Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma, or Solid Tumors With IDH1 or IDH2 Mutations

PRIMARY OBJECTIVES:

I. To estimate the overall response rates of olaparib in subjects with recurrent/progressive
IDH1/2-mutant solid tumors, who will be recruited to 3 cohorts: a. glioma, b.
cholangiocarcinoma, c. other solid malignant tumors.

SECONDARY OBJECTIVES:

I. To estimate the distribution of progression free survival (PFS) of olaparib in adults with
recurrent/progressive IDH1/2-mutant glioma and cholangiocarcinoma.

II. To estimate the overall survival (OS) in adults with recurrent/progressive IDH1/2- mutant
glioma and cholangiocarcinoma.

III. To determine the duration of response in adults with recurrent/progressive IDH1/2-mutant
glioma, cholangiocarcinoma or other solid malignant tumors.

IV. To confirm the safety and tolerability of olaparib monotherapy.

EXPLORATORY OBJECTIVES:

I. To describe 2HG concentration in plasma by mass spectrometry at baseline and at specific
timepoints and correlate with treatment response.

II. To describe 2HG levels in tumor biopsies from prior to the beginning of treatment and at
specific timepoints and correlate with treatment response.

III. To evaluate in tumor biopsies and in liquid biopsies performed at baseline and at
specific timepoints if co-occurring alterations detected via multiplexed immunofluorescence,
mass cytometry (CyTOF)-imaging mass cytometry (IMC), ribonucleic acid (RNA) sequencing and/or
deoxyribonucleic acid (DNA) sequencing can be associated with differential levels of 2HG
production, treatment response and resistance.

OUTLINE:

Patients receive olaparib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Subjects must be able to understand the nature of this trial and provide written
informed consent, prior to any study specific procedures; patients with Impaired
Decision Making Capacity (IDMC) who have a close caregiver or legally authorized
representative (LAR) may be considered eligible for this study at the treating
physician's discretion, provided that the physician is reasonably sure that the
possible risks and benefits of the study are clear and that the patient will take the
drug as prescribed

- Subjects must be diagnosed with a glioma, cholangiocarcinoma or other solid malignant
tumor that has progressed despite standard therapy, or for which no effective standard
therapy exists, with biopsy-confirmed evidence of an IDH1 or IDH2 mutation associated
with neomorphic activity of the encoded proteins; patients must have IDH1 or IDH2
mutation which must be detected in a clinical accredited laboratory using a Food and
Drug Administration (FDA)-approved molecular test or a validated deoxyribonucleic acid
(DNA)-based assay conducted in a Clinical Laboratory Improvement Amendments
(CLIA)-certified laboratory; only specific mutations that lead to a neomorphic
phenotype will be eligible for enrollment, and include IDH1: R132V, R132G, R132S,
R132L, R132C and R132H; IDH2: R140W, R140L, R140Q, R172W, R172G, R172S, R172M, R172K

- Patients must have tumors determined to be easily accessible for biopsy and must be
willing to have serial biopsies (with a third biopsy upon evidence of disease
progression); in case of multiple lesions, tumor biopsies will be performed on the
most accessible site of disease; all possible precautions to avoid complications will
be taken, including discussions in multidisciplinary meetings, if needed; patients
affected by glioma will not be considered for study biopsies

- Patients must be willing to undergo extra blood sampling for correlative studies

- Subjects with extracranial disease must have evaluable disease by Response Evaluation
Criteria in Solid Tumors version 1.1 (RECIST v1.1); subjects affected by glioma must
have evaluable disease by Response Assessment in Neuro-Oncology Criteria (RANO)
criteria

- For subjects with glioma, specific inclusion criteria are as follows:

- The disease should be recurrent or transformed glioma; subjects must not have had
prior surgery (biopsy allowed) or radiation therapy within 3 weeks of enrollment

- There must be an enhancing component of disease, as evaluated on pre-treatment
magnetic resonance imaging (MRI)

- For patients with World Health Organization (WHO) grade III or IV glioma and
progressive disease < 12 weeks after completion of chemoradiotherapy, progression
can be defined by the following set of criteria:

- New enhancement outside of the radiation field (beyond the high-dose region
or 80% isodose line)

- If there is unequivocal evidence of viable tumor on histopathologic sampling
(e.g., solid tumor areas. i.e., > 70% tumor cell nuclei in areas), high or
progressive increase in MIB-1 proliferation index compared with prior
biopsy, or evidence for histologic progression or increased anaplasia in
tumor);

- Note: Given the difficulty of differentiating true progression from
pseudoprogression, clinical decline alone, in the absence of radiographic or
histologic confirmation of progression, will not be sufficient for
definition of progressive disease in the first 12 weeks after completion of
concurrent chemoradiotherapy

- For patients with WHO grade III or IV glioma and progressive disease >= 12 weeks
after completion of chemoradiotherapy, progression can be defined by the
following set of criteria:

- New contrast-enhancing lesion outside of radiation field on decreasing,
stable, or increasing doses of corticosteroids

- Increase by >= 25% in the sum of the products of perpendicular diameters
between the first post-radiotherapy scan, or a subsequent scan with smaller
tumor size, and the scan at 12 weeks or later on stable or increasing doses
of corticosteroids

- For patients receiving antiangiogenic therapy, significant increase in
T2/fluid attenuated inversion recovery (FLAIR) non-enhancing lesion may also
be considered progressive disease; the increased T2/FLAIR must have occurred
with the patient on stable or increasing doses of corticosteroids compared
with baseline scan or best response after initiation of therapy and not be a
result of comorbid events (e.g., effects of radiation therapy,
demyelination, ischemic injury, infection, seizures, postoperative changes,
or other treatment effects)

- Note: Clinical deterioration alone is not attributable to concurrent
medication or comorbid conditions is sufficient to declare progression on
current treatment but not for entry onto a clinical trial for recurrence

- For patients with WHO grade II glioma progression is defined by any one of the
following:

- Development of new lesions or increase of enhancement (radiological evidence
of malignant transformation)

- A 25% increase of the T2 or FLAIR non-enhancing lesion on stable or
increasing doses of corticosteroids compared with baseline scan or best
response after initiation of therapy, not attributable to radiation effect
or to comorbid events

- For subject with extracranial disease, they must have 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) or >= 10 mm with calipers
by clinical exam OR at least one lesion (measurable and/or non-measurable) that can be
accurately assessed by CT/MRI/pain x-ray/clinical exam at baseline and follow up
visits

- Subjects must have progressive cancer at the time of study entry; prior experimental
(non-FDA approved) therapies (other than drugs that share the same target) and
immunotherapies are allowed; patients must not have received these therapies for 30
days or five half-lives of the drug (whichever is less) prior to the initiation of
study treatment; toxicities from these therapies should have recovered to =< grade 1,
with the exception of stable chronic grade 2 that is not overlapping with presumed
toxicities of olaparib

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Karnofsky >= 50%)

- Hemoglobin >= 10.0 g/dL with no blood transfusion in the past 28 days (within 28 days
prior to administration of study treatment)

- Leukocytes >= 3,000/mcL (within 28 days prior to administration of study treatment)

- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (within 28 days prior to
administration of study treatment)

- Platelet count >= 100 x 10^9/L (within 28 days prior to administration of study
treatment)

- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 28 days
prior to administration of study treatment)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal unless liver metastases are present in
which case they must be =< 5 x ULN (within 28 days prior to administration of study
treatment)

- Creatinine clearance estimated using the Cockcroft-Gault equation of >= 51 mL/min
(within 28 days prior to administration of study treatment)

- No features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
on peripheral blood smear

- Patients must have a life expectancy >= 16 weeks

- Patient 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

- No previous treatment with the specific assigned study drug or any other PARP
inhibitor

- Prior radiation therapy is allowed; patients must not have received radiation therapy
within 3 weeks prior to the initiation of study treatment

- Women of child-bearing potential are expected to use highly effective contraception
during the study and for 1 month after the last dose of study drug; postmenopausal 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 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)

- Male patients and their partners, who are sexually active and of childbearing
potential, must agree to the use of two highly effective forms of contraception in
combination, throughout the period of taking study treatment and for 3 months after
last dose of study drug(s) to prevent pregnancy in a partner

Exclusion Criteria:

- Patients should not enter the study if any of the following exclusion criteria are
fulfilled

- Involvement in the planning and/or conduct of the study

- Previous enrollment in the present study

- Participation in another clinical study with an investigational product during the
last 30 days or five half-lives of the drug (whichever is less) prior to the
initiation of study treatment (6 weeks for nitrosoureas or mitomycin C)

- Any previous treatment with PARP inhibitor, including olaparib

- Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
reasons) within 3 weeks prior to study treatment

- Other malignancy within the last 5 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, or other solid tumors including
lymphomas (without bone marrow involvement) curatively treated with no evidence of
disease for >= 5 years; patients with a history of localized triple negative breast
cancer may be eligible, provided they completed their adjuvant chemotherapy more than
three years prior to registration, and that the patient remains free of recurrent or
metastatic disease

- Resting electrocardiogram (ECG) with corrected QT interval (QTc) > 470 msec or family
history of long QT syndrome

- 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 olaparib 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 olaparib is 5 weeks for enzalutamide or phenobarbital and 3
weeks for other agents

- Persistent toxicities caused by previous cancer therapy; toxicities should have
recovered to =< grade 1, excluding alopecia and stable chronic grade 2 toxicity that
is not overlapping with presumed toxicities of olaparib

- Patients with myelodysplastic syndrome/acute myeloid leukemia or with features
suggestive of MDS/AML

- Patients with symptomatic uncontrolled brain metastases; a scan to confirm the absence
of brain metastases is not required; the patient can receive a stable dose of
corticosteroids before and during the study if these were started at least 4 weeks
prior to treatment; patients with spinal cord compression unless considered to have
received definitive treatment for this and evidence of clinically stable disease for
28 days; patients with known uncontrolled brain metastases should be excluded from
this clinical trial

- Major surgery within 2 weeks of starting study treatment; effects from surgeries
should have recovered to =< grade 1, with the exception of stable chronic grade 2 that
is not overlapping with presumed toxicities of olaparib

- Patients 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, 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 and would limit compliance with study
requirements

- Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study medication

- Women who are actively breast feeding

- Immunocompromised patients, e.g., patients who are known to be serologically positive
for human immunodeficiency virus (HIV); HIV-positive patients on combination
antiretroviral therapy are ineligible

- Patients with a known hypersensitivity to olaparib or any of the excipients of the
product; history of allergic reactions attributed to compounds of similar chemical or
biologic composition to olaparib

- Patients with known active hepatitis (i.e. hepatitis B or C)

- Previous allogeneic bone marrow transplant or double umbilical cord blood
transplantation (dUCBT)

- Whole blood transfusions in the last 120 days prior to entry to the study (packed red
blood cells and platelet transfusions are acceptable)

- Patients who are receiving any other investigational agents

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with olaparib