Comparison of Survival Benefit of Panitumumab With Supportive Care to Best Supportive Care Alone in Patients With Metastatic Colorectal Cancer

Amgen377 enrolled

Overview

The purpose of this study is to evaluate the benefit of panitumumab in addition to best supportive care compared to best supportive care alone in patients with chemorefractory wild-type KRAS (Kirsten rat sarcoma viral oncogene homolog) metastatic colorectal cancer.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

377

Conditions

Metastatic Colorectal Cancer

Interventions

Best Supportive Care (BSC)OTHER

BSC was defined as the best palliative care available as judged appropriate by the investigator and according to institutional guidelines and could include antibiotics, analgesics, radiation therapy for pain control (limited to bone metastases), corticosteroids, transfusions, psychotherapy, growth factors, palliative surgery, or any other symptomatic therapy as clinically indicated.

PanitumumabDRUG

Administered intravenously

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Diagnosis of metastatic colorectal cancer (CRC) * Wild-type (without mutation in codons 12 and 13) KRAS gene in tumor tissue confirmed by a central laboratory * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 * At least 1 measurable or non-measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. * Treatment failure (defined as failure due to either disease progression \[clinical or radiological\] or toxicity \[treatment intolerance\]) of a prior regimen containing irinotecan for metastatic disease and a prior regimen containing oxaliplatin for metastatic disease. Oxaliplatin and irinotecan may have been administered sequentially or in combination. * Disease relapse within 6 months after completing adjuvant chemotherapy (with either an irinotecan or oxaliplatin containing regimen) will also be considered as treatment failure of a prior regimen for metastatic disease * Must have previously received a thymidylate synthase inhibitor (eg, fluorouracil, capecitabine, raltitrexed, or fluorouracil-uracil) at any point for treatment of CRC * Man or woman at least 18 years of age * Adequate hematologic, renal, hepatic and metabolic function * Negative pregnancy test within 72 hours before randomization (for women of childbearing potential only) * Subject or subject's legally acceptable representative has provided informed consent. * Other protocol-specified criteria may apply Exclusion Criteria: * Symptomatic brain metastases requiring treatment * History of another primary cancer within 5 years of randomization * Prior anti-epidermal growth factor receptor (EGFR) antibody therapy (eg, panitumumab or cetuximab) or treatment with small molecule EGFR inhibitors (eg, gefitinib, erlotinib, lapatinib) * Antitumor therapy (eg, chemotherapy, hormonal therapy, immunotherapy, antibody therapy) within 21 days before randomization * Radiotherapy within 14 days before randomization. * Exclusion Criteria for corrected QT (QTc) Evaluation Subpart of the Study: Prolongation of QT/QTc interval \> 450 milliseconds at screening * Other protocol-specified criteria may apply

Locations (78)

Outcomes

Primary Outcomes

Overall Survival

Overall survival was defined as the time from the randomization date to the date of death. Participants who had not died by the analysis data cut-off date were censored at their last contact date and participants with survival data obtained after the planned analysis data cut-off date had survival censored at the cut-off date.

Time frame: From randomization to the last on-study or long-term follow-up visit, as of the data cut-off date of 10 June 2014. The median follow-up time was 34.9 weeks (panitumumab plus BSC: 41.0 weeks; BSC alone: 25.5 weeks).

Secondary Outcomes

Progression-free Survival

Progression-free survival (PFS) was defined as the time from the randomization date to the date of disease progression per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 or death. Progressive disease (PD): At least a 20% increase in the size of target lesions compared with the smallest size since treatment started and an absolute increase of at least 5 mm, any new lesions or an increase in size of non-target lesions thought be ≥ 20% and an absolute increase of at least 5 mm, or significant increase in pleural effusions, ascites or other fluid collections with cytologic proof of malignancy. Participants who were alive and did not meet the criteria for progression by the analysis data cut-off date were censored at their last evaluable disease assessment date.

Overall Survival in Participants With Wild-type RAS

A secondary efficacy endpoint was overall survival in participants with wild-type rat sarcoma viral oncogene homolog (RAS) (without mutation in exons 2 \[codons 12 and 13\], 3 \[codons 59 and 61\], and 4 \[codons 117 and 146\] of KRAS and neuroblastoma RAS viral oncogene (NRAS)). In participants with wild-type RAS, RAS mutation status was defined by KRAS exon 2 mutation status per clinical trial assay testing and mutation status of KRAS exon 3 and 4 and NRAS exons 2, 3 and 4 per Sanger bi-directional sequencing. Overall survival was defined as the time from the randomization date to the date of death. Participants who had not died by the analysis data cut-off date were censored at their last contact date and participants with survival data obtained after the planned analysis data cut-off date had survival censored at the cut-off date.

Data from ClinicalTrials.gov

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Research Site

Curitiba, Paraná, Brazil

Research Site

Natal, Rio Grande do Norte, Brazil

Research Site

Ijuí, Rio Grande do Sul, Brazil

Research Site

Porto Alegre, Rio Grande do Sul, Brazil

Research Site

Greenfield Park, Quebec, Canada

Research Site

Montreal, Quebec, Canada

Research Site

Montreal, Quebec, Canada

Research Site

Québec, Quebec, Canada

Research Site

Québec, Quebec, Canada

Research Site

Trois-Rivières, Quebec, Canada

...and 68 more locations

Time frame: From randomization to the last on-study or long-term follow-up visit, as of the data cut-off date of 10 June 2014. The median follow-up time was 36.1 weeks (panitumumab plus BSC: 43.7 weeks; BSC alone: 23.6 weeks).

Progression Free Survival (PFS) in Participants With Wild-type RAS

PFS was defined as the time from the randomization date to the date of disease progression per RECIST version 1.1 or death. Progressive disease (PD): At least a 20% increase in the size of target lesions compared with the smallest size since treatment started and an absolute increase of at least 5 mm, any new lesions, or an increase in size of non-target lesions thought be ≥ 20% with an absolute increase of at least 5 mm, or significant increase in pleural effusions, ascites or other fluid collections with cytologic proof of malignancy. Participants who were alive and did not meet the criteria for progression by the analysis data cut-off date were censored at their last evaluable disease assessment date.

Objective Response Rate

Objective response rate (ORR) is defined as the percentage of participants with either a complete response (CR) or partial response (PR) per RECIST version 1.1. Radiographic tumor assessments and investigator's assessment of response were performed at Week 4, Week 8, and then every 8 weeks until disease progression (radiographic or clinical progression). CR: Disappearance of all target and non-target lesions and no new lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the size of target lesions with no progression of non-target lesions and no new lesions, or, the disappearance of all target lesions with persistence of one or more non-target lesions not qualifying for either CR or PD and no new lesions.

Time frame: Response was assessed at Week 4, Week 8, and then every 8 weeks until the data cut-off date of 10 June 2014. The median follow-up time was 34.9 weeks (panitumumab plus BSC: 41.0 weeks; BSC alone: 25.5 weeks).

Objective Response Rate in Participants With Wild-type RAS

Objective response rate is defined as the percentage of participants with either a complete response (CR) or partial response (PR) per RECIST version 1.1. Radiographic tumor assessments and investigator's assessment of response were performed at Week 4, Week 8, and then every 8 weeks until disease progression (radiographic or clinical progression). CR: Disappearance of all target and non-target lesions and no new lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the size of target lesions with no progression of non-target lesions and no new lesions, or, the disappearance of all target lesions with persistence of one or more non-target lesions not qualifying for either CR or PD and no new lesions.

Time frame: Response was assessed at Week 4, Week 8, and then every 8 weeks until the data cut-off date of 10 June 2014. The median follow-up time was 36.1 weeks (panitumumab plus BSC: 43.7 weeks; BSC alone: 23.6 weeks).

Number of Participants With Adverse Events (AEs)

The severity of each AE was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (Grade 1 = Mild; 2 = Moderate (discomfort enough to cause interference with usual activity); 3 = Severe (incapacitating with inability to work or do usual activity); 4 = Life-threatening and 5 = Fatal), with the exception of the skin-or nail-related AEs which were graded using a CTCAE version 3.0 with modifications. A serious AE was defined as an AE that met at least 1 of the following criteria: • fatal, • life-threatening, • required in-patient hospitalization or prolongation of existing hospitalization, • resulted in persistent or significant disability/incapacity, • congenital anomaly/birth defect, and/or • other medically important serious event. Treatment-related AEs (TRAEs) are those the investigator considered there was reasonable possibility that the event might have been caused by study drug.

Time frame: From first dose until 30 days after last dose; median safety reporting periods were 4.2 months and 2.2 months for panitumumab plus BSC arm and BSC alone arm, respectively.

Maximum Post-baseline Change From Baseline in Corrected QT (QTc) Interval

QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle as measured by electrocardiogram (ECG). QTc is the QT interval corrected for heart rate. To evaluate the effect of panitumumab treatment on the QTc interval length among participants treated with panitumumab, ECGs were collected at the following time points from participants randomized to panitumumab arm at a limited number of sites: Week 1 prior to the first panitumumab infusion (Baseline) and within 30 minutes following the end of the first infusion of panitumumab (Cmax), Week 7 after 3 doses of panitumumab (steady state), and at the safety follow-up visit. The ECGs were submitted for independent central review to calculate the reported QTc interval. QTc was calculated using both the Bazett correction (QTcB) and the Fridericia correction (QTcF).

Time frame: Baseline (pre-dose), Week 1 and Week 7 (post-dose) and 4 weeks after the last dose (Safety Follow-up visit)