Danvatirsen And Durvalumab In Treating Patients With Advanced And Refractory Pancreatic, Non-Small Cell Lung Cancer, And Mismatch Repair Deficient Colorectal Cancer

Study Overview

Danvatirsen and Durvalumab in Treating Patients With Advanced and Refractory Pancreatic, Non-Small Cell Lung Cancer, and Mismatch Repair Deficient Colorectal Cancer

This phase II trial studies how well danvatirsen and durvalumab work in treating patients with pancreatic cancer, non-small cell lung cancer and mismatch repair deficient colorectal cancer that has spread to other places in the body and does not respond to treatment. Danvatirsen may be used to block the production of proteins needed for tumor cell growth. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving danvatirsen and durvalumab may work better at treating pancreatic cancer, non-small cell lung cancer and mismatch repair deficient colorectal cancer.

PRIMARY OBJECTIVES: I. Evaluate disease control rate (DCR) at 4 months. II. Evaluate tumor-based biomarkers in paired pre and post treatment biopsies (10 in each arm, 30 total) that may correlate with treatment or prospectively identify patients likely to respond to treatment with danvatirsen (AZD9150) in combination with durvalumab (MEDI4736) (may include PD-L1 expression, phosphorylated or total STAT3 expression, tumor genetics, characterization of immune infiltrates, or other stratification markers). III. Explore the relationship between PD-L1 protein levels in the membrane of circulating tumor cells obtained by peripheral blood draws prior to, during, and after treatment with clinical endpoints including treatment efficacy and toxicity. SECONDARY OBJECTIVES: I. Evaluate the frequency of dose limiting toxicities. II. Evaluate frequency of objective response (as defined as partial response [PR] or complete response [CR] according to Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 criteria). III. Evaluate duration of response (DOR) measured from the time measurement criteria are first met for CR or PR, whichever is first recorded, until the first date that recurrent or progressive disease (PD) is objectively documented. IV. Evaluate best overall response (including CR, PR, stable disease [SD], and PD, according to RECIST version 1.1 criteria). V. Evaluate progression free survival (PFS) from allocation to the first documentation of PD as determined by the investigator or death from any cause, whichever occurs first. EXPLORATORY OBJECTIVES: I. Explore the relationship between radiologic metrics (radiomics) prior to, during, and after treatment with clinical endpoints including treatment efficacy and toxicity. OUTLINE: Patients receive danvatirsen intravenously (IV) over 1 hour on days 7, 5 and 3 prior to cycle 1, then on days 1, 8, 15 and 22. Patients also receive durvalumab IV over 1 hour on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, 1-3 months, then every 2 months thereafter.

Advanced Colorectal Carcinoma
Advanced Lung Non-Small Cell Carcinoma
Lung Non-Small Cell Carcinoma
Mismatch Repair Deficiency
Refractory Colorectal Carcinoma
Refractory Lung Carcinoma
Refractory Pancreatic Carcinoma
Stage II Pancreatic Cancer AJCC v8
Stage III Colorectal Cancer AJCC v8
Stage III Lung Cancer AJCC v8
Stage III Pancreatic Cancer AJCC v8
Stage IIIA Colorectal Cancer AJCC v8
Stage IIIA Lung Cancer AJCC v8
Stage IIIB Colorectal Cancer AJCC v8
Stage IIIB Lung Cancer AJCC v8
Stage IIIC Colorectal Cancer AJCC v8
Stage IIIC Lung Cancer AJCC v8
Stage IV Colorectal Cancer AJCC v8
Stage IV Lung Cancer AJCC v8
Stage IV Pancreatic Cancer AJCC v8
Stage IVA Colorectal Cancer AJCC v8
Stage IVA Lung Cancer AJCC v8
Stage IVB Colorectal Cancer AJCC v8
Stage IVB Lung Cancer AJCC v8
Stage IVC Colorectal Cancer AJCC v8

DRUG: Danvatirsen
BIOLOGICAL: Durvalumab

2016-0108
NCI-2018-01296 (REGISTRY Identifier) (REGISTRY: CTRP (Clinical Trial Reporting Program))
2016-0108 (OTHER Identifier) (OTHER: M D Anderson Cancer Center)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2016-12-01	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2025-05-01
First Submitted that Met QC Criteria 2016-12-02	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2025-05-06
First Posted (ACTUAL) 2016-12-06	Results First Posted N/A	Last Verified 2025-05

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Na

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Treatment (danvatirsen, durvalumab) Patients receive danvatirsen IV over 1 hour on days 7, 5 and 3 prior to cycle 1, then on days 1, 8, 15 and 22. Patients also receive durvalumab IV over 1 hour on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxi	DRUG: Danvatirsen Given IV BIOLOGICAL: Durvalumab Given IV

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Treatment (danvatirsen, durvalumab)

Patients receive danvatirsen IV over 1 hour on days 7, 5 and 3 prior to cycle 1, then on days 1, 8, 15 and 22. Patients also receive durvalumab IV over 1 hour on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxi

DRUG: Danvatirsen

Given IV

BIOLOGICAL: Durvalumab

Given IV

Primary Outcome Measures	Measure Description	Time Frame
Incidence of adverse events (AEs), serious AEs		Up to 4 years
Physiological parameters (Laboratory evaluations)	Blood samples for routine coagulation assessments will be obtained at screening and once during week 4 of cycle 1.	Up to 4 years
Incidence of treatment-emergent AEs (TEAEs), SAEs and death(s)	Will be graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.03.	Up to 4 years
PD-L1 expression		Up to 4 years
Phosphorylated or total STAT3 expression levels		Up to 4 years
Characterization of immune infiltrates		Up to 4 years
Quantification and characterization of CD8 staining pattern		Up to 4 years
PD-L1 protein levels in the membrane of circulating tumor cells		Baseline up to 4 years
Physiological parameters	Vital signs will required at screening before dosing on Day -7 of the Lead-in; before dosing on Days 1, 8, 15, and 22 of each cycle; and at the EOT visit.	Up to 4 years
Physical Examinations	A complete physical examination is required at screening, before dosing on Day 7 of the Lead in, before dosing on Day 1 of each cycle, and at the EOT visit. A targeted physical examination as directed by disease, signs and symptoms is required before dosing on Day 15 of each cycle.	Up to 4 years

Secondary Outcome Measures	Measure Description	Time Frame
Disease control	Will be defined as a compete response (CR), partial response (PR) or stable disease (SD), according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria.	At 4 months
Objective response	Will be defined as a CR or PR according to RECIST version 1.1.	Up to 4 years
Duration of response according to RECIST version 1.1 criteria		From the time measurement criteria are first met for CR or PR, assessed up to 4 years
Best overall response (including CR, PR, SD, and progressive disease [PD], according to RECIST version 1.1 criteria)		Up to 4 years
Progression free survival		From allocation assessed up to 4 years
Overall survival		From start of treatment assessed up to 4 years

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

The patient/legal representative must be able to read and understand the informed consent form (ICF) and must have been willing to give written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act in the United States of America [USA]; European Union Data Privacy Directive in the European Union [EU]) before any study-specific procedures, including screening evaluations, sampling, and analyses
Has a histological confirmation of pancreatic cancer, mismatch deficient colorectal cancer, or non-small cell lung cancer (NSCLC) that is refractory to standard therapy or for which no standard of care regimen currently exists
Has an Eastern Cooperative Oncology Group (ECOG) performance score (PS) score of 0 or 1
Has measurable disease, defined as at least 1 lesion that can be accurately measured in at least 1 dimension (longest diameter to be recorded) with a minimum size of 10 mm by computerized tomography (CT) scan, except lymph nodes which must have minimum short axis size of 15 mm (CT scan slice thickness no greater than 5 mm in both cases). Indicator lesions must not have been previously treated with surgery, radiation therapy, or radiofrequency ablation unless there is documented progression after therapy
Transfusions intended to elevate any parameters below solely for the intent of meeting study eligibility are not permitted
Leukocytes >= 3000 mcL
Absolute neutrophil count >= 1500 mcL
Platelets > = 100 000 mcL
Hemoglobin >= 9 g/dL
Total bilirubin =< 1.5 x upper limit of normal (ULN)
Total bilirubin =< 3 x ULN in patients with documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or in the presence of liver metastases
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN if no demonstrable liver metastases or =< 5 x ULN in the presence of liver metastases
Creatinine within normal limits OR, for patients with levels above institutional normal: creatinine clearance measured by 24-hour urine collection >= 60 mL/min, OR calculated corrected creatinine clearance >= 60 mL/min/1.73 m^2 using the Cockcroft-Gault formula (Cockcroft and Gault 1976) corrected for the body surface area
Women of childbearing potential and men who are sexually active with a female partner of childbearing potential must be surgically sterilized, practicing abstinence, or agree to use 2 birth control methods before study entry, for the duration of study participation, and for 20 weeks after the final dose of study drug; cessation of birth control after this point should be discussed with a responsible physician. Women of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined as 12 months with no menses without an alternative medical cause). Two methods of contraception which are considered accurate per protocol must be combined. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control
Women of childbearing potential also may not be breast feeding and must have a negative serum or urine pregnancy test within 72 hours before the start of study treatment
The patient/legal representative must be willing to provide written consent for collection of formalin fixed paraffin-embedded blocks or slides from archival diagnostic histology samples, where available

Has a spinal cord compression unless asymptomatic, radiographically stable over the last 4 weeks, and not requiring steroids for at least 4 weeks before the start of study treatment
Presently has a second malignancy other than squamous cell carcinoma of the head and neck (SCCHN), or history of treatment for invasive cancer other than SCCHN in the past 3 years. Exceptions are:

Previously treated in-situ carcinoma (i.e., noninvasive)
Cervical carcinoma stage 1B or less
Noninvasive basal cell and squamous cell skin carcinoma
Radically treated prostate cancer (prostatectomy or radiotherapy) with normal prostate-specific antigen, and not requiring ongoing antiandrogen hormonal therapy
Patients must have completed previous cancer-related treatments before enrollment. Any concurrent chemotherapy, radiotherapy, immunotherapy, or biologic, or hormonal therapy for cancer excludes the patient (concurrent use of hormones for noncancer-related conditions [e.g., insulin for diabetes or hormone replacement therapy] is acceptable). The following intervals between end of the prior treatment and first dose of study drug must be observed:

Port-a-cath placement: no waiting required
Minor surgical procedures: >= 7 postoperative days
Major surgery: >= 4 weeks
Radiotherapy: >= 4 weeks
Chemotherapy: >= 4 weeks
Immunotherapy or investigational anticancer therapy with agents other than monoclonal antibodies (mAbs): >= 4 weeks
Immunotherapy or investigational anticancer therapy with mAbs: >= 6 weeks
Immunosuppressive medication: >= 4 weeks with the exceptions of intranasal or inhaled corticosteroids or systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent
Is still experiencing toxicity related to prior treatment and assessed as Common Terminology Criteria for Adverse Events (CTCAE) grade > 1. Exceptions are alopecia and/or anorexia. The eligibility of patients who are still experiencing irreversible toxicity that is not reasonably expected to be exacerbated by the study drugs in this study (e.g., hearing loss) must be reviewed and approved by both the principal investigator and medical monitor
Has experienced immune-related adverse events (AEs) (irAEs) while receiving prior immunotherapy (including anti-CTLA4 treatment) and assessed as CTCAE grade >= 3
Has active or prior documented autoimmune disease within the past 2 years with the exceptions of vitiligo, Grave's disease, and/or psoriasis not requiring systemic treatment
Has active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
Has a history of primary immunodeficiency
Has undergone an organ transplant that requires use of immunosuppressive treatment
Has a history of interstitial lung disease or pneumonitis from any cause
Has a history of allergic reactions attributed to the study treatments (AZD9150 or MEDI4736), their compounds, or agents of similar chemical or biologic composition (e.g., antibody therapeutics)
Suffers from a comorbidity that in the opinion of the investigator renders the patient unsuitable for participation in the study. Such comorbidity may include, but is not limited to, uncontrolled intercurrent illness such as active infection, severe active peptic ulcer disease or gastritis, myocardial infarction within 6 months before entry, congestive heart failure, symptomatic congestive heart failure, active cardiomyopathy, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension, or psychiatric illness/social situations that would limit compliance with study requirements
As judged by the investigator, has any evidence of severe or uncontrolled systemic diseases such as active bleeding diatheses, is positive for human immunodeficiency virus (HIV), or has active hepatitis B virus (HBV) and/or hepatitis C virus (HCV)
Has a known history of tuberculosis
Has a condition that, in the opinion of the investigator, would interfere with the evaluation of the study drugs or the interpretation of patient safety or study results
Has received a live attenuated vaccine within 28 days before the first dose of study drug
Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements
Patients with clinically active brain metastases (known or suspected) are excluded unless the brain metastases have been previously treated and are considered stable. Stable brain metastases are defined as no change on CT scan or magnetic resonance imaging (MRI) scan for a minimum of 2 months AND no change in steroid dose for a minimum of 4 weeks, unless change due to intercurrent infection or other acute event
Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

National Cancer Institute (NCI)
AstraZeneca

Investigators

PRINCIPAL_INVESTIGATOR: David S Hong, M.D. Anderson Cancer Center

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Tang C, Hartley GP, Couillault C, Yuan Y, Lin H, Nicholas C, Srinivasamani A, Dai J, Dumbrava EEI, Fu S, Karp DD, Naing A, Piha-Paul SA, Rodon Ahnert J, Pant S, Subbiah V, Yap TA, Tsimberidou AM, Guerrero P, Dhebat S, Proia T, Curran MA, Hong DS. Preclinical study and parallel phase II trial evaluating antisense STAT3 oligonucleotide and checkpoint blockade for advanced pancreatic, non-small cell lung cancer and mismatch repair-deficient colorectal cancer. BMJ Oncol. 2024 Jul 30;3(1):e000133. doi: 10.1136/bmjonc-2023-000133. eCollection 2024.

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