A Phase I Study Evaluating the Safety and Efficacy of SGI-110 Followed by Combined Durvalumab Plus Tremelimumab in Subjects With Extensive-stage Small Cell Lung Cancer (ES-SCLC)

Catherine Shu1 site in 1 country2 target enrollmentDecember 15, 2017

ConditionsExtensive-stage Small Cell Lung Cancer

InterventionsDurvalumab Tremelimumab SGI-110

Overview

Phase: Phase 1
Intervention: Durvalumab
Conditions: Extensive-stage Small Cell Lung Cancer
Sponsor: Catherine Shu
Enrollment: 2
Locations: 1
Primary Endpoint: Maximum tolerated dose (MTD) of SGI-110
Status: Completed
Last Updated: 7 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

The purpose of this study is to determine if a combination of investigational agents is safe to give to people with small cell lung cancer (SCLC) after standard chemotherapy has been attempted. Subjects enrolled in this trial will receive 3 investigational drugs: SGI-110 (guadecitabine), durvalumab (MEDI4736) and tremelimumab.

Detailed Description

SCLC accounts for approximately 15% of new cases of lung cancer, and an estimated 33,000 cases are expected to be diagnosed in the United States in 2016. Compared to NSCLC, SCLC typically has a more rapid doubling time, a higher growth fraction, and earlier development of distant metastases. Patients with limited stage (LS) disease are treated with curative intent using definitive, concurrent chemotherapy and thoracic radiotherapy. For patients with extensive stage (ES) disease, systemic chemotherapy can prolong survival in most cases, however long-term survival is rare. Despite the activity of several agents in SCLC, an etoposide plus platinum (i.e. cisplatin) doublet regimen remains the standard of care in the first-line setting because of its higher activity compared to other chemotherapy regimens, as well as the ease of combining it with radiation. Initial response rates may be as high as 70-90% in LS-SCLC and 50-70% in ES-SCLC. However, the disease typically recurs rapidly which is reflected by median survival rates of 9 to 11 months for ES-SCLC and a 2-year survival rate of less than 5%. This study has a 3 + 3 design that will be used to assess the safety of SGI-110 given prior to flat doses of durvalumab (1500 mg) and tremelimumab (75 mg). The starting dose of SGI-110 will be 30 mg/m2 (dose level 0) and the target dose that is predicted to be safe and most effective will be 45 mg/m2 (dose level 1). These doses have been chosen based on safety and efficacy data from phase 1 clinical trials in other solid tumors, as described above. Patients enrolled in any given dose level will be evaluated for safety (adverse events monitoring) and efficacy. There will be mandatory pre- and on-treatment tumor biopsies performed in alternating fashion on cycle 1 day 8 +/- 2 days or cycle 2 day 8 +/- 2 days. The dose-limiting toxicity (DLT) observation period will last for 4 weeks (28 days) and ends on C2D1. Delayed serious immune-mediated adverse events will also be monitored but will not be considered dose limiting toxicities.

Registry

clinicaltrials.gov

Start Date

December 15, 2017

End Date

November 26, 2018

Last Updated

7 years ago

Study Type

Interventional

Study Design

Single Group

Sex

All

Investigators

Sponsor

Catherine Shu

Responsible Party

Sponsor Investigator

Principal Investigator

Catherine Shu

Assistant Professor of Medicine

Columbia University

Eligibility Criteria

Inclusion Criteria

•For inclusion in the study, patients should fulfill the following criteria:
•Written informed consent and any locally-required authorization (e.g., HIPAA in the USA, EU Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
•Age ≥ 18 years at time of study entry
•Eastern Cooperative Oncology Group (ECOG performance status of 0 or 1)
•Life expectancy of ≥ 12 weeks
•Adequate normal organ and marrow function as defined below Hemoglobin ≥ 9.0 g/dL Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (\> 1500 per mm3) Platelet count ≥ 100 x 109/L (\>100,000 per mm3) Serum total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (for patients with a diagnosis of Gilbert's syndrome, direct bilirubin ≤ 1.5 x ULN) AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤ 5x ULN
•Serum creatinine CL\>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:
•Creatinine CL (mL/min) = Weight (kg) x (140 - Age) . 72 x serum creatinine (mg/dL)
•Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL)
•Females of childbearing potential who are sexually active with a non-sterilized male partner must use a highly effective method of contraception from the time of screening, and must agree to continue using such precautions for 180 days after the final dose of investigational product. Cessation of contraception after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Female subjects must also refrain from egg cell donation for 180 days after the final dose of investigational product.

Exclusion Criteria

•Subjects should not enter the study if any of the following exclusion criteria are fulfilled:
•Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
•Previous enrollment in the present study.
•Participation in another clinical study with an investigational product during the last 4 weeks.
•Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA4, including tremelimumab
•Any previous treatment with a hypomethylating agent, including decitabine, azacitidine, or SGI-
•History of another primary malignancy except for:
•Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of study drug and of low potential risk for recurrence
•Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
•Adequately treated carcinoma in situ without evidence of disease e.g., cervical cancer in situ

Arms & Interventions

Treatment

Subjects with ES-SCLC, progressive after platinum-based first-line chemotherapy will receive SGI-110 followed by combined durvalumab plus tremelimumab. 1. Dose escalation phase: 6-12 patients 2. MTD expansion cohort: 10 patients

Intervention: Durvalumab