Study of Sacituzumab Govitecan-hziy (IMMU-132) in Adults With Epithelial Cancer

Study Overview
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Brief Summary
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The primary objective in Phase I is to evaluate the safety and tolerability of sacituzumab govitecan-hziy (SG) as a single agent administered in 21-day treatment cycles in previously treated participants with advanced epithelial cancer. In Phase II, the primary objective is to evaluate the safety and efficacy of sacituzumab govitecan-hziy administered in 21-day treatment cycles at a dose selected in Phase I. Tumor types in the study will include: cervical, colorectal, endometrial, ovarian, esophageal, gastric adenocarcinoma, glioblastoma multiforme, head and neck cancers- squamous cell, hepatocellular, prostate, non-small-cell lung cancer, pancreatic, renal cell, small-cell lung cancer, non-triple negative breast cancer (non-TNBC), triple-negative breast cancer (TNBC) and metastatic urothelial cancer (mUC).

Detailed Description
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The outcome measures are planned to be assessed up to the data cutoff date. Following the data cutoff date, the participants will either stay on the study and will be followed for safety data collection or rolled into another Gilead-sponsored study. Therefore, only safety data will be collected after the data cutoff date.

Official Title
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A Phase I/II Study of IMMU-132 (hRS7-SN38 Antibody Drug Conjugate) in Patients With Epithelial Cancer

Conditions
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Gastric Adenocarcinoma, Esophageal Cancer, Hepatocellular Carcinoma, Non-small Cell Lung Cancer, Small Cell Lung Cancer, Ovarian Epithelial Cancer, Carcinoma Breast Stage IV, Hormone-refractory Prostate Cancer, Head and Neck Cancers- Squamous Cell, Renal Cell Cancer, Urinary Bladder Neoplasms, Cervical Cancer, Endometrial Cancer, Glioblastoma Multiforme, Triple Negative Breast Cancer, Pancreatic Cancer

Intervention / Treatment
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* Drug: Sacituzumab Govitecan-hziy (SG)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals able to understand and give written informed consent. Histologically or cytologically confirmed epithelial cancer of one of the following types: Gastric adenocarcinoma (GC) Esophageal cancer (EC) Hepatocellular carcinoma (HCC) Non-small-cell lung cancer (NSCLC) Small-cell lung cancer (SCLC) Epithelial ovarian cancer (EOC) Cervical Cancer Endometrial Cancer Triple-negative breast cancer (TNBC) Non-triple-negative breast cancer Papillary thyroid cancer (excludes follicular, medullary, Hurthle cell, and anaplastic thyroid cancer) Glioblastoma multiforme (GBM) Hormone-refractory prostate cancer (HRPC) Head and neck cancers- squamous cell (SCCHN) Renal cell cancer (clear cell) (RCC) Urothelial cancer Stage IV (metastatic) disease (except for individuals with GBM). Refractory to or relapsed after at least one prior standard therapeutic regimen Adequate performance status (ECOG 0 or 1) Expected survival ≥ 6 months. Measurable disease by CT or MRI. At least 2 weeks beyond treatment (chemotherapy, investigational drugs including small molecular inhibitors, immunotherapy and/or radiation therapy) or major surgery and recovered from all acute toxicities to Grade 1 or less (except alopecia). At least 2 weeks beyond high dose systemic corticosteroids (however, low dose corticosteroids < 20 mg prednisone or equivalent daily are permitted). Adequate hematology without ongoing transfusional support (hemoglobin > 9 g/dL, absolute neutrophil count (ANC) > 1,500 per mm^3, platelets > 100,000 per mm^3). Adequate renal and hepatic function (creatinine ≤ 2.0 x institutional upper limit of normal (IULN), bilirubin ≤ 1.5 IULN, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x IULN or 5 x IULN if know liver metastases). Otherwise, all toxicity at study entry ≤ Grade 1. Exclusion Criteria: Women who are pregnant or lactating. Women of childbearing potential and fertile men unwilling to use effective contraception during study until conclusion of 12-week post-treatment evaluation period. Individuals with Gilbert's disease. Individuals with brain metastases can be enrolled only if treated, non-progressive brain metastases and off high-dose steroids (> 20 mg prednisone or equivalent) for at least 4 weeks. Presence of bulky disease (defined as any single mass > 7 cm in its greatest dimension). Individuals with a mass over 7 cm, but otherwise eligible, may be considered for enrollment after discussion and approval with the medical monitor. Individuals with active ≥ grade 2 anorexia, nausea or vomiting, and/or signs of intestinal obstruction. Individuals with non-melanoma skin cancer or carcinoma in situ of the cervix are eligible, while individuals with other prior malignancies must have had at least a 3-year disease-free interval. Individuals known to be HIV positive, hepatitis B positive, or hepatitis C positive. Known history of unstable angina, MI, or CHF present within 6 months or clinically significant cardiac arrhythmia (other than stable atrial fibrillation) requiring anti-arrhythmia therapy. Known history of clinically significant active COPD, or other moderate-to-severe chronic respiratory illness present within 6 months. Prior history of clinically significant bleeding, intestinal obstruction, or GI perforation within 6 months of initiation of study treatment. Infection requiring intravenous antibiotic use within 1 week. History of an anaphylactic reaction to irinotecan or ≥ Grade 3 GI toxicity to prior irinotecan, Other concurrent medical or psychiatric conditions that, in the Investigator's opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations.

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sacituzumab Govitecan-hziy (SG) 8 mg/kg<br>Participants will receive sacituzumab govitecan-hziy (SG) 8 mg/kg of body weight via intravenous (IV) infusion on Days 1 and 8 of a 21-day treatment cycle until disease progression or unacceptable toxicity. | Drug: Sacituzumab Govitecan-hziy (SG)<br>* Administered via intravenous (IV) infusion<br>* Other names: IMMU-132;|
| Experimental: SG 10 mg/kg<br>Participants will receive SG 10 mg/kg of body weight via intravenous (IV) infusion on Days 1 and 8 of a 21-day treatment cycle until disease progression or unacceptable toxicity. | Drug: Sacituzumab Govitecan-hziy (SG)<br>* Administered via intravenous (IV) infusion<br>* Other names: IMMU-132;|
| Experimental: SG 12 mg/kg<br>Participants will receive SG 12 mg/kg of body weight via intravenous (IV) infusion on Days 1 and 8 of a 21-day treatment cycle until disease progression or unacceptable toxicity. | Drug: Sacituzumab Govitecan-hziy (SG)<br>* Administered via intravenous (IV) infusion<br>* Other names: IMMU-132;|
| Experimental: SG 18 mg/kg<br>Participants will receive SG 18 mg/kg of body weight via intravenous (IV) infusion on Days 1 and 8 of a 21-day treatment cycle until disease progression or unacceptable toxicity. | Drug: Sacituzumab Govitecan-hziy (SG)<br>* Administered via intravenous (IV) infusion<br>* Other names: IMMU-132;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Any Treatment Emergent Adverse Events and Serious Treatment Emergent Adverse Events | Treatment-emergent adverse events (TEAEs) were defined as any adverse events (AEs) that begin or worsen on or after the start of study drug through 30 days after the last dose of study drug. The severity was graded based on the National Cancer Institute's Common Terminology Criteria for Adverse Events Version 4.03. An AE that met one or more of the following outcomes was classified as serious: Fatal Life-threatening Disabling/incapacitating Results in hospitalization or prolongs a hospital stay A congenital abnormality Other important medical events may also be considered serious AEs if they may require medical or surgical intervention to prevent one of the outcomes listed above Per planned analysis, populations to be used for evaluation of this outcome measure were as follows: Triple Negative Breast Cancer (TNBC) Target Population, HR+/HER2- Metastatic Breast Cancer (mBC) Population, Metastatic Urothelial Cancer (mUC) Population, and Overall Safety Population. | First dose date up to last dose for data cutoff date of 01 March 2019 (maximum duration: 55.2 months) plus 30 days | 
| Percentage of Participants Who Permanently Discontinued Sacituzumab Govitecan-hziy (SG) Due to Any Adverse Events, Excluding Adverse Events Leading to Death | Per planned analysis, populations to be used for evaluation of this outcome measure were as follows: Triple Negative Breast Cancer (TNBC) Target Population, HR+/HER2- Metastatic Breast Cancer (mBC) Population, Metastatic Urothelial Cancer (mUC) Population, and Overall Safety Population (OSP). | First dose date up to last dose for data cutoff date of 01 March 2019 (maximum duration: 55.2 months) | 
| Percentage of Participants Who Required Dose Interruption Due to Any Adverse Events | Per planned analysis, populations to be used for evaluation of this outcome measure were as follows: Triple Negative Breast Cancer (TNBC) Target Population, HR+/HER2- Metastatic Breast Cancer (mBC) Population, Metastatic Urothelial Cancer (mUC) Population, and Overall Safety Population (OSP). | First dose date up to last dose for data cutoff date of 01 March 2019 (maximum duration: 55.2 months) | 
| Objective Response Rate (ORR) by Independent Central Review (ICR) | ORR was defined as the rate an overall best response of either complete response (CR) or partial response (PR) by ICR assessment according to RECIST1.1. CR was defined as the disappearance of all target lesions and reduction in short axis of any pathologic lymphnode to <10 mm. PR was defined as ≥ 30% decrease in the sum of diameters of target lesions, taking the baseline sum diameters. Per planned analysis, ORR by ICR was assessed for the TNBC Target Population only. | Up to data cutoff date of 01 March 2019 (maximum duration: 74 months) | 
| Objective Response Rate by Local Assessment | ORR was defined as the rate an overall best response of either complete response (CR) or partial response (PR) by local assessment. CR was defined as the disappearance of all target lesions and reduction in short axis of any pathologic lymphnode to <10 mm. PR was defined as ≥3 0% decrease in the sum of diameters of target lesions, taking the baseline sum diameters. Per planned analysis, ORR by Local Assessment was assessed for TNBC Target Population, HR+/HER2-mBC Population, and mUC Population. | Up to data cutoff date of 01 March 2019 (maximum duration: 74 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response by ICR | Duration of Response was defined as the duration of overall response measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Per planned analysis, ORR by ICR was assessed for the TNBC Target Population only. | Up to data cutoff date of 01 March 2019 (maximum duration: 74 months) | 
| Duration of Response by Local Assessment | Duration of Response was defined as the duration of overall response measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Per planned analysis, duration of response by local assessment was assessed for TNBC Target Population, HR+/HER2-mBC Population, and mUC Population. | Up to data cutoff date of 01 March 2019 (maximum duration: 74 months) | 
| Time to Response by ICR | Time to response was defined as the time from the first dose to the first documentation of response (PR or CR). Per planned analysis, time to response by ICR was assessed for the TNBC Target Population only. | Up to data cutoff date of 01 March 2019 (maximum duration: 74 months) | 
| Time to Response by Local Assessments | Time to response was defined as the time from the first dose to the first documentation of response (PR or CR). Per planned analysis, time to response by local assessment was assessed for TNBC Target Population, HR+/HER2-mBC Population, and mUC Population. | Up to data cutoff date of 01 March 2019 (maximum duration: 74 months) | 
| Clinical Benefit Rate (CBR) by Local Assessment | Clinical benefit rate (CR+PR+[stable disease (SD) ≥ 6 months]) is defined as those participants with best response as CR or PR or else SD with a duration of at least 6 months. SD for 6 months duration was defined as the time from the first dose to the first documentation of PD or to the last adequate response assessment prior to data cut-off date, whichever is earlier. Per planned analysis, CBR by local assessment was assessed for TNBC Target Population, HR+/HER2-mBC Population, and mUC Population. | Up to data cutoff date of 01 March 2019 (maximum duration: 74 months) | 
| Progression Free Survival (PFS) by Local Assessment | Progression-free survival (PFS) was defined as the interval from the first dose start date to the date of disease progression defined as documented progressive disease (PD) or death from any cause, whichever occurs first. Per planned analysis, PFS by local assessment was assessed for TNBC Target Population, HR+/HER2-mBC Population, and mUC Population. | Up to data cutoff date of 01 March 2019 (maximum duration: 74 months) | 
| Overall Survival by Local Assessment | Overall survival was defined as the time from the date of the first dose start date to the date of death due to any cause. Per planned analysis, overall survival by local assessment was assessed for TNBC Target Population, HR+/HER2-mBC Population, and mUC Population. | Up to data cutoff date of 01 March 2019 (maximum duration: 74 months) | 
| Pharmacokinetic (PK) Parameter: T1/2 of Total Antibody, SN-38 Glucuronide, Total SN-38, Sacituzumab Govitecan-hziy, and Free SN-38 | T1/2 was determined for 5 analytes: total antibody, SN-38 glucuronide, total SN-38, free SN-38, and sacituzumab govitecan-hziy, a derived antibody drug conjugate (ADC) concentration. SN-38 is one of the components of sacituzumab govitecan-hziy. T1/2 is defined as apparent terminal elimination half-life (h); calculated as 0.693/λz. The dose level evaluated for PK analysis was 10 mg/kg. | Cycle 1: Preinfusion, 30 minutes and 3-4 hours post infusion, then 1 day, 2 days, 3 days, and 7 days later (1 Cycle = 21 days). Infusion duration: 3 hours (± 30 minutes) for 1st infusion; 1-2 hours (± 30 minutes) for subsequent infusions | 
| PK Parameter: AUC0-24 of Total Antibody, SN-38 Glucuronide, Total SN-38, Sacituzumab Govitecan-hziy, and Free SN-38 | AUC0-24 was determined for 5 analytes: total antibody, SN-38 glucuronide, total SN-38, free SN-38, and sacituzumab govitecan-hziy, a derived antibody drug conjugate (ADC) concentration. SN-38 is one of the components of sacituzumab govitecan-hziy. AUC0-24 is defined as area under the serum concentration-time curve from time 0 to 24 hours. The dose level evaluated for PK analysis was 10 mg/kg. | Cycle 1: Preinfusion, 30 minutes and 3-4 hours post infusion, then 1 day, 2 days, 3 days, and 7 days later (1 Cycle = 21 days). Infusion duration: 3 hours (± 30 minutes) for 1st infusion; 1-2 hour (± 30 minutes) for subsequent infusions | 
| PK Parameter: AUC0-168 of Total Antibody, SN-38 Glucuronide, Total SN-38, Sacituzumab Govitecan-hziy, and Free SN-38 | AUC0-168 was determined for 5 analytes: total antibody, SN-38 glucuronide, total SN-38, free SN-38, and sacituzumab govitecan-hziy, a derived antibody drug conjugate (ADC) concentration. SN-38 is one of the components of sacituzumab govitecan-hziy. AUC0-168 is defined as area under the serum concentration-time curve from time 0 to 168 hours. The dose level evaluated for PK analysis was 10 mg/kg. | Cycle 1: Preinfusion, 30 minutes and 3-4 hours post infusion, then 1 day, 2 days, 3 days, and 7 days later (1 Cycle = 21 days). Infusion duration: 3 hours (± 30 minutes) for 1st infusion; 1-2 hour (± 30 minutes) for subsequent infusions | 
| PK Parameter: AUC0-inf of Total Antibody, SN-38 Glucuronide, Total SN-38, Sacituzumab Govitecan-hziy, and Free SN-38 | AUC0-inf was determined for 5 analytes: total antibody, SN-38 glucuronide, total SN-38, free SN-38, and sacituzumab govitecan-hziy, a derived antibody drug conjugate (ADC) concentration. SN-38 is one of the components of sacituzumab govitecan-hziy. AUC0-inf is defined as area under the serum concentration-time curve from time 0 extrapolated to infinity. The dose level evaluated for PK analysis was 10 mg/kg. | Cycle 1: Preinfusion, 30 minutes and 3-4 hours post infusion, then 1 day, 2 days, 3 days, and 7 days later (1 Cycle = 21 days). Infusion duration: 3 hours (± 30 minutes) for 1st infusion; 1-2 hour (± 30 minutes) for subsequent infusions | 
| PK Parameter: Cmax of Total Antibody, SN-38 Glucuronide, Total SN-38, Sacituzumab Govitecan-hziy, and Free SN-38 | Cmax was determined for 5 analytes: total antibody, SN-38 glucuronide, total SN-38, free SN-38, and sacituzumab govitecan-hziy, a derived antibody drug conjugate (ADC) concentration. SN-38 is one of the components of sacituzumab govitecan-hziy. Cmax is defined as maximum observed serum concentration obtained directly from the observed concentration-time data. The dose level evaluated for PK analysis was 10 mg/kg. | Cycle 1: Preinfusion, 30 minutes and 3-4 hours post infusion, then 1 day, 2 days, 3 days, and 7 days later (1 Cycle = 21 days). Infusion duration: 3 hours (± 30 minutes) for 1st infusion; 1-2 hour (± 30 minutes) for subsequent infusions |