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

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ClinicalTrials.gov Identifier: NCT04538378
Recruitment Status : Recruiting
First Posted : September 4, 2020
Last Update Posted : September 5, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

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....


Condition or disease Intervention/treatment Phase
EGFR-Mutated Non-Small-Cell Lung Carcinoma Small Cell/Neuroendocrine Drug: Olaparib Drug: Durvalumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 14 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial of Olaparib (LYNPARZA) Plus Durvalumab (IMFINZI) in EGFR-Mutated Adenocarcinomas That Transform to Small Cell Lung Cancer (SCLC) and Other Neuroendocrine Tumors.
Actual Study Start Date : July 7, 2021
Estimated Primary Completion Date : December 31, 2025
Estimated Study Completion Date : December 31, 2026


Arm Intervention/treatment
Experimental: 1/Arm 1
Combination of durvalumab and olaparib
Drug: Olaparib
Olaparib tablet will be administered at a total daily dose of 600 mg orally in two divided doses, approximately 12 hours apart.

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




Primary Outcome Measures :
  1. Best overall response [ Time Frame: Disease progression ]
    The clinical response rate of evaluable patients will be reported along with a 95% confidence interval.


Secondary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: Disease progression ]
    PFS and OS will be estimated by the Kaplan-Meier method. The median PFS and OS will be reported along with a 95% confidence interval.

  2. Safety and tolerability of a combination [ Time Frame: Treatment phase ]
    Patients will be assessed for toxicity by reporting the grades of toxicity and the type of toxicity observed for all patients.

  3. Overall survival (OS) [ Time Frame: Death ]
    PFS and OS will be estimated by the Kaplan-Meier method. The median PFS and OS will be reported along with a 95% confidence interval.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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:

    • white blood cell (WBC) count greater than or equal to 3 (SqrRoot) 10^9/L,
    • absolute neutrophil count (ANC) greater than or equal to 1.0 (SqrRoot) 10^9/L,
    • platelet count greater than or equal to 75 (SqrRoot) 10^9/L, and
    • 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 (SqrRoot) ULN; for subjects with documented/suspected Gilbert s disease, bilirubin less than or equal to 3 (SqrRoot) ULN
    • an AST level less than or equal to 2.5(SqrRoot) ULN, (less than or equal to 5X ULN if liver metastasis)
    • an ALT level less than or equal to 2.5 (SqrRoot) ULN, (less than or equal to 5X ULN if liver metastasis).
  • 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 and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from the time of screening throughout the total duration of the protocol treatment and for at least three months after the last dose of the study drug (s). 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 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 (bilateral oophorectomy or hysterectomy). Male patients must use a condom from the time of screening throughout the total duration of the protocol treatment and for 3 months after the last dose of study treatment when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential.
  • 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:

  • 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 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 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 ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, 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 TB testing), hepatitis B (known positive HBV 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 RNA..
  • 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 CD4 count > 150 cells/microliters) may be eligible if the PI determines no anticipated clinically significant drug-drug interactions.
  • History of allogenic organ transplantation, bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
  • Uncontrolled intercurrent illness or medical condition including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia requiring medications ((except chronic atrial fibrillation/flutter with controlled vascular rate), or psychiatric illness/social situations that may impair the patient s tolerance of study treatments and, in the judgment of the investigator, would make the patient inappropriate for the study.
  • Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication based on primary investigator decision.
  • Pregnant women are excluded from this study because olaparib is a PARP inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with durvalumab and olaparib, breastfeeding should be discontinued if the mother is treated with study drugs.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04538378


Contacts
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Contact: Linda C Sciuto, R.N. (240) 760-6117 lsciuto@mail.nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Anish Thomas, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04538378    
Other Study ID Numbers: 200149
20-C-0149
First Posted: September 4, 2020    Key Record Dates
Last Update Posted: September 5, 2021
Last Verified: August 31, 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Targeted Therapy
(PARP) Inhibitors
Poly (ADP-ribose) Polymerase
Monoclonal Antibody
Additional relevant MeSH terms:
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Adenocarcinoma
Small Cell Lung Carcinoma
Neuroendocrine Tumors
Carcinoma, Non-Small-Cell Lung
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Durvalumab
Olaparib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action