Phase II Open Label Non-Randomized Single Agent Study of the SMAC (Second Mitochondrial-Derived Activator of Caspases)-Mimetic Birinapant (TL32711; NSC 756502) in Relapsed Platinum Resistant or Refractory Epithelial Ovarian Cancer, Primary Peritoneal
- 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 NF-(K)B function, and activation
of apoptosis through either the extrinsic or intrinsic pathway. cIAP1 acts as a
critical switch to promote the pro-survival NF-?B pathway and prevent caspase
- In normal cells that are stimulated to undergo apoptosis by either the extrinsic or
intrinsic pathway, 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 TRAF2 complex. SMAC inhibits cIAP1 and cIAP2, leading to
inactivation of 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
- 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.
- The primary objective is to determine the efficacy as defined by 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.
- 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.
- 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
- 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 (CT scan).
Laboratory studies will be performed weekly prior to each dose except on week 4 (rest
- Tumor biopsy will be performed prior to birinapant initiation and an optional tumor
biopsy will be performed 2 - 48 hours after cycle 2 day 15 infusion.
- Peripheral blood mononuclear cells will also be harvested at the same time points as
- Reassessment imaging (CT scan) to document response will be performed at the end of 2
cycles and every 2 cycles thereafter.
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Objective response (CR or PR) or disease stabilization for > 6 months
Christina M Annunziata, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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