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
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.
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
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
This is an open label Phase II study
Patients will be treated with durvalumab (1,500 mg), IV, every 4 weeks and olaparib (BID, 600
mg total daily dose) 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.
- 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
- 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
- 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
- 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
- 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
- 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
- History of auto-immune disease requiring steroid maintenance, or history of primary
- 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.