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

Study Overview
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Brief Summary
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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
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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.

Official Title
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An Open-Label Study of Rovalpituzumab Tesirine in Subjects With Delta-Like Protein 3-Expressing Advanced Solid Tumors

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

Intervention / Treatment
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* Drug: Rovalpituzumab tesirine
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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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: Chemotherapy, small molecule inhibitors, radiation, and/or other investigational anticancer agents (excluding investigational monoclonal antibodies): 2 weeks. 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: 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. Known seropositivity for or active infection by human immunodeficiency virus (HIV). 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Rovalpituzumab Tesirine<br>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. | Drug: Rovalpituzumab tesirine<br> <br> * Other names: SC16LD6.5;Drug: Dexamethasone<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summary of Treatment-Emergent Adverse Events (TEAEs), by Dose and Neuroendocrine (NEC) or Non-NEC Disease Groups | 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. | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | 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. | Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 35.2 months. | 
| Clinical Benefit Rate (CBR) | 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). | Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 35.2 months. | 
| Duration of Response (DOR) | 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. | Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 35.2 months. | 
| Progression Free Survival (PFS) | 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. | Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 35.2 months. | 
| Overall Survival (OS) | 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. | Baseline, every 6 weeks until 6 months, then every 12 weeks until disease progression, assessed up to 35.2 months. | 
| 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) | Number of participants treated across each dose level reported to potentially have ATAs against rovalpituzumab tesirine at any time during the study. | Day 1 and 42 days after last dose. The overall mean number of 6-week treatment cycles was 1 (range 1.0, 5.0). |