Makhija 2010.

Methods	Phase II randomised placebo‐controlled double‐blind multi‐centre clinical trial
Participants	131 participants were enrolled at 30 US sites. A total of 130 participants were treated ‐ 65 per arm. Baseline characteristics were similar for participants in the 2 arms. One‐third of all participants were 65 years old, and 65% had an ECOG score of 0. Of the 130 treated participants, 115 had measurable disease at baseline. All participants received at least 1 prior platinum‐containing regimen. Fifteen participants in the gemcitabine + placebo arm and 14 participants in the gemcitabine + pertuzumab arm had received 1 non‐platinum‐containing regimen, most commonly doxorubicin. Most participants had received only 1 prior platinum‐based regimen and had a tumour‐free interval of less than 6 months. Placebo group: median age 61 years, range 18 to 85 years. Pertuzumab group: median age 58 years, range 18 to 81 years Placebo group Ovarian cancer: 59 (91%) Of which, epithelial (papillary serous or other): 51 (86%) Of which, other (clear cell, mucinous, or high‐grade adenocarcinoma): 8 (14%) Peritoneal carcinoma: 5 (8%) Fallopian tube carcinoma: 1 (2%) Pertuzumab group Ovarian cancer: 57 (88%) Of which, epithelial (papillary serous or other): 54 (95%) Of which, other (clear cell, mucinous, or high‐grade adenocarcinoma): 3 (5%) Peritoneal carcinoma: 5 (8%) Fallopian tube carcinoma: 3 (5%) ECOG performance status (all participants ECOG 0 or 1) Placebo group: 42 (65%) participants ECOG PS 0 Pertuzumab group: 43 (66%) participants ECOG PS 0 Measurable disease Placebo group: 58 (89%) Pertuzumab group: 57 (88%) Placebo group Prior treatment with platinum‐based chemotherapy: 65 (100%) 1 prior platinum‐based regimen: 42 (65%) 2 or more prior platinum‐based regimens: 23 (35%) Prior treatment for platinum‐resistant disease: 15 Doxorubicin: 9 (60%) Topotecan: 2 (13%) Taxane based: 2 (13%) Other: 3 (20%) Pertuzumab group Prior treatment with platinum‐based chemotherapy: 65 (100%) 1 prior platinum‐based regimen: 48 (74%) 2 or more prior platinum‐based regimens: 17 (26%) Prior treatment for platinum‐resistant disease: 14 Doxorubicin: 11 (79%) Topotecan: 1 (7%) Taxane based: 2 (14%) Other: 5 (36%) Baseline CA‐125 U/mL Placebo group: median 249, range 11 to 2292 Pertuzumab group: median 195, range 11 to 4287
Interventions	Intervention Gemcitabine (800 mg/m² on days 1 and 8 of a 21‐day cycle) plus pertuzumab (administered intravenously as an 840‐mg loading dose followed by 420 mg every 3 weeks) Treatment was administered until either tumour progression or unacceptable toxicity. Participants with non‐progressing disease after 17 cycles of treatment and acceptable toxicity were eligible to continue pertuzumab. Comparison Gemcitabine (800 mg/m² on days 1 and 8 of a 21‐day cycle) plus placebo. Treatment was administered until either tumour progression or unacceptable toxicity. Cross‐over to pertuzumab ± gemcitabine for a total of 17 cycles, administered every 3 weeks for up to 1 year, was allowed for participants randomly assigned to placebo who had objective evidence of disease progression.
Outcomes	Overall survival (OS) was defined as time from random assignment to death from any cause. Progression‐free survival (PFS) was defined as time from random assignment to documented disease progression or death from any cause within 30 days from the last dose of study medication. Objective response rate: objective response was defined as a complete or partial response on 2 consecutive occasions 4 weeks apart. Participants without a post‐baseline tumour or CA‐125 assessment were considered non‐responders. Adverse events Exploratory analyses of response by HER‐3 mRNA expression Quality of life was measured via FOSI questionnaires, completed by participants at baseline and at day 1 of each 3‐week cycle. (FOSI = Functional Assessment of Cancer Therapy ‐ Ovarian (FACT‐O) Symptom Index) "The FOSI score was derived from 8 items with higher scores indicating better health status (range 0‐32). Symptom deterioration was defined as a ≥ 3 point decrease in FOSI from baseline". (NB: QoL data have been published only in conference abstract format ‐ see Lalla 2008 in subsidiary references.) Cox regression for survival outcomes stratified by baseline ECOG performance status, number of prior regimens for platinum‐resistant disease, and disease measurability was used to estimate hazard ratio (HR). Unstratified Cox regression was used to explore pertuzumab treatment benefit in patient subsets.
Notes	Length of follow‐up not reported, but Kaplan‐Meier plots show that for overall survival, the maximum length of follow‐up was about 30 months. PFS and objective response analyses were performed after 103 PFS events were observed. All other data presented reflect the final analysis, which occurred after 91 deaths were observed. An open‐label cross‐over was allowed from placebo to pertuzumab in the presence of objective evidence of disease progression. Archival tumour tissue was also taken for correlative gene mRNA expression studies, to look at HER‐1, HER‐2, HER‐3, betacellulin, amphiregulin, and G6‐PDH. In the intervention group, all 65 participants received allocated treatment, all of whom discontinued blinded treatment (53 due to disease progression; 8 due to adverse events; 1 due to the participant's decision; 1 due to physician’s decision; 1 due to non‐compliance; 1 due to other reasons). In the comparison group, only 1 participant out of the 66 who were randomised did not receive allocated intervention (unclear why not). 65/66 participants did receive allocated intervention. Of these, 1/65 completed 17 cycles of blinded treatment and 64/65 discontinued blinded treatment (1 due to death; 56 due to disease progression; 2 due to adverse events; 3 due to the participant's decision; 2 due to physician’s decision). The 1 participant who did not receive the allocated control intervention was not analysed. All other participants were analysed as intention‐to‐treat. Median time‐to‐event data were estimated via the Kaplan‐Meier method. Median PFS was 2.9 months and 2.6 months in intervention and placebo groups, respectively. Median OS was 13 months and 13.1 months in intervention and placebo groups, respectively. Adverse events were recorded as the number of women who experienced an event (N = 65 in each group). Haematological toxicity Placebo group: neutropaenia: grade 3 or 4: 14, any grade: 28; thrombocytopaenia: grade 3 or 4: 5, any grade: 15; anaemia: grade 3 or 4: 3, any grade: 34 Pertuzumab group: neutropaenia: grade 3 or 4: 23, any grade: 32; thrombocytopaenia: grade 3 or 4: 9, any grade: 19; anaemia: grade 3 or 4: 3, any grade: 31 Gastrointestinal toxicity Placebo group: nausea: grade 3 or 4: 4, any grade: 43; diarrhoea: grade 3 or 4: 1, any grade: 23; dyspepsia: grade 3 or 4: 0, any grade: 8 Pertuzumab group: nausea: grade 3 or 4: 5, any grade: 49; diarrhoea: grade 3 or 4: 7, any grade: 44; dyspepsia: grade 3 or 4: 1, any grade: 14 Skin toxicity Placebo group: rash: grade 3 or 4: 0, any grade: 9; stomatitis: grade 3 or 4: 0, any grade: 7 Pertuzumab group: rash: grade 3 or 4: 0, any grade: 26; stomatitis: grade 3 or 4: 0, any grade: 19 Neurological toxicity Placebo group: headache: grade 3 or 4: 1, any grade: 17 Pertuzumab group: headache: grade 3 or 4: 1, any grade: 24 Cardiac toxicity Placebo group: congestive heart failure: grade 3 or 4: 0, any grade: 0; left ventricular ejection fraction decline ≥ 10 points (N = 59): 10 Pertuzumab group: congestive heart failure: grade 3 or 4: 1, any grade: 1; left ventricular ejection fraction decline ≥ 10 points (N = 60): 7 Other Placebo group: fatigue: grade 3 or 4: 11, any grade: 44; back pain: grade 3 or 4: 1, any grade: 15; epistaxis: grade 3 or 4: 0, any grade: 1; rhinorrhoea: grade 3 or 4: 0, any grade: 4 Pertuzumab group: fatigue: grade 3 or 4: 14, any grade: 51; back pain: grade 3 or 4: 6, any grade: 27; epistaxis: grade 3 or 4: 0, any grade: 15; rhinorrhoea: grade 3 or 4: 0, any grade: 10 Fatal adverse events occurred in 2 participants in the gemcitabine + placebo arm: sepsis and infection. Four participants in the gemcitabine + pertuzumab arm had fatal adverse events: acute renal failure; pneumonitis; haemolytic‐uraemic syndrome; sepsis, Clostridium difficile colitis, and hydronephrosis. Quality of life (reported only in conference abstract form ‐ see Lalla 2008 in subsidiary references) "The median time to symptom deterioration was 1.7 months in the gemcitabine+placebo arm vs. 3.8 months in the gemcitabine+pertuzumab arm (HR = 0.62, 95% CI: 0.36‐1.05). Symptom improvement (≥ 3 point increase in FOSI) occurred in 28 women (43%) given gemcitabine+pertuzumab, compared to 18 (28%) in those receiving gemcitabine+placebo". ClinicalTrials.gov identifier: NCT00096993 This study was included in the original version of this review; no new results have been identified.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Patients were randomly assigned in a 1:1 ratio to gemcitabine ... plus either placebo or pertuzumab".
Allocation concealment (selection bias)	Unclear risk	Not clear from the study
Blinding of participants and personnel (performance bias) Objective outcome measures (Overall Survival)	Low risk	Outcome unlikely to be affected by blinding
Blinding of participants and personnel (performance bias) Subjective outcome measures (PFS; Toxicity; QoL)	Unclear risk	Study was described as double‐blinded, but all but 1 participant discontinued blinded treatment.
Blinding of outcome assessment (detection bias) Objective outcome measures (overall survival)	Low risk	Outcome unlikely to be affected by blinding
Blinding of outcome assessment (detection bias) Subjective outcome measures (PFS, Toxicity, QoL)	Unclear risk	Study was described as double‐blinded, but it was unclear whether the outcome assessor was masked. Trial protocol was consulted but did not provide further details.
Incomplete outcome data (attrition bias) All outcomes	Low risk	% analysed: 130/131 (99%)
Selective reporting (reporting bias)	Low risk	All pertinent outcomes appear to have been reported, and exploratory analyses, unplanned beforehand, are clearly labelled as such.
Other bias	Unclear risk	Industry involvement and funding (from Genentech) were reported.