Clinical trial NCT01681368
Conditions: Epithelial Ovarian Cancer Peritoneal Neoplasms Fallopian Tube Neoplasms
Keywords: NF-Kappa B Pathway Response Biomarkers Progression-Free Survival Pharmacokinetics Pharmacodynamics
Sponsor: National Cancer Institute (NCI)
Start date: 2012-08-15; Completion date: 2014-04-30
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

\- Birinapant is an experimental cancer treatment drug. It removes certain proteins in cells, which helps to kill the cells. The drug is more likely to cause the death of cancer cells than normal cells because cancer cells have more of these proteins. Studies suggest that it can help treat ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. Researchers want to see how well Birinapant works against the three types of cancer.

Objectives:

\- To test the effectiveness of Birinapant for ovarian, primary peritoneal, or fallopian tube cancer.

Eligibility:

\- Women at least 18 years of age who have ovarian, primary peritoneal, or fallopian tube cancer that has not responded to standard treatment.

Design:

* Participants will be screened with a physical exam and medical history. Blood and urine samples will also be collected. Tumor tissue samples may be collected before treatment. Imaging studies will also be performed.
* Participants will have an infusion of Birinapant once per week for 3 weeks in a row, followed by a break for a week on the fourth week. This 4-week schedule is one cycle of treatment.
* Treatment will be monitored with frequent blood tests and imaging studies.
* Another optional tumor biopsy will be collected 6 weeks after the start of treatment.
* Treatment will continue as long as the cancer does not grow and the side effects are not severe.

Detailed description:
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.

Arms: arm 1: single arm
Interventions: intervention 1: Birinapant (TL32711)
Intervention descriptions: intervention 1: 47mg/m\^2 intravenous (IV) on days 1, 8 and 15 of each 28 day cycle

Protocol documents: