A Phase II Trial of Atezolizumab Plus Chemotherapy After Progression on PD-1 or PD-L1 Inhibitor in Cisplatin-ineligible Patients With Advanced Urothelial Carcinoma: HCRN GU17-295
Overview
- Phase
- Phase 2
- Intervention
- Carboplatin
- Conditions
- Urothelial Carcinoma
- Sponsor
- Nabil Adra
- Enrollment
- 6
- Locations
- 4
- Primary Endpoint
- Progression Free Survival (PFS)
- Status
- Terminated
- Last Updated
- 2 years ago
Overview
Brief Summary
This is a single arm phase II study assessing the activity of atezolizumab in combination with carboplatin + gemcitabine or docetaxel compared to historical controls of chemotherapy only in metastatic or recurrent urothelial carcinoma subjects. Subjects that received a PD 1 or PD-L1 inhibitor with no prior platinum chemotherapy for metastatic disease will be treated with atezolizumab + carboplatin + gemcitabine on trial. Subjects that received sequential or concurrent PD1/PDL1 inhibitor and carboplatin-based regimen will be treated with atezolizumab + docetaxel on trial.
Investigators
Nabil Adra
Sponsor-Investigator
Hoosier Cancer Research Network
Eligibility Criteria
Inclusion Criteria
- •Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
- •Age ≥ 18 years at the time of consent.
- •ECOG Performance Status of 0-2 within 28 days prior to registration.
- •Histological or cytological confirmed metastatic or unresectable locally advanced urothelial carcinoma (primary tumor: renal pelvis, ureters, urinary bladder, or urethra).
- •Patients with mixed histologies are eligible.
- •Cisplatin ineligible at the time of diagnosis with metastatic urothelial carcinoma based on consensus definition with any of the following criteria: ECOG PS 2, creatinine clearance \< 60mL/min, CTCAE v4 grade ≥ 2 hearing loss, CTCAE v4 grade ≥ 2 peripheral neuropathy, New York Heart Association (NYHA) class ≥ 3 heart failure.
- •Measurable disease according to RECIST 1.1 within 28 days prior to registration.
- •Must have had progressive metastatic disease after previous treatment with PD-1 or PD-L1 inhibitor (in the adjuvant or metastatic setting). Treatment regimen will be determined based on prior treatment:
- •PD1 or PDL1 inhibitor with no prior platinum chemotherapy for metastatic disease. These patients should be treated with atezolizumab + carboplatin + gemcitabine on trial.
- •Sequential or concurrent PD1/PDL1 inhibitor and carboplatin-based regimen. These patients should be treated with atezolizumab + docetaxel on trial.
Exclusion Criteria
- •Previous autoimmune complication from PD-1 or PD-L1 inhibitor requiring permanent discontinuation of therapy.
- •Previous permanent discontinuation from PD-1 or PD-L1 inhibitor due to an adverse event (patients who had temporary holds or discontinuation of PD-1 or PD-L1 inhibitor and then re-treated are eligible).
- •Any serious or uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy.
- •Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
- •Has a known additional malignancy that is progressing or required treatment ≤ 48 months of study registration. Exceptions: include malignancies with negligible risk of metastasis or death treated with expected curative outcome or undergoing surveillance per investigator's discretion (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, ductal carcinoma in situ treated surgically with curative intent, or very low risk or low risk prostate cancer per NCCN guidelines).
- •Active central nervous system (CNS) metastases. Subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression within 28 days prior to the first dose of atezolizumab administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (\> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
- •Treatment with any investigational drug within 30 days prior to registration.
- •Subjects with an active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids/immunosuppressive medications EXCEPT for syndromes which would not be expected to recur in the absence of an external trigger. (Subjects with vitiligo, autoimmune thyroiditis, or type I diabetes mellitus are permitted to enroll.).
- •As there is potential for hepatic toxicity with atezolizumab, drugs with a predisposition to hepatoxicity should be used with caution in subjects treated with atezolizumab-containing regimen.
- •Subjects should be excluded if they have known history of testing positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. Testing is not required.
Arms & Interventions
Chemotherapy and Atezolizumab
Subjects that received a PD 1 or PD-L1 inhibitor with no prior platinum chemotherapy for metastatic disease will be treated with atezolizumab + carboplatin + gemcitabine on trial. Subjects that received sequential or concurrent PD1/PDL1 inhibitor and carboplatin-based regimen will be treated with atezolizumab + docetaxel on trial.
Intervention: Carboplatin
Chemotherapy and Atezolizumab
Subjects that received a PD 1 or PD-L1 inhibitor with no prior platinum chemotherapy for metastatic disease will be treated with atezolizumab + carboplatin + gemcitabine on trial. Subjects that received sequential or concurrent PD1/PDL1 inhibitor and carboplatin-based regimen will be treated with atezolizumab + docetaxel on trial.
Intervention: Gemcitabine
Chemotherapy and Atezolizumab
Subjects that received a PD 1 or PD-L1 inhibitor with no prior platinum chemotherapy for metastatic disease will be treated with atezolizumab + carboplatin + gemcitabine on trial. Subjects that received sequential or concurrent PD1/PDL1 inhibitor and carboplatin-based regimen will be treated with atezolizumab + docetaxel on trial.
Intervention: Atezolizumab
Chemotherapy and Atezolizumab
Subjects that received a PD 1 or PD-L1 inhibitor with no prior platinum chemotherapy for metastatic disease will be treated with atezolizumab + carboplatin + gemcitabine on trial. Subjects that received sequential or concurrent PD1/PDL1 inhibitor and carboplatin-based regimen will be treated with atezolizumab + docetaxel on trial.
Intervention: Docetaxel
Outcomes
Primary Outcomes
Progression Free Survival (PFS)
Time Frame: From C1D1 until progression or death or up to a maximum of 26 months
Evaluate PFS among patients to be treated with atezolizumab in combination with carboplatin + gemcitabine or docetaxel, who have cisplatin-ineligible metastatic urothelial carcinoma and who have progressed on prior PD-1 or PD-L1 inhibitor. PFS defined as duration from date of treatment start until progression according to RECIST 1.1 criteria, or death from any cause. Per RECIST 1.1 criteria, Progressive disease can be defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions.
Secondary Outcomes
- Objective Response Rate (ORR) With irRECIST(From C1D1 until death or up to a maximum of 28 months.)
- Objective Response Rate (ORR) With RECIST 1.1(From C1D1 until death or up to a maximum of 28 months.)
- Overall Survival (OS)(From C1D1 until death or up to a maximum of 28 months)
- Clinical Benefit Rate (CBR) With RECIST 1.1(From C1D1 until death or up to a maximum of 28 months.)
- Clinical Benefit Rate (CBR) With irRECIST(From C1D1 until death or up to a maximum of 28 months.)
- Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Carboplatin + Gemcitabine or Docetaxel(From C1D1 until death or up to a maximum of 8 months)
- PFS by irRECIST(From C1D1 until progression or death or up to a maximum of 26 months)
- Progression Free Survival (PFS) Compared to Historical Controls(From C1D1 until progression or death or up to a maximum of 26 months)
- Progression Free Survival (PFS) for Atezolizumab + Carboplatin and Gemcitabine(From C1D1 until death or progression or up to a maximum of 26 months)
- Progression Free Survival (PFS) for Atezolizumab + Docetaxel(From C1D1 until progression or death)