Ovarian Neoplasms
Conditions
Brief summary
This study will determine the value of adding AMG 479 (fully human monoclonal antibody against IGF-1R) to paclitaxel and carboplatin first line chemotherapy in patients with optimally debulked (\<1 cm) FIGO stage III and IV (positive pleural cytology only) ovarian epithelial (including fallopian tube and primary peritoneal) carcinoma.
Interventions
DRUGAMG 479
Solution for infusion - 18 mg/kg on day 1 of each 21-day cycle
DRUGAMG 479 Placebo
Matching placebo administered Day 1 of each 21 day cycle.
Sponsors
Translational Research in Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically-confirmed optimally debulked (\< 1 cm) FIGO stage III or stage IV (positive pleural cytology only) ovarian epithelial (including fallopian tube and primary peritoneal) carcinoma. * Patients should have undergone surgical debulking, by a surgeon experienced in the management of ovarian cancer, with the aim of maximal surgical cytoreduction. All patients must be optimally debulked as defined as having no residual tumor of greater than 1 cm in the post surgical setting. * Patients with stage IV disease will be eligible if a positive pleural cytology is the only extra peritoneal disease. * Paraffin block (or 10 - 20 unstained slides) and fresh frozen surgical/biopsy specimens of the primary tumor are required at baseline. * No prior systemic treatment in the primary disease treatment setting. * Female ≥ 18 years of age or legal age. * ECOG performance status ≤ 2. * Adequate organ and bone marrow function * Non diabetic patients or Type 1 or 2 Diabetic Patients: • Diabetes must be controlled with HgbA1c \< 8% and fasting blood glucose level \<160 mg/dL. * Patient must be willing and able to comply with scheduled visits, and all study procedures. * Informed consent obtained. * Patients should be able to commence systemic therapy within 6 weeks of cytoreductive surgery. * Life expectancy \> 12 weeks. * Adequate coagulation parameters (within 14 days prior to randomization), International Normalized Ratio (INR) ≤1.5; Activated Prothrombin Time (APTT) ≤ 1.5 x ULN
Exclusion criteria
* Non-epithelial ovarian cancer, including malignant mixed Mullerian tumors. * Borderline tumors (tumors of low malignant potential). * Planned intraperitoneal cytotoxic chemotherapy. * Prior systemic anticancer therapy for ovarian cancer. * Any previous radiotherapy to the abdomen or pelvis. * Patients with synchronous primary endometrial carcinoma, or a past history of primary endometrial carcinoma, are excluded unless ALL of the following criteria for describing the endometrial carcinoma are met: Stage ≤ Ib, no more than superficial myometrial invasion, no lymphovascular invasion, not poorly differentiated (i.e., not Grade 3 or papillary serous or clear cell). * Diagnosis of any second malignancy within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ carcinoma of the cervix uteri or curatively treated DCIS/LCIS, or non-melanoma or in situ melanoma skin cancer. * Prior treatment with a humanized monoclonal antibody anticancer therapeutic. * Prior treatment with investigational treatment targeted to IGF axis including, but not limited to, CP 751,871, IM-A12, RO4858696. * Previous exposure to AMG 479. * Anticipation of a need for a major surgical procedure or radiation therapy during the study. * History of hypersensitivity to recombinant proteins. * Treatment with radiotherapy, surgery, or an investigational agent within 4 weeks of randomization. * Any of the following within 6 months prior to study enrollment: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, NYHA class III or IV congestive heart failure, cerebrovascular accident or transient ischemic attack, grade \> 2 peripheral neuropathy, pulmonary embolism, deep vein thrombosis, or other thromboembolic event. * History of brain metastases, spinal cord compression, or carcinomatous meningitis. * Patient of child-bearing potential is pregnant (eg, positive human chorionic gonadotropin test) or is breast feeding. * Patient of child-bearing potential is not willing to use adequate contraceptive precautions. * Known active infection, or on antiretroviral therapy for HIV disease. * Known positive test for chronic hepatitis B or C infection. * Any other underlying physical or mental condition rendering the patient unable to understand the nature, scope, and possible consequences of the study. * Refusal or inability to give informed consent to participate in the study. * Other severe acute or chronic medical or psychiatric condition, or significant laboratory abnormality requiring further investigation that may cause undue risk for the patient's safety, inhibit protocol participation, or interfere with interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS): Time From Randomization Until Date of Progression or Death. | Radiological tumor assessment: every 12(+/- 1) weeks for 3 years after randomization + CA 125: day 1 of each cycle | A patient may have been declared to have progressive disease on the basis of radiological measuremt of tumor lesions assessmt or CA125 evaluation (tumor measuremts taking precedence).Radiological progression was defined as per the RECIST guidelines (Therasse et al, JNCI2000) as at least 20% increase in the sum of the longest diameters of target lesions(ref the smallest sum of the longest diam recorded since the treatmt started or since the appearance of at least 1 new lesion).Serum CA125 progression was defined, according to the 2005 GCIG def: pts with: * Elevated CA125 pretreatmt and normalization of CA125 has to show evidence of CA125≥ 2 times the upper normal limit on 2 occasions at least 1 wk apart OR * Elevated CA125 pretreatmt which never normalized must show evidence of CA125≥ 2 times the nadir value on 2 occasions at least 1 wk apart OR * CA125 in the normal range pretreatmt had to show evidence of CA125 ≥ 2 times the upper normal limit on 2 occasions at least 1 wk apart |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time To Progression (TTP): Interval From the Date of Randomization to the Date of Disease Progression | Radiological tumor assessment: every 12 (+/- 1) weeks for 3 years after randomization + CA125: day 1 of each cycle | A patient may have been declared to have progressive disease on the basis of radiological measuremt of tumor lesions assessmt or CA125 evaluation (tumor measuremts taking precedence).Radiological progression was defined as per the RECIST guidelines (Therasse et al, JNCI2000) as at least 20% increase in the sum of the longest diameters of target lesions(ref the smallest sum of the longest diam recorded since the treatmt started or since the appearance of at least 1 new lesion).Serum CA125 progression was defined, according to the 2005 GCIG def: pts with: * Elevated CA125 pretreatmt and normalization of CA125 has to show evidence of CA125≥ 2 times the upper normal limit on 2 occasions at least 1 wk apart OR * Elevated CA125 pretreatmt which never normalized must show evidence of CA125≥ 2 times the nadir value on 2 occasions at least 1 wk apart OR * CA125 in the normal range pretreatmt had to show evidence of CA125 ≥ 2 times the upper normal limit on 2 occasions at least 1 wk apart |
| Overall Survival (OS) | Day 1 of each cycle up to 4 years after randomization | Interval between the date from randomization to death from any cause whichever came first. |
Countries
Canada, France, Germany, Ireland, Israel, Spain, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted over a total of 55 sites in 8 countries.
Participants by arm
| Arm | Count |
|---|---|
| A Control Placebo plus paclitaxel/carboplatin chemotherapy administered on Day 1 of each 21-day cycle for 6 cycles - then 6 additional cycles of placebo administered on Day 1 of each 21-day cycle.
AMG 479 Placebo: Matching placebo administered Day 1 of each 21 day cycle. | 84 |
| B Experimental AMG 479 plus paclitaxel/carboplatin chemotherapy administered on Day 1 of each 21-day cycle for 6 cycles - then 6 additional cycles of AMG 479 single agent administered on Day 1 of each 21-day cycle.
AMG 479: Solution for infusion - 18 mg/kg on day 1 of each 21-day cycle | 86 |
| Total | 170 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 13 | 17 |
| Overall Study | Withdrawal by Subject | 5 | 7 |
Baseline characteristics
| Characteristic | Total | A Control | B Experimental |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 50 Participants | 25 Participants | 25 Participants |
| Age, Categorical Between 18 and 65 years | 120 Participants | 59 Participants | 61 Participants |
| Age, Continuous | 57.6 years STANDARD_DEVIATION 11.2 | 58.1 years STANDARD_DEVIATION 10 | 57.2 years STANDARD_DEVIATION 12.3 |
| CA 125 status missing | 1 participants | 0 participants | 1 participants |
| CA 125 status with CA 125 in the normal range | 32 participants | 17 participants | 15 participants |
| CA 125 status with elevated CA 125 | 137 participants | 67 participants | 70 participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) Missing | 2 participants | 0 participants | 2 participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) PS 0 (fully active) | 68 participants | 36 participants | 32 participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) PS 1 (restricted in physically strenuous activity) | 89 participants | 43 participants | 46 participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) PS2(ambulatory and capable of all selfcare) | 11 participants | 5 participants | 6 participants |
| Histologic Grade G1 (well differentiated) | 6 participants | 1 participants | 5 participants |
| Histologic Grade G2 (moderately differentiated) | 33 participants | 15 participants | 18 participants |
| Histologic Grade G3 (poorly differentiated) | 122 participants | 65 participants | 57 participants |
| Histologic Grade Not done | 9 participants | 3 participants | 6 participants |
| Histopathologic type clear cell | 4 participants | 2 participants | 2 participants |
| Histopathologic type endometroid | 9 participants | 4 participants | 5 participants |
| Histopathologic type mixed | 8 participants | 5 participants | 3 participants |
| Histopathologic type mucinous | 1 participants | 0 participants | 1 participants |
| Histopathologic type other | 7 participants | 4 participants | 3 participants |
| Histopathologic type papillary serous | 141 participants | 69 participants | 72 participants |
| Number of prior therapies 1 therapy | 158 participants | 80 participants | 78 participants |
| Number of prior therapies 2 therapies | 12 participants | 4 participants | 8 participants |
| Origin of tumor Fallopian tube | 8 participants | 4 participants | 4 participants |
| Origin of tumor Missing | 1 participants | 1 participants | 0 participants |
| Origin of tumor Ovarian | 146 participants | 69 participants | 77 participants |
| Origin of tumor Ovarian + Fallopian tube | 2 participants | 2 participants | 0 participants |
| Origin of tumor Ovarian + Primary peritoneal | 1 participants | 0 participants | 1 participants |
| Origin of tumor Primary peritoneal | 12 participants | 8 participants | 4 participants |
| Region of Enrollment Canada | 10 participants | 4 participants | 6 participants |
| Region of Enrollment France | 10 participants | 7 participants | 3 participants |
| Region of Enrollment Germany | 82 participants | 44 participants | 38 participants |
| Region of Enrollment Israel | 4 participants | 2 participants | 2 participants |
| Region of Enrollment Spain | 2 participants | 1 participants | 1 participants |
| Region of Enrollment United Kingdom | 3 participants | 1 participants | 2 participants |
| Region of Enrollment United States | 59 participants | 25 participants | 34 participants |
| Sex: Female, Male Female | 170 Participants | 84 Participants | 86 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Stage at first diagnosis (International Federation of Gynecology and Obstetrics (FIGO)) IIIA | 5 participants | 3 participants | 2 participants |
| Stage at first diagnosis (International Federation of Gynecology and Obstetrics (FIGO)) IIIB | 16 participants | 10 participants | 6 participants |
| Stage at first diagnosis (International Federation of Gynecology and Obstetrics (FIGO)) IIIC | 137 participants | 65 participants | 72 participants |
| Stage at first diagnosis (International Federation of Gynecology and Obstetrics (FIGO)) IV | 12 participants | 6 participants | 6 participants |
| Time from diagnosis to randomization | 5.3 weeks STANDARD_DEVIATION 2.9 | 5.2 weeks STANDARD_DEVIATION 2.3 | 5.4 weeks STANDARD_DEVIATION 3.4 |
| Time from Surgery to first treatment dose | 5.1 weeks STANDARD_DEVIATION 1.3 | 5.1 weeks STANDARD_DEVIATION 1.2 | 5.1 weeks STANDARD_DEVIATION 1.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 77 / 77 | 86 / 88 |
| serious Total, serious adverse events | 31 / 77 | 30 / 88 |
Outcome results
Primary
Progression Free Survival (PFS): Time From Randomization Until Date of Progression or Death.
A patient may have been declared to have progressive disease on the basis of radiological measuremt of tumor lesions assessmt or CA125 evaluation (tumor measuremts taking precedence).Radiological progression was defined as per the RECIST guidelines (Therasse et al, JNCI2000) as at least 20% increase in the sum of the longest diameters of target lesions(ref the smallest sum of the longest diam recorded since the treatmt started or since the appearance of at least 1 new lesion).Serum CA125 progression was defined, according to the 2005 GCIG def: pts with: * Elevated CA125 pretreatmt and normalization of CA125 has to show evidence of CA125≥ 2 times the upper normal limit on 2 occasions at least 1 wk apart OR * Elevated CA125 pretreatmt which never normalized must show evidence of CA125≥ 2 times the nadir value on 2 occasions at least 1 wk apart OR * CA125 in the normal range pretreatmt had to show evidence of CA125 ≥ 2 times the upper normal limit on 2 occasions at least 1 wk apart
Time frame: Radiological tumor assessment: every 12(+/- 1) weeks for 3 years after randomization + CA 125: day 1 of each cycle
Population: Unstratified Intent To Treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A Control | Progression Free Survival (PFS): Time From Randomization Until Date of Progression or Death. | 16.690 months |
| B Experimental | Progression Free Survival (PFS): Time From Randomization Until Date of Progression or Death. | 15.737 months |
Secondary
Overall Survival (OS)
Interval between the date from randomization to death from any cause whichever came first.
Time frame: Day 1 of each cycle up to 4 years after randomization
Population: Unstratified Intent To Treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A Control | Overall Survival (OS) | NA months |
| B Experimental | Overall Survival (OS) | 45.207 months |
Secondary
Time To Progression (TTP): Interval From the Date of Randomization to the Date of Disease Progression
A patient may have been declared to have progressive disease on the basis of radiological measuremt of tumor lesions assessmt or CA125 evaluation (tumor measuremts taking precedence).Radiological progression was defined as per the RECIST guidelines (Therasse et al, JNCI2000) as at least 20% increase in the sum of the longest diameters of target lesions(ref the smallest sum of the longest diam recorded since the treatmt started or since the appearance of at least 1 new lesion).Serum CA125 progression was defined, according to the 2005 GCIG def: pts with: * Elevated CA125 pretreatmt and normalization of CA125 has to show evidence of CA125≥ 2 times the upper normal limit on 2 occasions at least 1 wk apart OR * Elevated CA125 pretreatmt which never normalized must show evidence of CA125≥ 2 times the nadir value on 2 occasions at least 1 wk apart OR * CA125 in the normal range pretreatmt had to show evidence of CA125 ≥ 2 times the upper normal limit on 2 occasions at least 1 wk apart
Time frame: Radiological tumor assessment: every 12 (+/- 1) weeks for 3 years after randomization + CA125: day 1 of each cycle
Population: Unstratified Intent To Treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A Control | Time To Progression (TTP): Interval From the Date of Randomization to the Date of Disease Progression | 17.840 months |
| B Experimental | Time To Progression (TTP): Interval From the Date of Randomization to the Date of Disease Progression | 16.066 months |