Birinapant for Advanced Ovarian, Fallopian Tube, and Peritoneal Cancer

BACKGROUND:

- Ovarian cancer is the ninth most common cancer in women (excluding skin cancer). It
ranks fifth as the cause of cancer death in women. In the United States, 21,550 new
cases and 14,600 deaths are estimated annually.

- Approximately 90% of primary malignant ovarian tumors are epithelial (carcinomas).

- Although over 70% of women with advanced disease respond to optimal debulking surgery
followed by platinum-taxane based chemotherapy, duration of response is short and
relapse is common. Subsequent responses to salvage therapy regimens tend to be brief
(less than six months) due to the tumors progressive resistance to chemotherapy(1).

- A family of proteins, known as the Inhibitors of Apoptotic Proteins (or IAPs), plays a
critical role in blocking the apoptotic signals at multiple points. IAPs regulate a
number of pathways including classical or alternative nuclear factor-kappa B (NF-(K)B)
function, and activation of apoptosis through either the extrinsic or intrinsic
pathway. Baculoviral IAP repeat-containing protein 1 (cIAP1) acts as a critical switch
to promote the pro-survival nuclear factor kappa-B (NF-B) pathway and prevent caspase
activation.

- In normal cells that are stimulated to undergo apoptosis by either the extrinsic or
intrinsic pathway, second mitochondrial-derived activation of caspares (SMAC) is
released from the mitochondria, which antagonizes IAP, removes blockade to activated
caspase function, and thereby enables apoptotic cell death. In tumor cells, however,
apoptosis is dysregulated due to insufficient amounts of SMAC or upstream blockades to
apoptotic activation.

- Classical activation of NF-(K)B is dependent on the presence of cIAP1 and cIAP2
proteins as part of the TNF receptor-associated factor 2 (TRAF2) complex. SMAC inhibits
cIAP1 and cIAP2, leading to inactivation of tumor necrosis factor alpha (TNFalpha)
mediated NF- B activation. SMAC inhibition of cIAP1 and cIAP2 leads to pathway
up-regulation. Birinapant (TL32711) is a synthetic peptidomimetic antagonist of IAPs (a
SMAC-mimetic), which mimics endogenous SMAC resulting in the rapid and irreversible
initiation of apoptotic cell death. SMAC-mimetics represent a novel targeted
therapeutic approach for cancer therapy. The addition of a SMAC mimetic, can inhibit
NF- B activity, down-regulate cell survival pathways, and overcome blockades to the
apoptotic pathway leading to increased tumor cell death.

- Our laboratory has demonstrated that serous ovarian cancers have cell-autonomous
activation of NF-B signaling which was shown to correlate with poor prognosis.

- Therefore, we hypothesize that the SMAC-mimetic activity of birinapant may be
selectively toxic to those ovarian cancers that display high canonical NF-(K)B
activity.

- To summarize, relapsed platinum refractory or resistant ovarian cancer is a disease
with limited therapeutic options and poor prognosis. Birinapant offers the opportunity
to develop an effective and well tolerated therapeutic for the significant unmet need.

OBJECTIVES:

- The primary objective is to determine the efficacy as defined by Gynecologic Oncology
Group (GOG) criteria2 as either objective response or progession-free survival lasting
greater than 6 months, in patients with relapsed platinum refractory or resistant
ovarian cancer, primary peritoneal cancer, fallopian tube cancer treated with
birinapant.

- The seconday objectives include overall survival, safety and tolerability of single
agent birinapant in this population.

ELIGIBILITY CRITERIA:

- Females greater than or equal to 18 years of age with histologically proven advanced
metastatic or unresectable epithelial ovarian cancer that is relapsed or refractory to
prior platinum-based standard care systemic regimen.

- Life expectancy greater than 3 months.

- Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.

- Adequate organ functionas defined by liver, kidney, and hematologic laboratory testing.

Design:

- This is an open label, non-randomized phase II trial to determine the efficacy of
administration of the SMAC-mimetic birinapant in patients with relapsed platinum
refractory or resistant ovarian cancer, primary peritoneal cancer, fallopian tube
cancer.

- Birinapant will be given as a single agent until disease progression once weekly for
three weeks of 4 week intervals.

- The primary endpoint will be efficacy defined according to the GOG guidelines as
overall response rate or progression-free survival lasting at least 6 months. Overall
survival, toxicity and modulation of signal events in tumor are secondary measures.

- Patients will be evaluated at baseline and prior to each cycle by history and physical
examination and every two cycles by examination and imaging studies (computed
tomography (CT) scan). Laboratory studies will be performed weekly prior to each dose
except on week 4 (rest week).

- Tumor biopsy will be performed prior to birinapant initiation and an optional tumor
biopsy will be performed 2 to 48 hours after cycle 2 day 15 infusion.

- Peripheral blood mononuclear cells will also be harvested at the same time points as
the biopsies.

- Reassessment imaging (computed tomography (CT) scan) to document response will be
performed at the end of 2 cycles and every 2 cycles thereafter.

- INCLUSION CRITERIA:

Study participants will be eligible for study participation if they are/have:

- Females greater than or equal to 18 years of age. Because no dosing or adverse event
data are currently available on the use of birinapant in patients < 18 years of age,
children are excluded from this study, but will be eligible for future pediatric
trials.

- Able to understand and voluntarily sign a written informed consent, and are willing
and able to comply with the protocol requirements including the requirement for
biopsies for research purposes.

- Advanced metastatic or unresectable epithelial ovarian cancer, primary peritoneal
cancer or fallopian tube cancer that is relapsed and resistant or refractory to prior
platinum-based standard care systemic regimen. Patients who are unable to receive
further platinum, due to either allergic reaction or other medical reason, are
eligible for the protocol. There is no limitation on the amount of prior therapies
allowed.

- Patients must be at least 4 weeks from previous therapy (chemotherapy, hormonal
therapy, and radiation therapy, immunotherapy and monoclonal antibodies, alternative
therapy or investigational therapeutic agents). Patients who have had cranial
radiation therapy need to have completed it greater than or equal to 8 weeks prior to
commencing on study. Patients are permitted to receive investigational imaging agents
while on study.

- Patients who have had major surgery must be fully recovered and require a recovery
period of greater than or equal to 4 weeks prior to enrolling on study.

- Histopathologic diagnosis must be confirmed in the Laboratory of Pathology (LP),
National Cancer Institute (NCI).

A block of the primary tumor, or access to recut slides is preferred. If this is
unavailable, a recent resection specimen of a metastatic site is required for entry. In
addition, access to archival formalin fixed paraffin embedded (FFPE) tumor blocks will be
requested to perform correlative studies. Study participants with the following histologic
epithelial ovarian cancer cell types are eligible: Serous adenocarcinoma, endometrioid
adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell
adenocarcinoma, mixed epithelial carcinoma, transitional cell carcinoma, malignant
Brenner's Tumor, or adenocarcinoma not otherwise specified (N.O.S).

- Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors
defined as at least one lesion that can be accurately measured in at least one
dimension (longest diameter to be recorded for non-nodal lesions and short axis for
nodal lesions) as greater than or equal to 20 mm with conventional techniques or as
greater than or equal to 10 mm with spiral computed tomography (CT) scan, magnetic
resonance imaging (MRI), or calipers by clinical exam and a sentinel lesion adequate
for core biopsy through percutaneous biopsy. See Section 13 for the evaluation of
measurable disease.

- Life expectancy greater than 3 months.

- Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to
less than or equal to 2.

- Adequate renal function, defined as serum creatinine less than or equal to 1.5 X
upper limit of normal (ULN), or measured creatinine clearance greater than or equal
to 60 ml/min/1.73m^2.

- Adequate hepatic function, defined as aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) levels less than or equal to 3 X ULN and total bilirubin < 1.5
X ULN, unless known diagnosis of Gilberts syndrome.

- Adequate bone marrow function, defined as absolute neutrophil (ANC) greater than or
equal to 1,500/mm^3 (greater than or equal to1.5 X10^6/L), platelet count greater
than or equal to 75,000/mm^3 (greater than or equal to 75 X10^6/L), and hemoglobin
greater than or equal to 10 mg/dL (transfusion to obtain hemoglobin greater than or
equal to 10 mg/dL within 24 hours prior to dosing is allowed).

- Contraception is not a consideration as these patients have all had surgical removal
of their reproductive organs. Pregnant women are excluded from this study because
birinapant may have 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 birinapant, breastfeeding should be discontinued prior
to enrollment.

EXCLUSION CRITERIA:

1. Known or suspected diagnosis of human immunodeficiency virus or chronic active
hepatitis B or C. Viral testing is not required. The reason for exclusion is
insufficient evidence demonstrating safety of administration of birinapant in
patients with human immunodeficiency virus (HIV), hepatitis B or C due to theoretical
risk of unmasking or exacerbating these serious viral illnesses since birinapant may
impair immunological function. Data are not currently available on risk of
interaction with antiretroviral drugs. HIV-positive patients on combination
antiretroviral therapy are ineligible because of the potential for pharmacokinetic
interactions with birinapant. The potential immune suppressive effects and T-cell
depletion associated with birinapant pose an additional increased risk to these
patients. Appropriate studies will be undertaken in patients receiving combination
antiretroviral therapy when indicated.

2. Symptomatic or uncontrolled brain metastases requiring current treatment (< 8 weeks
from last cranial radiation or < 4 weeks from last steroids). (Patients with abnormal
clinical exam or history will require a head CT or MRI to rule out or confirm brain
metastases).

3. Impaired cardiac function or clinically significant cardiac disease including the
following:

1. New York Heart Association grade III or IV congestive heart failure.

2. Myocardial infarction within the last 12 months prior to dosing with birinapant.

3. Subjects known to have impaired left ventricular ejection fraction (LVEF)
according to institutional standards must be excluded.

4. Lack of recovery of prior adverse events to Grade less than or equal to1 severity
(National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]
v 4.03) (except alopecia) due to therapy administered prior to the initiation of
study drug dosing. Stable persistent grade 2 peripheral neuropathy may be allowed as
determined on a case-by-case basis at the discretion of the Investigator as
birinapant has not been shown to cause or exacerbate peripheral neuropathy.

5. Known allergy to any of the formulation components of birinapant including citric
acid monohydrate, sodium citrate dehydrate, and sodium chloride.

6. Any concurrent disease and/or medical condition that in the opinion of the
Investigator would prevent the subjects participation, render the subject at
excessive risk or limit the subjects compliance with the protocols required
evaluations.

7. Patients with active infection will not be eligible, but may become eligible once
infection has resolved and they are at least 7 days from completion of antibiotics.

8. Another previous or current malignancy within the last 5 years, with the exception of
non-melanoma skin cancer, cervical carcinoma in situ curatively treated, ductal or
lobular carcinoma in situ curatively treated and without ongoing therapeutic
intervention. Patients with breast cancer (BRCA) 1 or 2 mutation, who have had a
previous diagnosis of breast cancer are eligible if the breast cancer was diagnosed 5
years previously and distant or local recurrence of breast cancer has been outruled.

9. Concomitant chronic (daily or almost daily for greater than or equal to1 month prior)
use of steroids or non-steroidal anti-inflammatory drugs (NSAIDS). Intermittent use
of steroids as pre-medications is allowed. Based on research to date the tumor and
tumor microenvironment production of tumor necrosis factor (TNF) alpha could promote
anti-tumor activity. Theoretically, anti-inflammatories could blunt local production,
limiting this possibly positive cofactor.

10. No concomitant use of complementary or alternative medication or other agents
(investigational therapeutic agents) will be allowed without approval of a principal
investigator (PI) or associate investigator (AI). Every effort will be made to
maximize patient safety and minimize changes in chronic medications.

11. Patients with a recent history (within last 5 years) of autoimmune disease or
inflammatory diseases will be excluded, for example, active rheumatoid
arthritis,active inflammatory bowel disease or any chronic inflammatory conditions
because birinapant synergizes with TNF in vitro.

INCLUSION OF MINORITIES:

Women from all racial/ethnic groups are eligible for this study if they meet the
eligibility criteria.

To date, there is no information that suggests that differences in drug metabolism or
disease response would be expected in one group compared to another. Efforts will be made
to extend accrual to a representative population, but in this preliminary study, a balance
must be struck between patient safety considerations and limitations on the number of
individuals exposed to potentially toxic and/or ineffective treatments on the one hand and
the need to explore ethnic aspects of clinical research on the other hand. If differences
in outcome that correlate to ethnic identity are noted, accrual may be expanded or a
follow-up study may be written to investigate those differences more fully. This study
will be recruited through internal referral, our local physician referral base, and
through Cancer Hotline information.