Pilot Trial of Olaparib in Patients with Unresectable or Metastatic Melanoma with Mutations in BRCA1/2 Genes

The purpose of this study is to evaluate how effective Olaparib is when given as a treatment
for primary or recurrent, unresectable or metastatic melanoma. This research study involves
targeted therapy.

-The name of the study drug involved in this study is: Olaparib (also known as Lynparza)

Inclusion Criteria:

- Subjects must have histologically or cytologically confirmed diagnosis of primary or
recurrent metastatic melanoma including cutaneous, mucosal, or uveal melanoma.

- Participants must have a germline or somatic DNA damage repair mutation or deletion in
BRCA1 or BRCA2. The result may have been obtained from one of the following test
providers: OncoPanel, SNaPshot Panel, Myriad Genetics, Invitae, Ambry, Quest, Colour
Genomics, IMPACT, Foundation Medicine (tissue or ctDNA based), Guardant, or another
CLIA approved tissue and/or serum based next generation sequencing-based assay.
(Variants of uncertain significance are excluded.)

- Participants must have measurable disease as defined by RECIST 1.1 criteria

- 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 Clinical examination) and which is suitable for accurate
repeated measurements.

- Subjects must have received prior checkpoint inhibitor therapy (defined as
anti-CTLA4 or anti-PD-1 or combination anti-CTLA4/anti-PD-1), either for
metastatic or unresectable disease or progressed on adjuvant therapy.

- Age ≥18 years. Because no dosing or adverse event data are currently available on
the use of olaparib in participants <18 years of age, children are excluded from
this study, but will be eligible for future pediatric trials.

- Patients must have a life expectancy ≥ 16 weeks.

- ECOG performance status ≤1(Karnofsky ≥60%, see Appendix A).

- Participants must have adequate organ and marrow function measured within 28 days
prior to administration of study treatment as defined below:

- Hemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days

- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

- Platelet count ≥ 100 x 109/L

- Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)

- 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 ≤ 5x ULN

- Patients must have creatinine clearance estimated of ≥51 mL/min using the
Cockcroft-Gault equation or based on a 24 hour urine test: Estimated creatinine
clearance = (140-age [years]) x weight (kg) (x F)a / serum creatinine (mg/dL) x
72 (where F=0.85 for females and F=1 for males).

- Participants must have the ability to swallow pills.

- Participants with a prior or concurrent malignancy whose natural history or treatment
does not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial.

- The effects of olaparib on the developing human fetus are unknown. For this reason and
because similar agents are known to be teratogenic, women of child-bearing potential
and men must agree to use adequate contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry and for the duration of study participation.
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. Men
must use a condom during treatment and for 3 months after the last dose of olaparib
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.

- 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)

- Measurable disease as defined by RECIST 1.1 criteria

-- At least one lesion, 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 Clinical examination) and
which is suitable for accurate repeated measurements.

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

- Participants who have had chemotherapy or radiotherapy (except for palliative reasons)
for melanoma within 3 weeks prior to entering the study.

- Participants who have not recovered from adverse events due to prior anti-cancer
therapy (i.e., have residual toxicities CTCAE > Grade 2) with the exception of
alopecia.

- Participants who are receiving any other investigational agents.

- Other malignancy unless curatively treated with no evidence of disease for ≥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. 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

- 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 as long as 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 a known hypersensitivity to olaparib or any of the excipients of the
product.

- 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. Because the lists of these agents are
constantly changing, it is important to regularly consult a frequently-updated medical
reference. As part of the enrollment/informed consent procedures, the participant will
be counseled on the risk of interactions with other agents, and what to do if new
medications need to be prescribed or if the participant is considering a new
over-the-counter medicine or herbal product.

- 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.

- Any previous treatment with a PARP inhibitor, including olaparib.

- 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.

- 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.

- Participants with psychiatric illness/social situations that would limit compliance
with study requirements.

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

- Major surgery within 2 weeks of starting study treatment and patients must have
recovered from any effects of any major surgery.

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

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

- Known HIV or AIDS-related illness.

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

- Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen
(HBsAg) result. Patients with a past or resolved HBV infection (defined as the
presence of hepatitis B core antibody and absence of HBsAg) are eligible.

- Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction is negative for HCV RNA.