This research study is a Phase I/II clinical trial, which has two parts. The participant will
be asked to participate in one part of the study. The first part tests the safety of the
combination of drugs and tries to define the appropriate dose to use for future studies. The
second part tests whether the combination of drugs is effective in treating small cell lung
cancer. "Investigational" means that the combination of drugs is being studied. It also means
that the U.S. Food and Drug Administration (FDA) has not approved the combination of drugs
for Small Cell Lung Cancer.
Olaparib (Lynparza) is FDA approved for the treatment of a type of ovarian cancer associated
with a particular DNA change. Olaparib works by blocking the activity of a protein called
poly (ADP-ribose) polymerase (PARP) which is involved in DNA repair. Cancer cells rely on
PARP to repair their DNA and enable them to continue dividing. Olaparib has been used in
research studies with other cancers. Information from those other research studies suggests
that this drug may help to treat patients with small cell lung cancer. While it is not
approved by the FDA for small cell lung cancer, it is considered part of standard treatment
for other cancer.
Temozolomide (Temodar) is approved by the FDA for the treatment of a type of brain tumor,
glioblastoma. It has been studied in small cell lung cancer in previous research studies.
While it is not approved by the FDA for small cell lung cancer, it is considered part of
standard treatment for relapsed disease.
In this research study, the investigators are looking for the maximum tolerated dose or MTD
of the combination of olaparib and temozolomide that can be given safely. The investigators
will also begin to collect information about the effects of the combination on small cell
- Patients must meet the following criteria on screening examination to be eligible to
participate in the study. The eligibility criteria apply to both the phase I and phase
II portions of the study.
- Participant must have histologically or cytologically confirmed small cell lung cancer
and may not be a candidate for potentially curative therapy.
- Presence of measurable disease (RECIST 1.1): At least one lesion, not previously
irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest
diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed
tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate
- The small cell lung cancer must have progressed radiographically following a
platinum-based (cisplatin and/or carboplatin) standard prior chemotherapy regimen. Any
number of interval prior lines of therapy is allowed. Patients who have received prior
platinum-based chemotherapy and radiation for limited stage SCLC and have subsequently
developed relapsed disease are eligible, as long as the platinum-based therapy was
given within 12 months prior to the time of relapse.
- Participant (male/female) must be ≥18 years of age.
- Participant must have normal organ and bone marrow function measured within 28 days
prior to administration of study treatment as defined below:
- Hemoglobin ≥ 10.0 g/dL
- Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
- Platelet count ≥100 x 10^9/L
- Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
- AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal (unless liver
metastases are present in which case it must be ≤5 x ULN)
- Serum creatinine ≤1.5 x institutional upper limit of normal (ULN)
- ECOG performance status 0-1
- Participant must have a life expectancy ≥ 16 weeks.
- Women of childbearing potential must have a negative urine or serum pregnancy test
within 28 days of initial dose of olaparib and temozolomide AND must agree to the use
of two highly effective forms of contraception (see Section 5.5) throughout their
participation in the study and for at least 3 months after the last dose of olaparib
and temozolomide, OR confirmed prior to treatment on day 1 to be postmenopausal or
surgically sterile. Postmenopausal is defined as:
- Amenorrheic for 1 year or more following cessation of exogenous hormonal
- LH and 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, or
surgical sterilisation (bilateral oophorectomy or hysterectomy).
- Participant is willing to comply with the protocol for the duration of the study, and
undergo treatment and scheduled visits and examinations including follow up.
Participant must obtain prior approval from insurance to reimburse for oral
temozolomide for the duration of the study or agree to self-pay for oral temozolomide.
- Participants who exhibit any of the following conditions at screening will not be
eligible for admission into the study. The exclusion criteria apply to both the phase
I and phase II portions of the study.
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site).
- Previous enrollment in the present study.
- Participation in another clinical study with an investigational product during the 21
days prior to first dose of olaparib and temozolomide.
- Participants receiving any systemic chemotherapy, radiotherapy (except for palliative
reasons), within 2 weeks from the last dose prior to study treatment (or a longer
period depending on the defined characteristics of the agents used). The patient can
receive a stable dose of bisphosphonates for bone metastases, before and during the
study as long as these were started at least 4 weeks prior to treatment with olaparib
- Participants are to discontinue the use of the following classes of inhibitors of
CYP3A4. Patients who are on these drugs are eligible if a washout period of a minimum
of 7 days occurs before start of olaparib and temozolomide.
- Azole antifungals
- Macrolide antibiotics
- Protease inhibitors
- Persistent clinically significant toxicities (>=CTCAE v. 4.0 grade 2) caused by
previous cancer therapy, with the exception of alopecia.
- Participants with a previously documented diagnosis of myelodysplastic syndrome (MDS)
(or any dysplastic leukocyte morphology suggestive of MDS) or acute myeloid leukaemia.
- Participants with symptomatic uncontrolled brain metastases. Baseline brain imaging by
CT or MRI is required for all patients. Participants with brain metastases that have
been treated with prior radiation therapy and are stable on a subsequent scan are
allowed. Participants with untreated possible brain metastases that are new at the
time of screening and are < 1 cm and asymptomatic are allowed. The participant can
receive corticosteroids as long as these were started and at a stable dose at least 28
days prior to treatment.
- Major surgery within 14 days of starting study treatment and patients must have
recovered from any effects of any major surgery.
- Participants considered a poor medical risk due to a serious, uncontrolled medical
disorder, non-malignant systemic disease or active, uncontrolled infection. Examples
include, but are not limited to, QTc prolongation > 470 msec, uncontrolled ventricular
arrhythmia, recent (within 3 months) myocardial infarction, unstable spinal cord
compression (untreated and unstable for at least 28 days prior to study entry),
extensive bilateral lung disease with less than 20% predicted lung function by DLCO
(Lung Diffusion Capacity Testing), or any psychiatric disorder that prohibits
obtaining informed consent.
- Participants unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study
- Pregnant or Breast feeding women. All patients (male and female) must agree to
practice a medically acceptable method of contraception as defined in section 5.5.
Should a woman become pregnant or suspect that she is pregnant while participating in
this study, she should inform her treating physician immediately.
- Patients who have a history of and are known to be serologically positive for human
immunodeficiency virus (HIV) and are receiving antiviral therapy. Baseline testing is
- Patients with known active Hepatitis B or C. Baseline testing is not required.
- Patients with a known hypersensitivity to olaparib or any of the excipients of the
- Patients with uncontrolled seizures.
- Patients with second primary cancer, except: adequately treated non-melanoma skin
cancer, curatively treated in-situ cancer of the cervix, or other solid tumors
curatively treated with no evidence of disease for ≥ 5 years.
- Patients with current and symptomatic pneumonitis, or extensive bilateral lung disease
on high resolution CT scan.
- Patients with whole blood transfusion in the last 120 days prior to entry to the
- Patients with previous allogeneic bone marrow transplant.
- Patients with active, uncontrolled infection.
- Patients who need to continue treatment with any prohibited medications listed in
- Patients who have not completed the appropriate washout period for the prohibited
medications in Section 5.6