Clinical Trials /

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

NCT04538378

Description:

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....

Related Conditions:
  • Lung Neuroendocrine Neoplasm
  • Non-Small Cell Lung Carcinoma
  • Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 200149
  • SECONDARY ID: 20-C-0149
  • NCT ID: NCT04538378

Conditions

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

Interventions

DrugSynonymsArms
Olaparib1/Arm 1
Durvalumab1/Arm 1

Purpose

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....

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 greater than or equal to18 years.

        -  Subjects must have measurable disease.

        -  ECOG performance status

      Design:

        -  This is an open label Phase II study

        -  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.
    

Trial Arms

NameTypeDescriptionInterventions
1/Arm 1ExperimentalCombination of durvalumab and olaparib
  • Olaparib
  • Durvalumab

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Targeted Therapy
  • (PARP) Inhibitors
  • Poly (ADP-ribose) Polymerase
  • Monoclonal Antibodies

Last Updated

September 17, 2020