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Digestive System Diseases

Rare Diseases

Sarcoma

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Colorectal Neoplasms

Rectal Neoplasms

Colonic Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Intestinal Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

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Antineoplastic Agents

All Drugs and Chemicals

Herbal and Botanical

Panitumumab

Rilotumumab

Antineoplastic Agents, Immunological

Cola

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.

Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.

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.

Ganitumab

Placebo

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.

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.

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

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

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

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.

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.

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.

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.

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.

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.

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.

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?"

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.

Validated immunoassays were used to detect anti-panitumumab, anti-rilotumumab and anti-ganitumab binding antibodies.

Concentration represents the Cmin from the previous dose (eg, Week 3 Cmin is the Cmin after the 1st dose).

Amgen

Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.

Part 1: Panitumumab + Rilotumumab

Part 2: Panitumumab Alone

Part 2: Panitumumab + Rilotumumab

Part 2: Panitumumab + Ganitumab

Total

Part 1 Participants

Part 2 Participants

Age, Continuous

Sex: Female, Male

White or Caucasian

Black or African American

Hispanic or Latino

Asian

Other

Race/Ethnicity, Customized

Colon cancer

Rectal cancer

Primary Tumor Type

Well differentiated

Moderately differentiated

Poorly differentiated

Undifferentiated

Unknown

Adenocarcinoma Differential of Primary Tumor

Data available for 9, 46, 46, and 45 participants in each treatment group respectively

Months Since Primary Diagnosis

Months Since Metastatic Disease Diagnosis

Safety analysis set, including participants who received at least one dose of respective investigational product in the corresponding parts of the study.

Study Director

The first 6 DLT evaluable participants, including participants who received at least 2 doses of panitumumab and rilotumumab as scheduled (ie, Week 1 and 3) and have a minimum 28 days follow-up for safety or, have received at least 1 dose of panitumumab and rilotumumab and had a DLT within the first 28 days on study.

Part 1: Number of Participants With Dose-limiting Toxicities (DLT)

For the primary analysis of objective response rate (ORR) for Part 2, a Beta(6.3, 33.7) and Beta(1.1, 5.9) was used as priors for panitumumab alone and combination regimens in calculating the posterior distribution of the ORR for each respective treatment group. The posterior mean and 95% credible region are reported.

The posterior mean difference in ORR and the 95% credible region for the difference in the ORR between panitumumab + rilotumumab compared to panitumumab alone.

The posterior mean difference in ORR and the 95% credible region for the difference in the ORR between panitumumab + ganitumab compared to panitumumab alone.

The posterior distribution of the odds ratio for an ORR was used to assess whether rilotumumab and/or ganitumab in combination with panitumumab has a higher ORR compared to panitumumab alone. A 95% credible region was calculated for the odds ratio.

The posterior probability of the odds ratio being \> 1 is reported as the P-value.

The posterior distribution of the odds ratio for an ORR was used to assess whether rilotumumab and/or ganitumab in combination with panitumumab has a higher ORR compared to panitumumab alone. A 95% credible region was calculated for the odds ratio. The posterior probability of the odds ratio being \> 1 is reported as the P-value.

Efficacy analysis set (enrolled participants who received at least one dose of respective investigational product in the corresponding parts of the study) with measurable baseline disease.

Part 2: Percentage of Participants With an Objective Response

Efficacy analysis set; participants with an objective response of CR or PR.

Part 2: Duration of Response

Part 2: Time to Response

Part 2: Percentage of Participants With Disease Control

Progression-free Survival

On-treatment Progression-free Survival

Overall Survival

Any adverse event

Worst grade of 3

Worst grade of 4

Worst grade of 5

Serious adverse event

AE leading to study drug / study discontinuation

Treatment-related adverse event (TRAE)

TRAE worst grade of 3

TRAE worst grade of 4

TRAE worst grade of 5

Serious treatment-related adverse event

TRAE leading to study drug / study discontinuation

Safety analysis set (all enrolled participants who received at least 1 dose of investigational product).

Number of Participants With Adverse Events (AEs)

Increased Alanine Amino Transferase

Decreased Albumin

Increased Alkaline Phosphatase

Increased Aspartate Amino Transferase

Decreased Calcium

Increased Calcium

Increased Creatinine

Decreased Glucose

Increased Glucose

Decreased Magnesium

Increased Magnesium

Decreased Phosphorus

Decreased Potassium

Increased Potassium

Decreased Sodium

Increased Sodium

Increased Total Bilirubin

Increased Uric Acid

Decreased Absolute Neutrophil Count

Decreased Hemoglobin

Decreased Lymphocytes

Decreased Platelets

Decreased Total Neutrophils

Decreased White Blood Cells

Number of Participants With Grade 3 or Higher Laboratory Toxicities

Anti-panitumumab antibodies

Anti-rilotumumab antibodies

Anti-ganitumab antibodies

Safety analysis set participants with at least one post-baseline immunoassay result.

Number of Participants With Antibody Formation to Panitumumab, Rilotumumab and Ganitumab

Cmax (n=6, 6)

Cmin (n=5, 4)

Pharmacokinetics of panitumumab in Part 1 participants who 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.

Pharmacokinetics of rilotumumab in Part 1 participants who 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.

Part 1 participants for whom intensive pharmacokinetic samples after the third dose (Week 5) were available.

Part 1: Maximum Observed Drug Concentration (Cmax) and Minimum Drug Concentration (Cmin) for Panitumumab and Rilotumumab

Part 1: Area Under the Drug Concentration-time Curve During a Dosing Interval (AUCtau) for Panitumumab and Rilotumumab

Week 1 (n=43, 42, 44)

Week 3 (n=38, 37, 38)

Week 5 (n=35, 35, 35)

Week 7 (n=30, 35, 29)

Week 13 (n=16, 17, 21)

Week 23 (n=10, 10, 9)

Part 2 participants with available pharmacokinetic data at each time point (indicated by n).

Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Panitumumab

Week 3 (n=39, 36, 36)

Week 5 (n=35, 34, 35)

Week 7 (n=29, 32, 31)

Week 13 (n=16, 17, 20)

Week 23 (n=8, 9, 9)

Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Panitumumab

Week 1 (n=43)

Week 3 (n=37)

Week 5 (n=38)

Week 7 (n=37)

Week 13 (n=18)

Week 23 (n=17)

Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Rilotumumab

Week 3 (n=38)

Week 5 (n=34)

Week 7 (n=33)

Week 13 (n=19)

Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Rilotumumab

Week 1 (n=40)

Week 3 (n=42)

Week 7 (n=35)

Week 13 (n=22)

Week 23 (n=16)

Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Ganitumab

Week 3 (n=39)

Week 5 (n=39)

Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Ganitumab

Participants randomized to Panitumumab Alone in Part 2 who had disease progression (radiographic or clinical) or intolerability were re-randomized in Part 3 to receive rilotumumab 10 mg/kg every 2 weeks until disease progression, intolerability, withdrawal, death, or sponsor decision.

Part 3: Rilotumumab

Participants randomized to Panitumumab Alone in Part 2 who had disease progression (radiographic or clinical) or intolerability were re-randomized in Part 3 to receive ganitumab 12 mg/kg every 2 weeks until disease progression, intolerability, withdrawal, death, or sponsor decision.

Part 3: Ganitumab

Part 1

Part 2

Part 3

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