Abraxane With Anti-PD1/PDL1 in Patients With Advanced Urothelial Cancer

Study Overview
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Brief Summary
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This is a phase 2, single arm, two-stage study of abraxane with an anti-PD1/PDL1 (pembrolizumab) in cisplatin-ineligible patients with advanced urothelial cancer. Each cycle last 21-days. All subjects will receive pembrolizumab via IV on day 1, and abraxane via IV on Day 1 and Day 8 of each cycle. Subjects may continue to receive the study regimen until they experience disease progression or unacceptable toxicity.

Official Title
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ABLE: Phase II, Single Arm, Two-stage Study of Abraxane With Anti-PD1/PDL1 in Patients With Advanced Urothelial Cancer

Conditions
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Urothelial Carcinoma

Intervention / Treatment
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* Drug: Pembrolizumab
* Drug: Abraxane


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with recurrent unresectable locally advanced or metastatic urothelial carcinoma (aka transitional cell carcinoma). Patients may be either cisplatin-ineligible or platinum-refractory. Histological or cytologically proven urothelial carcinoma. Have measurable disease based on RECIST 1.1 Has urothelial cancer that is not suitable for local therapy administered with curative intent if not already administered. Must have recovered (i.e., AE <= Grade 1 or stable) from AEs due to a previously administered agent. ECOG Performance Status of 0, 1 or 2. (Eastern Cooperative Oncology Group Performance Status: an attempt to quantify cancer patients' general well-being and activities of daily life. The score ranges from 0 to 5 where 0 is asymptomatic and 5 is death.) Prior neoadjuvant or adjuvant systemic therapy or local intravesical chemotherapy or immunotherapy is permitted. Adequate organ and marrow function Women of child-bearing potential must either commit to true abstinence or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting IP therapy, and while on study medication or for a longer period if required by local regulations following the last dose of IP; and have a negative serum pregnancy test result at screening Male subjects must practice true abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for 6 months following drug discontinuation, even if he has undergone a successful vasectomy. Patients must have < Grade 2 pre-existing peripheral neuropathy Be ≥18 years of age as of date of signing informed consent Voluntarily agree to participate by providing written informed consent/assent for the trial Exclusion Criteria: Prior exposure to immune-mediated therapy History of allogenic organ transplantation that requires ongoing use of immunosuppressive agents is NOT permitted Active or prior documented autoimmune or inflammatory disorders are NOT permitted Current or prior use of immunosuppressive medication(s) within 14 days before study treatment is NOT permitted. Brain metastases or spinal cord compression are NOT permitted unless they have been treated with the patient's condition being stable clinically and radiologically for 28 calendar days and off steroids for at least 14 days prior to the start of study treatment. Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) is NOT permitted. Receipt of live attenuated vaccine within 30 days prior to the first study treatment is NOT permitted. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 28 calendar days of the first dose of treatment. CTCAE Grade > 1 peripheral neuropathy is NOT permitted If subjects received major surgery they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting trial therapy Has a known additional malignancy that is progressing or requires active treatment Has a history of severe hypersensitivity reaction to nab-paclitaxel or anti-PD1/PDL1 Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial Pregnancies: Females: nab-paclitaxel can cause harm to an unborn child if given to a pregnant woman. Females may not take part in this study if pregnant or breast-feeding for 6 months after last dose of study drug. Males: Male subjects should avoid fathering a child while receiving study medication and for 6 months after the last dose of study medication. Males must agree to complete abstinence from heterosexual contact or use a condom during sexual contact with a female of child bearing potential while receiving study medication and within 6 months after last dose of study medication. Subjects (both males and female) should practice effective contraception during study and for 6 months after the last dose of study medication (Section 3.1.8 i, ii). Patients with biliary obstruction or biliary stent are excluded.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab and Abraxane<br>Pembrolizumab 200mg IV D1 Abraxane 100mg/m^2 IV D1 and D8 21 Day Cycles | Drug: Pembrolizumab<br>* 200mg IV D1<br>Drug: Abraxane<br>* 100mg/m^2 D1 and D8<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients that respond to treatment | The Overall Response Rate (ORR) will be the percentage of patients that achieve either complete response (CR) or partial response (PR). CR is defined as the disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions. PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. There can be no appearance of new lesions. | 24 months post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response | The duration of response (DOR) is measured from the time that response (PR or CR) criteria are met until the first date that recurrent or progressive disease is objectively documented. CR is defined as the disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions. PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. There can be no appearance of new lesions. | 24 months post treatment | 
| Progression free survival time | Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of progression or death. Progressive disease (PD) is defined as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions. | 24 months post treatment | 
| Median number of patients alive at 12 and 24 months | Overall survival will be documented as the median number of patients alive at 12 and 24 months. | 12 and 24 months post treatment | 
| Median duration of therapy |  | 24 months post treatment | 
| Percentage of patients that completely respond to treatment | The percentage of patients that achieve complete response to treatment. Complete response is defined as the disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions. | 24 months post treatment |