A Study of Chemotherapy and Radiation Therapy Compared to Chemotherapy and Radiation Therapy Plus MEDI4736 (Durvalumab) Immunotherapy for Bladder Cancer Which Has Spread to the Lymph Nodes, the INSPIRE Study
|
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT04216290 |
|
Recruitment Status :
Recruiting
First Posted : January 2, 2020
Last Update Posted : January 20, 2021
|
Sponsor:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Cancer Institute (NCI)
- Study Details
- Tabular View
- No Results Posted
- Disclaimer
- How to Read a Study Record
Brief Summary:
This phase II trial studies how well chemotherapy and radiation therapy alone works compared to chemotherapy and radiation therapy plus MEDI4736 (durvalumab) immunotherapy in treating bladder cancer which has spread to the lymph nodes. Standard chemotherapy drugs work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Immunotherapy with durvalumab may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving chemotherapy and radiation therapy with the addition of durvalumab may work better in helping tumors respond to treatment compared to chemotherapy and radiation therapy alone.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Bladder Urothelial Carcinoma Stage III Bladder Cancer AJCC v8 Stage IIIA Bladder Cancer AJCC v8 Stage IIIB Bladder Cancer AJCC v8 | Drug: Carboplatin Drug: Cisplatin Drug: Doxorubicin Hydrochloride Biological: Durvalumab Drug: Fluorouracil Drug: Gemcitabine Hydrochloride Drug: Methotrexate Drug: Mitomycin Other: Patient Observation Radiation: Radiation Therapy Drug: Vinblastine Sulfate | Phase 2 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 114 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Phase II Study of Bladder-SparIng ChemoradiatioN With MEDI4736 (Durvalumab) in Clinical Stage III, Node PosItive BladdeR CancEr (INSPIRE) |
| Actual Study Start Date : | August 25, 2020 |
| Estimated Primary Completion Date : | December 31, 2024 |
| Estimated Study Completion Date : | December 31, 2024 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Bladder cancer
MedlinePlus related topics:
Bladder Cancer
Drug Information available for:
Durvalumab
| Arm | Intervention/treatment |
|---|---|
|
No Intervention: Step I, Arm A (no intervention)
ARM A: Patients registered after completion of >= 3 cycles of induction chemotherapy proceed to Step 2 - Randomization.
|
|
|
Experimental: Step I, Arm B (chemotherapy)
Chemotherapy naive patients receive 1 of 4 chemotherapy regimens: gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 every 21 days for 3 cycles; carboplatin IV over 30-60 minutes on day 1 and gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 every 21 days for 3 cycles; gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 and cisplatin IV 30-60 minutes on day 1 every 21 days for 3 cycles; or methotrexate IV over 3 minutes, vinblastine sulfate IV over 3 minutes, adriamycin (doxorubicin hydrochloride) IV over 5 minutes, and cisplatin IV over 30-60 minutes on day 1 every 14 days for 3 cycles. Cycles repeat in the absence of disease progression or unacceptable toxicity.
|
Drug: Carboplatin
Given IV
Other Names:
Drug: Cisplatin Given IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Drug: Gemcitabine Hydrochloride Given IV
Other Names:
Drug: Methotrexate Given IV
Other Names:
Drug: Vinblastine Sulfate Given IV
Other Names:
|
|
Experimental: Step II, Arm C (durvalumab, radiation therapy, chemotherapy)
Patients undergo radiation therapy for 6.5-8 weeks. Beginning 4 days before or after starting radiation therapy, patients receive durvalumab IV over 60 minutes on day 1. Cycles repeat every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Beginning 4 days before or after starting radiation therapy, patients also receive gemcitabine hydrochloride IV over 30-60 minutes twice weekly for 6 weeks; cisplatin IV over 30-60 minutes for 6 weeks; or mitomycin IV over 30 minutes on day 1 of radiation and fluorouracil IV on days 1-5 and 16-20 of radiation in the absence of disease progression or unacceptable toxicity.
|
Biological: Durvalumab
Given IV
Other Names:
Drug: Fluorouracil Given IV
Other Names:
Drug: Gemcitabine Hydrochloride Given IV
Other Names:
Drug: Mitomycin Given IV
Other Names:
Radiation: Radiation Therapy Undergo radiation therapy
Other Names:
|
|
Active Comparator: Step II, Arm D (radiation therapy, chemotherapy)
Patients undergo radiation therapy for 6.5-8 weeks. Beginning 4 days before or after starting radiation therapy, patients also receive gemcitabine hydrochloride IV over 30-60 minutes twice weekly for 6 weeks; cisplatin IV over 30-60 minutes for 6 weeks; or mitomycin IV over 30 minutes on day 1 of radiation and fluorouracil IV on days 1-5 and 16-20 of radiation in the absence of disease progression or unacceptable toxicity.
|
Drug: Cisplatin
Given IV
Other Names:
Drug: Fluorouracil Given IV
Other Names:
Drug: Gemcitabine Hydrochloride Given IV
Other Names:
Drug: Mitomycin Given IV
Other Names:
Radiation: Radiation Therapy Undergo radiation therapy
Other Names:
|
|
Experimental: Step III, Arm E (durvalumab)
Patients previously randomized to Arm C (chemoradiation and durvalumab) who achieve clinical CR or clinical benefit receive durvalumab IV over 60 minutes on day 1. Cycles repeat every 28 days for 9 cycles in the absence of disease progression or unacceptable toxicity.
|
Biological: Durvalumab
Given IV
Other Names:
|
|
Active Comparator: Step III, Arm F (observation)
Patients previously randomized to Arm D who achieve clinical CR or clinical benefit, or patients previously randomized to Arm C with no clinical CR or clinical benefit undergo observation.
|
Other: Patient Observation
Undergo observation
Other Names:
|
Primary Outcome Measures :
- Clinical complete response (CR) [ Time Frame: Up to 6 years ]
Secondary Outcome Measures :
- Metastasis-free survival [ Time Frame: From randomization to first evidence of metastatic disease or death from any cause, assessed up to 6 years ]Will be estimated by the Kaplan-Meier method.
- Bladder-intact event-free survival (BI-EFS) [ Time Frame: From randomization to the first BI-EFS event, assessed up to 6 years ]Will be estimated by the Kaplan-Meier method.
- Bladder cancer specific survival [ Time Frame: From randomization to death from bladder cancer, assessed up to 6 years ]Will be estimated by the Kaplan-Meier method.
- Overall survival [ Time Frame: From randomization to death from any cause, assessed up to 6 years ]Will be estimated by the Kaplan-Meier method.
- Progression-free survival [ Time Frame: From randomization to first of local progression, nodal or distant metastasis, or death from any cause, assessed up to 6 years ]Will be estimated by the Kaplan-Meier method.
- Complete response duration [ Time Frame: From the date of the biopsy documenting the complete response to the time of muscle invasive recurrence, local progression, evidence of metastatic disease or death due to any cause, assessed up to 6 years ]Stratified Cox proportional hazards models will be used to estimate hazard ratios in all eligible patients.
- Salvage cystectomy rate [ Time Frame: Up to 6 years ]Rate will be reported as a proportion of patients who do not experience clinical benefit after chemoradiotherapy (chemoRT) +/- MEDI4736 (durvalumab) along with a 90% confidence interval. Stratified Cox proportional hazards models will be used to estimate hazard ratios in all eligible patients.
- Incidence of adverse events [ Time Frame: Up to 1 year ]Assessed using the Common Terminology Criteria for Adverse Events (CTCAE). Toxicity will be evaluated in all treated patients, regardless of eligibility.
Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Step 1 (Registration) Inclusion
- Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 at the time of registration
-
Patient must have histologically proven pure or mixed urothelial cancer of the bladder
- NOTE: Small cell carcinoma is excluded, however other variant histologies are permitted provided a component of urothelial carcinoma is present
-
Prior to receiving any induction chemotherapy, patient must have documented node-positive and non-metastatic disease (any T, N1-2 M0). Patients with clinical N3 disease are ineligible.
- NOTE: Node positivity will be defined by the official interpretation of imaging studies. Positive lymph nodes must be imaging read with suspicious lymph node (LN) >= 1.0 cm in short axis to be eligible, with or without biopsy as documented by a radiologist at the treating center. LN Biopsy is not mandatory but encouraged if feasible and safe per physician discretion. Patients with a negative biopsy of nodes determined to be suspicious on imaging are not eligible. Please note that for non-muscle invasive disease on TURBT, node-positive disease MUST be biopsy proven for patient to be eligible
-
Induction Chemotherapy Requirements
-
For patients registered to this protocol post-completion of induction systemic chemotherapy:
- Patient must have received at least 3 cycles of induction chemotherapy (cisplatin-based chemotherapy OR non-cisplatin based chemotherapy) with no evidence of progressive disease (PD) on post-chemotherapy imaging. The end of last cycle of induction chemotherapy must be within 12 weeks of registration
- Patient who have received more than 3 cycles of induction systemic chemotherapy are also eligible
-
Patient must have had a CR, PR or SD to induction chemotherapy on standard imaging
- NOTE: Patients who have only received 2 cycles of induction chemotherapy and demonstrated clinical response (complete response [CR] OR partial response [PR], OR stable disease [SD]) may be considered for enrollment only after consultation and approval by the study chair under exceptional circumstances where 3rd cycle cannot be delivered. Documentation of correspondences with the study chair must be kept on file. We encourage all patients to get 3 cycles of induction chemotherapy
-
For patients registered to this protocol prior to starting induction systemic chemotherapy:
- Patient must agree to a planned treatment with 3 cycles of induction chemotherapy (physician's choice)
- Patient will again be restaged after completion of induction chemotherapy and prior to randomization to chemoRT +/- MEDI4736 (durvalumab)
- Patient must have a CR, PR or SD to induction chemotherapy on standard imaging prior to randomization to chemoradiotherapy
-
- Patient must not have presence of concomitant active upper tract tumors or urethra tumors. History of previously adequately treated non-muscle invasive bladder cancer (NMIBC) are eligible; previously treated urothelial cancer or histological variant at any site outside of the urinary bladder are allowed, provided they have been Ta/T1/carcinoma in situ (CIS) and post treatment follow up imaging and endoscopic evaluation shows no evidence of disease
- Patients with previous exposure to immune checkpoint inhibitor for non-muscle invasive disease are eligible. If given for NMIBC, the last dose must have been completed > 12 months prior to registration
-
For patients registered on the study
- Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used
- All patients of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy
- A patient of childbearing potential is defined as any patient, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
-
For patients registered prior to induction chemotherapy only:
- Patients of childbearing potential and sexually active patients must not expect to conceive or father children by using accepted and effected method(s) of contraception or by abstaining from sexual intercourse from the time of registration for the duration of their participation in the study and continue for at least 3 months after the last dose of protocol treatment
- Leukocytes >= 3,000/mcL (obtained < 14 days prior to registration)
- Absolute neutrophil count >= 1,500/mcL (obtained < 14 days prior to registration)
- Hemoglobin >= 9 g/dL (obtained < 14 days prior to registration)
- Platelets >= 100,000/mcL (obtained < 14 days prior to registration)
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (obtained < 14 days prior to registration)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (obtained < 14 days prior to registration)
- Must have adequate renal function as evidenced by calculated (Cockcroft's formula) creatinine clearance or 24 hours actual creatinine clearance >= 30mL/min. The creatinine used to calculate the clearance result must have been obtained within 14 days prior to registration. Actual body weight, not ideal body weight, must be used in the calculation
- Patients with human immunodeficiency virus (HIV) on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial
- Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Site is encouraged to discuss with the study chair if needed prior to registration
- Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class IIB or better
- Step 2 (Randomization) Inclusion Criteria
- Patient must have an ECOG performance status of 0-2 at the time of randomization
- Patient must undergo selection of concurrent chemotherapy regimen
-
Patient must agree to undergo CT simulation and treatment planning within two days of randomization. If this is the first case registered at the site, then a pre-treatment radiation therapy (RT) review will be required and will take up to 3 business days. The patient cannot start radiation treatment prior to successful completion of this pre-treatment review. Therefore, careful planning is necessary to meet the deadline of starting radiation within 15 business days of randomization and within 12 weeks of the end of induction chemotherapy
- NOTE: Chemoradiotherapy should be planned to start up to 12 weeks after the end of induction chemotherapy, but after imaging and cystoscopic restaging, randomization, and any pretreatment radiation quality assurance (QA) that is required
-
Patients must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used
- All patients of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy
- A patient of childbearing potential is defined as any patient, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
- Patients of childbearing potential and/or sexually active patients must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse at least one week prior to the start of treatment and continue for at least 3 months after the last dose of the protocol treatment
- Leukocytes >= 3,000/mcL (obtained < 14 days prior to randomization)
- Absolute neutrophil count >= 1,500/mcL (obtained < 14 days prior to randomization)
- Hemoglobin >= 9 g/dL (obtained < 14 days prior to randomization)
- Platelets >= 100,000/mcL (obtained < 14 days prior to randomization)
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (obtained < 14 days prior to randomization)
- AST (SGOT)/ALT (SGPT) =< 2.5 x institutional ULN (obtained < 14 days prior to randomization)
- Must have adequate renal function as evidenced by calculated (Cockcroft's formula) creatinine clearance or 24 hours actual creatinine clearance >= 30 mL/min. The creatinine used to calculate the clearance result must have been obtained within 14 days prior to randomization. Actual body weight, not ideal body weight, must be used in the calculation
- Step 3 (Post chemoRT+/- MEDI4736 [durvalumab], prior to starting adjuvant MEDI4736 [durvalumab] versus [vs.] observation) Inclusion Criteria
- Patient must have evaluation to determine clinical outcome post chemoRT+/- MEDI4736 (durvalumab) with imaging and cystoscopy with biopsy confirmation to ensure no progression and absence of >= T2 disease in the bladder
- Patient must have achieved either complete clinical response OR have demonstrated clinical benefit prior to continuing onto adjuvant MEDI4736 (durvalumab)
- Patients who are to go on the adjuvant MEDI4736 (durvalumab) arm must have recovered to at least grade 2 or less immune related adverse events (AE) prior to starting treatment except for immune related alopecia, clinically asymptomatic endocrinopathies. For patients who may have gotten immune related AEs during chemoRT+ MEDI4736 (durvalumab), registration could be delayed up to additional 4 weeks to ensure recovery to at least grade 2 or lower prior to starting adjuvant therapy. However patients with MEDI4736 (durvalumab) related AEs that require permanent discontinuation of MEDI4736 (durvalumab) will not continue on the adjuvant treatment regardless of the response
- ANC >= 1,000 mcL (within 4 weeks of start of day 1 [D1] of adjuvant treatment)
- Hemoglobin >= 8 g/dL (within 4 weeks of start of D1 of adjuvant treatment)
- Platelets >= 70,000 mcL (within 4 weeks of start of D1 of adjuvant treatment)
- Patient on the chemoRT arm must have achieved either complete clinical response OR have demonstrated clinical benefit prior to be placed on the observation alone arm
Exclusion Criteria:
- Step 1 (Registration) Exclusion
- Patient must not have received any previous radiation therapy to the pelvic area
-
For patients with autoimmune conditions, patient must not have history of prior documented autoimmune disease within the past 2 years
- NOTE: Patient with vitiligo, Grave's disease, eczema or psoriasis (not requiring systemic treatment within the past 2 years) are not excluded. Patients with history of completely resolved childhood asthma or atopy are not excluded. Patients with asthma not requiring more than 10 mg/d or equivalent of prednisone are not excluded. Patients with well-controlled hypothyroidism on thyroxine replacement will be eligible as well. Patients with known history of hypoadrenalism on maintenance steroids will be eligible. Patients with type I diabetes mellitus will be eligible, provided their disease is well controlled. History of autoimmune related alopecia is also not an exclusion criteria
- Patient with active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) are not eligible
- Patient with a history of and/or confirmed pneumonitis will not be eligible
- Patient with a history of primary immunodeficiency will not be eligible
- Patient with history of allogeneic organ transplant are not eligible
- Patient must not have clinically significant liver disease that precludes patient from treatment regimens prescribed on the study (including, but not limited to, active viral, alcoholic or other autoimmune hepatitis, cirrhosis or inherited liver disease)
-
Patient must not have any unresolved toxicity (National Cancer Institute [NCI] CTCAE grade >= 2) from previous anti-cancer therapy with the exception of alopecia, vitiligo, and the laboratory values
- NOTE: Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study chair
- NOTE: Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with MEDI4736 (durvalumab) may be included only after consultation with the study chair. Documentation of correspondences with the study chair must be kept on file
- Step 2 (Randomization) Exclusion Criteria
-
Patient must have no signs of progression (CR/PR or SD) based on restaging imaging and cystoscopy after completion of induction chemotherapy, which consists of:
- Computed tomography (CT) chest, abdomen, or pelvis. Magnetic resonance imaging (MRI) pelvis can be used instead of CT per treating physician discretion. The imaging must be done within 4 weeks prior to randomization
- Cystoscopic evaluation and attempt to perform maximal transurethral resection of bladder tumor (TURBT) performed by the participating urologist ideally within 8 weeks but up to 10 weeks is allowed prior to randomization. If maximal TURBT is not possible for medical reasons, the enrollment must be discussed and approved with the study chair. Documentation of correspondences with the study chair must be kept on file
-
For patients with autoimmune conditions: Patient must not have a history of active or prior documented autoimmune disease within the past 2 years
- NOTE: Patient with vitiligo, Grave's disease, eczema or psoriasis (not requiring systemic treatment within the past 2 years) are not excluded. Patients with history of completely resolved childhood asthma or atopy are not excluded. Patients with asthma not requiring more than 10mg/d or equivalent of prednisone are not excluded. Patient with well-controlled hypothyroidism on thyroxine replacement will be eligible as well. Patients with known history of hypoadrenalism on maintenance steroids will be e
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04216290
Locations
Show 164 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Monika Joshi | ECOG-ACRIN Cancer Research Group |
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT04216290 |
| Other Study ID Numbers: |
NCI-2019-08628 NCI-2019-08628 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) EA8185 ( Other Identifier: ECOG-ACRIN Cancer Research Group ) EA8185 ( Other Identifier: CTEP ) U10CA180820 ( U.S. NIH Grant/Contract ) |
| First Posted: | January 2, 2020 Key Record Dates |
| Last Update Posted: | January 20, 2021 |
| Last Verified: | August 2020 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page. |
| URL: | https://grants.nih.gov/policy/sharing.htm |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
|
Urinary Bladder Neoplasms Urologic Neoplasms Urogenital Neoplasms Neoplasms by Site Neoplasms Urinary Bladder Diseases Urologic Diseases Gemcitabine Cisplatin Carboplatin Doxorubicin Liposomal doxorubicin Fluorouracil Methotrexate Durvalumab |
Mitomycins Mitomycin Vinblastine Immunoglobulins Antibodies, Monoclonal Immunoglobulin G Antineoplastic Agents Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Antiviral Agents Anti-Infective Agents Enzyme Inhibitors Immunosuppressive Agents Immunologic Factors |