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Ovarian Cancer

Ovarian Epithelial Cancer

47mg/m\^2 intravenous (IV) on days 1, 8 and 15 of each 28 day cycle

Birinapant (TL32711)

Christina M Annunziata, M.D.

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.

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.

Birinapant for Advanced Ovarian, Fallopian Tube, and Peritoneal Cancer

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

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.

Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.

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.

Levels of Birinapant were measured in core needle biopsies of tumor that had been frozen at the time of acquisition.

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.

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).

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.

Clearance is a quantitative measure of the rate at which a drug substance is removed from the body.

National Cancer Institute (NCI)

Principal Investigator

single arm

Birinapant (TL32711): 47mg/m\^2 intravenous (IV) on days 1, 8 and 15 of each 28 day cycle

Birinapant for Advanced Ovarian,Fallopian Tube & Peritoneal Ca

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

ECOG: 0 (Normal activity. Fully active, able to carry on all pre-disease performance without restriction.), 1 (Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work), and 2 (In bed \<50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hour.).

Eastern Cooperative Oncology Group (ECOG)

Histologic subtype, No.

No. of Prior Therapies

Chemotherapy

Biologic

Hormonal

Vaccine

Type of Prior Therapy, No.

Dr. Christina Annunziata

Complete Response

Partial Response

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

Number of Participants With Adverse Events

Predose

30 minutes post end of infusion (EOI)

60 minutes post end of infusion (EOI)

120 minutes post end of infusion (EOI)

240 minutes post end of infusion (EOI)

Mean Plasma Concentration-Time Curve of Birinapant

4 patients did not have the second paired biopsy due to patient refusal.

Birinapant Concentration in Tumor Tissue

Calculated Volume of Distribution of Birinapant at Steady State (Vss) in Tumor Tissue

Calculated Volume of Distribution of Birinapant at Steady State (Vss) in Plasma

Ratio of Phosphorylated NF-kappaB-p65 Protein to Total NF-kappaBp65 Protein in Tumor Biopsy Samples

Only 2 pairs of adequate pre- and post-treatment biopsy samples were available for analysis. The remaining paired samples were inadequate for immunohistochemistry because of necrotic debris in the post-treatment biopsy sample (1 specimen) or contamination with blood (4 specimens).

Coexpression of Cleaved Caspase 3 and Gamma-H2AX in Fixed Specimens

Total Clearance of Birinapant After Administration

Overall Study

Blood and Lymph Conditions

Immune System Diseases

Lymphoma

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

30 minute intravenous (IV) infusion administered once weekly for three consecutive weeks followed by a one week off (Cycle) repeated every 4 weeks as tolerated

Ravi Amaravadi, MD

Lainie P Martin, MD

Alex Adjei, MD, PhD

A Phase 1 open-label, non-randomized dose escalation study to determine the maximum tolerated dose (MTD) and characterize the safety and tolerability of Birinapant (TL32711).

The purpose of this Phase 1 open-label, non-randomized dose escalation study is to determine the maximum tolerated dose (MTD) and characterize the safety and tolerability of Birinapant (TL32711) when administered as a 30 minute intravenous infusion once weekly for three weeks per repeated 4 week intervals in subjects with refractory solid tumors or lymphoma. Additionally study will assess anti-tumor activity, pharmacokinetics, and exploratory biomarkers as a measurement of pharmacodynamic effects.

Dose Escalation Safety Study of TL32711 in Adults With Refractory Solid Tumors or Lymphoma

A Phase 1, Open-Label, Non-randomized, Dose Escalation Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of TL32711 in Adults With Refractory Solid Tumors or Lymphoma

TetraLogic Pharmaceuticals

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Birinapant for Advanced Ovarian, Fallopian Tube, and Peritoneal Cancer	NCT01681368	Epithelial Ovar... Peritoneal Neop... Fallopian Tube ...	Birinapant (TL3...	18 Years -	National Institutes of Health Clinical Center (CC)
Dose Escalation Safety Study of TL32711 in Adults With Refractory Solid Tumors or Lymphoma	NCT00993239	Cancer	Birinapant (TL3...	18 Years -	TetraLogic Pharmaceuticals
Dose Escalation Safety Study of TL32711 in Adults With Refractory Solid Tumors or Lymphoma	NCT00993239	Cancer	Birinapant (TL3...	18 Years -	TetraLogic Pharmaceuticals

Spots Global Cancer Trial Database for birinapant (tl32711)