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

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ClinicalTrials.gov Identifier: NCT02709889
Recruitment Status : Terminated (Strategic considerations)
First Posted : March 16, 2016
Results First Posted : October 19, 2020
Last Update Posted : October 19, 2020
Sponsor:
Information provided by (Responsible Party):
AbbVie

Tracking Information
First Submitted Date  ICMJE March 2, 2016
First Posted Date  ICMJE March 16, 2016
Results First Submitted Date  ICMJE August 11, 2020
Results First Posted Date  ICMJE October 19, 2020
Last Update Posted Date October 19, 2020
Actual Study Start Date  ICMJE September 23, 2016
Actual Primary Completion Date August 27, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 21, 2020)
Summary of Treatment-Emergent Adverse Events (TEAEs), by Dose and Neuroendocrine (NEC) or Non-NEC Disease Groups [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: March 10, 2016)
  • Maximum tolerated dose [ Time Frame: 1 year ]
  • Number of subjects with adverse events as a measure of safety and tolerability [ Time Frame: 1 year ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 21, 2020)
  • Objective Response Rate (ORR) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: Cycle 1: 0, 0.5, 6, 48, 168, 336, 672 hours postdose ]
  • Number of Participants With Anti-therapeutic Antibodies (ATA) [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 10, 2016)
  • Objective response rate [ Time Frame: Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 48 months. ]
  • Duration of response [ Time Frame: Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 48 months. ]
  • Progression free survival [ Time Frame: Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 48 months. ]
  • Overall survival [ Time Frame: Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 48 months. ]
  • Clinical benefit rate [ Time Frame: Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 48 months. ]
  • Maximum Plasma Concentration (Cmax) [ Time Frame: Cycles 1, 2 and 4: day 1 (pre-dose, 30 min post-dose, 6 hours post-dose), 3, 8, 15, 29; Cycles 3, 5 and above: day 1, 8, 15, 29; up to 1 year. ]
  • Area Under the Curve (AUC) [ Time Frame: Cycles 1, 2 and 4: day 1 (pre-dose, 30 min post-dose, 6 hours post-dose), 3, 8, 15, 29; Cycles 3, 5 and above: day 1, 8, 15, 29; up to 1 year. ]
  • Anti-therapeutic Antibodies (ATA) [ Time Frame: Cycles 1, 2 and 4: day 1 (pre-dose, 30 min post-dose, 6 hours post-dose), 3, 8, 15, 29; Cycles 3, 5 and above: day 1, 8, 15, 29; up to 1 year. ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Rovalpituzumab Tesirine in Delta-Like Protein 3-Expressing Advanced Solid Tumors
Official Title  ICMJE An Open-Label Study of Rovalpituzumab Tesirine in Subjects With Delta-Like Protein 3-Expressing Advanced Solid Tumors
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Malignant Melanoma
  • Medullary Thyroid Cancer
  • Glioblastoma
  • Large-Cell Neuroendocrine Carcinoma
  • Neuroendocrine Prostate Cancer
  • High Grade Gastroenteropancreatic Neuroendocrine Carcinoma
  • Other Neuroendocrine Carcinoma
  • Other Solid Tumors
Intervention  ICMJE
  • Drug: Rovalpituzumab tesirine
    Other Name: SC16LD6.5
  • Drug: Dexamethasone
    Dexamethasone will be provided through a participant's local prescription by Investigator or other provider (i.e., dexamethasone will not be provided by the Sponsor).
Study Arms  ICMJE Experimental: 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.
Interventions:
  • Drug: Rovalpituzumab tesirine
  • Drug: Dexamethasone
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: March 15, 2019)
200
Original Estimated Enrollment  ICMJE
 (submitted: March 10, 2016)
378
Actual Study Completion Date  ICMJE August 27, 2019
Actual Primary Completion Date August 27, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 99 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02709889
Other Study ID Numbers  ICMJE SCRX001-006
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Clinical Study Report (CSR)
Time Frame: Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered.
Access Criteria: Access to this clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). For more information on the process, or to submit a request, visit the following link.
URL: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html
Responsible Party AbbVie
Study Sponsor  ICMJE AbbVie
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: AbbVie Inc. AbbVie
PRS Account AbbVie
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP