Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

All Conditions

Rare Diseases

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Carcinoma

Fallopian Tube Neoplasms

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endocrine System Diseases

Gonadal Disorders

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Fallopian Tube Diseases

Ovarian Cancer

Ovarian Epithelial Cancer

Fallopian Tube Cancer

Antineoplastic Agents

All Drugs and Chemicals

Conatumumab

Antineoplastic Agents, Immunological

Dose Escalation:

Dose Level (1) - 13 mg/m2 (twice a week for 3 of 4 weeks); Dose Level (-1) - 11 mg/m2 (twice a week for 3 of 4 weeks); Dose Level (2) - 13 mg/m2 (twice weekly for 4 weeks );

Birinapant

10 mg/kg IV on Day 1 and 15 of each cycle

This is a dose escalation study in female subjects with relapsed ovarian cancer (including epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer). Approximately 30 to 40 subjects will be administered a combination of conatumumab and birinapant.

In the initial dose-escalation stage of the study, adult female subjects will receive conatumumab in combination with increasing doses of birinapant in dose-escalation cohorts to determine the MTD of birinapant when administered with a fixed dose of conatumumab.

In safety expansion stage, adult female subjects will receive conatumumab in combination with birinapant at the MTD of the combination.

Study of Birinapant in Combination With Conatumumab in Subjects With Relapsed Ovarian Cancer

A Phase 1b, Open-label, Non-randomized Multicenter Study of Birinapant in Combination With Conatumumab in Subjects With Relapsed Epithelial Ovarian Cancer, Primary Peritoneal Cancer or Fallopian Tube Cancer

TetraLogic Pharmaceuticals

Symptoms and General Pathology

Blood and Lymph Conditions

Syndrome

Preleukemia

Myelodysplastic Syndromes

Bone Marrow Diseases

Hematologic Diseases

Precancerous Conditions

Azacitidine

Decitabine

Antimetabolites

Enzyme Inhibitors

Dose escalation part: (Drug escalation dose levels)

* Dose Level (1) - 13mg/m2 (twice a week for 3 of 4 weeks)
* Dose Level (-1) - 11 mg/m2 (twice a week for 3 of 4 weeks)
* Dose Level (2) - 13mg/m2 (twice weekly x 4 weeks)
* Dose Level (3a) - 17mg/m2 (twice weekly × 4 weeks)OR
* Dose Level (3b) - 17mg/m2 (twice a week for 3 of 4 weeks)

5-Azacitidine

Gautam Borthakur, MD

This is a dose escalation followed by dose expansion study of TL32711 in combination with 5-Azacitidine in subjects with Myelodysplastic syndrome who are naïve, have relapsed or have failed prior 5-azacitidine therapy. Pre-clinical and mechanistic studies support that 5-Azacitidine may modulate pathways that enable birinapant-mediated anti-tumor activity.

This is a Phase 1b/2a, open-label, non-randomized study in male and female subjects with MDS who are naïve, refractory or have relapsed to 5-Azacitidine therapy.

Primary Objective is to determine the maximum tolerated dose (MTD), recommended Phase 2 dose, and pharmacodynamics (PD) of birinapant (TL32711) when administered in combination with 5-azacitidine (5 AZA) in subjects with myelodysplastic syndrome (MDS) who are naïve, refractory or have relapsed to 5-AZA therapy.

Secondary Objectives are to determine the clinical activity using the International Working Group (IWG) (Cheson, 2006) Response Criteria for MDS during the Phase 1b dose escalation stage of the study and in the Phase 2a expansion cohort, to determine the pharmacokinetics (PK) of birinapant when administered with 5-AZA in plasma and to assess exploratory translational biomarkers of anti-tumor activity of birinapant in combination therapy.

Birinapant With 5-azacitidine in MDS Subjects Who Are Naïve, Have Relapsed or Are Refractory to 5-azacitidine Therapy

A Phase 1b/2a, Open-label, Non-randomized Study of Birinapant in Combination With 5-azacitidine in Subjects With Myelodysplastic Syndrome Who Are Naïve, Refractory or Have Relapsed to 5-azacitidine Therapy

Pembrolizumab

Immune Checkpoint Inhibitors

Birinapant in combination with pembrolizumab

Birinapant intravenous (IV) on Days 1 and 8 of each 21-Day Cycle. The following escalating doses of birinapant to be studied: 5.6, 11, 17, and 22 mg/m2. In the expansion phase the assigned recommended phase two dose will be administered in all cohorts

200 mg pembrolizumab IV on Day 1 of each 21-Day Cycle

An ascending dose study in patients with solid tumors to evaluate the safety, tolerability, pharmacodynamics and efficacy of birinapant when given in combination with pembrolizumab. A dose expansion phase of 4 cohorts will also be included.

This study will be conducted in two phases. The Phase 1 portion of the study will employ a sequential group dose-escalation design to determine the dose-limiting toxicity (DLT) and recommended Phase 2 dose (RP2D) of birinapant administered in combination with 200 mg pembrolizumab, both administered as a 30-minute intravenous (IV) infusion. The following proposed doses of birinapant are to be evaluated: 5.6, 11, 17, and 22 mg/m2.

The Phase 2 portion, the dose expansion phase, will compromise 4 cohorts of 26-30 patients.

The 4 cohorts will include the following:

* Colorectal cancer
* Ovarian Cancer
* Cervical cancer
* Various solid tumors (30 patients, including 5 patients with each of the following 6 tumor types: Head and Neck Squamous Cell Carcinoma (HNSCC)-checkpoint-inhibitor naïve; and HNSCC checkpoint-inhibitor experienced; Gastroesophageal carcinoma; Mesothelioma; Small cell lung cancer (SCLC); Cholangiocarcinoma

A Simon's 2-stage design will be used for each of the cohorts in colorectal cancer, ovarian cancer and cervical cancer. A predefined interim analysis allowing stopping each of these cohorts for futility and safety will be conducted in the first stage to limit undue exposure before further inclusion into a given cohort. The design of the various solid tumors cohort will limit undue exposure in any of the selected tumor types by limiting the number of enrolled patient to five in each tumor type.

Dose-escalation Study of Birinapant and Pembrolizumab in Solid Tumors

A Phase 1/2 Multicenter, Single-Arm, Open-Label, Dose-Escalation Study of Birinapant in Combination With Pembrolizumab (KEYTRUDA®) in Patients With Relapsed or Refractory Solid Tumors

To be evaluated according to immune response evaluation criteria in solid tumors (iRECIST)

Measured by inhibitor of apoptosis proteins (IAPs), cytokines, tumor infiltrating lymphocytes (TILs) cluster of differentiation (CD)3, CD4, CD8, and CD19 as well as absolute neutrophil and lymphocyte counts

Measured by: Programmed death ligand 1 (PD-1L), programmed cell death protein 1 receptor (PD-1) and related proteins, genome analysis, IAP gene copy number and TILs cluster of differentiation (CD)3, CD4, CD8 and CD19

The plasma concentrations of birinapant was to be measured and summarized descriptively

Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through blood pressure.

Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through electrocardiogram.

Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through amylase and lipase.

Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through thyroxine free.

Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through Thyrotropin.

Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through hemoglobin.

Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through physical exam.

Evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. A responder was a patient who showed best overall response of complete response (CR, disappearance of all target lesions) or partial response (PR, ≥30% decrease in the sum of the longest diameter of target lesions), which was confirmed again at least 4 weeks after the initial assessment.

Analysis of progression-free survival (PFS); time to progression, where progressive disease (PD) corresponds to ≥20% increase in the sum of the longest diameter of target lesions.

Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through blood pressure.

Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through electrocardiogram.

Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through amylase and lipase.

Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through thyroxine free.

Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through thyrotropin.

Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through hemoglobin.

Evaluation of the safety and tolerability of the RP2D of birinapant when given in combination with pembrolizumab assessed through physical exam.

Merck Sharp & Dohme LLC

Medivir

Dose escalation (Phase 1): 5.6 mg birinapant + pembrolizumab

Phase 1 - 5.6 mg

Dose escalation (Phase 1): 11 mg birinapant + pembrolizumab

Phase 1 - 11 mg

Dose escalation (Phase 1): 17 mg birinapant + pembrolizumab

Phase 1 - 17 mg

Dose escalation (Phase 1): 22 mg birinapant + pembrolizumab

Phase 1 - 22 mg

Dose expansion (Phase 2): 22 mg birinapant + pembrolizumab in colorectal cancer cohort

Phase 2 CRC - 22 mg

Dose expansion (Phase 2): 22 mg birinapant + pembrolizumab

Phase 2 - 22 mg

Total

Age, Continuous

Sex: Female, Male

Hispanic or Latino

Not Hispanic or Latino

Unknown

Race/Ethnicity, Customized

United States

Region of Enrollment

The dose escalation (Phase 1) part was analyzed per the protocol. Based on data from the interim analysis of the colorectal cancer cohort (dose expansion \[Phase 2\] part), the study was closed early due to futility on recommendation by the data monitoring committee (DMC).

Chief Medical Officer

Systolic blood pressure at baseline

Systolic blood pressure at follow-up

Diastolic blood pressure at baseline

Diastolic blood pressure at follow-up

As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed.

Blood Pressure (Safety and Tolerability in the Dose Escalation Phase)

Electrocardiogram QT interval at baseline

Electrocardiogram QT interval at follow-up

Electrocardiogram: QT Interval (Safety and Tolerability in the Dose Escalation Phase)

Amylase at baseline

Amylase at follow-up

Lipase at baseline

Lipase at follow-up

Amylase and Lipase (Safety and Tolerability in the Dose Escalation Phase)

Thyroxine free at baseline

Thyroxine free at last assessment

Thyroxine Free (Safety and Tolerability in the Dose Escalation Phase)

Thyrotropin at baseline

Thyrotropin at last assessment

Thyrotropin (Safety and Tolerability in the Dose Escalation Phase)

Hemoglobin at baseline

Hemoglobin at follow-up

Hemoglobin (Safety and Tolerability in the Dose Escalation Phase)

Clinically significant physical exam abnormalities - baseline

Clinically significant physical exam abnormalities - last assessment

Physical Exam (Safety and Tolerability in the Dose Escalation Phase)

Dose expansion (Phase 2): 22 mg birinapant + pembrolizumab in colorectal cancer cohort.

For phase 2, only the colorectal cancer (CRC) cohort was analyzed for overall response rate. Patients were not recruited to the ovarian cancer or cervical cancer cohorts due to early termination of the study.

Overall Response (Applicable for: Dose Escalation Phase and Dose Expansion Phase in Cohorts of Colorectal Cancer, Ovarian Cancer and Cervical Cancer)

Tumor Response Evaluated Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1:

Dose expansion (Phase 2): 22 mg birinapant + pembrolizumab in colorectal cancer cohort (CRC)

Blood Pressure (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)

Electrocardiogram: QT Interval (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)

Amylase and Lipase (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)

Thyroxine Free (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)

Thyrotropin (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)

Hemoglobin (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)

Physical Exam (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)

Tumor activity according to iRECIST was not analyzed due to early termination of the study.

Assess Tumor Activity

Biomarkers in blood were not analyzed due to early termination of the study.

Translational Biomarker Assessments Obtained From Blood

Biomarkers in tumor biopsy samples were not analyzed due to early termination of the study.

Translational Biomarker Assessments of Tumor Biopsy Samples

Birinapant pharmacokinetics was not analyzed due to early termination of the study.

Pharmacokinetics of Birinapant in Plasma

Overall Study

Adenocarcinoma

Recurrence

Cystadenocarcinoma, Serous

Cystadenocarcinoma

Disease Attributes

Neoplasms, Cystic, Mucinous, and Serous

Adenocarcinoma of the Appendix

Carboplatin

Patients receive birinapant IV over 30 minutes on days 1 and 8, and carboplatin IV over 30 minutes to 1 hour on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Pharmacological Study

Sanaz Memarzadeh

This phase I/II trial studies how well birinapant and carboplatin work in treating patients with ovarian, fallopian tube, or primary peritoneal cancer that has come back. Drugs used in chemotherapy, such as birinapant and carboplatin work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

PRIMARY OBJECTIVES:

I. To assess whether addition of birinapant to carboplatin therapy can reduce the percentage of platinum resistant tumor initiating cells by 50% compared to pre-therapy biopsies in participants with recurrent high grade serous ovarian carcinomas (HGSOC) whose tumors score positive in the in vitro organoid bioassay test.

II. Assess target engagement by comparing levels of cellular inhibitor of apoptosis protein (cIAP) and percentage of apoptotic cells in pre-versus post therapy tumor biopsies (obtained after three cycles of treatment).

SECONDARY OBJECTIVES:

I. To see if there is an increase in progression free survival of participants treated with co-therapy (birinapant/carboplatin) compared with historic controls.

TERTIARY OBJECTIVES:

I. Develop a companion diagnostic test by correlating clinical response seen in participants with two biomarker assays developed in our laboratory.

1. Measuring levels of cIAP protein by western blot in tumor biopsies obtained from participants prior to start of therapy.
2. Measuring percentage of cIAP positive cells by immunohistochemistry in tumor biopsies obtained from participants prior to start of therapy.

OUTLINE:

Patients receive birinapant intravenously (IV) over 30 minutes on days 1 and 8, and carboplatin IV over 30 minutes to 1 hour on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 2 years from Course 1, Day 1.

Birinapant and Carboplatin in Treating Patients With Recurrent High Grade Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

A Phase I/II, Single Center, Proof-of-Concept Study of Birinapant in Combination With Platinum Based Chemotherapy Targeting Recurrent High Grade Serous Ovarian Carcinomas (HGSOC)

Evaluated using non parametric receiver operator characteristic (ROC) methods with the corresponding accuracy statistics reported.

Evaluated using non parametric ROC methods with the corresponding accuracy statistics reported.

Will be measured using a 3-dimensional organoid assay; population analysis using flow cytometry to measure the overall percentage of platinum resistant tumor initiating cells and by immunohistochemistry. Percent cellular inhibitor of apoptosis (cIAP) positive and amount of cIAP protein will be computed using either the non parametric Wilcoxon signed rank test or the paired t test if the data follow a normal distribution. Full summary statistics including the mean and median difference and the corresponding 95% confidence bounds will be reported. We will report scatter plots and the non parametric Spearman correlation coefficients among these four measures of platinum resistant tumor initiating cells pre-therapy as well as the post- minus pre-treatment difference.

Will measure the level of cIAP protein in pre- versus (vs). post-therapy tumors, measured by quantitative western blot, compared to a purified cIAP standard of known amount loaded on the same gel. Percent cIAP positive and amount of cIAP protein will be computed using either the non parametric Wilcoxon signed rank test or the paired t test if the data follow a normal distribution. Full summary statistics including the mean and median difference and the corresponding 95% confidence bounds will be reported. We will report scatter plots and the non parametric Spearman correlation coefficients among these four measures of platinum resistant tumor initiating cells pre-therapy as well as the post- minus pre-treatment difference.

The secondary analysis in each group will be comparison of PFS to known historical PFS. The PFS curve will be estimated using the Kaplan-Meier method and the sample PFS curve will be compared to the known historical population curve using the one sample log rank test.

Alpha Stem Cell Clinic (ASCC)

California Institute for Regenerative Medicine (CIRM)

Jonsson Comprehensive Cancer Center

Leukemia

Leukemia, Myelomonocytic, Chronic

Leukemia, Myelomonocytic, Juvenile

Leukemia, Myelomonocytic, Acute

Leukemia, Myeloid

Myeloproliferative Disorders

Myelodysplastic-Myeloproliferative Diseases

Chronic Disease

Chronic Graft Versus Host Disease

Chronic Myelomonocytic Leukemia

Juvenile Myelomonocytic Leukemia

Acute Graft Versus Host Disease

Chronic Myeloproliferative Disorders

Myelodysplastic/myeloproliferative Disease

Azacitidine 75 mg/m2 IV on days 1-5, 8 \& 9 OR days 1-7 and birinapant 13 mg/m2 IV twice a week (days 1 \& 4) for 3 out of 4 weeks

Azacitidine 75mg/m2 IV days 1-5, 8 \& 9 OR days 1-7 and placebo IV twice a week (days 1 \& 4) for 3 out of 4 weeks

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Birinapant in Combination With Conatumumab in Subjects With Relapsed Ovarian Cancer	NCT01940172	Relapsed Epithe... Relapsed Primar... Relapsed Fallop...	Birinapant Conatumumab	18 Years -	TetraLogic Pharmaceuticals
Birinapant With 5-azacitidine in MDS Subjects Who Are Naïve, Have Relapsed or Are Refractory to 5-azacitidine Therapy	NCT01828346	Myelodysplastic...	Birinapant 5-Azacitidine	18 Years -	TetraLogic Pharmaceuticals
Birinapant With 5-azacitidine in MDS Subjects Who Are Naïve, Have Relapsed or Are Refractory to 5-azacitidine Therapy	NCT01828346	Myelodysplastic...	Birinapant 5-Azacitidine	18 Years -	TetraLogic Pharmaceuticals
Birinapant With 5-azacitidine in MDS Subjects Who Are Naïve, Have Relapsed or Are Refractory to 5-azacitidine Therapy	NCT01828346	Myelodysplastic...	Birinapant 5-Azacitidine	18 Years -	TetraLogic Pharmaceuticals
Dose-escalation Study of Birinapant and Pembrolizumab in Solid Tumors	NCT02587962	Solid Tumors	Birinapant Pembrolizumab	18 Years -	Medivir
Birinapant and Carboplatin in Treating Patients With Recurrent High Grade Ovarian, Fallopian Tube, or Primary Peritoneal Cancer	NCT02756130	High Grade Fall... High Grade Ovar... Primary Periton... Recurrent Fallo... Recurrent Ovari... Recurrent Prima...	Birinapant Carboplatin Laboratory Biom... Pharmacological...	18 Years -	Jonsson Comprehensive Cancer Center
Study of Azacitidine With or Without Birinapant in Subjects With MDS or CMMoL	NCT02147873	Myelodysplastic... Chronic Myelomo...	birinapant Azacitidine Placebo	18 Years -	TetraLogic Pharmaceuticals
Study of Birinapant in Combination With Conatumumab in Subjects With Relapsed Ovarian Cancer	NCT01940172	Relapsed Epithe... Relapsed Primar... Relapsed Fallop...	Birinapant Conatumumab	18 Years -	TetraLogic Pharmaceuticals
Dose Escalation, Combination Chemotherapy Safety Study of Birinapant (TL32711), in Subjects With Advanced or Metastatic Solid Tumors	NCT01188499	Cancer	Birinapant	18 Years -	TetraLogic Pharmaceuticals

Spots Global Cancer Trial Database for birinapant

Every month we try and update this database with for birinapant cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for birinapant

Every month we try and update this database with for birinapant cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for birinapant cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.