Clinical trial NCT02709889: Rovalpituzumab Tesirine in Delta-Like Protein 3-Expressing Advanced Solid Tumors
Official title: An Open-Label Study of Rovalpituzumab Tesirine in Subjects With Delta-Like Protein 3-Expressing Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
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
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
First posted: 2016-03-16
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Summary of Treatment-Emergent Adverse Events (TEAEs), by Dose and Neuroendocrine (NEC) or Non-NEC Disease Groups
timeFrame: 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).
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 35.2 months.
measure: Clinical Benefit Rate (CBR)
timeFrame: Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 35.2 months.
measure: Duration of Response (DOR)
timeFrame: Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 35.2 months.
measure: Progression Free Survival (PFS)
timeFrame: Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 35.2 months.
measure: Overall Survival (OS)
timeFrame: Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 35.2 months.
measure: Serum Concentrations of Rovalpituzumab Tesirine Over Time
timeFrame: Cycle 1: 0, 0.5, 6, 48, 168, 336, 672 hours postdose
measure: Number of Participants With Anti-therapeutic Antibodies (ATA)
timeFrame: Day 1 and 42 days after last dose. The overall mean number of 6-week treatment cycles was 1 (range 1.0, 5.0).
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Ctr /ID# 155424
state: Arizona
city: Scottsdale
country: United States
facility: Mayo Clinic - Scottsdale /ID# 155419
state: Arizona
city: Los Angeles
country: United States
facility: University of California, Los Angeles /ID# 155429
state: California
city: San Francisco
country: United States
facility: Univ California, San Francisco /ID# 155409
state: California
city: West Hollywood
country: United States
facility: Cedars-Sinai Medical Center - West Hollywood /ID# 155428
state: California
city: Aurora
country: United States
facility: Univ of Colorado Cancer Center /ID# 155415
state: Colorado
city: Denver
country: United States
facility: Sarah Cannon Research Institute at HealthONE - Denver /ID# 155420
state: Colorado
city: Gainesville
country: United States
facility: University of Florida - Archer /ID# 155414
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center /ID# 170220
state: Florida
city: Atlanta
country: United States
facility: Emory University Hospital /ID# 155417
state: Georgia
city: Lexington
country: United States
facility: University of Kentucky Chandler Medical Center /ID# 155423
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins University /ID# 155412
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital /ID# 155411
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute /ID# 171044
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic - Rochester /ID# 155416
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University-School of Medicine /ID# 155425
state: Missouri
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of NJ /ID# 162010
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico /ID# 205054
state: New Mexico
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center /ID# 162015
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College /ID# 155418
state: New York
city: Durham
country: United States
facility: Duke University Medical Center /ID# 155421
state: North Carolina
city: Cleveland
country: United States
facility: Univ Hosp Cleveland /ID# 155410
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University /ID# 162011
state: Oregon
city: Greenville
country: United States
facility: Greenville Hospital System /ID# 155427
state: South Carolina
city: Dallas
country: United States
facility: Mary Crowley Cancer Research /ID# 162014
state: Texas
city: Fort Worth
country: United States
facility: Texas Oncology - Forth Worth /ID# 162045
state: Texas
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center /ID# 155413
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah /ID# 155426
state: Utah
city: Fairfax
country: United States
facility: Virginia Cancer Specialists /ID# 162006
state: Virginia
city: Vancouver
country: United States
facility: Northwest Cancer Specialists, P.C. /ID# 155431
state: Washington
Study officials:
affiliation: AbbVie
name: AbbVie Inc.
role: STUDY_DIRECTOR
References:
citation: Xie H, Kaye FJ, Isse K, Sun Y, Ramoth J, French DM, Flotte TJ, Luo Y, Saunders LR, Mansfield AS. Delta-Like Protein 3 Expression and Targeting in Merkel Cell Carcinoma. Oncologist. 2020 Sep;25(9):810-817. doi: 10.1634/theoncologist.2019-0877. Epub 2020 May 14.