Rovalpituzumab Tesirine (SC16LD6.5) in Recurrent Small Cell Lung Cancer
Phase I/II Open Label Dose Escalation Study of the Safety, Pharmacokinetics, and Preliminary Efficacy of SC16LD6.5 as a Single Agent in Patients With Recurrent Small Cell Lung Cancer
The purpose of this study is to assess the safety and tolerability of rovalpituzumab tesirine (SC16LD6.5) at different dose levels in patients with small cell lung cancer whose cancer has progressed or recurred following standard chemotherapy. Once a safe and tolerable dose is determined, the anti-cancer activity of SC16LD6.5 will be assessed by measuring the extent of tumor shrinkage. SC16LD6.5 is an antibody-drug conjugate (ADC). The antibody (SC16) targets a protein that appears to be expressed on the surface of most small cell lung cancers that have been assessed using an immunohistochemical assay. The drug, D6.5, is a very potent form of chemotherapy, specifically a DNA-damaging agent, that is cell cycle independent. ADC's theoretically provide more precise delivery of chemotherapy to cancer cells, possibly improving effectiveness relative to toxicities.
Rovalpituzumab tesirine will be administered as a single agent, at increasing dose levels as permitted based on real-time assessment of safety and tolerability, intravenously over 30 minutes. Doses will be repeated on Day 1 of each 21-day or 42-day cycle until either unacceptable toxicity or evidence of disease progression occurs.
Inclusion Criteria Provision of informed consent Male or female ≥18 years of age Histologic or cytologic confirmed diagnosis of small cell lung cancer, either limited or extensive disease at initial presentation is allowed Evidence of progressive disease during or following 1 or 2 prior chemotherapy regimens At least 1 prior regimen must have contained a platinum salt 'Adjuvant therapy' will constitute a prior treatment regimen No more than 2 prior regimens are allowed Measurable disease (only for the phase II portion) Eastern Cooperative Oncology Group (ECOG) Performance status 0-1 A minimum life expectancy of 12 weeks Adequate bone marrow, hepatic and renal function as evidenced by: Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Platelet count ≥ 100 x 109/L Hemoglobin ≥ 9.0 g/dL Serum bilirubin < 1.5 x ULN Aspartate aminotransferase (AST)/Alanine transferase (ALT) (SGOT/SGPT) < 2.5 x ULN for the reference laboratory or < 5 x ULN in the presence of liver metastases Serum creatinine < 1.5 x ULN No 'active' CNS metastases. Prior CNS metastases are allowed, provided adequate palliative therapy has been administered and CNS disease control has been established prior to study entry. • A brain MRI scan, ≤ 28 days from day 1, is required Female patients who are not of child-bearing potential, and female patients of child-bearing potential who agree to use adequate contraceptive measures and who have a negative serum pregnancy test within 1 week prior to initial study treatment. (See Appendix B) Male patients willing to use adequate contraceptive. (See Appendix B) At least 21 days must have elapsed prior to day 1 cycle 1, from chemotherapy, radiotherapy, immunotherapy or following major surgery and any surgical incision should be completely healed. At least 14 days must have elapsed prior to Day 1 Cycle 1 for "limited palliative radiotherapy", defined as a course of therapy encompassing < 25% total bone marrow volume and not exceeding 30 Gy. At least 14 days must have elapsed for chemotherapy regimens, biologic, and targeted therapy given continuously or on a weekly basis with limited potential for delayed toxicity. Exclusion Criteria: Patients who are pregnant or breastfeeding. Active involvement of the Central Nervous System (CNS). Uncontrolled infection or systemic disease. Clinically significant cardiac disease not well controlled with medication (e.g., congestive heart failure, symptomatic coronary artery disease e.g. angina, and cardiac arrhythmias) or myocardial infarction within the last 12 months. Chemotherapy regimens within the last 21 days (or within 6 weeks for prior nitrosourea or mitomycin C). Chemotherapy regimens, biologic, and targeted therapy given continuously or on a weekly basis with limited potential for delayed toxicity within the last 14 days. No concurrent systemic chemotherapy or anticancer biologic therapy is allowed. Note: Patients on hormonal treatment for breast cancer or prostate cancer may continue on treatment and enter into study. Known hypersensitivity to any components of SC16LD6.5 study drug product. Patients with known human immunodeficiency virus (HIV) or Hepatitis B or C (active, previously treated or both), a history of solid organ or bone marrow transplantation would generally be considered to have met exclusion criteria, however exceptions may be considered on a case-by-case basis by the medical monitor. Psychiatric disorder or social or geographic situation that would preclude study participation. QT interval measurement corrected by Fridericia's formula (QTcF) interval of >450 msec (males) or >470 msec (females)
|Event Type||Organ System||Event Term||Phase 1a: Cohort 1 (SCLC)||Phase 1a: Cohort 2 (SCLC)||Phase 1a: Cohort 3 (SCLC)||Phase 1a: Cohort 4 (SCLC)||Phase 1a: Cohort 5 (SCLC)||Phase 1a: Cohort 6 (SCLC)||Phase 1a: Cohort 7 (SCLC)||Phase 1a: Cohort 8 (SCLC)||Phase 1a: Cohort 8 (LCNEC)||Phase 1b: Retreatment (SCLC)||Phase 1b: Retreatment (LCNEC)||Phase 1b: Maintenance (SCLC)||Phase 1b: Maintenance (LCNEC)|
MTD was determined by testing increasing doses from 0.05 mg/kg up to 0.8 mg/kg on Day 1 of every 21-day or 42-day cycle, Phase 1a cohorts 1 to 8. MTD will be defined as the dose level immediately below the dose level at which ≥ 2 of the first 3 subjects per cohort (or ≥ 2 of 6 subjects) during the first cycle experience a study drug related dose limiting toxicity (DLT).
Overall response was assessed at each visit post-baseline based on a subject's lesion measurements or assessments (complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD], or not evaluable as defined by RECIST v1.1, plus an additional category of early death). The best overall response was then determined. A subject was defined as having an objective response if they had a best overall response of CR or PR prior to receiving any subsequent anticancer therapy; confirmed response is confirmation of CR or PR at least 4 weeks from the initial determination per RECIST v1.1. Subjects with a post-baseline assessment were included in the calculations for objective response rate (ORR). Outcome is based on data reported by Investigator (INV); available and evaluable radiographic scans were collected retrospectively for review by an Independent Review Committee (IRC).
Duration of response (DOR) was defined as the number of months from the initial CR or PR to the time of disease progression or death, whichever occurred first. Outcome is based on data reported by Investigator (INV); available and evaluable radiographic scans were collected retrospectively for review by an Independent Review Committee (IRC).
Clinical Benefit is defined as a subject with best Overall Response of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) prior to receiving any subsequent anticancer therapy; as defined by RECIST version 1.1. CBR is defined as the proportion of subjects with Clinical Benefit based on assessment of overall response. CBR will be presented as a number and percentage with 95% confidence bounds. Any subjects not exhibiting a response (CR or PR or SD) are considered non-responders. Outcome is based on data reported by Investigator (INV); available and evaluable radiographic scans were collected retrospectively for review by an Independent Review Committee (IRC).
Progression-free survival (PFS) was defined as the number of months from the first day of study drug administration to disease recurrence or progression, or death on study. Outcome is based on data reported by Investigator (INV); available and evaluable radiographic scans were collected retrospectively for review by an Independent Review Committee (IRC).
The maximum serum concentration (Cmax; measured in μg/mL) is the highest concentration that a drug achieves in the blood after administration in a dosing cycle.
Overall survival (OS) was defined as the time from the first day of study treatment to death. Subjects who were alive were censored at the date of last known alive.
The area under the serum concentration-time curve (AUC; measured in μg•d/mL) is a method of measurement to determine the total exposure of a drug in blood serum.