Status and phase
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About
Background:
Lung cancers with 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....
Full description
Background:
Targeted therapies designed for specific genetic alterations, known as cancer driver mutations, have changed the treatment paradigm in advanced non-small cell lung carcinoma (NSCLC). Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective in NSCLC with activating mutation in the EGFR. Although most patients achieve robust responses to EGFR TKIs with tumor shrinkage and symptomatic relief, drug resistance eventually develops in the majority of patients.
Small cell lung cancer (SCLC) transformation has been reported as one of the mechanisms of acquired resistance to EGFR TKIs.
Several phase III trials showed durable response with poly (ADP-ribose) polymerase (PARP) inhibitors in the breast and ovarian cancer with BRCA mutation, a tumor suppressor gene involving homologous recombination repair (HRR) pathway, and several PARP inhibitors are now FDA approved for these cancers.
Immune checkpoint blockade appears to be most effective against hypermutated tumors, suggesting that clinical responses correlate with an increased propensity to produce neoantigens.
EGFR-mutated transformed SCLC is an aggressive cancer whose clinical course is similar to that of SCLC. There are no standard treatments for this disease and prospective studies have not been conducted to date. Immune checkpoint inhibitors alone are not effective for EGFR-mutated transformed SCLC. Analyses of EGFR transformed SCLC tumors suggest that these tumors are HRR deficient.
Objective:
To assess the efficacy of a combination of durvalumab and olaparib with respect to best overall response (BOR) according to Response Evaluation Criteria (RECIST 1.1) in patients with EGFR-mutated non-small-cell lung carcinoma (NSCLC) that transform to SCLC and other neuroendocrine carcinomas.
Eligibility:
Subjects with initial diagnosis of EGFR-mutated non-small-cell lung carcinoma (NSCLC) and histologically or cytologically confirmed transformation to small cell/neuroendocrine tumors 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 >=18 years.
Subjects must have measurable disease.
ECOG performance status <= 2
Adequate organ function
Design:
-This is an open label Phase II study evaluating the combination of durvalumab and olaparib
in participants with EGFR-mutated non-small-cell lung carcinoma and histologically or cytologically confirmed transformation to small cell/neuroendocrine tumors following
treatment with EGFR tyrosine kinase inhibitor.
Patients will be treated with durvalumab (1,500 mg), IV, every 28 days and olaparib (300
mg BID for total daily dose of 600 mg) in a 28-day cycles.
Patients will be evaluated for toxicity every 4 weeks by CTCAE v5.0, and for response every 8 (+/-1) weeks by RECIST 1.1
Treatment will continue until disease progression or unacceptable toxicity.
Enrollment
Sex
Ages
Volunteers
Inclusion and exclusion criteria
INCLUSION CRITERIA:
Subjects with initial diagnosis of 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 RECIST 1.1.
ECOG performance status less than or equal to 2.
Adequate hematological function within 28 days prior to enrollment as defined below:
Adequate hepatic function within 28 days prior to enrollment as defined by:
Adequate renal function within 28 days prior to enrollment as defined by:
Creatinine OR Measured or calculated creatinine clearance (CrCl) (eGFR may also be used in place of CrCl)
---< 1.5x institution upper limit of normal OR
greater than or equal to 51 mL/min/1.73 m2 for participant with creatinine levels
greater than or equal to 1.5 X institutional ULN<TAB>
Creatinine clearance (CrCl) or eGFR should be calculated per institutional standard.
-The effects of the study treatment on the developing human fetus are unknown; thus, women of childbearing potential must agree to use 1 highly effective form of contraception and their partners must use a male condom, or they must totally/truly abstain from any form of sexual intercourse from the time of screening throughout the total duration of the protocol treatment and for at least 6 months after the last dose of the study drugs. Male participants and their partners must use a highly effective form of contraception from the time
of screening throughout the total duration of the protocol treatment and for 3 months after the last dose of study treatment.
Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
---Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of enrollment and confirmed prior to treatment on day 1. Postmenopausal is defined as: amenorrheic for 1 year (12 months in a row) or more following cessation of exogenous hormonal treatments; luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the post-menopausal range for women under 50, radiation-induced oophorectomy with last menses >1 year ago; chemotherapy-induced menopause with more than one-year interval since last menses; surgical sterilization for female participants (bilateral oophorectomy or hysterectomy) or male partners..
Patients with symptomatic brain metastases will be excluded from trial secondary to poor prognosis. However, patients who have had treatment for their brain metastasis and whose brain disease is stable without steroid therapy for 2 weeks may be enrolled. Imaging to rule out brain metastases is not required for screening but should be performed prior to study enrollment if clinically indicated.
Subjects must be able to understand and willing to sign a written informed consent document
EXCLUSION CRITERIA:
Note: dihydropyridine calcium - channel blockers are permitted for management of underling disease.
Primary purpose
Allocation
Interventional model
Masking
4 participants in 1 patient group
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Central trial contact
Anish Thomas, M.D.; Linda C Sciuto, R.N.
Data sourced from clinicaltrials.gov
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