Atezolizumab With or Without Bevacizumab in Cisplatin-ineligible Patients

Urothelial Carcinoma Clinical Trial

Official title:

A Randomized Phase II Trial of Atezolizumab With or Without Bevacizumab in Cisplatin-ineligible Patients With Advanced/Unresectable Urothelial Cancer

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03133390
• Other study ID #: 16-01918
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: September 1, 2017
• Est. completion date: January 2020

Study information

• Verified date: February 2019
• Source: New York University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a randomized phase II study assessing the activity of bevacizumab combined with atezolizumab compared to atezolizumab alone in metastatic urothelial carcinoma subjects who are ineligible for cisplatin-based therapy. Eligible subjects will be randomized to receive treatment with either (Arm A) atezolizumab 1200 mg (flat dose) IV plus bevacizumab 15 mg/kg IV every 21 days versus (Arm B) atezolizumab 1200 mg (flat dose) IV monotherapy every 21 days. Cross-sectional imaging will be performed every 9 weeks on therapy for the first 12 months and then every 12 weeks thereafter to assess for response.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 2
• Est. completion date: January 2020
• Est. primary completion date: July 9, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• ECOG Performance Status of 0, 1 or 2 within 28 days prior to randomization.

• Histological or cytological evidence urothelial (transitional cell) carcinoma of the renal pelvis, ureter, bladder or urethra.

• Locally advanced/unresectable disease as determined by site attending urologic oncologist or metastatic disease.

• Evaluable untreated tumor tissue for biomarker analysis (25 unstained slides or FFPE tissue block). Untreated tumor tissue is defined as no intervening intravesical or systemic therapy since acquisition. Subjects without tissue available must be willing and safe to undergo biopsy repeat biopsy (core needle or excisional) prior to enrollment.

• Willing to undergo a core needle or excisional biopsy on-treatment. Subjects will be assessed at the time of biopsy for safety of undergoing the procedure.

• Measurable disease according to RECIST v1.1 within 28 days prior to randomization.

• No prior chemotherapy for locally advanced or metastatic urothelial cancer.

• Perioperative chemotherapy previously administered in the neoadjuvant and/or adjuvant setting is permitted.

• Prior chemotherapy administered in the context of chemoradiation as definitive treatment for bladder preservation is also permitted, provided that disease progression outside the prior radiotherapy field is demonstrated histologically or cytologically.

• Ineligible for cisplatin as defined by presence of one or more of the following:

• Impaired renal function (GFR = 30 but = 60 cc/min). GFR should be assessed by direct measurement (i.e. creatinine clearance or ethylenediaminetetra-acetate) or, if not available, by calculation from serum/plasma creatinine by Cockroft-Gault equation.

• Grade = 2 Hearing Loss (measured by loss of >25 dB at two contiguous frequencies in at least one ear)

• Grade = 2 peripheral neuropathy

• ECOG Performance Status of 2

• Solitary Kidney

• If palliative radiotherapy administered, completion of palliative radiation therapy must be = 2 weeks prior to Cycle 1 Day 1 of protocol therapy

• Demonstrate adequate organ function as defined in the table below.

• Females of childbearing potential must have a negative serum pregnancy test within 28 days prior to registration.

Exclusion Criteria:

• Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 3 weeks prior to initiation of study treatment; the following exceptions are allowed:

• Palliative radiotherapy for bone metastases or soft tissue lesions should be completed > 7 days prior to baseline imaging

• Hormone-replacement therapy or oral contraceptives

• Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to enrollment

• Active or untreated CNS metastases as determined by CT or MRI evaluation during screening and prior radiographic assessments.

• Subjects with treated asymptomatic CNS metastases are eligible, provided they meet all of the following criteria:

• Evaluable or measurable disease outside the CNS

• No metastases to midbrain, pons, medulla, cerebellum, or within 10 mm of the optic apparatus (optic nerves and chiasm)

• No history of intracranial or spinal cord hemorrhage

• No evidence of significant vasogenic edema

• No ongoing requirement for dexamethasone as therapy for CNS disease; anticonvulsants at a stable dose allowed

• No stereotactic radiation, whole-brain radiation within 4 weeks prior to Cycle 1 Day 1

• Subjects with CNS metastases treated by neurosurgical resection or brain biopsy within 3 months prior to Cycle 1, Day 1 will be excluded.

• Radiographic demonstration of interim stability (i.e., no progression) between the completion of CNS-directed therapy and the screening radiographic study

• Screening CNS radiographic study = 4 weeks since completion of radiotherapy or surgical resection and = 2 weeks since discontinuation of corticosteroids

• Leptomeningeal disease

• Uncontrolled tumor-related pain

• Subjects requiring pain medication must be on a stable regimen at study entry.

• Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or metastases causing nerve impingement) should be treated prior to enrollment.

• Asymptomatic metastatic lesions whose further growth would likely cause functional deficits or intractable pain (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to enrollment.

• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)

• Subjects with indwelling drainage catheters are allowed.

• Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab.

• Subjects who are receiving bisphosphonate therapy or denosumab specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible.

• Subjects who are receiving denosumab prior to enrollment must be willing and eligible to receive a bisphosphonate instead while in the study.

• Malignancies other than urothelial cancer within 5 years prior to Cycle 1 Day 1, with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent) or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (T1/T2a, Gleason score = 3 + 4, and PSA = 0.5 ng/mL undergoing active surveillance and treatment naive).

• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).

• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

• Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab or bevacizumab formulation

• History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, granulomatosis with polyangiitis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. (see Appendix 2 for a more comprehensive list of autoimmune diseases)

• Subjects with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study.

• Subjects with controlled Type I diabetes mellitus on a stable dose of insulin regimen may be eligible for this study.

• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan

• History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

• History of confirmed positive test for HIV

• Subjects with active hepatitis B virus (HBV) (chronic or acute, defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C virus (HCV)

• Subjects with past HBV infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBc Ab] and absence of HBsAg) are eligible.

• Subjects positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

• Active tuberculosis

• Severe infections within 4 weeks prior to Cycle 1 Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia

• Signs or symptoms of active infection within 2 weeks prior to Cycle 1 Day 1

• Received therapeutic oral or IV antibiotics within 1 week prior to Cycle 1 Day 1

• Subjects receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or to prevent chronic obstructive pulmonary disease exacerbation) are eligible.

• Significant cardiovascular disease, such as:

• New York Heart Association Congestive Heart Failure Class II or greater

• Myocardial infarction, unstable angina or unstable arrhythmias within 3 months of enrollment.

• History of stroke or TIA within 3 months of enrollment

• Other clinically significant arterial vascular disease within 6 months of enrollment (e.g. aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis). Prior history of adequately treated venous thromboembolism > 7 days prior to C1D1 on stable dose of therapeutic anticoagulation is permitted

• Subjects with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate.

• Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1 Day 1 or anticipation of need for a major surgical procedure during the course of the study

• Prior allogeneic stem cell or solid organ transplant

• Administration of a live, attenuated vaccine within 4 weeks before Cycle 1 Day 1 or anticipation that such a live attenuated vaccine will be required during the study

• Influenza vaccination should be given during influenza season only (approximately October to March). Subjects must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to Cycle 1 Day 1 or at any time during the study.

• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the subject at high risk from treatment complications

Atezolizumab-Specific Exclusion Criteria:

• Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies.

• Prior cancer vaccines and cellular immunotherapy are permitted.

• Treatment with systemic immunostimulatory agents (including but not limited to IFNs, interleukin [IL]-2) within 6 weeks or five half-lives of the drug, whichever is shorter, prior to Cycle 1 Day 1

• Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1 Day 1, or anticipated requirement for systemic immunosuppressive medications during the trial

• Subjects who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled.

• The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids (i.e., for adrenal insufficiency), and mineralocorticoids (e.g., fludrocortisone for adrenal insufficiency) is allowed.

Bevacizumab-Specific Exclusion Criteria:

• Inadequately controlled hypertension (defined as persistent systolic blood pressure (SBP) > 150 and/or diastolic blood pressure (DBP) > 100 mmHg)

• Prior history of hypertensive crisis or hypertensive encephalopathy

• Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)

• Current or recent (within 10 days of study enrolment) use of aspirin (> 325 mg/day), clopidogrel (> 75 mg/day), or current or recent (within 10 days prior to first dose of bevacizumab) use of therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes

• NOTE: The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to the medical standard of the institution) and the subject has been on a stable dose of anticoagulants for at least two weeks at the time of study enrollment. Prophylactic use of anticoagulants is allowed.

• History of hemoptysis (= 1/2 teaspoon of bright red blood per episode) within 1 month of study enrollment.

• Minor surgical procedure within 7 calendar days prior to Cycle 1 Day 1

• History of abdominal or tracheoesophageal fistula or gastrointestinal perforation within 6 months prior to enrollment

• Clinical signs or symptoms of gastrointestinal obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding

• Evidence of abdominal free air not explained by paracentesis or recent surgical procedure

• Serious non-healing or dehiscing wound, active ulcer, or untreated or non-healing bone fracture

• On-going gross hematuria associated with clots

Related Conditions & MeSH terms

• Carcinoma, Transitional Cell
• Urothelial Carcinoma

Intervention

Drug:
• Atezolizumab 1200 mg
1200 mg (flat dose) in 250 mL normal saline (NS) Intravenously (IV); 3 weeks (21 days)
• Bevacizumab 15 mg/kg IV
Bevacizumab 15 mg/kg1 in normal saline (NS) Intravenously (IV); 3 weeks (21 days)

Locations

Country	Name	City	State
United States	New York University School of Medicine	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
New York University School of Medicine

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival	Overall survival will be defined as the time from randomization until death by any cause, and will be analyzed using the Kaplan Meier method. At the time of analysis, if a subject has not died, the subject will be censored on the date of last follow-up.	21 Days
Secondary	Objective Response Rate (ORR)	Objective response rate is defined as the proportion of subjects achieving either partial response or complete response by RECIST v1.1.	21 Days
Secondary	Duration of Response (DoR)	Duration of response is defined as the period measured from the time that measurement criteria are met for complete or partial response (whichever status is recorded first) until the date that recurrent or progressive disease is objectively documented. DoR will be reported as an estimate of the median with range for each treatment arm and unstratified survival analysis will be applied.	21 Days
Secondary	Disease Control Rate (ORR + SD)	The disease control rate is the proportion of all subjects with stable disease (SD) or partial response (PR), or complete response (CR) according to RECIST 1.1, from the start of treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the start of treatment).	21 Days
Secondary	Progression-Free Survival (PFS)	Progression-Free survival will be defined as the time from the date of randomization until the criteria for disease progression is met as defined by RECIST 1.1 or death occurs. Subjects who have not progressed nor died at the time of last follow up will be censored at the date of the last disease evaluation.	21 Days