Birinapant for Advanced Ovarian, Fallopian Tube, and Peritoneal Cancer

Phase 2

Terminated

Conditions: Peritoneal Neoplasms
Fallopian Tube Neoplasms
Epithelial Ovarian Cancer

Interventions: Drug: Birinapant (TL32711)

Registration Number: NCT01681368

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 11

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Birinapant for Advanced Ovarian,Fallopian Tube & Peritoneal Ca	Birinapant (TL32711)	single arm

Primary Outcome Measures

Name	Time	Method
Objective Response (Complete Response (CR) or Partial Response (PR) Defined by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Criteria) or Disease Stabilization for Greater Than 6 Months	6 months	Per the RECIST criteria, CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10mm. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events	8 months	Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
Mean Plasma Concentration-Time Curve of Birinapant	30, 60, 120, 180 minutes after administration of first dose of Birinapant	Measurement of the plasma concentration of the Birinapant over time. It is used to characterize drug absorption. The single values were analyzed with liquid chromatography/tandem mass spectrometry via a proprietary methodology (TetraLogic Pharma,Malvern, Pa). The values were grouped and averaged for each of the patients to obtain the mean value for each time point.
Birinapant Concentration in Tumor Tissue	Prior to treatment and 12 to 22 hours following Cycle 2 Day 15	Levels of Birinapant were measured in core needle biopsies of tumor that had been frozen at the time of acquisition.
Calculated Volume of Distribution of Birinapant at Steady State (Vss) in Tumor Tissue	0-24hr	Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
Calculated Volume of Distribution of Birinapant at Steady State (Vss) in Plasma	0-24hr	Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
Ratio of Phosphorylated NF-kappaB-p65 Protein to Total NF-kappaBp65 Protein in Tumor Biopsy Samples	0-6 weeks	Proteins were measured using capillary western blot and ratio was calculated between phosphorylated and total NF-kappaB p65. Core 1 tumor samples and peripheral blood mononuclear cells (PBMCs) from each time point were lysed in T-PER buffer (Thermo Scientific) for protein quantification by an automated capillary electrophoresis immunoassay system (Simple Western). The tumor protein lysate (40-60 ng) or PBMC protein lysate (16-77 ng) was analyzed according to the manufacturer's instructions (ProteinSimple, Santa Clara, Calif).
Coexpression of Cleaved Caspase 3 and Gamma-H2AX in Fixed Specimens	Pre treatment and post treatment of Birinapant, approximately 0-6 weeks	Tumor biopsies were measured for cleaved caspase 3 and gamma-H2A.X by immunofluorescence microscopy. Fold change was calculated by comparing the post-treatment measurements to the pre-treatment levels.
Total Clearance of Birinapant After Administration	0-24hr	Clearance is a quantitative measure of the rate at which a drug substance is removed from the body.