Panitumumab Combination Study With Rilotumumab or Ganitumab in Wild-type Kirsten Rat Sarcoma Virus Oncogene Homolog (KRAS) Metastatic Colorectal Cancer (mCRC)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Amgen
ClinicalTrials.gov Identifier:
NCT00788957
First received: October 23, 2008
Last updated: June 23, 2015
Last verified: June 2015
  Purpose

This study is a global, multicenter, open-label phase 1b and randomized, double-blinded, 2 part, phase 2 study designed to evaluate the safety and efficacy of rilotumumab or ganitumab in combination with panitumumab versus panitumumab alone in patients with metastatic colorectal cancer whose tumors are wild-type KRAS status.


Condition Intervention Phase
Colon Cancer
Colorectal Cancer
Gastrointestinal Cancer
Metastatic Colorectal Cancer
Rectal Cancer
Drug: Panitumumab
Drug: Ganitumab
Drug: Rilotumumab
Drug: Placebo
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Phase 1b/2 Trial of AMG 102 or AMG 479 in Combination With Panitumumab Versus Panitumumab Alone in Subject With Wild-Type KRAS Metastatic Colorectal Cancer

Resource links provided by NLM:


Further study details as provided by Amgen:

Primary Outcome Measures:
  • Part 1: Number of Participants With Dose-limiting Toxicities (DLT) [ Time Frame: 7 weeks ] [ Designated as safety issue: Yes ]
    A DLT is defined as any grade 3 or 4 rilotumumab-related or combination (panitumumab and rilotumumab)-related adverse event or laboratory abnormality that is deemed clinically significant by the investigator

  • Part 2: Percentage of Participants With an Objective Response [ Time Frame: From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks. ] [ Designated as safety issue: No ]
    An objective response is defined as a confirmed complete (CR) or partial response (PR) no less than 4 weeks after the criteria for response are first met, determined by the investigator considering the radiologic response of all existing target and non-target lesions, evidence of new lesions, and cytology evaluation (as appropriate) according to the Modified-Response Evaluation Criteria In Solid Tumors (RECIST) v1.0 criteria: CR: Disappearance of all target and non-target and no new lesions. PR: At least a 30% decrease in the size of target lesions with no increase in non-target lesions, or, the disappearance of all target lesions and persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease. Participants without a post-baseline assessment were considered non-responders. Tumor assessments up to the initiation of another anti-tumor therapy including the Part 3 treatment, if applicable, were used.


Secondary Outcome Measures:
  • Part 2: Duration of Response [ Time Frame: From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks. ] [ Designated as safety issue: No ]
    The interval from the first visit of a confirmed objective response to disease progression as defined by the modified RECIST v1.0 criteria. Participants who did not progress by the earlier of the analysis data cutoff date, initiating a new line of anti-tumor therapy, and the start of Part 3 dosing where applicable were censored at their last evaluable disease assessment date prior to the end of reporting period. Progressive disease is defined as at least a 20% increase in the size of target lesions, or unequivocal progression of existing non-target lesions, or any new lesions.

  • Part 2: Time to Response [ Time Frame: From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks. ] [ Designated as safety issue: No ]
    The interval from the first dose of study therapy to the date of the first confirmed objective response, calculated only for participants with an objective response.

  • Part 2: Percentage of Participants With Disease Control [ Time Frame: From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks. ] [ Designated as safety issue: No ]
    The percentage of participants with an overall objective response of CR, PR, or stable disease (SD). CR: Disappearance of all target and non-target and no new lesions. PR: At least a 30% decrease in the size of target lesions with no increase in non-target lesions, or, the disappearance of all target lesions and persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease (PD). SD: Neither sufficient shrinkage of target lesions to qualify for PR nor sufficient increase to qualify for PD and no progression of non-target lesions, or the persistence of one or more non-target lesion(s) not qualifying for either CR or PD.

  • Progression-free Survival [ Time Frame: From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks. ] [ Designated as safety issue: No ]
    The interval from the first dose of study therapy to the earlier date of disease progression (per modified-RECIST v1.0) or death. Participants who did not progress or die by the analysis data cutoff date were censored at their last evaluable disease assessment date prior to the earlier of the analysis data cutoff date, initiating a new line of anti-tumor therapy, and receiving study treatment in Part 3 where applicable. Participants enrolled into Part 3 or who started a new line of anti-tumor therapy before radiographic progression but subsequently died were considered as having an event with the event date same as the death date.

  • On-treatment Progression-free Survival [ Time Frame: From the date of first dose until 28 days after the last dose until the data cut-off date of 23 July 2010. Median time on treatment was 3.7, 4.9 and 5.1 months in each treatment arm respectively. ] [ Designated as safety issue: No ]
    An event is defined as a radiographic progression or death that occurred from the first dose to 28 days since the last dose of study therapy. Participants who did not progress or die during this period were censored at their last evaluable disease assessment before the end of the 28-day period. Participants who received Part 3 treatment before 28 days since their last dose of study drug in Part 2 and did not have radiographic progression or die were censored at their last evaluable disease assessment prior to receiving therapy in Part 3. Radiographic progressions after start of a new anti-tumor therapy, including Part 3 treatment, or after 28 days since the last dose in Part 2 were excluded from the analysis. Participants who died with no prior radiographic disease progression during Part 3 treatment, but within the 28-day period since the last dose in Part 2 were considered as having an event.

  • Overall Survival [ Time Frame: From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks. ] [ Designated as safety issue: No ]
    The interval from the first dose of study therapy to the date of death. Participants still alive at the analysis data cutoff date were censored at their last contact date.

  • Number of Participants With Adverse Events (AEs) [ Time Frame: From the first dose date to 30 days after the last dose of study drug, up to the data cutoff date of 08 February 2012. Median time on treatment was 5.2 months for Part 1, 2.8, 3.9 and 4.2 months for each Part 2 treatment arm respectively. ] [ Designated as safety issue: Yes ]
    A serious adverse event (SAE) is defined as an AE that is fatal, life threatening (places the participant at immediate risk of death), requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or other significant medical hazard. AEs were graded for severity according to the National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE) version 3: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal. AEs were assessed by the investigator for the relationship of the AE to each one or more of the investigational products by the question: "Is there a reasonable possibility that the event may have been caused by the investigational product?"

  • Number of Participants With Grade 3 or Higher Laboratory Toxicities [ Time Frame: From the first dose date to 30 days after the last dose of study drug, up to the data cutoff date of 08 February 2012. Median time on treatment was 5.2 months for Part 1, 2.8, 3.9 and 4.2 months for each Part 2 treatment arm respectively. ] [ Designated as safety issue: Yes ]
    The severity of laboratory toxicities was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE) version 3: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal.

  • Number of Participants With Antibody Formation to Panitumumab, Rilotumumab and Ganitumab [ Time Frame: From the first dose date to 30 days after the last dose of study drug, up to the data cutoff date of 08 February 2012. Median time on treatment was 5.2 months for Part 1, 2.8, 3.9 and 4.2 months for each Part 2 treatment arm respectively. ] [ Designated as safety issue: Yes ]
    Validated immunoassays were used to detect anti-panitumumab, anti-rilotumumab and anti-ganitumab binding antibodies.

  • Part 1: Maximum Observed Drug Concentration (Cmax) and Minimum Drug Concentration (Cmin) for Panitumumab and Rilotumumab [ Time Frame: Week 5 (third dose) at pre-dose, 5 minutes after infusion and at 24, 48 and 96, and 168 hours post infusion. ] [ Designated as safety issue: No ]
  • Part 1: Area Under the Drug Concentration-time Curve During a Dosing Interval (AUCtau) for Panitumumab and Rilotumumab [ Time Frame: Week 5 (third dose) at pre-dose, 5 minutes after infusion and at 24, 48 and 96, and 168 hours post infusion. ] [ Designated as safety issue: No ]
  • Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Panitumumab [ Time Frame: Pre-dose and 5 minutes after the completion of infusion at Weeks 1, 3, 5, 7, 13 and 23. ] [ Designated as safety issue: No ]
  • Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Panitumumab [ Time Frame: Pre-dose at Weeks 3, 5, 7, 13 and 23. ] [ Designated as safety issue: No ]
    Concentration represents the Cmin from the previous dose (eg, Week 3 Cmin is the Cmin after the 1st dose).

  • Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Rilotumumab [ Time Frame: Pre-dose and 5 minutes after the completion of infusion at Weeks 1, 3, 5, 7, 13 and 23. ] [ Designated as safety issue: No ]
  • Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Rilotumumab [ Time Frame: Pre-dose at Weeks 3, 5, 7, 13 and 23. ] [ Designated as safety issue: No ]
    Concentration represents the Cmin from the previous dose (eg, Week 3 Cmin is the Cmin after the 1st dose).

  • Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Ganitumab [ Time Frame: Pre-dose and 5 minutes after the completion of infusion at Weeks 1, 3, 5, 7, 13 and 23. ] [ Designated as safety issue: No ]
  • Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Ganitumab [ Time Frame: Pre-dose at Weeks 3, 5, 7, 13 and 23. ] [ Designated as safety issue: No ]
    Concentration represents the Cmin from the previous dose (eg, Week 3 Cmin is the Cmin after the 1st dose).


Enrollment: 153
Study Start Date: October 2008
Study Completion Date: October 2013
Primary Completion Date: February 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part 1: Panitumumab + Rilotumumab
Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Drug: Panitumumab
Panitumumab for intravenous infusion
Other Name: Vectibix®
Drug: Rilotumumab
Rilotumumab for intravenous infusion
Other Name: AMG 102
Active Comparator: Part 2: Panitumumab Alone
Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Drug: Panitumumab
Panitumumab for intravenous infusion
Other Name: Vectibix®
Drug: Placebo
Placebo intravenous infusion
Experimental: Part 2: Panitumumab + Rilotumumab
Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Drug: Panitumumab
Panitumumab for intravenous infusion
Other Name: Vectibix®
Drug: Rilotumumab
Rilotumumab for intravenous infusion
Other Name: AMG 102
Experimental: Part 2: Panitumumab + Ganitumab
Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.
Drug: Panitumumab
Panitumumab for intravenous infusion
Other Name: Vectibix®
Drug: Ganitumab
Ganitumab for intravenous infusion
Other Name: AMG 479

Detailed Description:

This study consisted of 3 parts:

Part 1: determination of the tolerable dose of rilotumumab in combination with panitumumab to be administered in Part 2.

Part 2: Comparison of the safety and efficacy of rilotumumab or ganitumab in combination with panitumumab versus that of panitumumab alone. In Part 2, participants were randomized 1:1:1 into 3 cohorts: 6 mg/kg panitumumab plus 10 mg/kg rilotumumab, 6 mg/kg panitumumab plus 12 mg/kg ganitumab, or 6 mg/kg panitumumab and placebo (panitumumab alone cohort). Panitumumab was administered open-label, and rilotumumab and ganitumab were double-blinded.

Part 3: Exploratory evaluation of the safety and efficacy of the rilotumumab and ganitumab monotherapy following treatment with panitumumab in Part 2. In Part 3, eligible participants who terminated panitumumab treatment in the Panitumumab Alone arm of Part 2 due to disease progression or intolerability could be randomized 1:1 into 2 double-blind cohorts: 10 mg/kg rilotumumab or 12 mg/kg ganitumab.

Participants who permanently discontinued all the investigational products completed a safety follow-up visit 30 days and a follow-up visit 60 days after the last dose of investigational product. Participants were followed for radiographic disease progression and survival every 3 months after the 30-day safety follow-up visit for up to 2 years after the last participant was enrolled in Part 2.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • metastatic adenocarcinoma of the colon or rectum
  • wild-type KRAS tumor status
  • radiographic evidence of disease progression during or following treatment with irinotecan and/or oxaliplatin containing chemotherapy for mCRC
  • measurable disease >/= 20 mm per Response Evaluation Criteria In Solid Tumors (RECIST)
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • adequate laboratory values

Exclusion Criteria:

  • history of central nervous system (CNS) metastases
  • history of another primary cancer, unless:
  • curatively resected non-melanomatous skin cancer
  • curatively treated cervical carcinoma in situ
  • other primary solid tumor treated with curative intent and no known active disease present for >/= 5 years
  • prior treatment with an anti-epithelial growth factor receptor (EGFR), hepatocyte growth factor receptor (HGFR, c-MET), and/or insulin-like growth factor receptor (IGFR) inhibitor
  • prior treatment with AMG 102 or AMG 479
  • prior treatment with chemotherapy or radiotherapy </= 21 days
  • prior treatment with targeted therapy </= 30 days
  • known allergy or hypersensitivity to panitumumab, AMG 102, or AMG 479
  • history of interstitial lung disease
  • clinically significant cardiovascular disease </= 1 year
  • active inflammatory bowel disease
  • known human immunodeficiency virus (HIV), hepatitis C, or hepatitis B infection
  • any co-morbid disease or condition that could increase the risk of toxicity
  • serious or non-healing wound </= 35 days
  • any uncontrolled concurrent illness or history of any medical condition that could interfere with the interpretation of the study results
  • major surgical procedure </= 35 days or minor surgical procedure </= 14 days
  • other investigational procedures or drugs </= 30 days
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00788957

Sponsors and Collaborators
Amgen
Investigators
Study Director: MD Amgen
  More Information

Additional Information:
Publications:
Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT00788957     History of Changes
Other Study ID Numbers: 20060447
Study First Received: October 23, 2008
Results First Received: March 24, 2015
Last Updated: June 23, 2015
Health Authority: Canada: Health Canada
European Union: European Medicines Agency
United States: Food and Drug Administration
United States: Quorom Institutional Review Board
United States: Western Institutional Review Board

Keywords provided by Amgen:
panitumumab
vectibix
AMG 102
AMG 479
colon cancer
rectal cancer
colorectal cancer
metastatic colorectal cancer
EGFR inhibitor
IGF inhibitor
c-MET inhibitor

Additional relevant MeSH terms:
Colorectal Neoplasms
Gastrointestinal Neoplasms
Colonic Diseases
Digestive System Diseases
Digestive System Neoplasms
Gastrointestinal Diseases
Intestinal Diseases
Intestinal Neoplasms
Neoplasms
Neoplasms by Site
Rectal Diseases
Antibodies, Monoclonal
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 03, 2015