|E.1 Medical condition or disease under investigation |
|E.1.1||Medical condition(s) being investigated || |
|Metastatic urothelial carcinoma patients or patients with irresectable disease who were previously treated with chemotherapy - or are cisplatin-ineligible - and have progressed during or after treatment with anti-PD1 or anti-PD-L1 therapy. |
|E.1.1.1||Medical condition in easily understood language || |
|Advanced urinary tract cancer patients that have received both immunotherapy and chemotherapy. |
|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 ||LLT |
|E.1.2||Classification code ||10022880 |
|E.1.2||Term ||Invasive bladder cancer stage IV |
|E.1.2||System Organ Class ||100000004864 |
|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 || |
|Establish clinical efficacy (ORR) of a combined schedule of paclitaxel and tremelimumab (high-dose), and/or establish clinical efficacy (ORR) of a combined schedule of paclitaxel, tremelimumab and durvalumab. |
|E.2.2||Secondary objectives of the trial || |
|Establish safety of a combined scheduled of paclitaxel and tremelimumab +/- durvalumab in treatment of metastatic urothelial carcinoma patients and determine whether durable clinical responses occur by measurement of additional efficacy criteria (Overall Survival, Progression-Free Survival, Duration of response). |
|E.2.3||Trial contains a sub-study || No |
|E.3||Principal inclusion criteria || |
|For inclusion in the study, patients should fulfill the following criteria: |
1.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, European Union [EU] Data Privacy Directive) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
2.Patients with histologically or cytologically documented metastatic or irresectable (i.e. T4b, N1-3 and/or M1a/b) urothelial cell carcinoma (including renal pelvis, ureters, urinary bladder, and urethra).
3.Patients ineligible for cisplatin-based chemotherapy OR previous treatment with platinum-based chemotherapy, either in the neo-adjuvant setting or in any other setting. This is defined as progression on or after at least 2 cycles of platinum-based chemotherapy (e.g. MVAC, cisplatin/gemcitabine, carpoblatin/gemcitabine). Patients who had to stop platinum-based therapy because of toxicity after at least 2 cycles are eligible if they have progressive disease.
4.Previous treatment with anti-PD(L)1 immunotherapy. The following conditions apply for inclusion:
a.Must not have experienced a toxicity that led to permanent discontinuation of prior anti-PD(L)1 immunotherapy.
b.All treatment-related AEs while receiving prior anti-PD(L)1 immunotherapy must have completely resolved or resolved to baseline prior to screening for this study.
c.Must not have experienced a ≥Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior anti-PD(L)1 immunotherapy.
d.Patients with endocrine AE of ≤Grade 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.
e.Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of >10 mg prednisone or equivalent per day.
5.At least 1 lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have a Revised Clinical Study Protocol short axis ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and that is suitable for accurate repeated measurements as per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) guidelines.
6.Age >18 years at time of study entry
7.World Health Organisation (WHO) performance status of 0 or 1
8.Body weight >30kg
9.Adequate normal organ and marrow function as defined below:
a.Haemoglobin ≥9.0 g/dL = 5.6 mmol/L
b.Absolute neutrophil count (ANC) ≥1.5 x 109/L
c.Platelet count ≥100 x 109/L
d.Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). (Does not apply to patients with confirmed Gilbert’s syndrome, who will be allowed only in consultation with their physician.)
e.AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN
f.Measured creatinine clearance (CL) >30 mL/min or Calculated creatinine clearance CL>30 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:
Creatinine CL (mL/min)=Weight (kg) x (140 – Age)
72 x serum creatinine (mg/dL)
Creatinine CL (mL/min)=Weight (kg) x (140 – Age) x 0.85
72 x serum creatinine (mg/dL)
10.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).
11.Patient is 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.
12.Must have a life expectancy of at least 12 weeks
|E.4||Principal 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.Participation in another clinical study with an investigational product
3.Concurrent enrollment in another clinical study, unless it is an observational study
4.Receipt of the last dose of anticancer therapy ≤28 days prior to the first dose of study drug.
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
6.Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal therapy for cancer treatment.
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 drug
8.Major surgical procedure within 28 days prior to the first dose of IP.
9.History of allogenic organ transplantation.
10.Active or prior documented autoimmune or inflammatory disorders
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 ≥2 years before the first dose of IP 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
•Curatively treated localized prostate cancer without PSA recurrence
13.History of leptomeningeal carcinomatosis
14.Brain metastases or spinal cord compression, unless they show radiographic stability
15.History of active primary immunodeficiency
16.Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings), 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 (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)
18.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.
19.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 tremelimumab, durvalumab, or durvalumab + tremelimumab combination therapy.
20.Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
21.Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.
22.Previous treatment with anti-CTLA-4 immunotherapy.
23.Known allergy or hypersensitivity to IP or any excipient
|E.5 End points |
|E.5.1||Primary end point(s)|| |
|Objective Response Rate (ORR) by investigator-assessed RECIST v1.1 by measuring change in tumor burden. These criteria are described in “New response evaluation criteria in solid tumors: revised RECIST guideline version 1.1 Patients will be evaluated after 12 weeks (=8 weeks after introducing tremelimumab ± durvalumab) and then every 8 weeks for RECIST1.1 response by CT-scan, for the first 12 months. For subjects who achieve disease control following 12 months of treatment, tumor assessments should be performed every 12 weeks (± 1 week) relative to the date of first infusion thereafter until confirmed PD. For subjects who discontinue tremelimumab and/or durvalumab due to toxicity (or symptomatic deterioration), tumor assessments should be performed relative to the date of first infusion as follows: every 8 weeks (± 1 week) for the first 48 weeks, then every 12 weeks (± 1 week) until confirmed PD by RECIST v1.1 by investigational site review. |
|E.5.1.1||Timepoint(s) of evaluation of this end point|| |
|Patients will be evaluated after 12 weeks (=8 weeks after introducing tremelimumab ± durvalumab) and then every 8 weeks for RECIST1.1 response by CT-scan, for the first 12 months. For subjects who achieve disease control following 12 months of treatment, tumor assessments should be performed every 12 weeks (± 1 week) relative to the date of first infusion thereafter until confirmed PD. |
|E.5.2||Secondary end point(s)|| |
|1) Establish safety of a combined schedule of paclitaxel, tremelimumab +/- durvalumab in treatment of mUC patients. The safety evaluation will include AEs, SAEs, and changes from baseline in laboratory evaluations, vital signs, electrocardiograms, and physical examinations. The number and percentage of subjects reporting treatment-emergent AEs will be summarized overall and by the worst CTCAE grade, system organ class, and preferred term. Similarly, the number and percentage of subjects reporting treatment-emergent AEs considered related to investigational product will be summarized. At each level of subject summarization, a subject will be counted once using the highest grade and level of causality if one or more occurrences of the same system organ class/preferred term are reported. Adverse events will be graded according to the National Cancer Institute (NCI) CTCAE v5.0 and coded using the Medical Dictionary for Regulatory Activities. Laboratory abnormalities will be graded according to the NCI CTCAE v5.0, if applicable. |
2) Determine clinical efficacy by additional measurements: OS and PFS by Kaplan-Meier method, 1-year OS and PFS, Duration of response.
|E.5.2.1||Timepoint(s) of evaluation of this end point|| |
|Patients and adverse events will be closely monitored until 90 days after end of treatment. Overall survival (OS) will be monitored afterwards. |
|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|| Yes |
|E.6.10||Pharmacogenetic|| No |
|E.6.11||Pharmacogenomic|| Yes |
|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.22.214.171.124||Other trial type description|| |
|Phase lb single arm safety/efficacy trial |
|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|| Yes |
|E.8.1.1||Randomised|| Yes |
|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|| Yes |
|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)|| Yes |
|E.8.2.2||Placebo || No |
|E.8.2.3||Other|| No |
|E.8.2.4||Number of treatment arms in the trial||3 |
|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||4 |
|E.8.5||The trial involves multiple Member States|| No |
|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 || |
|E.8.9 Initial estimate of the duration of the trial |
|E.8.9.1||In the Member State concerned years||4 |
|E.8.9.1||In the Member State concerned months||0 |
|E.8.9.1||In the Member State concerned days||0 |