Trial of Atezolizumab Plus Chemotherapy After Progression on PD-1 or PD-L1 in Cisplatin-ineligible Patients With Advanced Urothelial Carcinoma

NCT03737123 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: GU17-295
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 4

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.

Conditions

Urothelial Carcinoma

Outcome Measures

Primary Outcomes (1)

• Progression Free Survival (PFS)

  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.

  From C1D1 until progression or death or up to a maximum of 26 months

Secondary Outcomes (10)

• 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

• Objective Response Rate (ORR) With RECIST 1.1

  From C1D1 until death or up to a maximum of 28 months.

• Objective Response Rate (ORR) With irRECIST

  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.

Study Arms (1)

Chemotherapy and Atezolizumab

EXPERIMENTAL

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.

Drug: Carboplatin; Drug: Gemcitabine; Drug: Atezolizumab; Drug: Docetaxel

Interventions

Carboplatin DRUG

Carboplatin AUC 4 IV Day 1 of each 21 day cycle

Also known as: paraplatin

Chemotherapy and Atezolizumab

Gemcitabine DRUG

Gemcitabine 1,000 mg/m2 IV Day 1 and Day 8 of each 21 day cycle

Also known as: Gemzar

Chemotherapy and Atezolizumab

Atezolizumab DRUG

Atezolizumab 1,200 mg IV Day 1 of each 21 day cycle

Also known as: Tecentriq

Chemotherapy and Atezolizumab

Docetaxel DRUG

Docetaxel 75 mg/m2 IV Day 1 of each 21 day Cycle.

Also known as: Taxotere

Chemotherapy and Atezolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• A subject with prior brain metastasis may be considered if they have completed their treatment for brain metastasis at least 4 weeks prior to study registration, have been off of corticosteroids for ≥ 2 weeks, and are asymptomatic.
• Previous neoadjuvant or adjuvant chemotherapy that was completed 6 months prior to study enrollment is allowed.
• REQUIRED archival tumor tissue (prior to treatment with single agent PD-1 or PD-L1 inhibitor) must be identified prior to registration and obtained during the screening period. Confirmation of acquisition should occur prior to C1D1 treatment. Unavailability of tissue will render the subject ineligible for study. Biopsy should be excisional, incisional or core needle. Fine needle aspiration is insufficient. Sample requirement is FFPE block + 1 H\&E stained slide or 25 unstained slides + 1 H\&E stained slide.
• Demonstrate adequate organ function as defined in the table below. All screening labs to be obtained within 28 days prior to registration.
• White blood cell (WBC) ≥ 2 k/mm3

You may not qualify if:

• 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.
• Subjects should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Testing is not required.
• History of allergy to atezolizumab or respective chemotherapy regimen (carboplatin + gemcitabine or docetaxel).

Sponsors & Collaborators

• Nabil Adra: lead
• Genentech, Inc.: collaborator
• Indiana University School of Medicine: collaborator

Study Sites (4)

Indiana University Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, 46202, United States

Location

Nebraska Methodist Hosptial

Omaha, Nebraska, 68114, United States

Location

University of New Mexico Comprehensive Cancer Center

Albuquerque, New Mexico, 87102, United States

Location

University of Cincinnati Cancer Institute

Cincinnati, Ohio, 45267, United States

Location

MeSH Terms

Conditions

Carcinoma, Transitional Cell

Interventions

Carboplatin; Gemcitabine; atezolizumab; Docetaxel

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes

Results Point of Contact

• Title: Annesha Majumdar
• Organization: Hoosier Cancer Research Network

amajumdar@hoosiercancer.org

3179212050

Study Officials

• Nabil Adra, MD

  Indiana University Melvin and Bren Simon Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor-Investigator

Study Record Dates

• First Submitted: November 8, 2018
• First Posted: November 9, 2018
• Study Start: December 19, 2018
• Primary Completion: March 8, 2022
• Study Completion: May 18, 2022
• Last Updated: September 13, 2023
• Results First Posted: September 13, 2023

Record last verified: 2023-08

Locations

US (4)