Olaparib (LYNPARZA) Plus Durvalumab (IMFINZI) in EGFR-Mutated Adenocarcinomas That Transform to Small Cell Lung Cancer (SCLC) and Other Neuroendocrine Tumors

NCT04538378 | Terminated Phase 2 Results FDA Drug

• 2 other identifiers: 20014920-C-0149
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Lung cancers with epidermal growth factor receptor (EGFR) mutations may develop resistance to therapies targeting this protein by evolving/being transformed into small cell or neuroendocrine cancers. There are no standard treatments for it. Researchers want to see if a new combination of drugs can help. Objective: To see if the combination of durvalumab and olaparib will cause tumors to shrink. Eligibility: Adults age 18 and older who had EGFR-mutated non-small-cell lung carcinoma (NSCLC) that was treated and now transformed to SCLC or another neuroendocrine tumor. Design: Participants will be screened under a separate protocol. They may have a tumor biopsy. Participants will have a physical exam. They will have a review of their symptoms, their medicines, and their ability to do their normal activities. They will have blood tests. They will have an electrocardiogram to evaluate their heart. Participants will have a computed tomography (CT) scan, a series of x-rays taken of parts of the body. Participants will get durvalumab on Day 1 of each 28-day cycle. It is given through a small plastic tube that is put in an arm vein. They will take olaparib by mouth twice every day. They will keep a medicine diary. Participants will take the study drugs until their disease gets worse or they have unacceptable side effects. About 30 days after they stop taking the study drugs, participants will have a follow-up visit. Then they will be contacted every 6 months for the rest of their life....

Conditions

EGFR-Mutated Non-Small-Cell Lung Carcinoma; Small Cell/Neuroendocrine

Keywords

Targeted Therapy; (PARP) Inhibitors; Poly (ADP-ribose) Polymerase; Monoclonal Antibody

Outcome Measures

Primary Outcomes (1)

• Best Overall Response (BOR)

  BOR is the best response recorded from the start of the treatment until disease progression/recurrence. The clinical response rate of evaluable participants will be reported along with a 95% confidence interval according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Complete response (CR) is the disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

  Disease progression; an average of 53 days

Secondary Outcomes (3)

• Progression-free Survival (PFS)

  Disease progression, an average of 7 weeks

• Number of Participants With Grades 1, 2, 3, 4 and/or 5 Serious and/or Non-serious Toxicity

  Treatment phase, an average of 12 weeks

• Overall Survival (OS)

  At death, an average of 275 days

Other Outcomes (1)

• Number of Participants With Serious and/or Non-Serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).

  From the first study intervention, Study Day 1 of Cycle 1 through 30 days after the study agent (s) was/were administered, an average of 11.4 weeks

Study Arms (1)

1/Arm 1: Combination of Durvalumab and Olaparib

EXPERIMENTAL

Combination of durvalumab and olaparib

Drug: Olaparib; Drug: Durvalumab; Diagnostic Test: EKG; Procedure: Tumor biopsy; Diagnostic Test: CT chest, abdomen and pelvis; Diagnostic Test: MRI chest, abdomen and pelvis

Interventions

Olaparib DRUG

Olaparib tablet will be administered at a total daily dose of 600 mg orally in two divided doses, approximately 12 hours apart.

Also known as: Lynparza

1/Arm 1: Combination of Durvalumab and Olaparib

Durvalumab DRUG

Durvalumab will be administered intravenous (IV) into a peripheral or central vein on Day 1 of every cycle at a flat dose of 1,500 mg.

Also known as: Imfinzi

1/Arm 1: Combination of Durvalumab and Olaparib

EKG DIAGNOSTIC_TEST

Screening and all cycles Day 1 and Day 15 (+/- 3) days. One cycle is 28 days.

Also known as: Electrocardiogram

1/Arm 1: Combination of Durvalumab and Olaparib

Tumor biopsy PROCEDURE

Baseline and all cycles Day 15 (+/- 3) days. One cycle is 28 days.

Also known as: Tumor bx

1/Arm 1: Combination of Durvalumab and Olaparib

CT chest, abdomen and pelvis DIAGNOSTIC_TEST

Screening and baseline and every 8 (+/-1) weeks after start of therapy.

Also known as: Computed tomography chest, abdomen and pelvis

1/Arm 1: Combination of Durvalumab and Olaparib

MRI chest, abdomen and pelvis DIAGNOSTIC_TEST

Screening and baseline and every 8 (+/-1) weeks after start of therapy.

Also known as: Magnetic resonance imaging chest, abdomen and pelvis

1/Arm 1: Combination of Durvalumab and Olaparib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects with initial diagnosis of epidermal growth factor receptor (EGFR)-mutated non-small-cell lung carcinoma (NSCLC) and histologically or cytologically confirmed transformation to small cell or neuroendocrine tumor following treatment with EGFR tyrosine kinase inhibitor.
• Subjects should have received platinum-based chemotherapy with or without immunotherapy for small cell/neuroendocrine transformation or refused such therapy.
• Age greater than or equal to 18 years.
• Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.
• Adequate hematological function within 28 days prior to enrollment as defined below:
• white blood cell (WBC) count greater than or equal to 3x10\^9/L,
• absolute neutrophil count (ANC) greater than or equal to 1.0x10\^9/L,
• platelet count greater than or equal to 75x10\^9/L, and
• Hemoglobin (Hgb) greater than or equal to 9 g/ dL if no blood transfusion within 4 weeks prior to enrollment OR \>10 g/dL if no blood transfusion within 2 weeks prior to enrollment.
• Adequate hepatic function within 28 days prior to enrollment as defined by:
• a total bilirubin level less than or equal to 1.5 x upper limit of normal (ULN); for subjects with documented/suspected Gilbert's disease, bilirubin less than or equal to 3 x ULN
• an aspartate aminotransferase (AST) level less than or equal to 2.5 x ULN, (less than or equal to 5X ULN if liver metastasis)
• an alanine aminotransferase (ALT) level less than or equal to 2.5 x ULN, (less than or equal to 5X ULN if liver metastasis).
• Adequate renal function within 28 days prior to enrollment as defined by:

You may not qualify if:

• Patients who are receiving any other investigational agents. Patients may be on other clinical trials or treatment during screening to determine eligibility
• Systemic anti-cancer treatment or major surgery within 2 weeks prior to enrollment.
• Palliative radiation within 24 hours prior to enrollment.
• High-dose consolidative chest radiation within 2 weeks prior to enrollment.
• Major surgical procedure (as defined by the Investigator) within 28 days prior to enrollment. Note: local surgery of isolated lesions for palliative intent is acceptable.
• Patients receiving any medications or substances that are moderate and strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4).
• Note: dihydropyridine calcium - channel blockers are permitted for management of underling disease.
• History of auto-immune disease requiring steroid maintenance, or history of primary immunodeficiency.
• Current or prior use of immunosuppressive medication within 14 days before the enrollment, with the exception 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. In the case of short-term use of systemic corticosteroids (less than 24 hours within 28 days) of greater than 10 mg/day of prednisone or an equivalent corticosteroid, the required washout period prior to enrollment is 7 days.
• Patients with myelodysplastic syndrome/acute myeloid leukemia; or baseline clinical features suggestive of myelodysplastic syndrome or acute myelogenous leukemia.
• Persistent toxicities (greater than or equal to Common Terminology Criteria for Adverse Events (CTCAE) grade 2) with the exception of alopecia, caused by previous cancer therapy.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition of olaparib or durvalumab.
• Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, Q wave and the T wave (QT) corrected for heart rate by Fridericia's cube root formula (QTcF) prolongation \>500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis (TB) testing), hepatitis B (known positive hepatitis B virus (HBV) hepatitis B surface antigen (HBsAg) result), hepatitis C. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) and patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HBV or HCV ribonucleic acid (RNA).
• Human immunodeficiency virus (HIV)-positive patients on antiretroviral therapy are ineligible because of potential pharmacokinetic interactions with study drugs. However, patients with long-standing (\>5 years) HIV on antiretroviral therapy \> 1 month (undetectable HIV viral load and cluster of differentiation 4 (CD4) count \> 150 cells/microliters) may be eligible if the PI determines no anticipated clinically significant drug-drug interactions.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Interventions

olaparib; durvalumab; Electrocardiography

Intervention Hierarchy (Ancestors)

Heart Function Tests; Diagnostic Techniques, Cardiovascular; Diagnostic Techniques and Procedures; Diagnosis; Electrodiagnosis

Results Point of Contact

• Title: Dr. Anish Thomas
• Organization: National Cancer Institute

anish.thomas@nih.gov

240-760-7343

Study Officials

• Anish Thomas, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 3, 2020
• First Posted: September 4, 2020
• Study Start: July 7, 2021
• Primary Completion: March 22, 2023
• Study Completion: February 27, 2024
• Last Updated: January 27, 2025
• Results First Posted: January 27, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data are made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.

Locations

US (1)