Summary
EudraCT Number:2018-004148-53
Sponsor's Protocol Code Number:M18ICR
National Competent Authority:Netherlands - Competent Authority
Clinical Trial Type:EEA CTA
Trial Status:Ongoing
Date on which this record was first entered in the EudraCT database:2018-12-19
Trial results
A. Protocol Information
A.1Member State ConcernedNetherlands - Competent Authority
A.2EudraCT number2018-004148-53
A.3Full title of the trial
ICRA (Improve Checkpoint-blockade Response in Advanced urothelial cancer), an adaptive clinical study to determine efficacy of combining weekly paclitaxel with tremelimumab +/- durvalumab (MEDI4736)
A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
paclitaxel (chemotherapy) in combination with tremelimumab (immunotherapy), with or without durvalumab (immunotherapy), for advanced urinary tract cancer (ICRA)
A.4.1Sponsor's protocol code numberM18ICR
A.7Trial is part of a Paediatric Investigation Plan No
A.8EMA Decision number of Paediatric Investigation Plan
B. Sponsor Information
B.Sponsor: 1
B.1.1Name of SponsorNKI-AVL
B.1.3.4CountryNetherlands
B.3.1 and B.3.2Status of the sponsorNon-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1Name of organisation providing supportAstraZeneca AB
B.4.2CountryNetherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1Name of organisationNKI-AVL
B.5.2Functional name of contact pointMichiel van der Heijden
B.5.3 Address:
B.5.3.1Street AddressPlesmanlaan 121
B.5.3.2Town/ cityAmsterdam
B.5.3.3Post code1066 CX
B.5.3.4CountryNetherlands
B.5.4Telephone number0031205126273
B.5.6E-mail[email protected]
D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3IMP RoleTest
D.2 Status of the IMP to be used in the clinical trial
D.2.1IMP to be used in the trial has a marketing authorisation No
D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
D.2.5.1Orphan drug designation number
D.3 Description of the IMP
D.3.1Product nameDurvalumab
D.3.2Product code MEDI4736
D.3.4Pharmaceutical form Concentrate for solution for infusion
D.3.4.1Specific paediatric formulation No
D.3.7Routes of administration for this IMPIntravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INNDURVALUMAB
D.3.9.1CAS number 1428935-60-7
D.3.9.2Current sponsor codeMEDI4736
D.3.9.4EV Substance CodeSUB176342
D.3.10 Strength
D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
D.3.10.2Concentration typeequal
D.3.10.3Concentration number50
D.3.11 The IMP contains an:
D.3.11.1Active substance of chemical origin No
D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
The IMP is a:
D.3.11.3Advanced Therapy IMP (ATIMP) No
D.3.11.3.1Somatic cell therapy medicinal product No
D.3.11.3.2Gene therapy medical product No
D.3.11.3.3Tissue Engineered Product No
D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
D.3.11.5Radiopharmaceutical medicinal product No
D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
D.3.11.7Plasma derived medicinal product No
D.3.11.8Extractive medicinal product No
D.3.11.9Recombinant medicinal product Yes
D.3.11.10Medicinal product containing genetically modified organisms No
D.3.11.11Herbal medicinal product No
D.3.11.12Homeopathic medicinal product No
D.3.11.13Another type of medicinal product No
D.IMP: 2
D.1.2 and D.1.3IMP RoleTest
D.2 Status of the IMP to be used in the clinical trial
D.2.1IMP to be used in the trial has a marketing authorisation No
D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
D.2.5.1Orphan drug designation number
D.3 Description of the IMP
D.3.1Product nameTremelimumab
D.3.2Product code MEDI1123
D.3.4Pharmaceutical form Concentrate for solution for infusion
D.3.4.1Specific paediatric formulation No
D.3.7Routes of administration for this IMPIntravenous use
Unknown use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INNTremelimumab
D.3.9.1CAS number 745013-59-6
D.3.9.2Current sponsor codeMEDI1123
D.3.9.3Other descriptive nameMEDI1123
D.3.9.4EV Substance CodeSUB37101
D.3.10 Strength
D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
D.3.10.2Concentration typeequal
D.3.10.3Concentration number20
D.3.11 The IMP contains an:
D.3.11.1Active substance of chemical origin No
D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
The IMP is a:
D.3.11.3Advanced Therapy IMP (ATIMP) No
D.3.11.3.1Somatic cell therapy medicinal product No
D.3.11.3.2Gene therapy medical product No
D.3.11.3.3Tissue Engineered Product No
D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
D.3.11.5Radiopharmaceutical medicinal product No
D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
D.3.11.7Plasma derived medicinal product No
D.3.11.8Extractive medicinal product No
D.3.11.9Recombinant medicinal product Yes
D.3.11.10Medicinal product containing genetically modified organisms No
D.3.11.11Herbal medicinal product No
D.3.11.12Homeopathic medicinal product No
D.3.11.13Another type of medicinal product No
D.IMP: 3
D.1.2 and D.1.3IMP RoleComparator
D.2 Status of the IMP to be used in the clinical trial
D.2.1IMP to be used in the trial has a marketing authorisation Yes
D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
D.2.5.1Orphan drug designation number
D.3 Description of the IMP
D.3.1Product namePaclitaxel
D.3.4Pharmaceutical form Concentrate for solution for infusion
D.3.4.1Specific paediatric formulation No
D.3.7Routes of administration for this IMPIntravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INNPaclitaxel
D.3.9.1CAS number 33069-62-4
D.3.9.2Current sponsor codePaclitaxel
D.3.9.3Other descriptive namePaclitaxel
D.3.9.4EV Substance CodeSUB07483MIG
D.3.10 Strength
D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
D.3.10.2Concentration typeequal
D.3.10.3Concentration number1
D.3.11 The IMP contains an:
D.3.11.1Active substance of chemical origin Yes
D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
The IMP is a:
D.3.11.3Advanced Therapy IMP (ATIMP) No
D.3.11.3.1Somatic cell therapy medicinal product No
D.3.11.3.2Gene therapy medical product No
D.3.11.3.3Tissue Engineered Product No
D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
D.3.11.5Radiopharmaceutical medicinal product No
D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
D.3.11.7Plasma derived medicinal product No
D.3.11.8Extractive medicinal product No
D.3.11.9Recombinant medicinal product No
D.3.11.10Medicinal product containing genetically modified organisms No
D.3.11.11Herbal medicinal product No
D.3.11.12Homeopathic medicinal product No
D.3.11.13Another type of medicinal product No
D.8 Information on Placebo
E. General Information on the Trial
E.1 Medical condition or disease under investigation
E.1.1Medical 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.1.1.1Medical condition in easily understood language
Advanced urinary tract cancer patients that have received both immunotherapy and chemotherapy.
E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
MedDRA Classification
E.1.2 Medical condition or disease under investigation
E.1.2Version 20.0
E.1.2Level LLT
E.1.2Classification code 10022880
E.1.2Term Invasive bladder cancer stage IV
E.1.2System Organ Class 100000004864
E.1.3Condition being studied is a rare disease No
E.2 Objective of the trial
E.2.1Main 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.2.2Secondary 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.2.3Trial contains a sub-study No
E.3Principal 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:

Males:
Creatinine CL (mL/min)=Weight (kg) x (140 – Age)
72 x serum creatinine (mg/dL)

Females:
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.4Principal 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.5.1Primary 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.5.1.1Timepoint(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.5.2Secondary 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.5.2.1Timepoint(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.6Scope of the trial
E.6.1Diagnosis No
E.6.2Prophylaxis No
E.6.3Therapy Yes
E.6.4Safety Yes
E.6.5Efficacy Yes
E.6.6Pharmacokinetic No
E.6.7Pharmacodynamic No
E.6.8Bioequivalence No
E.6.9Dose response Yes
E.6.10Pharmacogenetic No
E.6.11Pharmacogenomic Yes
E.6.12Pharmacoeconomic No
E.6.13Others No
E.7Trial type and phase
E.7.1Human pharmacology (Phase I) Yes
E.7.1.1First administration to humans No
E.7.1.2Bioequivalence study No
E.7.1.3Other Yes
E.7.1.3.1Other trial type description
Phase lb single arm safety/efficacy trial
E.7.2Therapeutic exploratory (Phase II) Yes
E.7.3Therapeutic confirmatory (Phase III) No
E.7.4Therapeutic use (Phase IV) No
E.8 Design of the trial
E.8.1Controlled Yes
E.8.1.1Randomised Yes
E.8.1.2Open Yes
E.8.1.3Single blind No
E.8.1.4Double blind No
E.8.1.5Parallel group Yes
E.8.1.6Cross over No
E.8.1.7Other No
E.8.2 Comparator of controlled trial
E.8.2.1Other medicinal product(s) Yes
E.8.2.2Placebo No
E.8.2.3Other No
E.8.2.4Number of treatment arms in the trial3
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.8.4.1Number of sites anticipated in Member State concerned4
E.8.5The trial involves multiple Member States No
E.8.6 Trial involving sites outside the EEA
E.8.6.1Trial being conducted both within and outside the EEA No
E.8.6.2Trial being conducted completely outside of the EEA No
E.8.7Trial 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
LVLS
E.8.9 Initial estimate of the duration of the trial
E.8.9.1In the Member State concerned years4
E.8.9.1In the Member State concerned months0
E.8.9.1In the Member State concerned days0
F. Population of Trial Subjects
F.1 Age Range
F.1.1Trial has subjects under 18 No
F.1.1.1In Utero No
F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
F.1.1.3Newborns (0-27 days) No
F.1.1.4Infants and toddlers (28 days-23 months) No
F.1.1.5Children (2-11years) No
F.1.1.6Adolescents (12-17 years) No
F.1.2Adults (18-64 years) Yes
F.1.2.1Number of subjects for this age range: 25
F.1.3Elderly (>=65 years) Yes
F.1.3.1Number of subjects for this age range: 25
F.2 Gender
F.2.1Female Yes
F.2.2Male Yes
F.3 Group of trial subjects
F.3.1Healthy volunteers No
F.3.2Patients Yes
F.3.3Specific vulnerable populations No
F.3.3.1Women of childbearing potential not using contraception No
F.3.3.2Women of child-bearing potential using contraception No
F.3.3.3Pregnant women No
F.3.3.4Nursing women No
F.3.3.5Emergency situation No
F.3.3.6Subjects incapable of giving consent personally No
F.3.3.7Others No
F.4 Planned number of subjects to be included
F.4.1In the member state50
F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
After the 30-day and 90-day visit, patients will enter follow up phase and will be contacted every 6 months for survival monitoring.
G. Investigator Networks to be involved in the Trial
N. Review by the Competent Authority or Ethics Committee in the country concerned
N.Competent Authority Decision Authorised
N.Date of Competent Authority Decision2018-12-19
N.Ethics Committee Opinion of the trial applicationFavourable
N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
N.Date of Ethics Committee Opinion2019-03-19
P. End of Trial
P.End of Trial StatusOngoing