Carboplatin-based Chemotherapy With or Without Panitumumab in Platinum-sensitive Recurrent Ovarian Cancer

Study Overview
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Brief Summary
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The purpose of this trial is to estimate the therapeutic efficacy of the experimental targeted regimen including the EGFR antibody panitumumab (in combination with carboplatin and either pegylated liposomal doxorubicin or gemcitabine) in relation to the respective standard combination in patients with a KRAS wildtype with platinum-sensitive recurrent ovarian cancer. It is expected that the progression free survival rate at 12 months is improved by the targeted regimen.

Official Title
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PROVE A Randomized Phase II Trial of Standard Carboplatin-based Chemotherapy With or Without Panitumumab in Platinum-sensitive Recurrent Ovarian Cancer

Conditions
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Ovarian Cancer

Intervention / Treatment
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* Drug: Panitumumab
* Drug: pegylated liposomal doxorubicin (PLD)
* Drug: Carboplatin
* Drug: Gemcitabine
* Drug: Carboplatin
* Drug: Panitumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patients with pretreated epithelial ovarian cancer, primary peritoneal carcinomatosis or fallopian tube cancer with histological confirmation of the tumor Wild-type k-ras status Patients must have pretreated platinum-sensitive ovarian cancer with recurrence more than 6 months after completion of a platinum-containing regimen Presence of at least one measurable or non-measurable disease (e.g. malignant ascites) following RECIST criteria by radiologic evaluation OR histological confirmation of recurrence by biopsy. The presence of non-measurable lesions only requires in addition a 2-fold increase of CA-125 elevation above normal lab value (confirmed by two measurements). No more than 2 prior treatment regimens for these epithelial cancers Age > 18 years. ECOG Performance Status of 0 or 1 Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to screening: Hemoglobin > 9.0 g/dl Leukocyte count >3.000/mm3 ; absolute neutrophil count (ANC) >1.500/mm3 Platelet count ≥ 100.000/μl Total bilirubin < 1,0 times the upper limit of normal ALT and AST < 2,5 x upper limit of normal (< 5 x upper limit of normal for patients with liver involvement of their cancer) Alkaline phosphatase < 4 x ULN PT-INR/PTT < 1.5 x upper limit of normal [Patients who are being therapeutically anticoagulated with an agent such as coumarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists.] Serum creatinine < 1.5 x upper limit of normal and creatinine clearance > 50 ml/min. Magnesium ≥ lower limit of normal; calcium ≥ lower limit of normal Signed and dated informed consent before the start of specific protocol procedures. Exclusion Criteria: Clinically significant cardiovascular disease (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 1 year before enrolment. History of interstitial lung disease, e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline chest CT scan. History of HIV infection or chronic hepatitis B or C Active clinically serious infections (> grade 2 NCI-CTC version 3.0) Pre-existing neuropathy > grade 1 (NCI CTCAE), except for loss of tendon reflex Prior radiological or clinical evidence of CNS metastases including previously treated, resected, or asymptomatic brain lesions or leptomeningeal involvement by head CT scan or MRI Patients with seizure disorder requiring medication (such as steroids or anti-epileptics) History of organ allograft Patients with evidence or history of bleeding diathesis Patients undergoing renal dialysis Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors [Ta, Tis & T1] or any cancer curatively treated > 3 years prior to study entry. Patients in a closed institution according to an authority or court decision Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study Excluded therapies and medications, previous and concomitant: Anticancer chemotherapy within 4 weeks prior to study entry. Prior anti-EGFR therapy Radiotherapy during study or within 4 weeks of start of study drug. (Palliative radiotherapy of non-target lesions will be allowed) and prior radiotherapy of > 25% of the bone marrow Major surgery within 4 weeks of start of study Autologous bone marrow transplant or stem cell rescue within 12 months of study Investigational drug therapy outside of this trial during or within 4 weeks of study entry Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental arm (A):<br>Caelyx 30 mg/m² d1 Carboplatin AUC 5 d1 Panitumumab 6 mg/kg/KG d1 + 15 q4w until progressive disease or for a max. of 6 cycles OR Gemcitabine 1000 mg/m² d1 + 8 Carboplatin AUC 4 d1 Panitumumab 9 mg/kg/KG d1 q3w until progressive disease or for a max. of 6 cycles The backbone chemotherapy (Caelyx or Gemcitabine-based) is specified by the investigator before randomization of a patient. | Drug: Panitumumab<br>* Panitumumab 6 mg/kg/BW d1 + 15 q4w until progressive disease or for a max. of 6 cycles In case of CR, PR or SD at the end of the combination treatment in experimental arm, panitumumab monotherapy is to be continued with 9 mg/kg/BW d1 q3w until time of tumor progression or up to a maximum of 6 months.<br>* Other names: Vectibix;Drug: pegylated liposomal doxorubicin (PLD)<br>* pegylated liposomal doxorubicin (PLD) 30 mg/m² d1 q4w until progressive disease or for a max. of 6 cycles<br>* Other names: Caelyx;Drug: Carboplatin<br>* Carboplatin AUC 5 d1 q4w until progressive disease or for a max. of 6 cycles<br>* Other names: multiple generics in existence;Drug: Gemcitabine<br>* gemcitabine 1000 mg/m² d1 + 8 q3w until progressive disease or for a max. of 6 cycles<br>* Other names: Gemzar;Drug: Carboplatin<br>* Carboplatin AUC 4 d1 q3w until progressive disease or for a max. of 6 cycles<br>* Other names: multiple generics in existence;Drug: Panitumumab<br>* Panitumumab 9 mg/kg/BW d1 q3w until progressive disease or for a max. of 6 cycles In case of CR, PR or SD at the end of the combination treatment in experimental arm, panitumumab monotherapy is to be continued with 9 mg/kg/BW d1 q3w until time of tumor progression or up to a maximum of 6 months.<br>* Other names: Vectibix;|
| Active Comparator: Standard arm (B):<br>Caelyx 30 mg/m² d1 Carboplatin AUC 5 d1 q4w until progressive disease or for a max. of 6 cycles OR Gemcitabine 1000 mg/m² d1 + 8 Carboplatin AUC 4 d1 q3w until progressive disease or for a max. of 6 cycles The backbone chemotherapy (Caelyx or Gemcitabine-based) is specified by the investigator before randomization of a patient. | Drug: pegylated liposomal doxorubicin (PLD)<br>* pegylated liposomal doxorubicin (PLD) 30 mg/m² d1 q4w until progressive disease or for a max. of 6 cycles<br>* Other names: Caelyx;Drug: Carboplatin<br>* Carboplatin AUC 5 d1 q4w until progressive disease or for a max. of 6 cycles<br>* Other names: multiple generics in existence;Drug: Gemcitabine<br>* gemcitabine 1000 mg/m² d1 + 8 q3w until progressive disease or for a max. of 6 cycles<br>* Other names: Gemzar;Drug: Carboplatin<br>* Carboplatin AUC 4 d1 q3w until progressive disease or for a max. of 6 cycles<br>* Other names: multiple generics in existence;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) rate after 12 months. | PFS is defined as the time from randomisation to the time of disease progression or relapse (according to RECIST, not CA-125 only!) or death, or to the date of last tumor assessment without any such event (censored observation). | 12 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Tumor-Response | according to RECIST, including measurable disease patients only, and including patients with CA-125 defined disease as well | Duration of Therapy (Therapy is planned for 6 cycles of 3 resp. 4 weeks each, shorter or longer durations are possible) | 
| Progression-free survival |  | End of Follow-up (up to 1 year) | 
| Overall survival |  | End of Follow-up (up to 1 year) | 
| Maximum toxicity resp. AE grade per patient per toxicity resp. AE during therapy | Toxicities resp. (S)AE during therapy will be documented, reported and analyzed according to NCI CTC 3.0 with special focus on skin toxicity. Results are given as maximum grade per patient per toxicity resp. AE during therapy. | Duration of Therapy (Therapy is planned for 6 cycles of 3 resp. 4 weeks each, shorter or longer durations are possible) | 
| Tumor Response Rate | according to RECIST, including measurable disease patients only, and including patients with CA-125 defined disease as well | Duration of Therapy (Therapy is planned for 6 cycles of 3 resp. 4 weeks each, shorter or longer durations are possible) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ovarian cancer, fallopian cancer, recurrent, platinum-sensitive, KRAS-Wildtype