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

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

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....

Study Overview

• Status: Recruiting
• Conditions: EGFR-Mutated Non-Small-Cell Lung Carcinoma; Small Cell/Neuroendocrine
• Intervention / Treatment: Drug: Olaparib; Drug: Durvalumab

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 14
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Linda C Sciuto, R.N.; Phone Number: (240) 760-6117; Email: linda.sciuto@nih.gov
• Study Contact Backup: Name: Anish Thomas, M.D.; Phone Number: (240) 760-7343; Email: anish.thomas@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office; Phone Number: 888-624-1937

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• 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 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:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best overall response	The clinical response rate of evaluable patients will be reported along with a 95% confidence interval.	Disease progression

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	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.	Disease progression
Safety and tolerability of a combination	Patients will be assessed for toxicity by reporting the grades of toxicity and the type of toxicity observed for all patients.	Treatment phase
Overall survival (OS)	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.	Death

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Anish Thomas, M.D., National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): July 7, 2021
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: September 3, 2020
• First Submitted That Met QC Criteria: September 3, 2020
• First Posted (Actual): September 4, 2020

Study Record Updates

• Last Update Posted (Actual): April 18, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: April 16, 2024

More Information

Terms related to this study

• Keywords: Monoclonal Antibody; Targeted Therapy; (PARP) Inhibitors; Poly (ADP-ribose) Polymerase
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Adenocarcinoma; Small Cell Lung Carcinoma; Neuroendocrine Tumors; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Poly(ADP-ribose) Polymerase Inhibitors; Olaparib; Durvalumab
• Other Study ID Numbers: 200149; 20-C-0149

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.@@@@@@All collected IPD will be shared with collaborators under the terms of collaborative agreements.
• IPD Sharing Time Frame: Clinical data available during the study and indefinitely.@@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
• IPD Sharing Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. @@@@@@Genomic data are made available via dbGaP through requests to the data custodians.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No