Study in Patients with surgically non removeable Urothelial Cancer with Durvalumab in Combination with Chemotherapy and Durvalumab in Combination with Tremelimumab and Chemotherapy Versus Chemotherapy Alone

Phase 3

Active, not recruiting

• Conditions: Urolithiasis,

• Registration Number: CTRI/2019/07/020184
• Lead Sponsor: AstraZeneca AB

Brief Summary

This is a randomized, open-label, controlled,multi-center, global Phase III study to determine the efficacy and safety ofcombining durvalumab ± tremelimumab with 6 cycles of standard of care (SoC) chemotherapy(cisplatin + gemcitabine or carboplatin + gemcitabine doublet) followed bydurvalumab monotherapy versus SoC alone as first-line chemotherapy in patients withhistologically or cytologically documented transitional cell carcinoma(transitional cell and mixed transitional/non-transitional cell histologies) ofthe urothelium (including renal pelvis, ureters, urinary bladder, and urethra),unresectable, locally advanced or metastatic (ie, T4b, any N; or any T, N2-N3;or M1).The study will plan to enrol approximately1265 patients globally in order to randomize (1:1:1) approximately 885 patientsto durvalumab + SoC, durvalumab + tremelimumab + SoC combination therapy, orSoC (cisplatin + gemcitabine or carboplatin + gemcitabine). Therefore, approximately 295 patients will be randomized to each of thetreatment arms.The primary aim of thisstudy is to assess the efficacy of durvalumab + SoC combination therapycompared with SoC in terms of OS and PFS in patients with unresectable locallyadvanced or metastatic UC.Antitumor activity will beassessed according to RECIST 1.1 guidelines. The co-primary analysis of PFSwill be based on programmatically derived PFS calculated from the tumor assessmentsaccording to RECIST 1.1 by BICR. In addition, PFS by RECIST 1.1 modified for confirmationof progression and Immune-related Response Evaluation Criteria in Solid Tumors,version 1.1, using BICR assessments will also be performed for exploratorypurposes.Other secondary efficacy endpoints of proportion ofpatients alive and progression-free at 12 months from randomization (APF12),overall survival at 24 months after randomization (OS24), duration of response(DoR), disease control rate (DCR), and time from randomization to secondprogression (PFS2) will be examined to further evaluate the antitumor effectand survival benefit of durvalumab + SoC compared with SoC, and durvalumab +tremelimumab + SoC compared with SoC. ORR, APF12, DoR, and DCR will be assessedusing investigator and BICR assessments according to RECIST 1.1. Additionally,the secondary endpoints of OS and PFS will be examined to further evaluate theefficacy of durvalumab + tremelimumab + SoC compared with durvalumab + SoC. The patient-reported outcome measures, namelythe European Organisation for Research and Treatment of Cancer 30-item corequality of life questionnaire (EORTC QLQ-C30); patient reported outcomesversion of the Common Terminology Criteria for Adverse Events (PROCTCAE); PatientGlobal Impression of Change (PGIC), Patient Global Impression of Severity (PGIS);and EuroQol 5-dimension, 5-level health state utility index (EQ-5D-5L) will beused. Biological samples will be used to explore potential biomarkers in tumortissue, whole blood, plasma, serum, and urine that may influence pathogenesis,response, and clinical characteristics.

Detailed Description

Not available

Study Timeline

• Study Start: 2019-08-28
• Last Update Posted: 2024-02-01

Recruitment & Eligibility

• Status: Closed to Recruitment of Participants
• Sex: All
• Target Recruitment: 1265

Inclusion Criteria

• Inclusion criteria: Informed consent 1.Capable of giving signed informed consent that includes compliance with the requirements and restrictions listed in the ICF and in this protocol. 2.Provision of signed and dated, written ICF prior to any mandatory study-specific procedures, sampling, and analyses Age 3.Age greater or equal to 18 years at the time of screening. Type of patient and disease characteristics 4. Individuals with histologically or cytologically documented transitional cell carcinoma (transitional cell and mixed transitional/non-transitional cell histologies) of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra), unresectable, locally advanced, or metastatic (ie, T4b, any N; or any T, N2-N3, or M1; based on clinical TNM [tumor/node/metastasis] staging) (who have not been previously treated with first-line chemotherapy.(Patients who have received prior definitive chemoradiation, adjuvant or neoadjuvant treatment for locally advanced disease are eligible provided that progression to locally advanced or metastatic disease has occurred greater than 12 months from the last therapy [for chemoradiation and adjuvant treatment] or Greater than 12 months from the last surgery [for neoadjuvant treatment] 5. World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at enrolment 6. At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 target lesion (TL) at baseline. Tumor assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be performed within 28 days prior to randomization. 7.Tumor PD-L1 status, with immunohistochemistry (IHC) assay confirmed by a reference laboratory, must be known prior to randomization. As such, all patients must be able to provide a newly acquired tumor biopsy (<3 months) during screening (preferred) or provide an available tumor sample taken ≤3 years prior to screening. Tumor lesions used for newly acquired biopsies should not be target lesions, unless there are no other lesions suitable for biopsy, and in this instance, only core needle (not excisional/incisional) biopsy is allowed. For patients with a single target lesion, if screening biopsy is collected prior to screening imaging for baseline tumor assessment, allow at least approximately 2 weeks before imaging scans are acquired. Samples with limited tumor content and fine-needle aspirate specimens are not acceptable. Specimens from metastatic bone lesions are typically unacceptable unless there is a significant soft-tissue component. The tumor specimen submitted to establish eligibility should be of sufficient quantity to allow for PD-L1 IHC and exploratory biomarker analyses, as appropriate and is preferred in formalin-fixed paraffin-embedded blocks. 8. Patients eligible or ineligible for cisplatin-based chemotherapy, Cisplatin ineligibility is defined as meeting one of the following criteria: a)Creatinine clearance less than 60 mL/min and greater than 30 mL/min calculated by Cockcroft-Gault equation or by measured 24-hour urine collection.(In cases where both are performed, measured 24-hour urine collection will be used to determine eligibility, providing an adequate collection was performed.) b) Common Terminology Criteria for Adverse Events (CTCAE) Grade greater or equal to 2 audiometric hearing loss c) CTCAE Grade greater or equal to 2 peripheral neuropathy 9. Adequate organ and marrow function as defined below: a) Hemoglobin greater than or equal to 9.0 g/dL b) Absolute neutrophil count greater than or equal to 1.5×109/L c) Platelet count greater than or equal to 100×109/L d) Serum bilirubin ≤1.5 × the ULN. This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia [predominantly unconjugated bilirubin] in the absence of evidence of hemolysis or hepatic pathology), who will be allowed in consultation with their physician and AstraZeneca. e) ALT and AST ≤2.5×ULN; for patients with hepatic metastases, ALT and AST≤5×ULN F) Measured creatinine clearance (CL) >30 mL/min calculated by Cockcroft-Gault (using actual body weight) or by measured 24-hour urine collection for determination. (In cases where both are performed, measured 24-hour urine collection will be used to determine eligibility, providing an adequate collection was performed) Males: Creatinine CL equals Weight (kg) × (140.
• Age) (mL/min) 72 × serum creatinine (mg/dL) Females: Creatinine CL equals Weight (kg) × (140.
• Age) × 0.85 (mL/min) 72 × serum creatinine (mg/dL) 10. Life expectancy gretaer than or equal to 12 weeks in the opinion of the investigator Weight 11. Body weight greater than 30 kg Reproduction 12. 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 amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply: a) Women <50 years of age would be considered post-menopausal if they have been amenorrhoeic 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). b) Women ≥50 years of age would be considered post-menopausal if they have been amenorrhoeic 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). Other inclusions 13. Genetic research (optional): All patients will be asked to participate in the genetic research component of this study. Participation is voluntary, and if a patient declines to participate, there will be no penalty or loss of benefit, and he/she will not be excluded from any other component of the study. A patient is eligible to be included in the voluntary/optional genetics (deoxyribonucleic acid [DNA]) research component of the study only if all of the above inclusion criteria and none of the exclusion criteria described below apply, and he/she provides signed and dated written genetic informed consent prior to collection of the sample for genetic analysis.

Exclusion Criteria

• History of allogeneic organ transplantation.
• 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: a)Patients with vitiligo or alopecia b)Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement c)Patients with any chronic skin condition that does not require systemic therapy d)Patients without active disease in the last 5 years may be included but only after consultation with the study physician e)Patients with celiac disease controlled by diet alone 3.
• Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhoea, 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 4.
• 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 IP and of low potential risk for recurrence a) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease b) Adequately treated carcinoma in situ without evidence of disease 5.
• History of leptomeningeal carcinomatosis 6.
• History of active primary immunodeficiency 7.
• 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 HBV surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus (positive HIV ½ antibodies).
• Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg, DNA negative) are eligible.
• Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• 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 a) Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician.
• b) Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab or SoC chemotherapy may be included only after consultation with the study physician.
• Untreated central nervous system metastases and/or carcinomatous meningitis identified either on the baseline brain imaging obtained during the screening period or identified prior to signing the ICF.
• Patients with a history of brain metastases or with suspected brain metastases at screening must have an MRI (preferred) or CT each preferably with IV contrast of the brain prior to study entry.
• 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-convulsant for at least 14 days prior to the start of treatment.
• Brain metastases will not be recorded as RECIST target lesions at baseline.
• Any medical contraindication to platinum (cisplatin or carboplatin)-based doublet chemotherapy 11.
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients Prior/concomitant therapy 12.
• Prior exposure to immune-mediated therapy (with exclusion of Bacillus Calmette Guerin), including but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, except therapeutic anticancer vaccines, which are permitted.
• Prior local intervesical chemotherapy or immunotherapy is allowed if completed at least 28 days prior to the initiation of study treatment.
• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
• Note: Patients, if enrolled, should not receive live vaccine while receiving IP and up to 30 days after the last dose of IP.
• Patients who may be eligible for or are being considered for radical resection during the course of the study.
• Major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of IP.
• 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: a) Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular injection) b) Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent c) Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
• Premedication with steroids for chemotherapy is also acceptable.
• Previous IP assignment in the present study 19.
• 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 20.
• Participation in another clinical study with an IP administered in the last 4 weeks 21.
• Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment (until the primary endpoint of the previous study has read out) Other exclusions 22.
• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site) 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 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab + tremelimumab combination therapy.
• Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements 25.
• Genetic research study (optional): Exclusion criteria for participation in the optional (DNA) genetics research component of the study include the following: a) Previous allogeneic bone marrow transplant b) Non-leukocyte-depleted whole blood transfusion in 120 days of genetic sample collection.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
To assess the efficacy of Treatment Arm 1 versus Treatment Arm 3 in terms of PFS/OS in patients with unresectable locally advanced or metastatic Urothelial Cancer	To assess the efficacy of Treatment Arm 1 versus Treatment Arm 3 in terms of PFS/OS in patients with unresectable locally advanced or metastatic Urothelial Cancer

Secondary Outcome Measures

Name	Time	Method
To assess the efficacy of Treatment Arm 2 compared to Treatment Arm 3 in terms of PFS/OS in patients with UC	a) PFS using BICR assessments according to RECIST 1.1b

Trial Locations

Locations (12)

Action Cancer hospital; 🇮🇳 Delhi, DELHI, India

All India Institute of Medical Sciences(AIIMS); 🇮🇳 Delhi, DELHI, India

Artemis Hospital; 🇮🇳 Gurgaon, HARYANA, India

HCG - Bharath Hospital and Institute of Oncology; 🇮🇳 Mysore, KARNATAKA, India

HCG Cancer Centre; 🇮🇳 Ahmadabad, GUJARAT, India

Meditrina Institute of Medical Sciences; 🇮🇳 Nagpur, MAHARASHTRA, India

MVR Cancer Centre & Research Institute; 🇮🇳 Kozhikode, KERALA, India

Rajiv Gandhi Cancer Institute and Research Centre; 🇮🇳 Delhi, DELHI, India

Sahyadri Speciality, Hospital; 🇮🇳 Pune, MAHARASHTRA, India

Shatabdi Hospital; 🇮🇳 Mumbai, MAHARASHTRA, India

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Action Cancer hospital

🇮🇳Delhi, DELHI, India

Dr Samit Purohit

Principal investigator

011-49222222

samitmedonc@gmail.com