PARP-inhibition and CTLA-4 Blockade in BRCA-deficient Ovarian Cancer

The mechanism of action of Olaparib, a potent inhibitor of mammalian PARP-1, PARP-2, and
PARP-3, has been proposed to involve the trapping of inactivated PARP onto single-stranded
breaks preventing their repair and generating a potential block for cellular DNA replication.
In tumors with homologous recombination deficiency, such as those with BRCA mutations, single
agent treatment with Olaparib can lead to cell death and tumor regressions by a process known
as synthetic lethality.

Tremelimumab is a human monoclonal immunoglobulin G2 (IgG2) antibody specific for human
cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a co-inhibitory receptor expressed on
activated T cells. Tremelimumab has been shown to block the inhibitory signal mediated by
interaction of human CTLA-4 on activated T cells with B7-1 and B7-2 on antigen-presenting
cells. This is thought to maintain T cell activation in the tumor microenvironment and
promote the establishment of tumor-specific immune responses.

Like melanoma, ovarian cancer is associated with significant tumor heterogeneity, and is also
a rational target for immune therapy. Although antitumor effects have been observed in
patients with epithelial ovarian cancer in response to anti-CTLA-4 antibody treatment,
evidence of clinical disease regression has not been demonstrated. Based on data indicating
that a subset of ovarian cancers associated with germline mutations in BRCA1/2 genes may be
more immunogenic, we hypothesized that BRCA-negative tumors would be particularly vulnerable
to checkpoint blockade, and that immune priming with targeted cytotoxic therapy using a
PARP-inhibitor would sensitize ovarian tumors to immune therapy and optimize patient
survival. We have demonstrated this in pre-clinical models of high grade BRCA1-negative
ovarian cancer.

Based on significant therapeutic benefit demonstrated in pre-clinical models, this clinical
trial evaluates the combination of Olaparib and Tremelimumab in women with recurrent
BRCA-deficient ovarian cancers.

Inclusion Criteria:

- Patients must have recurrent epithelial ovarian, fallopian tube, or primary peritoneal
carcinoma for which standard curative measures do not exist.

- Patients must have a confirmed germline mutation in the BRCA1 or BRCA2 gene

- Patients must have measurable disease as defined by World Health Organization (WHO)
criteria: at least 1 lesion that can be accurately measured in at least 1 dimension
(longest diameter to be recorded). Each lesion must be >1.0cm when measured by CT,
MRI, or caliper measurement by clinical exam; or >2.0cm when measured by chest x-ray.
Lymph nodes must be >1.5cm in short axis when measured by CT or MRI

- Patients with platinum-sensitive or platinum-resistant disease are eligible

- Patients must have received at least 1 prior course of platinum-based chemotherapy for
the management of primary disease including carboplatin, cisplatin, or another
platinum compound

- There are no restrictions on the total number of prior regimens patients may have
received

- Gynecologic Oncology Group (GOG) performance status of 0, 1, or 2

- Adequate organ and marrow function as defined below:

- Absolute neutrophil count (ANC) >1,500/mcl

- Platelets > 100,000/mcl

- Creatinine < 1.5x the institutional upper limit of normal (ULN)

- Bilirubin < 1.5x ULN

- Aspartate aminotransferase and Alanine aminotransferase < 3x ULN

- Alkaline phosphatase < 2.5x ULN

- Women of child-bearing potential must have a negative pregnancy test prior to study
entry and agree to use adequate contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry, for the duration of study participation,
and for 180 days following completion of therapy

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

- Patients must meet pre-entry requirements as specified

Exclusion Criteria:

- Recovery from effects of recent surgery, radiotherapy, or chemotherapy must be
demonstrated

- Patients should be free of active infection requiring antibiotic therapy (except for
uncomplicated urinary tract infections)

- Hormonal therapy directed at treatment for the cancer must be discontinued at least 1
week prior to enrollment. Hormone replacement therapy for symptom management is
permitted.

- Any other therapy directed at treating the cancer including chemotherapy,
biologic/targeted agents, and immunologic agents, must be discontinued at least 3
weeks prior to enrollment.

- Any prior radiation therapy must be discontinued at least 4 weeks prior to enrollment.

- A history of autoimmune disorders other than vitiligo (e.g., psoriasis, extensive
atopic dermatitis, asthma, inflammatory bowel disease, multiple sclerosis, uveitis,
vasculitis), chronic inflammatory condition, or any condition requiring concurrent use
of any systemic immunosuppressants or steroids for any reason are excluded from the
study. Any patient with an allo-transplant of any kind would be excluded as well,
including xenograft heart valve. Mild, intermittent asthma requiring only occasional
beta-agonist inhaler use or mild localized eczema will not be excluded.

- Chronic use of immune-suppressive drugs (i.e., systemic corticosteroids used in the
management of cancer or non-cancer related illnesses, e.g., COPD).

- Known HIV-positive patients and those with other acquired/inherited immunodeficiencies
are ineligible due the possibility of affecting the response to tremelimumab, and the
higher risk of active opportunistic infections.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to olaparib or tremelimumab, or other agents used in study.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Concomitant use of known potent cytochrome P450 isoform 3A4 (CYP3A4) inhibitors

- Persistent toxicities (> Common Terminology Criteria for Adverse Event (CTCAE) grade
2) caused by prior cancer therapy, excluding alopecia

- Must not be pregnant or nursing as the potential of this regimen to harm nursing
infants has not been evaluated.

- Patients who are receiving any other investigational agent

For Phase 2, the inclusion/exclusion criteria above apply. In addition, the following
exclusion criteria apply:

- Resting electrocardiogram with corrected QT interval (QTc) >470msec on two or more
time points within a 24hr period, or a family history of long QT syndrome

- Patients who have previously received anti-CTLA-4 antibody therapy