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Mapatumumab, Cisplatin and Radiotherapy for Advanced Cervical Cancer

Primary Purpose

Advanced Cervical Cancer

Status
Completed
Phase
Phase 1
Locations
Netherlands
Study Type
Interventional
Intervention
mapatumumab
cisplatin
radiotherapy
Sponsored by
University Medical Center Groningen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Advanced Cervical Cancer focused on measuring TRAIL, TRM1, advanced cervical cancer, mapatumumab, Uterine cervical neoplasm, Radiotherapy, Cisplatin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

  1. Patients with histologically or cytologically confirmed stage IB2, IIA2, IIB, III, and IVA cervical cancer, according to the FIGO classification
  2. Adequate bone marrow, renal and liver function:

    • Absolute neutrophil count ≥ 1.5 x 109 /L.
    • Platelet count ≥ 100 x 109 /L.
    • Serum creatinine level ≤ 1.5 x upper limit of normal (ULN).
    • Total bilirubin < 1.25 x ULN.
    • Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN.
  3. Performance status of 0 to 1 on the Eastern Cooperative Oncology Group (ECOG) Scale.
  4. Age 18 years or older.
  5. Life expectancy of ≥ 12 weeks.
  6. Have the ability to understand the requirements of the study, provide written informed consent (including consent for the use and disclosure of research-related health information), and comply with the study and follow-up procedures.

Exclusion Criteria:

  1. Any co-morbid condition that in the judgment of the investigator renders the subject at high risk of treatment complications or reduces the possibility of assessing clinical effect.
  2. Cytotoxic agent, hormonal therapy, or radiation therapy within 3 weeks (6 weeks for nitrosoureas or mitomycin-C) prior to day 1, cycle 1; investigational agent within 4 weeks prior to day 1, cycle 1.
  3. Need for concomitant anticancer therapy (surgery, radiation therapy, chemotherapy, immunotherapy, radiofrequency ablation) or other investigational agents during the study treatment period.
  4. Major surgery within 4 weeks before enrollment; minor surgery (except for insertion of vascular access device) within 2 weeks before enrollment; or not yet recovered from the effects of the surgery.
  5. Systemic steroids within 1 week before enrollment except steroids used as part of an antiemetic regimen or maintenance-dose steroids for non-cancerous disease.
  6. History of any infection requiring hospitalization or antibiotics within 2 weeks before enrollment.
  7. Known brain or spinal cord metastases unless adequately treated (surgery or radiotherapy) with no evidence of progression and neurologically stable off anticonvulsants and steroids.
  8. Known human immunodeficiency virus infection.
  9. Unstable angina, myocardial infarction, cerebrovascular accident, > Class II congestive heart failure according to the New York Heart Association Classification for Congestive Heart Failure within 6 months before enrollment.
  10. Pregnant female or nursing mother.

Sites / Locations

  • University Medical Center Groningen

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Advanced cervical cancer patients

Arm Description

Outcomes

Primary Outcome Measures

Phase 1b: safety and tolerability of mapatumumab in combination with cisplatin and radiotherapy Phase 2: efficacy of mapatumumab in combination with cisplatin and radiotherapy
Phase 2: pathological complete response rate

Secondary Outcome Measures

Disease free survival, overall survival
Apoptotic pathway biomarkers, PK parameters

Full Information

First Posted
March 10, 2010
Last Updated
April 21, 2015
Sponsor
University Medical Center Groningen
Collaborators
Human Genome Sciences Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01088347
Brief Title
Mapatumumab, Cisplatin and Radiotherapy for Advanced Cervical Cancer
Official Title
A Phase 1b/2 Study With the Agonistic TRAIL-R1 Antibody, Mapatumumab, in Combination With Cisplatin and Radiotherapy as a First Line Therapy in Patients With Advanced Cervical Cancer.
Study Type
Interventional

2. Study Status

Record Verification Date
April 2015
Overall Recruitment Status
Completed
Study Start Date
March 2010 (undefined)
Primary Completion Date
March 2014 (Actual)
Study Completion Date
March 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Medical Center Groningen
Collaborators
Human Genome Sciences Inc.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Chemoradiotherapy has become the standard of care for women with locally advanced cervical cancer. The available data support a 30 to 50% reduction in the risk of death from cervical cancer for women with locally advanced disease undergoing radiotherapy (RT) and concomitant cisplatin-based chemotherapy compared to RT alone. Despite the fact that this is currently the best treatment of locally advanced cervical cancer, 5-year overall survival is still only 52%. The fully human, agonist monoclonal antibody mapatumumab binds to the Tumor necrosis factor-Related Apoptosis-Inducing Ligand Receptor 1 (TRAIL-R1, DR4) and induces cytotoxicity in multiple tumor cell lines in vitro and in vivo. In multiple phase I and phase II studies, mapatumumab appeared to be safe both as single agent and in combination with chemotherapy, including cisplatin. In cervical cancer cell lines, mapatumumab induced apoptosis in 51% of the cells. Mapatumumab in combination with irradiation increased apoptosis to 83%. In this phase 1b/2 study, the investigators will evaluate the safety, tolerability and efficacy of mapatumumab in combination with cisplatin and radiotherapy in patients with locally advanced cervical cancer.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Advanced Cervical Cancer
Keywords
TRAIL, TRM1, advanced cervical cancer, mapatumumab, Uterine cervical neoplasm, Radiotherapy, Cisplatin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
9 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Advanced cervical cancer patients
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
mapatumumab
Intervention Description
Mapatumumab (10 or 30 mg/kg) intravenously on days 1, 22, and 45. In phase 2 the MTD established in phase 1 will be used.
Intervention Type
Drug
Intervention Name(s)
cisplatin
Intervention Description
Cisplatin 40 mg/m2 intravenously on days 8, 15, 22, 29, 36, and 45
Intervention Type
Radiation
Intervention Name(s)
radiotherapy
Intervention Description
Radiotherapy: a total dose of 45 Gy will be given in fractions of 1.8 Gy, five fractions per week (days 8-12, 15-19, 22-26, 29-33, and 36-40), by external beam irradiation by photon beam of at least 6 MV. After completing the five weeks of external beam irradiation, evaluation will take place to determine whether the boost can be given by brachytherapy. If brachytherapy is not feasible, the boost will be given by external beam irradiation to a total dose of 70.2 Gy in fractions of 1.8 Gy.
Primary Outcome Measure Information:
Title
Phase 1b: safety and tolerability of mapatumumab in combination with cisplatin and radiotherapy Phase 2: efficacy of mapatumumab in combination with cisplatin and radiotherapy
Description
Phase 2: pathological complete response rate
Time Frame
5 months
Secondary Outcome Measure Information:
Title
Disease free survival, overall survival
Time Frame
From enrollment until recurrence of disease, from enrollment until death
Title
Apoptotic pathway biomarkers, PK parameters
Time Frame
During the study, until 5 months after enrollment

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with histologically or cytologically confirmed stage IB2, IIA2, IIB, III, and IVA cervical cancer, according to the FIGO classification Adequate bone marrow, renal and liver function: Absolute neutrophil count ≥ 1.5 x 109 /L. Platelet count ≥ 100 x 109 /L. Serum creatinine level ≤ 1.5 x upper limit of normal (ULN). Total bilirubin < 1.25 x ULN. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN. Performance status of 0 to 1 on the Eastern Cooperative Oncology Group (ECOG) Scale. Age 18 years or older. Life expectancy of ≥ 12 weeks. Have the ability to understand the requirements of the study, provide written informed consent (including consent for the use and disclosure of research-related health information), and comply with the study and follow-up procedures. Exclusion Criteria: Any co-morbid condition that in the judgment of the investigator renders the subject at high risk of treatment complications or reduces the possibility of assessing clinical effect. Cytotoxic agent, hormonal therapy, or radiation therapy within 3 weeks (6 weeks for nitrosoureas or mitomycin-C) prior to day 1, cycle 1; investigational agent within 4 weeks prior to day 1, cycle 1. Need for concomitant anticancer therapy (surgery, radiation therapy, chemotherapy, immunotherapy, radiofrequency ablation) or other investigational agents during the study treatment period. Major surgery within 4 weeks before enrollment; minor surgery (except for insertion of vascular access device) within 2 weeks before enrollment; or not yet recovered from the effects of the surgery. Systemic steroids within 1 week before enrollment except steroids used as part of an antiemetic regimen or maintenance-dose steroids for non-cancerous disease. History of any infection requiring hospitalization or antibiotics within 2 weeks before enrollment. Known brain or spinal cord metastases unless adequately treated (surgery or radiotherapy) with no evidence of progression and neurologically stable off anticonvulsants and steroids. Known human immunodeficiency virus infection. Unstable angina, myocardial infarction, cerebrovascular accident, > Class II congestive heart failure according to the New York Heart Association Classification for Congestive Heart Failure within 6 months before enrollment. Pregnant female or nursing mother.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
An KL Reyners, MD,PhD
Organizational Affiliation
University Medical Center Groningen
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Medical Center Groningen
City
Groningen
ZIP/Postal Code
9700 RB
Country
Netherlands

12. IPD Sharing Statement

Citations:
PubMed Identifier
18793956
Citation
Maduro JH, de Vries EG, Meersma GJ, Hougardy BM, van der Zee AG, de Jong S. Targeting pro-apoptotic trail receptors sensitizes HeLa cervical cancer cells to irradiation-induced apoptosis. Int J Radiat Oncol Biol Phys. 2008 Oct 1;72(2):543-52. doi: 10.1016/j.ijrobp.2008.06.1902.
Results Reference
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PubMed Identifier
19690193
Citation
Mom CH, Verweij J, Oldenhuis CN, Gietema JA, Fox NL, Miceli R, Eskens FA, Loos WJ, de Vries EG, Sleijfer S. Mapatumumab, a fully human agonistic monoclonal antibody that targets TRAIL-R1, in combination with gemcitabine and cisplatin: a phase I study. Clin Cancer Res. 2009 Sep 1;15(17):5584-90. doi: 10.1158/1078-0432.CCR-09-0996. Epub 2009 Aug 18. Erratum In: Clin Cancer Res. 2009 Nov 1;15(21):6744.
Results Reference
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Mapatumumab, Cisplatin and Radiotherapy for Advanced Cervical Cancer

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