Birinapant for Advanced Ovarian, Fallopian Tube, and Peritoneal Cancer
- 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.
- To test the effectiveness of Birinapant for ovarian, primary peritoneal, or fallopian tube cancer.
- Women at least 18 years of age who have ovarian, primary peritoneal, or fallopian tube cancer that has not responded to standard treatment.
- 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.
Epithelial Ovarian Cancer
Fallopian Tube Neoplasms
Drug: Birinapant (TL32711)
|Study Design:||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||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|
- Clinical benefit defined as objective response (CR or PR defined by RECIST version 1.1 criteria) or disease stabilization for greater than 6 months [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- Overall survival, safety and tolerability of single agent birinapant [ Time Frame: end of treatment ] [ Designated as safety issue: Yes ]
- Correlation of a gene index score based on the ratio of cFLIPl/cFLIPs and RIPK1 (and others candidate genes) with response to single agent birinapant [ Time Frame: end of treatment ] [ Designated as safety issue: No ]
- Relationship of serum and tumor levels of TNF alpha and TRAIL pre- and post- treatment with single agent birinapant [ Time Frame: end of treatment ] [ Designated as safety issue: No ]
- Pharmacodynamic changes in levels of the apoptosis/NFB pathway proteins cIAP1, cIAP2, cleaved PARP, cFLIP, RIPK1, activated caspase-8 and cleaved caspase 3 in paired pre and post-treatment tumor specimens and PBMCs [ Time Frame: end of treatment ] [ Designated as safety issue: No ]
- Correlation of clinical outcome with changes in the quantity of pre and post-treatment levels of cIAP1, cIAP2, PARP, c-FLIP, RIP1K, cleaved caspase-3 and and activated caspase-8 [ Time Frame: end of treatment ] [ Designated as safety issue: No ]
- Assessment of T-cell deficiency as a consequence of T-cell apoptosis induced by birinapant [ Time Frame: end of treatment ] [ Designated as safety issue: No ]
- Pharmacokinetics of birinapant in plasma and tumor tissues (if sufficient material) and to establish PK/PD correlations between drug exposure and efficacy/safety [ Time Frame: end of treatment ] [ Designated as safety issue: Yes ]
|Study Start Date:||August 2012|
|Study Completion Date:||April 2014|
|Primary Completion Date:||April 2014 (Final data collection date for primary outcome measure)|
Drug: Birinapant (TL32711)
47mg/m2 IV on days 1, 8 and 15 of each 28 day cycle
Hide Detailed Description
- 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 activation.
- 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 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.
- 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 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 (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 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 (CT scan) to document response will be performed at the end of 2 cycles and every 2 cycles thereafter.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01681368
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Christina M Annunziata, M.D.||National Cancer Institute (NCI)|