A Study Of PF-05212384 Plus Irinotecan Vs Cetuximab Plus Irinotecan In Patients With KRAS And NRAS Wild Type Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This study will investigate whether the combination of PF-05212384 plus Irinotecan improves progression free survival in patients with KRAS and NRAS wild type metastatic colorectal cancer when compared with the combination of cetuximab plus Irinotecan. A Japanese Lead in Cohort will assess the safety of the combination of PF-05212384 + irinotecan in patients enrolled at Japanese sites.

Official Title
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A RANDOMIZED PHASE 2 STUDY OF PF-05212384 PLUS IRINOTECAN VERSUS CETUXIMAB PLUS IRINOTECAN IN PATIENTS WITH KRAS AND NRAS WILD TYPE METASTATIC COLORECTAL CANCER

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: PF-05212384
* Drug: irinotecan
* Drug: Cetuximab
* Drug: Irinotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: KRAS and NRAS wild type metastatic colorectal cancer Progression following treatment for colorectal cancer with irinotecan, oxaliplatin and fluoropyrimidine therapy in the metastatic setting. Eastern Cooperative Oncology Group [ECOG] Performance Status of 0, 1, or 2 At least one measurable lesion by Response Evaluation Criterion in Solid Tumors [RECIST] Exclusion Criteria: More than 2 prior cytotoxic chemotherapy regimens for metastatic colorectal cancer. Prior treatment with a PI3K, mTOR, AKT or EGFR inhibitor Patients who have discontinued treatment with prior irinotecan therapy due to toxicity. Prior radiation to the pelvis or abdomen Patients with history of interstitial lung disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>PF-05212384 plus Irinotecan | Drug: PF-05212384<br>* 30 minute IV infusion of PF-05212384 on days 2, 9, 16 and 23 of each cycle. Intra-patient dose escalation will commence with 110mg and will increase depending on tolerability.<br>* Other names: PKI-587;Drug: irinotecan<br>* 90 minutes IV infusion of irinotecan 180mg/m^2 on days 1 and 15 of each cycle<br>* Other names: Camptosar, Campto, CPT-11;|
| Active Comparator: Arm B<br>Cetuximab plus Irinotecan | Drug: Cetuximab<br>* 120 minute IV infusion of cetuximab 400mg/m^2 on cycle 1 day 1; 60 minute IV infusion of cetuximab on days 8, 15, and 22 of each cycle, and on day 1 of each cycle after cycle 1<br>* Other names: Erbitux;Drug: Irinotecan<br>* 90 minutes IV infusion of Irinotecan 180mg/m^2 on days 1 and 15 of each cycle<br>* Other names: Camptosar, Campto, CPT-11;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) as Assessed by Investigators | Progression-free survival (PFS) was the time from the first dose of study treatment to the first documentation of objective tumor progression or death due to any cause, whichever occurred first. Objective progression was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 mm. Median PFS was estimated based on the Kaplan-Meier method. | From date of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Common Terminology Criteria for Adverse Events (CTCAE) Grade | TEAEs were those AEs with initial onset or increasing in severity after the first dose of study drug. CTCAE version 4.0 was used to grade the severity of TEAEs. Grade 1 referred to mild AEs; Grade 2 referred to moderate AEs; Grade 3 referred to severe AEs; Grade 4 referred to AEs with life-threatening consequences, and urgent intervention was needed to manage them; Grade 5 referred to death related to AE. | Administration of the first dose of study drug through 28 calendar days after the last administration of study drug | 
| Number of Participants With Laboratory Test (Hematology) Abnormalities | The following hematology parameters were evaluated in this study: hemoglobin, white blood cells (WBC) with differential, and platelets. | 2 years | 
| Number of Participants With Laboratory Test (Chemistry) Abnormalities | The following chemistry parameters were evaluated in this study: sodium, potassium, magnesium, chloride, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, albumin, blood urea nitrogen (BUN) or urea, creatinine, total calcium, glycosylated hemoglobin (HbA1c), glucose, uric acid, phosphorus or phosphate, insulin, and C-peptide. | 2 years | 
| Number of Participants With Laboratory Test (Urinalysis) Abnormalities | Urinalysis included urine dipstick for protein and blood: if positive, perform a microscopic analysis. Number of participants with urine protein tested positive is presented. | 2 years | 
| Number of Participants With Laboratory Test (Coagulation) Abnormalities | Coagulation analysis included partial thromboplastin time (PTT) and international normalized ratio (INR) or prothrombin time (PT). | 2 years | 
| Number of Participants With ECG Post-Baseline Maximum Absolute Values Meeting Pre-defined Criteria | The number of participants with ECG post-baseline maximum absolute values meeting the following criteria was reported: (1) maximum QTc interval ranged from 450 to 480 msec; >480-500 msec; >500 msec; (2) maximum QTcB (QT corrected for heart rate using Bazett's formula) interval ranged from 450 to 480 msec; >480-500 msec; >500 msec; (3) maximum QTcF (QT corrected for heart rate using Fridericia's formula) interval ranged from 450 to 480 msec; >480-500 msec; >500 msec. | 2 years | 
| Number of Participants With ECG Maximum Increase From Baseline Meeting Pre-defined Criteria | The number of participants with ECG maximum increase from baseline meeting the following criteria was reported: Criterion A: maximum QTc interval increase from baseline >30 msec and ≤60 msec; criterion B: maximum QTc interval increase from baseline >60 msec; criterion C: maximum QTcB interval increase from baseline >30 msec and ≤60 msec; criterion D: maximum QTcB interval increase from baseline >60 msec; criterion E: maximum QTcF interval increase from baseline >30 msec and ≤60 msec; criterion F: maximum QTcF interval increase from baseline >60 msec. | 2 years | 
| Maximum Plasma Concentration (Cmax) of PF-05212384 | Cmax of PF-05212384 was observed directly from data. | Pre-dose (0 hour), 0.5, 1, 2, 4, 6, 24, 72, 120 hours post PF-05212384 infusion on Cycle 1 Day 9 and Cycle 1 Day 16. | 
| Maximum Plasma Concentration (Cmax) of Irinotecan | Cmax of irinotecan was observed directly from data. | Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1. | 
| Maximum Plasma Concentration (Cmax) of SN-38 | SN-38 is an irinotecan metabolite. Cmax of SN-38 was observed directly from data. | Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1. | 
| Time for Maximum Plasma Concentration (Tmax) of PF-05212384 | Tmax of PF-05212384 was observed directly from data as time of first occurrence. | Pre-dose (0 hour), 0.5, 1, 2, 4, 6, 24, 72, 120 hours post PF-05212384 infusion on Cycle 1 Day 9 and Cycle 1 Day 16. | 
| Time for Maximum Plasma Concentration (Tmax) of Irinotecan | Tmax of irinotecan was observed directly from data as time of first occurrence. | Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1. | 
| Time for Maximum Plasma Concentration (Tmax) of SN-38 | SN-38 is an irinotecan metabolite. Tmax of SN-38 was observed directly from data as time of first occurrence. | Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1. | 
| Terminal Elimination Half Life (t½) of PF-05212384 | T½ was calculated as loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression. | Pre-dose (0 hour), 0.5, 1, 2, 4, 6, 24, 72, 120 hours post PF-05212384 infusion on Cycle 1 Day 9 and Cycle 1 Day 16. | 
| Terminal Elimination Half Life (t½) of Irinotecan | T½ was calculated as loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression. | Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1. | 
| Terminal Elimination Half Life (t½) of SN-38 | T½ was calculated as loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression. | Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1. | 
| Area Under Plasma Concentration Time Profile From Time Zero to the Time for the Last Quantifiable Concentration (AUClast) of PF-05212384 | AUClast refers to the area under plasma concentration time profile from time zero to the time for the last quantifiable concentration. AUClast of PF-05212384 was determined using linear/log trapezoidal method. | Pre-dose (0 hour), 0.5, 1, 2, 4, 6, 24, 72, 120 hours post PF-05212384 infusion on Cycle 1 Day 9. | 
| Area Under Plasma Concentration Time Profile From Time Zero to the Time for the Last Quantifiable Concentration (AUClast) of Irinotecan | AUClast refers to the area under plasma concentration time profile from time zero to the time for the last quantifiable concentration. AUClast of irinotecan was determined using linear/log trapezoidal method. | Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1. | 
| Area Under Plasma Concentration Time Profile From Time Zero to the Time for the Last Quantifiable Concentration (AUClast) of SN-38 | AUClast refers to the area under plasma concentration time profile from time zero to the time for the last quantifiable concentration. AUClast of SN-38 (an irinotecan metabolite) was determined using linear/log trapezoidal method. | Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1. | 
| Area Under Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-05212384 | AUCinf refers to the area under plasma concentration time profile from time zero extrapolated to infinite time. AUCinf of PF-05212384 was calculated using the formula: AUCinf = AUClast + (Clast*/kel), where Clast* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis. | Pre-dose (0 hour), 0.5, 1, 2, 4, 6, 24, 72, 120 hours post PF-05212384 infusion on Cycle 1 Day 9. | 
| Area Under Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Irinotecan | AUCinf refers to the area under plasma concentration time profile from time zero extrapolated to infinite time. AUCinf of irinotecan was calculated using the formula: AUCinf = AUClast + (Clast*/kel), where Clast* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis. | Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1. | 
| Area Under Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of SN-38 | AUCinf refers to the area under plasma concentration time profile from time zero extrapolated to infinite time. AUCinf of SN-38 (an irinotecan metabolite) was calculated using the formula: AUCinf = AUClast + (Clast*/kel), where Clast* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis. | Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1. | 
| Levels of Signaling Proteins in Paired and Single Tumor Biopsies | Pre defined signaling proteins included Akt (protein kinase B), p-Akt (phosphorylated Akt), p-S6 (phosphorylated ribosomal protein S6), p-Met (phosphorylated Met, a receptor tyrosine kinase), p-mTOR (phosphorylated mammalian target of rapamycin), EGFR (epithelial growth factor receptor), and p-EGFR (phosphorylated EGFR). | 2 years | 
| Number of Participants With Expression of Pre-defined Gene Sequences in Biopsied Tumor Tissues | Pre-defined gene sequences were those related to EGFR, PI3K (phosphoinositide-3 kinase) and other oncogenic pathways; examples included but were not limited to PIK3CA (this gene encodes the catalytic subunit of PI3K), PIK3R1 (this gene encodes the regulatory subunit of PI3K), KRAS, NRAS and BRAF (this gene encodes serine/threonine-protein kinase B-Raf) sequences and PIK3CA gene amplification. Due to early termination of this study, these pre-defined gene sequences were not analyzed, except for KRAS and NRAS. Number of participants who had KRAS and NRAS wild type status confirmed by the central laboratory is presented. | 2 years | 
| Change From Baseline in Functional Assessment of Cancer Therapy-Colorectal (FACT-C) | Functional Assessment of Cancer Therapy-Colorectal (FACT-C) was used in this study to assess Health-Related Quality of Life (HRQoL) and CRC-related symptoms in participants enrolled to the randomized portion of the study. The FACT-C is part of the Functional Assessment of Chronic Illness Therapy (FACIT) measurement system, a comprehensive and extensive set of self-reported instruments for the assessment of health-related quality of life in participants with cancer or other chronic illnesses. | 2 years | 
| Number of Participants With Unacceptable Toxicity in Cycle 1 (Japanese LIC Only) | Unacceptable toxicity (according to Common Terminology Criteria for Adverse Events [CTCAE], Version 4.0) was any of the following occurrences: (1) Grade 4 neutropenia >7 days, or febrile neutropenia, or Grade 4 thrombocytopenia; (2) Grade >=3 nausea/vomiting despite optimal antiemetic treatment, or Grade >=3 diarrhea despite optimal anti diarrheal treatment; (3) unmanageable Grade >=3 hyperglycemia; (4) mean QTc interval (time from electrocardiogram [ECG] Q wave to the end of the T wave corresponding to electrical systole, corrected for heart rate) >501 msec in triplicate 12-lead ECG, or myocardial infarction, or ventricular arrhythmia; (5) Grade >=3 non-hematologic toxicity; (6) treatment delay of >=2 weeks due to study drug related toxicity; (7) persistent, intolerable toxicities which resulted in failure to deliver at least 75% of doses of both PF-05212384 and irinotecan during Cycle 1; (8) Grade >=2 respiratory toxicities. | 28 days | 
| Percentage of Participants With Objective Response | Percentage of participants with objective response was based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1. Confirmed PR was defined as disappearance of all target lesions. Confirmed PR was defined as >=30% decrease in sum of the longest dimensions of the target lesions taking the baseline sum as a reference. Confirmed responses were those that persisted on repeat imaging study >=4 weeks after initial documentation of response. | 2 years | 
| Duration of Response | For participants with an objective response (CR or PR), duration of response was defined as the time from first documentation of CR or PR to date of first documentation of objective progression or death. Date of first documentation of progression and date of first documentation of CR or PR were based on Investigator's assessment of response. | 2 years | 
| Overall Survival (OS) | Overall survival (OS) was defined as the duration from enrollment to death. Participants last known to be alive were censored at date of last contact. | 2 years | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. An SAE was defined as any untoward occurrence at any dose that resulted in death; was life threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); resulted in congenital anomaly/birth defect. AEs included both serious and non-serious AEs. Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study drug. | Administration of the first dose of study drug through 28 calendar days after the last administration of study drug | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic colorectal cancer, colorectal cancer, KRAS, colon cancer, mCRC, CRC, PF-05212384, KRAS wild type colorectal cancer, irinotecan, cetuximab, NRAS