Neoplasms

Symptoms and General Pathology

All Conditions

Digestive System Diseases

Neoplasm Metastasis

Disease Progression

Colorectal Neoplasms

Liver Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Neoplastic Processes

Liver Diseases

Antineoplastic Agents

All Drugs and Chemicals

Micronutrients

Hematinics

Vitamins

Oxaliplatin

Bevacizumab

Leucovorin

Fluorouracil

Levoleucovorin

Folic Acid

Liver Extracts

Panitumumab

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Folinic Acid

Folate

Vitamin B9

6 cycles before and 6 cycles after surgery consisting in:

Hour 0: Oxaliplatin 85 mg/m² IV 2-h infusion

Hour 0: Folinic Acid 400 mg/m² (DL form) or 200 mg/m2 (L form) IV 2-h infusion

Hour 2: 5-FU 400 mg/m² IV bolus over 2-4 minutes

Hour 2: 5-FU 2400 mg/m² given as a continuous infusion over 46h.

On day 1 of a 14 day cycle

6 cycles before and 6 cycles after surgery consisting in:

Hour 0: Oxaliplatin 85 mg/m2 2-h infusion

Hour 0: Folinic Acid 400 mg/m2 (DL form) or 200 mg/m2 (L form) 2-h infusion

Hour 2 (before 5-FU bolus): Bevacizumab 5 mg/kg IV over 90 minutes infusion\*.

Hour 3.5: 5-FU bolus 400 mg/m2 IV bolus over 2-4 minutes

Hour 3.5: 5-FU 2400 mg/m² given as a continuous infusion over 46h.

On day 1 of a 14 day cycle

Experimental: Arm B: modified FOLFOX6 + Bevacizumab and Surgery

6 cycles before and 6 cycles after surgery consisting in:

Hour - 1 (pre chemotherapy): Panitumumab 6 mg/kg IV over 60 minutes (≤ 1000 mg) or 90 minutes (\> 1000 mg) +/- 15 min. infusion\*.

Hour 0: Oxaliplatin 85 mg/m² IV 2-h infusion

Hour 0: Folinic Acid 400 mg/m² (DL form) or 200 mg/m2 (L form) IV 2-h infusion

Hour 2: 5-FU 400 mg/m² IV bolus over 2-4 minutes

Hour 2: 5-FU 2400 mg/m² given as a continuous infusion over 46h.

On day 1 of a 14 day cycle

FOLFOX6

Surgery

Bernard Nordlinger, Pr.

Stephane Benoist, Pr.

Patients presenting with multiple innumerable liver metastases will probably never come to resection, however, for all others, including patients with numerous multiple metastases or large metastases,resection should be considered after limited chemotherapy.

There is consensus for a backbone chemotherapy consisting of fluoropyrimidine + oxaliplatin. FOLFOX was used in the previous EORTC study and is again recommended.

The addition of targeted agents to standard chemotherapy in the perioperative strategy for mCRC might increase the ORR and R0 resectability, without significant increase in toxicity, therefore translating to a better outcome.

It was therefore decided to design an open label, randomized, multi-center, 3-arm late phase II study.

Arm A: (standard) mFOLFOX6 + Surgery Arm B: (experimental) mFOLFOX6 + Bevacizumab + Surgery Arm C: (experimental) mFOLFOX6 + Panitumumab + Surgery

Efficacy of FOLFOX Alone, FOLFOX Plus Bevacizumab and FOLFOX Plus Panitumumab in Patients With Resectable Liver Metastases

Randomized Phase II Trial Evaluating the Efficacy of FOLFOX Alone, FOLFOX Plus Bevacizumab and FOLFOX Plus Panitumumab as Perioperative Treatment in Patients With Resectable Liver Metastases From Wild Type KRAS/NRAS Colorectal Cancer

Increase in progression free survival rate at 1 year in each experimental arm (mFOLFOX6 + bevacizumab or panitumumab) compared to mFOLFOX6 alone arm.

Increase in major pathological response rate between mFOLFOX6 alone arm and each experimental arm.

Compare the percentage of patients with total resection with these three treatments.

Overall survival is defined as the time interval between the date of randomization and the date of death. Patients who are still alive when last traced will be censored at the date of last follow-up.

All adverse events will be recorded; the investigator will assess whether those events are drug related (reasonable possibility, no reasonable possibility) and this assessment will be recorded in the database for all adverse events.

Amgen

Roche Pharma AG

European Organisation for Research and Treatment of Cancer - EORTC

Cetuximab

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

5 mg/kg intravenously administered over 90 minutes (can be reduced to 30 minutes at the minimum) on day 1 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.

250 mg/m2 intravenously administered over 60 minutes (400 mg/m2 over 120 minutes as the initial dose) on day 1 and day 8 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.

85 mg/m2 intravenously administered over 120 minutes on day 1 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.

L-OHP

200 mg/m2 intravenously administered over 120 minutes on day 1 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.

l-LV

400 mg/m2 intravenous bolus on day 1 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.

5-FU

2400 mg/m2 continuous infusion over 46 hours on day 1 and 2 of a 2-week cycle. Liver resection if resectable after 8 cycles or continue until progression of disease.

Yoshihiko Maehara, MD,PhD,FACS

Naohiro Tomita, MD, PhD

Ichinosuke Hyodo, MD, PhD

Michiaki Unno, MD, PhD

The purpose of this study is to evaluate efficacy and safety of mFOLFOX6+bevacizumab and mFOLFOX6+cetuximab for liver only metastasis from KRAS Exon 2 wild type (under protocol 1.0-1.2 edition) and RAS wild type (under protocol 2.0 edition) colorectal cancer.

Description: The purpose of this study is to evaluate efficacy and safety of mFOLFOX6+bevacizumab and mFOLFOX6+cetuximab for liver only metastasis from KRAS Exon 2 wild type (under protocol 1.0-1.2 edition) and RAS wild type (under protocol 2.0 edition) colorectal cancer.

Achievement of Improved Survival by Molecular Targeted Chemotherapy and Liver Resection for Not Optimally Resectable Colorectal Liver Metastases

Randomized Phase II Study of mFOLFOX6 + Bevacizumab or mFOLFOX6 + Cetuximab in Liver Only Metastasis From KRAS Wild Type Colorectal Cancer

pathologically confirmed R0 liver resection rate

All the assessment is repeated for a maximum of 4 years.

EPS Corporation

Herbal and Botanical

Irinotecan

Gedatolisib

Topoisomerase I Inhibitors

Enzyme Inhibitors

Protein Kinase Inhibitors

Cola

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.

PF-05212384

90 minutes IV infusion of irinotecan 180mg/m\^2 on days 1 and 15 of each cycle

irinotecan

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

90 minutes IV infusion of Irinotecan 180mg/m\^2 on days 1 and 15 of each cycle

Pfizer CT.gov Call Center

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.

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

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

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

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.

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.

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.

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.

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.

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.

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.

The following hematology parameters were evaluated in this study: hemoglobin, white blood cells (WBC) with differential, and platelets.

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.

Urinalysis included urine dipstick for protein and blood: if positive, perform a microscopic analysis. Number of participants with urine protein tested positive is presented.

Coagulation analysis included partial thromboplastin time (PTT) and international normalized ratio (INR) or prothrombin time (PT).

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.

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.

Cmax of PF-05212384 was observed directly from data.

Cmax of irinotecan was observed directly from data.

SN-38 is an irinotecan metabolite. Cmax of SN-38 was observed directly from data.

Tmax of PF-05212384 was observed directly from data as time of first occurrence.

Tmax of irinotecan was observed directly from data as time of first occurrence.

SN-38 is an irinotecan metabolite. Tmax of SN-38 was observed directly from data as time of first occurrence.

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.

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.

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.

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.

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.

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.

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 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).

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.

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.

Pfizer

PF-05212384 was administered intravenously (IV) every week (Days 2, 9, 16 and 23 of each 28-day cycle) at a starting dose level of 110 mg. During Cycle 1, PF-05212384 was only dosed on Days 9, 16 and 23. After one cycle of dosing with PF-05212384, in subsequent cycles, the dose level remained at 110 mg or was escalated based on the occurrences of dose limiting toxicities (DLTs) in previous cycle and at the discretion of the investigator. Participants enrolled in Korea remained at the 110 mg starting dose level of PF-05212384. Irinotecan was administered IV every other week (Days 1 and 15 of each 28-day cycle) at a dose level of 180 mg/m\^2. Both the dose levels of PF-05212384 and irinotecan were adjusted according to severity of toxicities. Infusion of PF-05212384 followed irinotecan infusion by at least 24 hours (+/- 10%).

PF-05212384 + Irinotecan: Arm A

Cetuximab was administered IV every week (Days 1, 8, 15 and 22 of each 28-day cycle) at a starting dose level of 400 mg/m\^2 on Cycle 1 Day 1 followed by 250 mg/m\^2 in subsequent infusions. Irinotecan was administered IV every other week (Days 1 and 15 of each 28-day cycle) at a dose level of 180 mg/m\^2. Both the dose levels of cetuximab and irinotecan were adjusted according to severity of toxicities.

Cetuximab + Irinotecan: Arm B

PF-05212384 was administered intravenously (IV) every week (Days 2, 9, 16 and 23 of each 28-day cycle) at a starting dose level of 110 mg. During Cycle 1, PF-05212384 was only dosed on Days 9, 16 and 23. Irinotecan was administered IV every other week (Days 1 and 15 of each 28 day cycle) at a dose level of 180 mg/m\^2. Both the dose levels of PF 05212384 and irinotecan were adjusted according to severity of toxicities. Infusion of PF-05212384 followed irinotecan infusion by at least 24 hours (+/- 10%).

PF-05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)

PF-05212384 was administered intravenously (IV) every week (Days 2, 9, 16 and 23 of each 28-day cycle) at a starting dose level of 110 mg. During Cycle 1, PF-05212384 was only dosed on Days 9, 16 and 23. Irinotecan was administered IV every other week (Days 1 and 15 of each 28-day cycle) at a dose level of 180 mg/m\^2. Both the dose levels of PF-05212384 and irinotecan were adjusted according to severity of toxicities. Infusion of PF-05212384 followed irinotecan infusion by at least 24 hours (+/- 10%).

Total

<18 years

18-64 years

>=65 years

Age, Customized

Sex: Female, Male

The baseline analysis population included all enrolled participants who received the study drug.

This study was terminated by sponsor due to strategic reasons and not due to any safety or efficacy concerns with treatment of PF-05212384.

Pfizer ClinicalTrials.gov Call Center

All participants who were randomized, with KRAS (Kirsten ras oncogene) and NRAS (neuroblastoma ras viral oncogene homolog) wild type status confirmed by central lab, and with treatment arm assignment designated according to randomization. As pre-specified in the protocol, this outcome measure was not analyzed for Japanese Lead-In Cohort.

Progression Free Survival (PFS) as Assessed by Investigators

The analysis population included all participants enrolled into Japanese LIC. As pre-specified in protocol, this outcome measure was not analyzed for reporting arms: "PF-05212384 + Irinotecan: Arm A" and "Cetuximab + Irinotecan: Arm B".

Number of Participants With Unacceptable Toxicity in Cycle 1 (Japanese LIC Only)

Response evaluable analysis set was used for the analysis of objective response, and it included all participants in the full analysis set (all participants who were randomized, with treatment arm assignment designated according to randomization) who had an adequate baseline assessment of disease and measurable disease.

Percentage of Participants With Objective Response

The analysis population included all participants who achieved CR or PR in Arm A and Arm B. As pre-specified in protocol, this outcome measure was not analyzed for reporting arm "PF 05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)".

Duration of Response

Per protocol analysis set, i.e. all participants who were randomized, with KRAS and NRAS wild type status confirmed by central lab and with treatment arm assignment designated according to randomization. As pre-specified in protocol, this outcome measure was not analyzed for reporting arm "PF 05212384 + Irinotecan: Japanese Lead-In Cohort (LIC)".

Overall Survival (OS)

SAEs

Safety analysis set included all participants who received at least one dose of study treatment, with treatment arm assignment designated according to actual study treatment received.

Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Common Terminology Criteria for Adverse Events (CTCAE) Grade

Anemia

Hemoglobin increased

Lymphocyte count increased

Lymphopenia

Neutrophils (absolute)

Platelets

White blood cells

Number of Participants With Laboratory Test (Hematology) Abnormalities

Alkaline phosphatase

Total bilirubin

Creatitine

Hypercalcemia

Hyperglycemia

Hyperkalemia

Hypermagnesemia

Hypernatremia

Hypoalbuminemia

Hypocalcemia

Hypoglycemia

Hypokalemia

Hypomagnesemia

Hyponatremia

Hypophosphatemia

Number of Participants With Laboratory Test (Chemistry) Abnormalities

Number of Participants With Laboratory Test (Urinalysis) Abnormalities

PTT (number of participants =7, 6, 5)

PT (number of participants =7, 5, 6)

PT INR

Number of Participants With Laboratory Test (Coagulation) Abnormalities

Maximum QTc interval: 450-480 msec

Maximum QTc interval: >480-500 msec

Maximum QTc interval: >500 msec

Maximum QTcB interval: 450-480 msec

Maximum QTcB interval: >480-500 msec

Maximum QTcB interval: >500 msec

Maximum QTcF interval: >450-480 msec

Maximum QTcF interval: >480-500 msec

Maximum QTcF interval: >500 msec

QTc analysis set included all participants in the safety analysis set who had at least one ECG assessment after receiving study treatment.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Efficacy of FOLFOX Alone, FOLFOX Plus Bevacizumab and FOLFOX Plus Panitumumab in Patients With Resectable Liver Metastases	NCT01508000	Colorectal Canc... Liver Metastase... KRAS Wild Type ...	FOLFOX6 Bevacizumab Panitumumab Surgery	18 Years - 75 Years	European Organisation for Research and Treatment of Cancer - EORTC
Achievement of Improved Survival by Molecular Targeted Chemotherapy and Liver Resection for Not Optimally Resectable Colorectal Liver Metastases	NCT01836653	Liver Only Meta...	Bevacizumab Cetuximab L-OHP l-LV 5-FU 5-FU	20 Years - 80 Years	EPS Corporation
A Study Of PF-05212384 Plus Irinotecan Vs Cetuximab Plus Irinotecan In Patients With KRAS And NRAS Wild Type Metastatic Colorectal Cancer	NCT01925274	Metastatic Colo...	PF-05212384 irinotecan Cetuximab Irinotecan	18 Years -	Pfizer

Spots Global Cancer Trial Database for kras wild type colorectal cancer