Clinical trial NCT03084471: An Open-Label, Multi-Centre, Study to Assess the Safety of Fixed-Dose Durvalumab + Tremelimumab Combination Therapy or Durvalumab Monotherapy in Advanced Solid Malignancies.
Official title: An Open-Label, Multi-Centre, Safety Study of Fixed-Dose Durvalumab + Tremelimumab Combination Therapy or Durvalumab Monotherapy in Advanced Solid Malignancies.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Advanced Solid Malignancies
Keywords: Programmed death ligand 1 (PD-L1)
Cytotoxic T-lymphocyte antigen-4 (CTLA-4)
Durvalumab in combination with tremelimumab
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2017-03-21
Enrollment: 867
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: To evaluate the safety, tolerability, and anti-tumor activity of the combination of durvalumab + tremelimumab or durvalumab alone in different solid tumors.

Detailed description: 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

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Adverse Events of Special Interest (AESIs)
timeFrame: From screening to safety follow up visit (90 days after last dose), up to approximately 3 years.
Secondary outcomes:
measure: Overall Survival
timeFrame: From screening to final data cutoff (maximum up to 4 years) following date of first patient treatment initiation.
measure: Number of Participants With Adverse Events
timeFrame: From screening to safety follow up visit (90 days after last dose), maximum up to 4 years.
Other outcomes:
Locations:
city: Santa Rosa
country: United States
facility: Research Site
state: California
city: Washington
country: United States
facility: Research Site
state: District of Columbia
city: Tinley Park
country: United States
facility: Research Site
state: Illinois
city: Omaha
country: United States
facility: Research Site
state: Nebraska
city: Hackensack
country: United States
facility: Research Site
state: New Jersey
city: East Setauket
country: United States
facility: Research Site
state: New York
city: Greenville
country: United States
facility: Research Site
state: South Carolina
city: Knoxville
country: United States
facility: Research Site
state: Tennessee
city: Blacksburg
country: United States
facility: Research Site
state: Virginia
city: Spokane
country: United States
facility: Research Site
state: Washington
city: Moncton
country: Canada
facility: Research Site
state: New Brunswick
city: Brampton
country: Canada
facility: Research Site
state: Ontario
city: Hamilton
country: Canada
facility: Research Site
state: Ontario
city: Kingston
country: Canada
facility: Research Site
state: Ontario
city: London
country: Canada
facility: Research Site
state: Ontario
city: Newmarket
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Greenfield Park
country: Canada
facility: Research Site
state: Quebec
city: Quebec
country: Canada
facility: Research Site
city: Besançon Cedex
country: France
facility: Research Site
city: Bordeaux Cedex
country: France
facility: Research Site
city: Bordeaux
country: France
facility: Research Site
city: Brest
country: France
facility: Research Site
city: Dijon
country: France
facility: Research Site
city: Lille
country: France
facility: Research Site
city: Lyon Cedex 08
country: France
facility: Research Site
city: Marseille
country: France
facility: Research Site
city: Montpellier
country: France
facility: Research Site
city: Nice
country: France
facility: Research Site
city: Nimes
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Pierre Benite
country: France
facility: Research Site
city: Poitiers Cedex
country: France
facility: Research Site
city: Rouen
country: France
facility: Research Site
city: Saint Herblain Cedex
country: France
facility: Research Site
city: STRASBOURG Cedex
country: France
facility: Research Site
city: Toulouse
country: France
facility: Research Site
city: Tours CEDEX
country: France
facility: Research Site
city: Villejuif
country: France
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Bielefeld
country: Germany
facility: Research Site
city: Dresden
country: Germany
facility: Research Site
city: Duisburg
country: Germany
facility: Research Site
city: Erlangen
country: Germany
facility: Research Site
city: Essen
country: Germany
facility: Research Site
city: Guetersloh
country: Germany
facility: Research Site
city: Hamburg
country: Germany
facility: Research Site
city: Jena
country: Germany
facility: Research Site
city: Kiel
country: Germany
facility: Research Site
city: Münster
country: Germany
facility: Research Site
city: Stuttgart
country: Germany
facility: Research Site
city: Würzburg
country: Germany
facility: Research Site
city: Ancona
country: Italy
facility: Research Site
city: Arezzo
country: Italy
facility: Research Site
city: Avellino
country: Italy
facility: Research Site
city: Bari
country: Italy
facility: Research Site
city: Catania
country: Italy
facility: Research Site
city: Lecce
country: Italy
facility: Research Site
city: Meldola
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Modena
country: Italy
facility: Research Site
city: Padova
country: Italy
facility: Research Site
city: Pisa
country: Italy
facility: Research Site
city: Ravenna
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Rozzano
country: Italy
facility: Research Site
city: Udine
country: Italy
facility: Research Site
city: Busan
country: Korea, Republic of
facility: Research Site
city: Goyang-si
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Leiden
country: Netherlands
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Newcastle
country: United Kingdom
facility: Research Site
city: Sheffield
country: United Kingdom
facility: Research Site
Study officials:
References:
citation: Sonpavde GP, Sternberg CN, Loriot Y, Marabelle A, Lee JL, Flechon A, Roubaud G, Pouessel D, Zagonel V, Calabro F, Banna GL, Shin SJ, Vera-Badillo FE, Powles T, Hellmis E, Miranda PAP, Lima AR, Emeribe U, Oh SM, Hotte SJ. Primary results of STRONG: An open-label, multicenter, phase 3b study of fixed-dose durvalumab monotherapy in previously treated patients with urinary tract carcinoma. Eur J Cancer. 2022 Mar;163:55-65. doi: 10.1016/j.ejca.2021.12.012. Epub 2022 Jan 15.