg combination therapy or durvalumab 1500
mg monotherapy in patients with advanced solid malignancies. This study is modular in design,
one or more of the modules will be opened in a given country / region based on local patient
population prevalence, and results of feasibility studies. The total number of patients to be
enrolled overall and in each module will depend on the types and number of tumor modules
added to the main study and country-specific ancillary studies. The number of patients and
sites to be involved in individual countries will be dependent on each module or ancillary
study. This study consisted of a screening period, a treatment period, a 90 day safety
follow-up period and a survival follow-up period. Patients will receive the investigation
product (IP) via intravenous (IV) infusion once every 4 weeks (Q4W) in combination therapy or
monotherapy as mentioned below - Combination therapy: Durvalumab 1,500 mg + tremelimumab 75
mg on Week 0, for up to a maximum of 4 doses (or cycles) followed by durvalumab 1,500 mg
starting 4 weeks after the last infusion of the combination or discontinuation of
tremelimumab.
Monotherapy: Durvalumab 1,500 mg on week 0.
Patients will attend a safety follow-up visit 90 days after study treatment discontinuation.
Thereafter, patients will be contacted by phone or electronic communication every 3 months
for survival status up to 5 years following date of first patient treatment initiation. All
patients will be followed for a minimum of 6 months following enrolment of last patient. It
is anticipated that the total enrolment period for the overall study will be approximately 2
to 3 years, with an overall duration of approximately 5 years
Inclusion criteria:
1. Must have a life expectancy of at least 12 weeks.
2. Age ≥18 years at the time of screening. For patients aged <20 years and enrolled in
Japan, a written informed consent should be obtained from the patient and his or her
legally acceptable representative
3. Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and in this
protocol. Written informed consent and any locally required authorization (eg, Health
Insurance Portability and Accountability Act in the US, 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. For
patients aged <20 years and enrolling in Japan, a written informed consent should be
obtained from the patient and his or her legally acceptable representative.
4. Disease not amenable to curative surgery
5. Eastern Cooperative Oncology Group (ECOG) performance status as defined in the
specific module.
6. Body weight >30 kg.
7. No prior exposure to anti-PD-1 or anti-PD-L1, including on another AstraZeneca study.
Exposure to other investigational agents may be permitted after discussion with the
Sponsor.
8. Adequate organ and marrow function as defined below
- Hemoglobin ≥9.0 g/dL
- Absolute neutrophil count ≥1.0 × 109 /L
- Platelet count ≥75 × 109/L
- Serum bilirubin ≤1.5 × the upper limit of normal (ULN). This will not apply to
patients with confirmed Gilbert's syndrome, who will be allowed in consultation
with their physician.
- ALT and AST ≤2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤5 ×
ULN
- Measured creatinine clearance (CL) >40 mL/min or calculated creatinine clearance
(CL) >40 mL/min as determined by Cockcroft-Gault (using actual body weight)
Males:
Creatinine CL = Weight (kg) × (140 - Age) (mL/min) 72 × serum creatinine (mg/dL)
Females:
Creatinine CL = Weight (kg) × (140 - Age) x 0.85 (mL/min) 72 × serum creatinine
(mg/dL)
9. Female patients of childbearing potential (ie, not surgically sterile or post
menopausal) who are sexually active with a non sterilized male partner must use at
least one highly effective method of contraception from the time of screening and must
agree to continue using such precautions for 180 days after the last dose of
durvalumab + tremelimumab combination therapy or 90 days after the last dose of
durvalumab monotherapy (see Section 3.8 and specifically Table 1).
10. Evidence of post-menopausal status or negative urinary or serum pregnancy test (per
Section 4) 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:
11. 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).
Non sterilized male patients who are sexually active with a female partner of childbearing
potential must use a male condom plus spermicide from screening through 180 days after
receipt of the final dose of durvalumab + tremelimumab combination therapy or 90 days after
receipt of the final dose of durvalumab monotherapy.
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. Previous IP assignment in the present study.
3. Concurrent enrollment in another clinical study, or another sub-study of this
protocol, unless it is an observational (non-interventional) clinical study or during
the follow up period of an interventional study.
4. Participation in another clinical study with an investigational product during the
last 28 days or 5 half-lives, whichever is longer, prior to the first dose of study
treatment.
5. Any concurrent chemotherapy, investigational agent, biologic, or hormonal therapy for
cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions
(eg, hormone replacement therapy) is acceptable.
6. Local treatment of isolated lesions for palliative intent is acceptable (eg, local
surgery or radiotherapy).
7. Receipt of any investigational anticancer therapy within 28 days or 5 half-lives,
whichever is longer, prior to the first dose of study treatment.
8. 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. Note: Local treatment of
isolated lesions, excluding target lesions, for palliative intent is acceptable.
9. Major surgical procedure (as defined by the Investigator) within 28 days prior to the
first dose of IP. Note: Local surgery of isolated lesions for palliative intent is
acceptable.
10. History of allogenic organ transplantation.
11. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, ILD, serious chronic GI 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 investigational product (durvalumab + tremelimumab) 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. Has untreated central nervous system (CNS) metastases and/or carcinomatous meningitis
identified either on baseline brain imaging (please refer to RECIST for details on the
imaging modality) obtained during the screening period or identified prior to signing
the ICF. Patients whose brain metastases have been treated may participate provided
they show radiographic stability (defined as 2 brain images, both of which are
obtained after treatment to the brain metastases. These imaging scans should both be
obtained at least 4 weeks apart and show no evidence of intracranial progression). In
addition, any neurologic symptoms that developed either as a result of the brain
metastases or their treatment must have resolved or be stable either, without the use
of steroids, or are stable on a steroid dose of ≤10 mg/day of prednisone or its
equivalent and anti-convulsants for at least 14 days prior to the start of treatment.
Brain metastases will not be recorded as RECIST Target Lesions at baseline.
15. History of active primary immunodeficiency.
16. Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and tuberculosis testing in
line with local practice), hepatitis B (known positive hepatitis B virus [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 virus (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
18. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [eg, 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.]). 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
- Patients with celiac disease controlled by diet alone
19. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to
30 days after the last dose of IP.
20. Known allergy or hypersensitivity to study drug(s) or compounds of similar biologic
composition to the study drug(s), or any of the study drug excipients.
21. Any unresolved NCI CTCAE Grade ≥2 toxicities from prior anti cancer therapy with the
exception of vitiligo, alopecia, 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
22. For women only, currently pregnant (confirmed with positive pregnancy test) or breast
feeding.
23. 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 180 days after the last dose of durvalumab + tremelimumab combination
therapy or 90 days after the last dose of durvalumab monotherapy.
24. Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical
study regardless of treatment arm assignment.
