PRIMARY OBJECTIVE:
I. To assess the toxicity and feasibility of sequential treatment with olaparib, thoracic
radiotherapy (TRT)/durvalumab, and olaparib/durvalumab for consolidation and maintenance
therapy in patients status post (s/p) chemoimmunotherapy for ES-SCLC.
SECONDARY OBJECTIVE:
I. To assess the efficacy of sequential treatment with olaparib, TRT/durvalumab, and
olaparib/durvalumab for consolidation and maintenance therapy in patients s/p
chemoimmunotherapy for ES-SCLC.
EXPLORATORY OBJECTIVES:
I. Perform a comparative analysis of patient clinical outcome according to tumor biomarkers
in circulating tumor cell (CTC), blood samples and tumor tissue, such as SLFN11 expression H-
scores and stratifying tumors as SLFN11 positive or negative on the basis of H-score >= 1.
II. Perform a comparative analysis of patient clinical outcome according to immune biomarkers
in blood and tumor tissue, such as PD-L1 immunohistochemistry (IHC) 22C3 pharmDx assay and
stratifying tumors as PD-L1 positive or negative on the basis of PD-L1 combined positive
score >= 1% in patients treated with anti- PD-L1 therapy.
III. Perform whole exome sequencing (WES) and methylation profiling on tumor samples and from
circulating-free deoxyribonucleic acid (cfDNA) to evaluate whether tumor mutational burden
(TMB) or specific genomic alterations are associated with improved progression free survival
(PFS) with the trial regimen.
IV. Gene and protein expression of tumor tissue through ribonucleic acid (RNA) sequencing and
Reverse Phase Protein Array (RPPA).
V. Quantify pre-treatment, pre- and post-olaparib, post-TRT, and at progression levels for
blood-based biomarkers, such as cytokines associated with immune activation (e.g., STING
pathway cytokines, CXCL10 and CCL5) to establish correlations with PFS and overall survival
(OS).
VI. Using longitudinal blood samples (e.g. pre-treatment, pre- and post-olaparib, post-TRT,
and at progression), assess CTC number, CTC (single-cell) biomarker expression (such as
SLFN11 and PD-L1 expression), and immune profile of PBMCs.
VIa. Correlate baseline expression or changes with PFS and OS. VII. Assess pre- and
post-olaparib, and at progression tumor tissue for immune markers, such as CD8+ T cells,
through multiplex IHC.
VIII. Assessment of single-cell biomarker expression on CTCs and tumor tissue (such as SLFN11
and PD-L1 expression) and immune profile of peripheral blood mononuclear cells (PBMCs).
VIIIa. Correlate pre-treatment expression or changes with PFS and/or OS. IX. Generation of
CTC-derived and/or biopsy-derived xenograft models from individual patients
OUTLINE:
CHEMO-IMMUNOTHERAPY: Patients receive durvalumab intravenously (IV) over 60 minutes on day 1,
carboplatin IV over 60 minutes on day 1, etoposide IV over 60 minutes on days 1-3. Treatment
repeats every 21 days for up to 4 cycles in the absence of disease progression or
unacceptable toxicity. Patients with response or stable disease (SD) after cycle 4 and are
candidates for TRT proceed to Induction. Patients that are not candidates for TRT proceed to
Single-Agent Maintenance.
INDUCTION (WEEKS 13-14): Patients receive olaparib orally (PO) twice daily (BID) on days 1-11
in the absence of disease progression or unacceptable toxicity.
IMMUNORADIATION (WEEKS 15-18): Patients receive durvalumab IV over 60 minutes on day 1.
Patients also undergo consolidative TRT daily on days 1-5 and 8-12 in the absence of disease
progression or unacceptable toxicity.
MAINTENANCE (WEEKS 19 AND BEYOND): Patients without progressive disease receive durvalumab IV
over 60 minutes on day 1, and olaparib PO BID. Cycles repeat every 28 days in the absence of
disease progression or unacceptable toxicity.
SINGLE-AGENT MAINTENANCE: Patients receive durvalumab IV over 60 minutes on day 1. Cycles
repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed for 30 days, then every 3 months.
Inclusion Criteria:
- Provision of signed and dated written informed consent form prior to any mandatory
study specific procedures, sampling, and analyses. For inclusion in i) the optional
exploratory genetic research and ii) the optional biomarker research, patients must
fulfill the following criteria:
- Provision of informed consent for genetic research prior to collection of sample;
- Provision of informed consent for biomarker research prior to collection of
sample;
- If a patient declines to participate in the optional exploratory genetic research
or the optional biomarker research, there will be no penalty or loss of benefit
to the patient. The patient will not be excluded from other aspects of the study
- At least one lesion (measurable and/or non-measurable) that can be accurately assessed
at baseline by computed tomography (CT) and is suitable for repeated assessment
- Patients with previously treated brain metastases that are asymptomatic for at least
14 days and only require prednisone equivalent of 10 mg daily or less prior to study
treatment
- Histological or cytological documented ES-SCLC: American Joint Committee on Cancer
(AJCC) stage IV SCLC (T any, N any, M1 a/b), including patients with T3-4 due to
multiple lung nodules that are too extensive or have tumor/nodal volume that is too
large to be encompassed in a tolerable radiation plan
- No prior systemic therapy for ES-SCLC, including, but not limited to, chemotherapy,
PARP inhibitor, and PD-1/PD-L1 checkpoint inhibitors. Palliative radiation is allowed
if completed a minimum of three days prior to beginning of study treatment
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 at enrollment
- Body weight > 30 kg
- Hemoglobin >=10.0 g/dL with no blood transfusion in the past 28 days (measured within
28 days prior to administration of study treatment)
- Absolute neutrophil count >= 1.5 x 10^9 /L (measured within 28 days prior to
administration of study treatment)
- Platelet count >= 100 x 10^9/L (measured within 28 days prior to administration of
study treatment)
- Serum bilirubin =<1.5 x institutional upper limit of normal (ULN) (measured within 28
days prior to administration of study treatment)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x
institutional ULN, unless liver metastases are present in which case they must be =< 5
x ULN (measured within 28 days prior to administration of study treatment)
- Calculated estimated creatinine clearance >= 51 mL/min using the Cockcroft- Gault
equation or based on a 24-hour urine test (measured within 28 days prior to
administration of study treatment)
- Evidence of post-menopausal status or evidence of non-childbearing status for women of
childbearing potential: negative urine or serum pregnancy test within 28 days of study
treatment and confirmed prior to treatment on day 1. Postmenopausal status 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 > 1-year interval since last menses
- Surgical sterilization (bilateral oophorectomy or hysterectomy)
- Women of childbearing potential and their partners, who are sexually active, must
agree to the use of TWO highly effective forms of contraception in combination.
This should be started from the signing of the informed consent and continue
throughout the period of taking study treatment and for at least 3 months after
last dose of study drug(s)
- Male patients must use a condom during 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. Male patients should not donate sperm throughout the period of taking
study treatment and for 3 months following the last dose of study treatment
- Subject is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including
follow-up
Exclusion Criteria:
- Histology other than SCLC
- Prior systemic therapy for ES-SCLC (e.g. chemotherapy, PARP inhibitor, other DNA
damage response [DDR] inhibitors, PD-1/PD-L1 inhibitors)
- Patients with untreated brain metastases
- Patients with spinal cord compression unless considered to have received definitive
treatment for this and evidence of clinically stable disease for 28 days
- Major surgical procedure (as defined by the Investigator) within 28 days prior to the
first dose of study treatment and patients must have recovered from any effects of any
major surgery. Note: Local surgery of isolated lesions for palliative intent is
acceptable
- Other malignancy unless curatively treated with no evidence of disease for >= 3 years
except:
- Adequately treated non-melanoma skin cancer.
- Curatively treated in situ cancer of the cervix; ductal carcinoma in situ (DCIS);
stage 1, grade 1 endometrial carcinoma; and in situ bladder cancer
- Any concurrent anticancer therapy
- Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible
cardiac conditions, as judged by the investigator (e.g. unstable ischemia,
uncontrolled symptomatic arrhythmia, congestive heart failure, QT corrected by
Fridericia [QTcF] prolongation > 500 ms, electrolyte disturbances, etc.), or patients
with congenital long QT syndrome
- Current or prior use of immunosuppressive medication within 14 days prior to cycle 1
(C1) of study treatment, with the exceptions 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
- Active or prior documented autoimmune disease within the past 2 years. NOTE: vitiligo,
alopecia, chronic skin condition that does not require systemic therapy, psoriasis not
requiring systemic treatment (within the past 2 years), and hypothyroidism (if stable
on hormonal therapy) are not exclusion criteria
- Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
ulcerative colitis) or pneumonitis
- Immunocompromised patients, e.g., patients who are known to be serologically positive
for human immunodeficiency virus (HIV)
- Previous allogenic bone marrow transplant or double umbilical cord blood
transplantation (dUCBT)
- Patients considered high medical risk due to a serious, uncontrolled medical disorder,
non-malignant systemic disease or active, uncontrolled infection. Examples include,
but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months)
myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord
compression, superior vena cava syndrome, extensive interstitial bilateral lung
disease on high resolution computed tomography (HRCT) scan or any psychiatric disorder
that prohibits obtaining informed consent
- Patients with myelodysplastic syndrome (MDS) / acute myeloid leukemia (AML) or with
features suggestive of MDS/AML
- Whole blood transfusions in the last 120 days prior to entry to the study (packed red
blood cells and platelet transfusions are acceptable outside of 28 days prior to
treatment)
- Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study medication
- Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin,
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g.
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
period prior to starting study treatment is 2 weeks
- Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin,
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or
moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout
period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital
and 3 weeks for other agents
- Participation in another clinical study with an investigational product (IP)
administered in the last 6 months
- Involvement in the planning and/or conduct of the study
- Previous enrollment in the present study
- Receipt of live attenuated vaccination within 30 days prior to study entry
- Female subjects who are pregnant, breast-feeding or male or female patients of
reproductive potential who are not employing two highly effective methods of birth
control
- Any condition that, in the opinion of the investigator, would interfere with
evaluation of study treatment or interpretation of patient safety or study results
- Known allergy or hypersensitivity to durvalumab, olaparib or any excipients
- Any persistent toxicity National Cancer Institute (NCI) Common Terminology Criteria
for Adverse Events (CTCAE) version (v) 5.0 grade >= 2 from previous anticancer therapy
with the exception of alopecia, vitiligo, and the laboratory values defined in the
inclusion criteria.
- Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis
after consultation with the study physician
- Patients with irreversible toxicity not reasonably expected to be exacerbated by
study treatment may be included only after consultation with the study physician
