Clinical trial NCT01246440: Catumaxomab as a Consolidation Therapy in Patients With Ovarian Cancer in Second or Third Clinical Disease Remission
Official title: A Phase II of Intraperitoneal Catumaxomab as a Consolidation Therapy in Patients With Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Carcinoma in Second or Third Complete Clinical Disease Remission
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ovarian Cancer
Lead sponsor: Grupo Español de Investigación en Cáncer de Ovario
Sponsor class: OTHER
Collaborators: name: Neovii Biotech
First posted: 2010-11-23
Enrollment: 39
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the efficacy and safety of catumaxomab as consolidation treatment in patients with epithelial ovarian cancer in second or third complete remission.

Detailed description: Epithelial ovarian cancer is the most lethal malignant gynecological tumor and the fourth most common cause of death by cancer among women. The highest incidence rates are observed in Eastern and Northern Europe, and in the United Status. In Spain, 3,262 new cases were diagnosed in 2002, and the figure is expected to rise to 3,722 cases in 2015 (Globocan 2002, International Agency for Research on Cancer -IARC).

The majority of patients with ovarian cancer are diagnosed at an advanced stage, and are treated with maximum cytoreductive surgery followed by intraperitoneal and/or intravenous chemotherapy. What is considered standard chemotherapy consists of a platinum (carboplatin or cisplatin) combined with a taxane, usually paclitaxel (Ozols, 2003; Armstrong 2006). Although many patients respond to the initial treatment, the majority experience subsequent recurrence of the disease, which is why they need to be treated with successive salvage therapies in an attempt to control the disease until it is converted into totally refractory (Markman, 2004). Only 20-30% of patients can be cured with current treatments, which is why it is necessary to investigate and develop new treatments and/or treatment strategies (Yap, 2009).

Although with the initial treatment based on cytoreductive surgery and platinum-based chemotherapy the large majority of patients achieve complete remission of the disease, 90% of the patients with sub-optimum cytoreductive surgery and 70% with optimum cytoreductive surgery develop a recurrence in the first 24 months. One of the treatment strategies being investigated to try and improve the results is the administration of consolidation or maintenance treatment to those patients that have achieved a complete response of their disease to reduce the risk of subsequent recurrence (Sabbatini, 2006).

In the last few years, various studies have established that investigating a possible therapeutic effect of consolidation or maintenance treatment following second or third complete clinical remission, obtained with a salvage chemotherapy, produces several advantages over the same strategy applied on a first complete clinical response: the median of progression-free survival after second or third complete response is shorter and more predictable -10 months-, and moreover the recurrence is practically universal (Markman 2004; Harrison, 2007; Levine, 2007; Markman, 2008; Juretza, 2008).

Catumaxomab has proven to be effective in patients with refractory tumours and recurring malignant ascites, i.e. patients with a very advanced disease, a large tumour and no treatment options. These clinical conditions are the worst for researching into any immune-based therapy, hence it seems logical to study the efficacy of catumaxomab in more favourable conditions.

Patients with ovarian cancer in second or third complete remission may be a more suitable population for investigating the intraperitoneal administration of catumaxomab as consolidation treatment: 1. 100% of the epithelial ovarian cancers express EpCAM (Epithelial cell adhesion molecule )(Kim, 2003; Bellone, 2009). 2. These patients present a minimal residual disease that cannot be eliminated with standard chemotherapy and is responsible for a subsequent recurrence in practically every patient, with a median progression-free survival of 10 months (Markman, 2004; Harrison, 2007). 3. The peritoneal cavity is a very common location for residual disease and/or recurrence in ovarian cancer (Ferrandina, 2006). 4. The absence of macroscopic disease in the peritoneal cavity may bring about a greater absorption of catumaxomab on the blood level, with a hypothetical greater efficacy on the systemic level without entailing a greater risk of toxicity (Heiss, 2008; Lordick, 2008).

The intention in this phase II study is to estimate the clinical benefit of consolidation treatment with catumaxomab in patients with epithelial ovarian cancer in second or third complete remission, by measuring progression-free survival, the percentage of progression-free patients at 12, 18 and 24 months, and comparing individually for each patient the duration of progression-free survival obtained following consolidation with catumaxomab with that observed in her first complete remission. If we observe a median of progression-free survival equal to or greater than 14 months, accompanied by a significant percentage of progression-free patients at 18 and 24 months, we will assess the possibility of subsequently designing a phase III study of consolidation with catumaxomab.

To improve the tolerability of catumaxomab, premedication will be administered with low-dose corticoids before each infusion of catumaxomab. The low doses of corticoids have been shown not to interfere with the efficacy of catumaxomab, but by reducing the release of certain cytokines like TNF-α (Tumor Necrosis Factor Alpha) they may reduce the associated adverse effects (Waltz, 2005).

Eligibility criteria: Inclusion Criteria:

* Signed Informed consent.
* Initial histopathologic diagnosis of epithelial ovarian cancer, cancer of the fallopian tube or primary peritoneal carcinoma
* Women ≥ 18 years
* ECOG performance status ≤ 1 (Eastern Cooperative Oncology Groupperformance)
* Initial surgical cytoreduction as primary treatment combinated with Platinum- based chemotherapy administered as part of primary therapy.

Failure of the primary treatment as manifested by recurrent disease that have achieved a second or third complete response with a second or third-line chemotherapy (platinum-based or not).

The complete response to the second or third-line chemotherapy is defined as non symptoms of cancer persistence, normal CA-125 (cancer antigen 125), negative medical examination, and no evidence of disease in a TAC.

* At least 4 cycles of second or third-line chemotherapy must have been administered
* Surgery performed at first or second relapse in conjunction with second or third-line chemotherapy is permitted.

Exclusion Criteria:

* Acute or chronic infection
* Concomitant treatment with cancer chemo- and/or radiotherapy
* Exposure to an investigational product within 28 days of first infusion
* Previous treatment with murine monoclonal antibodies
* Inadequate renal function: creatinine \>1.5 upper limit of normal \[ULN\] and/ or calculated creatinine clearance ≥ 50 mL/min
* Inadequate hepatic function (AST, ALT, \>2.5 xULN; bilirubin \>1.5 xULN), Hypoalbuminaemia \< 3 g/dL
* Platelets \<80000 cells/mm3; absolute neutrophil count (ANC) \<1000 cells/mm3,
* Hb \< 8g/dL and PTT \> 2 x ULN
* Patients with occlusive intestinal or symptomatic sub-occlusive intestinal within the last 30 days.
* Significant cardiovascular disease including unstable angina or myocardial infarction within 6 months before initiating study treatment or a history of ventricular arrhythmia
* Unable or unwilling to comply fully with the protocol.
* Any co-morbid disease that would increase risk of toxicity according to investigator judgment
* Any kind of disorder that compromises the ability of the subject to give written informed consent and/or comply with the study procedures
* Exposure to investigational product, cancer, chemo-or radiotherapy within the last 28 days (6 weeks for nitrosoureas or mitomycin C) before first infusion
* Known or suspected hypersensitivity to catumaxomab or similar antibodies
* Long-lasting steroid treatment (≥ 7 days), Patients should only be included after stepwise discontinuation and free of steroids for a minimum of 5 days

Primary outcomes:
measure: Progression-free survival (PFS)
timeFrame: 3 years
Secondary outcomes:
measure: Second progression-free survival (2PFS)
timeFrame: 3 years
measure: Third progression-free survival (3PFS)
timeFrame: 3 years
measure: Progression-free survival per protocol
timeFrame: 3 years
measure: First progression-free survival
timeFrame: 3 years
measure: Duration of the treatment-free interval
timeFrame: 3 years
measure: Overall survival rate
timeFrame: 3 years
measure: Incidence, intensity and causalidad of every adverse event.
timeFrame: 3 years
measure: Therapeutic compliance
timeFrame: 3 years
measure: The level of cells involved in the immune response
timeFrame: 3 years
measure: Interval between the administration of the last dose of chemotherapy and the beginning of the treatment with catumaxomab
timeFrame: 3 years
Other outcomes:
Locations:
city: Girona
country: Spain
facility: Institut Català d'Oncologia de Girona
state: Barcelona
city: Sabadell
country: Spain
facility: Corporació Sanitaria Parc Taulí
state: Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
state: Madrdi
city: Alcorcon
country: Spain
facility: Hospital Universitario Fundación Alcorcon
state: Madrid
city: Barcelona
country: Spain
facility: Hospital de la Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Gregorio Marañon
city: Madrid
country: Spain
facility: M.D. Anderson
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Mallorca
country: Spain
facility: Hospital Son Dureta
city: Murcia
country: Spain
facility: Hospital Jose Maria Morales Meseguer
city: Santander
country: Spain
facility: Hospital Universitario de Valdecilla
city: Santiago de Compostela
country: Spain
facility: Hosptial Clinico Universitario de Santiago de Compostela
city: Valencia
country: Spain
facility: Hospital Universitario La Fe de Valencia
city: Valencia
country: Spain
facility: Instituto Valenciano de Oncología
city: Zaragoza
country: Spain
facility: Hospital Miguel Servet
Study officials:
affiliation: Hospital de la Vall d'Hebron
name: Ana Oaknin, Dra.
role: STUDY_CHAIR
affiliation: M.D. Anderson
name: Antonio Gonzalez, Dr.
role: STUDY_CHAIR
affiliation: Institut Calatà d'Oncologia de Girona
name: Miguel Beltran, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Corporació Sanitaria Parc Tauli
name: Yolanda García, Dra.
role: PRINCIPAL_INVESTIGATOR
affiliation: Instituto Valenciano de Oncología
name: Andrés Póveda, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario La Fe de Valencia
name: Ana Santaballa, Dra.
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital José Maria Morales Meseguer
name: Mª Elena García, Dra.
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario La Paz
name: Andrés Redondo, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Miguel Servet
name: Ana Herrero, Dra.
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Clínico Universitario de Santiago de Compostela
name: Juan Fernando Cuevas, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Son Dureta
name: Arantxa Gonzalez, Dra.
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario Ramon y Cajal
name: Eva Guerra, Dra.
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario Fundación Alcorcon
name: Jesus García, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Gregorio Marañon
name: Jose Angel Arranz, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario de Valdecilla
name: Ana de Juan, Dra.
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital San Carlos, Madrid
name: Antonio Casado, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario 12 de Octubre
name: César Mendiola, Dr.
role: PRINCIPAL_INVESTIGATOR
References: