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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

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:

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.

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

NCT ID

NCT01088347

First Posted

March 10, 2010

Last Updated

April 21, 2015

Sponsor

University Medical Center Groningen

Collaborators

Human Genome Sciences Inc.

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

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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