Rovalpituzumab Tesirine in Delta-Like Protein 3-Expressing Advanced Solid Tumors

Phase 1

Terminated

Conditions: Malignant Melanoma
Medullary Thyroid Cancer
Glioblastoma
Large-Cell Neuroendocrine Carcinoma
Neuroendocrine Prostate Cancer
High Grade Gastroenteropancreatic Neuroendocrine Carcinoma
Other Neuroendocrine Carcinoma
Other Solid Tumors

Interventions: Drug: Rovalpituzumab tesirine
Drug: Dexamethasone

Registration Number: NCT02709889

Lead Sponsor: AbbVie

Brief Summary: The primary objective of this study is to assess the safety and tolerability of rovalpituzumab tesirine in subjects with specific delta-like protein 3-expressing advanced solid tumors.

Detailed Description: This is a multicenter, open-label study involving multiple specific advanced solid tumor types, consisting of a dose escalation part A followed by an expansion part B. Cancer subtypes will be studied in separate disease-specific cohorts in both Parts. Eight separate cohorts will enroll malignant melanoma, medullary thyroid cancer (MTC), glioblastoma, large cell neuroendocrine carcinoma (LCNEC), neuroendocrine prostate cancer (NEPC), high-grade gastroenteropancreatic neuroendocrine carcinoma (GEP NEC), other NEC, and solid tumors other than the above.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 200

Inclusion Criteria

Histologically confirmed, unresectable advanced solid malignancy with documented disease progression after at least 1 prior systemic therapy
Disease is relapsed/refractory to prior standard systemic therapy or for which standard or curative therapy does not exist or is not considered appropriate by the Investigator.
Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Delta-like protein 3 (DLL3)-expressing malignancy based on central immunohistochemical (IHC) testing of representative baseline tumor tissue (archived tissue or on-study biopsy). Positive is defined as staining in ≥ 1% of tumor cells.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Minimum life expectancy of at least 12 weeks
Subjects with a history of central nervous system (CNS) metastases must have documentation of stable or improved brain imaging for at least 2 weeks after completion of definitive treatment and within 2 weeks prior to first dose of Study Drug, off or on a stable dose of corticosteroids. Definitive treatment may include surgical resection, whole brain irradiation, and/or stereotactic radiation therapy. (Applicable to tumor types of non-CNS primary origin only)
Recovery to Grade 1 of any clinically significant toxicity (excluding alopecia) prior to initiation of study drug administration
Adequate hematologic and organ function as confirmed by laboratory values
Last dose of any prior therapy administered by the following time intervals before the first dose of study drug:
1. Chemotherapy, small molecule inhibitors, radiation, and/or other investigational anticancer agents (excluding investigational monoclonal antibodies): 2 weeks.
2. Immune-checkpoint inhibitors (e.g., anti-programmed death protein 1 [PD-1], anti-programmed death-ligand 1 [PD-L1], or anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]), monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or T-cell or other cell-based therapies: 4 weeks (2 weeks with documented disease progression).
Females of childbearing potential must have a negative beta human chorionic gonadotropin (β-hCG) pregnancy test result within 7 days prior to the first dose of study drug. Females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy.

Exclusion Criteria

Any significant medical condition, including any suggested by screening laboratory findings that, in the opinion of the investigator or sponsor, may place the subject at undue risk from the study, including but not necessarily limited to uncontrolled hypertension and/or diabetes, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease requiring hospitalization within 3 months) or neurological disorder (e.g., seizure disorder active within 3 months).
Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class III-IV within 6 months prior to their first dose of study drug.
Recent or ongoing serious infection, including:
1. Any active grade 3 or higher (per National Cancer Institute Common Terminology Criteria for Adverse Events version [NCI CTCAE] 4.03) viral, bacterial, or fungal infection within 2 weeks of the first dose of the study drug. Routine antimicrobial prophylaxis is permitted.
2. Known seropositivity for or active infection by human immunodeficiency virus (HIV).
3. Active Hepatitis B (by surface antigen expression or polymerase chain reaction) or C (by polymerase chain reaction) infection or on hepatitis-related antiviral therapy within 6 months of first dose of study drug.
Women who are pregnant or breastfeeding
Systemic therapy with corticosteroids at >20 mg/day prednisone or equivalent within 1 week prior to the first dose of study drug
History of another invasive malignancy that has not been in remission for at least 3 years. Exceptions to the 3year limit include non-melanoma skin cancer, curatively treated localized prostate cancer, ductal carcinoma in situ, and cervical cancer in situ on biopsy or squamous intraepithelial lesion on pap smear.
Prior exposure to a pyrrolobenzodiazepine (PBD)-based drug, prior participation in a rovalpituzumab tesirine clinical trial, or known hypersensitivity to rovalpituzumab tesirine or excipient contained in the drug formulation, unless undergoing retreatment with rovalpituzumab tesirine in the context of this protocol

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Rovalpituzumab Tesirine	Rovalpituzumab tesirine	Rovalpituzumab tesirine 0.2-0.4 mg/kg administered intravenously on Day 1 of each 6-week cycle. Dexamethasone 8 mg administered orally twice daily on Day -1, Day 1 (the day of dosing), and Day 2 of each 6-week cycle.
Rovalpituzumab Tesirine	Dexamethasone	Rovalpituzumab tesirine 0.2-0.4 mg/kg administered intravenously on Day 1 of each 6-week cycle. Dexamethasone 8 mg administered orally twice daily on Day -1, Day 1 (the day of dosing), and Day 2 of each 6-week cycle.

Primary Outcome Measures

Name	Time	Method
Summary of Treatment-Emergent Adverse Events (TEAEs), by Dose and Neuroendocrine (NEC) or Non-NEC Disease Groups	From first dose of study drug through 30 days after last dose. The overall mean number of 6-week treatment cycles was 1 (range 1.0, 5.0).	The number of participants with TEAEs, serious TEAEs, study drug-related TEAEs, and study drug discontinuations or dose reductions due to TEAEs, summarized by dose received and neuroendocrine (NEC) or non-NEC disease groups. An adverse event (AE) is defined as any untoward medical occurrence which does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) is any untoward medical occurrence that at any dose: is fatal or life-threatening; results in death or hospitalization; is disabling/incapacitating or a congenital anomaly/birth defect; is medically significant. AE severity was graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03 terminology: grade 1=mild; grade 2=moderate; grade 3=severe; grade 4 life-threatening; grade 5=death. TEAEs were defined as AEs that were newly occurring or worsened following study treatment.

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 35.2 months.	ORR is defined as percentage of participants whose best overall response was either complete response (CR) or partial response (PR), according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. PR: A ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Clinical Benefit Rate (CBR)	Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 35.2 months.	CBR is defined as the percentage of participants with best overall response (confirmed or unconfirmed) of CR, PR or stable disease (SD) per RECIST v1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. PR: A ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressed disease (PD), taking as reference the smallest sum diameters while on study. SD criteria must have met at least once after study entry at a minimum interval of 42 days (-7 days to allow for scheduled visit window per the protocol).
Duration of Response (DOR)	Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 35.2 months.	DOR is defined as the time from the first assessment on therapy of a CR or PR response (per RECIST v1.1) to the date of progressive disease or death. CR: Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. PR: A ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants who did not have progression were censored at the last non-missing response assessment on-therapy or baseline. Based on Kaplan-Meier estimates.
Progression Free Survival (PFS)	Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 35.2 months.	PFS is defined as the time from the first dose date to the date of disease progression or death. Participants who did not have progression or death are censored at the last non-missing response assessment on-therapy or baseline. Based on Kaplan-Meier estimates.
Overall Survival (OS)	Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 35.2 months.	Overall survival is defined as the time from the first dose date to death for any reason. Subjects who were alive at the clinical data cut-off are censored at the last known alive date. Based on Kaplan-Meier estimates.
Serum Concentrations of Rovalpituzumab Tesirine Over Time	Cycle 1: 0, 0.5, 6, 48, 168, 336, 672 hours postdose
Number of Participants With Anti-therapeutic Antibodies (ATA)	Day 1 and 42 days after last dose. The overall mean number of 6-week treatment cycles was 1 (range 1.0, 5.0).	Number of participants treated across each dose level reported to potentially have ATAs against rovalpituzumab tesirine at any time during the study.

Trial Locations

Locations (30): Johns Hopkins University /ID# 155412
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Baltimore, Maryland, United States
Virginia Cancer Specialists /ID# 162006
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Fairfax, Virginia, United States
Rutgers Cancer Institute of NJ /ID# 162010
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New Brunswick, New Jersey, United States
Cedars-Sinai Medical Center - West Hollywood /ID# 155428
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West Hollywood, California, United States
Weill Cornell Medical College /ID# 155418
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New York, New York, United States
Banner MD Anderson Cancer Ctr /ID# 155424
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Gilbert, Arizona, United States
Mayo Clinic - Scottsdale /ID# 155419
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Scottsdale, Arizona, United States
University of California, Los Angeles /ID# 155429
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Los Angeles, California, United States
University of Kentucky Chandler Medical Center /ID# 155423
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Lexington, Kentucky, United States
University of Florida - Archer /ID# 155414
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Gainesville, Florida, United States
University of New Mexico /ID# 205054
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Albuquerque, New Mexico, United States
Greenville Hospital System /ID# 155427
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Greenville, South Carolina, United States
Mary Crowley Cancer Research /ID# 162014
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Dallas, Texas, United States
Texas Oncology - Forth Worth /ID# 162045
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Fort Worth, Texas, United States
Northwest Cancer Specialists, P.C. /ID# 155431
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Vancouver, Washington, United States
Washington University-School of Medicine /ID# 155425
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Saint Louis, Missouri, United States
Roswell Park Comprehensive Cancer Center /ID# 162015
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Buffalo, New York, United States
Sarah Cannon Research Institute at HealthONE - Denver /ID# 155420
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Denver, Colorado, United States
Univ California, San Francisco /ID# 155409
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San Francisco, California, United States
Univ of Colorado Cancer Center /ID# 155415
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Aurora, Colorado, United States
Moffitt Cancer Center /ID# 170220
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Tampa, Florida, United States
Dana-Farber Cancer Institute /ID# 171044
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Boston, Massachusetts, United States
Duke University Medical Center /ID# 155421
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Durham, North Carolina, United States
Oregon Health and Science University /ID# 162011
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Portland, Oregon, United States
Emory University Hospital /ID# 155417
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Atlanta, Georgia, United States
Massachusetts General Hospital /ID# 155411
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Boston, Massachusetts, United States
Univ Hosp Cleveland /ID# 155410
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Cleveland, Ohio, United States
Mayo Clinic - Rochester /ID# 155416
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Rochester, Minnesota, United States
University of Utah /ID# 155426
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Salt Lake City, Utah, United States
University of Texas MD Anderson Cancer Center /ID# 155413
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Houston, Texas, United States