Guadecitabine, Durvalumab, and Tremelimumab in Treating Patients with Extensive-Stage Small Cell Lung Cancer

Status: Active

Description

This phase I trial studies the side effects and best dose of guadecitabine and to see how well it works with durvalumab and tremelimumab in treating patients with extensive-stage small cell lung cancer. Drugs used in chemotherapy, such as guadecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as durvalumab and tremelimumab, may interfere with the ability of tumor cells to grow and spread. Giving guadecitabine together with durvalumab and tremelimumab may work better in treating patients with extensive-stage small cell lung cancer.

Eligibility Criteria

Inclusion Criteria

  • Written informed consent and any locally-required authorization (e.g., Health Insurance Portability and Accountability Act [HIPAA] in the United States of America [USA], European Union [EU] Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
  • Eastern Cooperative Oncology Group (ECOG performance status of 0 or 1)
  • Life expectancy of >= 12 weeks
  • Hemoglobin >= 9.0 g/dL
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (>= 1500 per mm^3)
  • Platelet count >= 100 x 10^9/L (>= 100,000 per mm^3)
  • 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)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be =< 5 x ULN
  • Serum creatinine clearance (CL) > 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
  • 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 * Females of childbearing potential are defined as those who are not surgically sterile (i.e. bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or those who are not postmenopausal (defined as 12 months with no menses with postmenopausal gonadotropin levels [luteinizing hormone and follicle-stimulating hormone], or estradiol levels within the postmenopausal range according to local guidelines without an alternative medical cause) ** A highly effective method of contraception is defined as one that results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly
  • Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
  • Subjects must have a histologically confirmed diagnosis of small cell lung carcinoma
  • Subjects must agree to pre-treament and on-treatment biopsies * Patients that have available tissue that fulfills the pre-treatment biopsy requirement or other deviations in terms of the tissue requirement, may not need a fresh biopsy at baseline if discussed and approved by the medical monitor
  • Subjects must have extensive-stage disease (by National Comprehensive Cancer Network [NCCN] criteria) that has been previously treated with first line platinum-based chemotherapy; patients must either have persistent or progressive disease after platinum based therapy
  • Tumor burden must be radiographically measurable by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
  • At time of day 1 of protocol treatment, subjects with central nervous system metastases must have been treated and must be asymptomatic and meet the following: * No concurrent treatment, inclusive of but not limited to surgery, radiation, and/or corticosteroids * Neurologic stability (lack of signs and symptoms greater than baseline prior to x-ray therapy [XRT]) until the time of dosing * For radiation treatment, patients must not receive stereotactic radiosurgery or gamma knife treatment within 7 days of day 1 of protocol treatment; for whole brain radiotherapy (WBRT), there should be at least 28 days between last day of WBRT and day 1 of protocol treatment * Note: patients with leptomeningeal disease or cord compression are excluded from the study

Exclusion Criteria

  • 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-110
  • 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
  • Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, gamma-knife, other investigational agent) =< 14 days prior to the first dose of study drug; for WBRT, the washout period is 28 days; local treatment of isolated lesions for palliative radiation therapy (RT) (by radiotherapy, for example) is acceptable
  • Mean QT interval corrected for heart rate (corrected QT interval [QTc]) >= 470 ms calculated from electrocardiogram (in triplicate, if applicable) using Fridericia’s correction
  • Liver cirrhosis or chronic liver disease Child-Pugh B or C
  • Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab or tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
  • Receipt of the tyrosine kinase inhibitor sunitinib within 90 days before the first dose of study therapy
  • Any unresolved toxicity (> Common Terminology Criteria for Adverse Events [CTCAE] grade 2) from previous anti-cancer therapy
  • Any prior grade >= 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > grade 1
  • Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects with vitiligo, Graves disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded
  • Active or prior documented history of pneumonitis or interstitial lung disease
  • Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis)
  • History of primary immunodeficiency
  • History of allogeneic organ transplant
  • History of hypersensitivity to durvalumab, tremelimumab, SGI-110, or any excipient
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
  • Known history of active tuberculosis
  • Leptomeningeal carcinomatosis or cord compression
  • Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab or tremelimumab
  • Female subjects who are pregnant or breast-feeding, or male or female patients of reproductive potential who are not willing to employ a highly effective method of contraception from screening to 180 days after the last dose of investigational therapy
  • Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
  • Subjects with uncontrolled seizures
  • Known significant mental illness or other conditions such as active alcohol or other substance abuse/addiction that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol

Locations & Contacts

New York

New York
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center
Status: Active
Contact: Catherine Ann Shu
Phone: 212-305-3997
Email: Cas2145@cumc.columbia.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose of guadecitabine (SGI-110) when given prior to durvalumab and tremelimumab, as determined by the rate of dose-limiting toxicity (DLT). (Dose escalation phase)

II. To estimate the rate of treatment related adverse events for combination therapy with SGI-110 (at the maximum tolerated dose [MTD]), durvalumab, and tremelimumab in order to guide phase 2 trial design. (Dose expansion phase)

SECONDARY OBJECTIVES:

I. To measure changes in expression levels of predicted neoantigens before and after epigenetic therapy with SGI-110 by performing whole exome sequencing (WES) and reverse transcriptase-polymerase chain reaction (RT-PCR) on tumor biopsies.

II. To estimate overall response rate (ORR), median duration of response (mDOR), median progression-free survival (mPFS), and median overall survival (mOS) with this treatment.

TERTIARY OBJECTIVES:

I. To use banked tumor and blood specimen for future scientific studies regarding the mechanism and immunologic effects of the treatment combination.

OUTLINE: This is a dose-escalation study of guadecitabine.

Patients receive guadecitabine subcutaneously (SC) daily on days 1-5 of courses 1-4, durvalumab intravenously (IV) over 1 hour on day 8, and tremelimumab IV over 1 hour on day 8 of courses 1-4. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unaccepted toxicity.

After completion of study treatment, patients are followed up for 90 days, at 2, 3, 6, 9, and 12 months, and then every 3 months for up to 24 months.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center

Principal Investigator
Catherine Ann Shu

Trial IDs

Primary ID AAAQ8257
Secondary IDs NCI-2017-01393
Clinicaltrials.gov ID NCT03085849