Mapatumumab, Cisplatin and Radiotherapy for Advanced Cervical Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Human Genome Sciences Inc.
Information provided by (Responsible Party):
A.K.L. Reyners, University Medical Centre Groningen
ClinicalTrials.gov Identifier:
NCT01088347
First received: March 10, 2010
Last updated: June 2, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Advanced Cervical Cancer
Drug: mapatumumab
Drug: cisplatin
Radiation: radiotherapy
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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.

Resource links provided by NLM:


Further study details as provided by University Medical Centre Groningen:

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 [ Time Frame: 5 months ] [ Designated as safety issue: Yes ]
    Phase 2: pathological complete response rate


Secondary Outcome Measures:
  • Disease free survival, overall survival [ Time Frame: From enrollment until recurrence of disease, from enrollment until death ] [ Designated as safety issue: No ]
  • Apoptotic pathway biomarkers, PK parameters [ Time Frame: During the study, until 5 months after enrollment ] [ Designated as safety issue: No ]

Enrollment: 9
Study Start Date: March 2010
Estimated Study Completion Date: December 2014
Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Advanced cervical cancer patients Drug: mapatumumab
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.
Drug: cisplatin
Cisplatin 40 mg/m2 intravenously on days 8, 15, 22, 29, 36, and 45
Radiation: radiotherapy
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01088347

Locations
Netherlands
University Medical Center Groningen
Groningen, Netherlands, 9700 RB
Sponsors and Collaborators
University Medical Centre Groningen
Human Genome Sciences Inc.
Investigators
Principal Investigator: An KL Reyners, MD,PhD University Medical Centre Groningen
  More Information

Publications:
Responsible Party: A.K.L. Reyners, Medical Oncologist, University Medical Centre Groningen
ClinicalTrials.gov Identifier: NCT01088347     History of Changes
Other Study ID Numbers: 24-11-2009 (versions 2.0), 2009-015941-22
Study First Received: March 10, 2010
Last Updated: June 2, 2014
Health Authority: Netherlands: Medical Ethics Review Committee (METC)
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by University Medical Centre Groningen:
TRAIL
TRM1
advanced cervical cancer
mapatumumab
Uterine cervical neoplasm
Radiotherapy
Cisplatin

Additional relevant MeSH terms:
Uterine Cervical Neoplasms
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Uterine Cervical Diseases
Uterine Diseases
Genital Diseases, Female
Cisplatin
Antibodies, Monoclonal
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents
Physiological Effects of Drugs
Immunologic Factors

ClinicalTrials.gov processed this record on July 28, 2014