An Open-label, Single-Arm, Phase 2 Study Evaluating the Efficacy, Safety and Pharmacokinetics of Rovalpituzumab Tesirine (SC16LD6.5) for Third-line and Later Treatment of Subjects with Relapsed or Refractory Delta-Like Protein 3-Expressing Small Cell Lung Cancer (TRINITY)
- Clements University Hospital
David Gerber, M.D.
This is an open-label, single-arm, phase 2 study of rovalpituzumab tesirine in DLL3-expressing SCLC subjects with relapsed or refractory disease after receiving at least 2 previous regimens, including at least one platinum-based regimen. only subjects with tumor cell expression based on an immunohistochemistry (iHC) assay specification will be enrolled. enrollment will continue until up to approximately 123 DLL3 high, third-line subjects are treated. enrollment will be carried out in two stages. Stage 1: up to 60 evaluable, DLL3 high (per iHC assay specification), subjects may be enrolled. if among the 60 evaluable, DLL3 high (per iHC assay specification) subjects, more than 9 subjects achieve complete response or partial response, then enrollment will continue to Stage 2. at least 63 additional subjects that are DLL3 high will be enrolled in Stage 2. otherwise enrollment will terminate. of the enrolled DLL3 positive subjects, less than or equal to 30% can be fourth-line or later.
all enrolled subjects will receive 0.3 mg/kg rovalpituzumab tesirine intravenously (iV) on Day 1 of every six-week treatment cycle for two cycles. an additional two cycles of rovalpituzumab tesirine (retreatment) is permitted for subjects who tolerated their initial two doses of rovalpituzumab tesirine, achieved clinical benefit as defined by stable disease or better, have received no other systemic anti-cancer therapy after rovalpituzumab tesirine as administered per this protocol, and with central radiographic assessment-confirmed disease progression at least 12 weeks after the second dose. additional retreatment, beyond a total of four cycles will require approval from the Medical Monitor.
all subjects in the long-term follow-up will continue disease assessments every 6 weeks for 6 months, then every 12 weeks thereafter. Subjects will be followed until disease progression per ReCiST (v 1.1) or initiation of new anticancer treatment, whichever occurs first will afterwards be followed for survival until death or study termination, whichever occurs first.
Blood samples for PK, immunogenicity, biomarker and pharmacodynamics assessments will be collected at protocol-defined time points to support the study endpoints.
The primary efficacy endpoints of the study will be the best objective response rate at the end of treatment assessment (42 (+-) 3 days after last dose) and overall survival. Safety will be assessed by pre- and post-treatment measurements of vital signs and clinical laboratory assessments, and through the recording of adverse clinical events. PK and cytokine data will be collected at select sites only.
-Primary efficacy endpoints
This study has two co-primary endpoints:
* objective response rate through the end of Treatment (42 (+-) 3 days after last dose) for subjects with an iHC assessment that is [GreaterThanorequalTo] 50% positive and for subjects with an iHC assessment that is [GreaterThanorequalTo] 1% positive
* overall survival for subjects with an iHC assessment that is [GreaterThanorequalTo] 50% positive and for subjects with an iHC assessment that is [GreaterThanorequalTo] 1% positive
-Secondary efficacy endpoints
* Duration of response
* Clinical Benefit Rate
* Progression-free survival
Safety assessments include physical exam, vital signs, body weight, eCoG score, clinical adverse events, laboratory tests (hematology, serum chemistries, urinalysis, and coagulation), eCGs, echocardiogram, fluid retention questionnaire, and monitoring of concomitant therapies.
-Pharmacokinetics, Biomarker and Pharmacodynamic endpoints
Pharmacokinetic assessments will include blood samples for rovalpituzumab tesirine and anti-therapeutic antibodies (aTas).
Pharmacodynamic and biomarker assessments will include analyses of tumor tissue for DLL3 expression, and of blood samples for tumor markers, circulating tumor cells, and soluble biomarkers such as soluble DLL3.
1. Adult aged 18 years or older
2. Histologically confirmed small-cell lung cancer (SCLC) with documented disease progression after at least 2 prior systemic regimens, including at least one platinum-based regimen
3. DLL3-expressing SCLC based on central immunohistochemistry (IHC) assessment of banked or otherwise representative tumor tissue. Positive is defined as staining in >= 1% of tumor cells.
4. Measurable disease, defined as at least 1 tumor lesion >=10 mm in the longest diameter or a lymph node >=15 mm in short-axis measurement assessed by CT scan (RECIST v1.1)
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. See Appendix 12.2 for conversion of performance status using Karnofsky scales, if applicable
6. Minimum life expectancy of at least 12 weeks
7. Subjects with a history of central nervous system (CNS) metastases must have documentation of stable or improved status based on 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
8. Recovery to Grade 1 of any clinically significant toxicity (excluding alopecia) prior to initiation of study drug administration
9. Satisfactory laboratory parameters:
a. Absolute neutrophil count (ANC) >= 1,500/microliters
b. Platelet count >= 75,000/microliters
c. Hemoglobin >= 8.0 g/dL
d. Serum total bilirubin <= 1.5X upper limit of normal (ULN) or <= 3X ULN for subjects with Gilbert[Single Quote]s disease
e. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <=2.5X ULN (<= 5X ULN if evidence of hepatic involvement by malignant disease)
f. Serum creatinine <= 1.5X ULN or estimated glomerular filtration rate (eGFR) >= 30 mL/min/1.73m^2 as calculated by the 4-variable Modification of Diet in Renal Disease (MDRD) study equation (GFR (mL/min/1.73 m^2) = 175 x (serum creatinine [mg/dL])-1.154 x (age [years])-0.203 x 0.742 (if female) x 1.212 (if African American))
10. Last dose of any prior therapy administered by the following time intervals before the first dose of study drug:
a. Chemotherapy, small molecule inhibitors, radiation, and/or other investigational anticancer agents (excluding investigational monoclonal antibodies): 2 weeks
b. Immune-checkpoint inhibitors (i.e., anti-PD-1, anti-PD-L1, or anti-CTLA-4): 4 weeks
c. Other monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or T-cell or other cell-based therapies: 4 weeks (2 weeks with documented disease progression)
11. Females of childbearing potential must have a negative beta human chorionic gonadotropin ([BETA]-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.
12. Females of childbearing potential and males who have partners of childbearing potential must agree to use an effective contraception method during the study and for 1 year following the last dose of study drug. Effective birth control includes (a) intrauterine device (IUD) plus 1 barrier method; or (b) 2 barrier methods. Effective barrier methods include male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm).