After the fourth protocol amendment two study arms are evaluated in this clinical protocol: PD-0325901 (oral MEK inhibitor) plus PF-05212384 (intravenous PI3K/mTOR inhibitor) and PF-05212384 plus irinotecan. The study will assess safety, pharmacokinetics and pharmacodynamics of these combinations in patients with advanced cancer. Once the maximum tolerated doses are identified, further assessment of these combinations will be done in patients with previously treated metastatic colorectal or pancreatic cancer for the PF-05212384 plus irinotecan arm and in patients with ovarian cancer or KRAS mutated non small cell lung cancer for the combination of PF-05212384 plus PD-0325901.
The study was prematurely discontinued as a result of an internal portfolio review on April 1, 2015. The decision to terminate was not due to any safety or efficacy data.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
105
PF-05212384 intravenous infusion weekly starting at 110 mg.
PD-0325901 Oral twice daily (BID) dosing 2 mg BID 3 weeks on 1 week off
PF-05212384 intravenous infusion weekly starting at 95 mg.
Irinotecan by intravenous infusion at 180 mg/m2 every two weeks (Q x 2 week)
Ronald Reagan UCLA Medical Center
Los Angeles, California, United States
Ronald Reagan UCLA Medical Center
Los Angeles, California, United States
UCLA Medical Center
Los Angeles, California, United States
UCLA Oncology Center
Los Angeles, California, United States
Santa Monica - UCLA Medical Center and Orthopaedic Hospital
Santa Monica, California, United States
UCLA Santa Monica Hematology Oncology
Santa Monica, California, United States
Anschutz Cancer Pavilion
Aurora, Colorado, United States
University of Colorado Denver (CTRC)
Aurora, Colorado, United States
University of Colorado Hospital Anschutz Inpatient Pavilion
Aurora, Colorado, United States
University of Colorado Hospital
Aurora, Colorado, United States
...and 8 more locations
Percentage of Participants With Dose-Limiting Toxicities (DLTs) in First Cycle (28 Days)
DLT was defined as any of the following hematologic or non-hematologic events which were attributable to the combination study drug and occurring in the first 28-day cycle: 1) Grade 4 neutropenia lasting greater than (\>)7 days; 2) Febrile neutropenia (defined as neutropenia greater than or equal to \[≥\]Grade 3 and a body temperature ≥38.5°C); 3) Grade ≥3 neutropenic infection; 4) Grade 3 thrombocytopenia with bleeding; 5) Grade 4 thrombocytopenia; 6) Grade ≥3 toxicities; 7) Persistent, intolerable toxicities which resulted in failure to deliver at least 75% of doses during the first cycle; 8) Persistent, intolerable toxicities which resulted in delay of start of Cycle 2 by more than 2 weeks of scheduled day; 9) Persistent Grade 3 QTc prolongation (QTc \>500 msec) after correction of any reversible causes.
Time frame: Baseline up to 28 days
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Time frame: Baseline up to End of Treatment (EOT) (within 28 days after last treatment administration)
Number of Participants With Treatment-Emergent AEs (TEAEs) by National Cancer Institute (NCI) Common Terminology Criteria (CTC) for AEs (CTCAE) (Version 4.0) Grade
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent AEs are events which occurred between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs were graded by the NCI CTCAE (Version 4.0).
Time frame: Baseline up to End of Treatment (EOT) (within 28 days after last treatment administration)
Number of Participants With Laboratory Test Abnormalities (Hematology)
Number of participants with NCI CTCAE (version 4.0) grade 1 to 4 hematological test abnormalities. Hematological tests included platelet count, hemoglobin, and white blood cell (WBC) count with 5- part differential.
Time frame: Baseline, Days 1, 15, and 23 of Cycle 1, Days 1 and 15 of Cycle 2, Day 1 of Cycle 3 and subsequent cycles, up to End of Treatment (within 28 days of last treatment administration)
Number of Participants With Laboratory Test Abnormalities (Coagulation)
Number of participants with NCI CTCAE (version 4.0) grade 1 to 4 coagulation test abnormalities. Coagulation tests included partial thromboplastin time (PTT) and prothrombin time (PT) international normalized ratio (INR).
Time frame: Baseline, Days 1 and 15 of Cycle 1, Days 1 and 15 of Cycle 2, Day 1 of Cycle 3 and subsequent cycles, up to End of Treatment (within 28 days of last treatment administration)
Number of Participants With Laboratory Test Abnormalities (Chemistry)
Number of participants with NCI CTCAE (version 4.0) grade 1 to 4 chemistry test abnormalities. Chemistry tests included aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]), alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]), serum creatinine, total bilirubin, direct/indirect bilirubin, alkaline phosphatase, chloride, uric acid, phosphorus, calcium, magnesium, potassium, sodium, blood urea nitrogen (BUN) or urea, total protein, albumin, glucose, and insulin.
Time frame: Baseline, Days 1, 15, and 23 of Cycle 1, Days 1 and 15 of Cycle 2, Day 1 of Cycle 3 and subsequent cycles, up to End of Treatment (within 28 days of last treatment administration)
Number of Participants With Laboratory Test Abnormalities (Urinalysis)
Number of participants with NCI CTCAE (version 4.0) grade 1 to 4 urinalysis test abnormalities for urine protein.
Time frame: Baseline, Days 1 and 15 of Cycle 1, Days 1 and 15 of Cycle 2, Day 1 of Cycle 3 and subsequent cycles, up to End of Treatment (within 28 days of last treatment administration)
Number of Participants With Vital Signs Values Meeting Prespecified Criteria
Number of participants with vital signs values meeting prespecified criteria. Criteria defined as: 1) absolute systolic blood pressue (SBP) less than or equal to (\<=) 100 millimeter of mercury (mmHg); 2) absolute SBP greater than or equal to (\>=) 160 mmHg, 3) SBP maximum increase of \>=20 mmHg from baseline; 4) SBP maximum increase of \>=40 mmHg from baseline; 5) SBP maximum increase of \>=60 mmHg from baseline; 6) absolute diastolic blood pressure (DBP) \<=60 mmHg; 7) absolute DBP \>=100 mmHg; 8) DBP maximum increase of \>=10 mmHg from baseline; 9) DBP maximum increase of \>=20 mmHg from baseline; 10) DBP maximum increase of \>=30 mmHg from baseline; 11) absolute heart rate (HR) \<50 beats per minute (bpm); 12) absolute HR \>120 bpm.
Time frame: Baseline, Days 1, 15, and 23 of Cycle 1, Days 1 and 15 of Cycle 2, Day 1 of Cycle 3 and subsequent cycles, up to End of Treatment (within 28 days of last treatment administration)
Maximum Plasma Concentrations (Cmax) for PF-05212384 on Cycle 1 Day 2 and Day 16 for Arm C
Time frame: Cycle 1 Day 2 and Cycle 1 Day 16: Pre-dose and 0.5, 1, 2, 4, 6, 8, 24, 72, and 120 hours post-dose.
Maximum Plasma Concentrations (Cmax) for PF-05212384 on Cycle 0 Day -14 and Cycle 1 Day 15 for Arm D
Time frame: Cycle 0 Day -14 and Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 4, 6, 8, 24, 72, and 120 hours post-dose.
Maximum Plasma Concentrations (Cmax) for PD-0325901 on Cycle 0 Day -1 and Cycle 1 Day 1 for Arm D
Time frame: Cycle 0 Day -1 and Cycle 1 Day 1: Pre-dose and 1, 2, 4, 6 and 8 hours post-dose.
Maximum Plasma Concentrations (Cmax) for PD-0325901 on Cycle 0 Day -7 and Cycle 1 Day 12 for Arm A
Time frame: Cycle 0 Day -7: Pre-dose and 1, 2, 4, 6, 8, 24, and 72 hours post-dose. Cycle 1 Day 12: Pre-dose and 1, 2, 4, 6 and 8 hours post-dose.
Maximum Plasma Concentrations (Cmax) for PF-04691502 on Cycle 0 Day -7 and Cycle 1 Day 12 for Arm A
Time frame: Cycle 0 Day -7 at 0 hours (pre-dose), 1, 2, 4, 6, 8, 24, and 72 hours, and at Cycle 1 Day 12 at 0 hours (pre-dose), 1, 2, 4, 6, 8, and 24 hours.
Maximum Plasma Concentrations (Cmax) for PF-04691502 on Cycle 0 Day -7 and Cycle 1 Day 12 for Arm B
Time frame: Cycle 0 Day -7 at 0 hours (pre-dose) and 1, 2, 4, 6, 8, 24, and 72 hours post-dose. Cycle 1 Day 12 at 0 hours (pre-dose), 1, 2, 4, 6 8 and 24 hours post-dose.
Time to Reach Maximum Plasma Concentration (Tmax) for PF-05212384 on Cycle 1 Day 2 and Day 16 for Arm C
Time frame: Cycle 1 Day 2 and Cycle 1 Day 16: Pre-dose and 0.5, 1, 2, 4, 6, 8, 24, 72, and 120 hours post-dose.
Time to Reach Maximum Plasma Concentration (Tmax) for PF-05212384 on Cycle 0 Day -14 and Cycle 1 Day 15 for Arm D
Time frame: Day -14 and Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 4, 6, 8, 24, 72, and 120 hours post-dose.
Time to Reach Maximum Plasma Concentration (Tmax) for PD-0325901 on Cycle 0 Day -1 and Cycle 1 Day 1 for Arm D
Time frame: Cycle 0 Day -1 and Cycle 1 Day 1: Pre-dose and 1, 2, 4, 6 and 8 hours post-dose.
Time to Reach Maximum Plasma Concentration (Tmax) for PD-0325901 on Cycle 0 Day -7 and Cycle 1 Day 12 for Arm A
Time frame: Cycle 0 Day -7: Pre-dose and 1, 2, 4, 6, 8, 24, and 72 hours post-dose. Cycle 1 Day 12: Pre-dose and 1, 2, 4, 6 and 8 hours post-dose.
Time to Reach Maximum Plasma Concentration (Tmax) for PF-04691502 on Cycle 0 Day -7 and Cycle 1 Day 12 for Arm A
Time frame: Cycle 0 Day -7 at 0 hours (pre-dose), 1, 2, 4, 6, 8, 24, and 72 hours, and at Cycle 1 Day 12 at 0 hours (pre-dose), 1, 2, 4, 6, 8, and 24 hours.
Time to Reach Maximum Plasma Concentration (Tmax) for PF-04691502 on Cycle 0 Day -7 and Cycle 1 Day 12 for Arm B
Time frame: Cycle 0 Day -7 at 0 hours (pre-dose) and 1, 2, 4, 6, 8, 24, and 72 hours post-dose. Cycle 1 Day 12 at 0 hours (pre-dose), 1, 2, 4, 6 8 and 24 hours post-dose.
Terminal Elimination Half Life (t½) for PF-05212384 on Cycle 1 Day 2 and Day 16 for Arm C
Time frame: Cycle 1 Day 2 and Cycle 1 Day 16: Pre-dose and 0.5, 1, 2, 4, 6, 8, 24, 72, and 120 hours post-dose.
Terminal Elimination Half Life (t½) for PF-05212384 on Cycle 0 Day -14 and Cycle 1 Day 15 for Arm D
Time frame: Day -14 and Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 4, 6, 8, 24, 72, and 120 hours post-dose.
Terminal Elimination Half Life (t½) for PD-0325901 on Cycle 0 Day -7 for Arm A
Time frame: Cycle 0 Day -7: Pre-dose and 1, 2, 4, 6, 8, 24, and 72 hours post-dose.
Terminal Elimination Half Life (t1/2) for PF-04691502 on Cycle 0 Day -7 and Cycle 1 Day 12 for Arm A
Time frame: Cycle 0 Day -7 at 0 hours (pre-dose), 1, 2, 4, 6, 8, 24, and 72 hours, and at Cycle 1 Day 12 at 0 hours (pre-dose), 1, 2, 4, 6, 8, and 24 hours.
Terminal Elimination Half Life (t1/2) for PF-04691502 on Cycle 0 Day -7 and Cycle 1 Day 12 for Arm B
Time frame: Cycle 0 Day -7 at 0 hours (pre-dose), 1, 2, 4, 6, 8, 24, and 72 hours, and at Cycle 1 Day 12 at 0 hours (pre-dose), 1, 2, 4, 6, 8, and 24 hours.
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for PF-05212384 on Cycle 1 Day 2 and Cycle 1 Day 16 for Arm C
Time frame: Cycle 1 Day 2 and Cycle 1 Day 16: Pre-dose and 0.5, 1, 2, 4, 6, 8, 24, 72, and 120 hours post-dose.
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for PF-05212384 on Cycle 0 Day -14 and Cycle 1 Day 15 for Arm D
Time frame: Cycle 0 Day -14 and Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 4, 6, 8, 24, 72, and 120 hours post-dose.
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for PD-0325901 on Cycle 0 Day -7 for Arm A
Time frame: Cycle 0 Day -7: Pre-dose and 1, 2, 4, 6, 8, 24, and 72 hours post-dose.
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for PF-04691502 on Cycle 0 Day -7 for Arm A
Time frame: Cycle 0 Day -7 at 0 hours (pre-dose), 1, 2, 4, 6, 8, 24, and 72 hours, and at Cycle 1 Day 12 at 0 hours (pre-dose), 1, 2, 4, 6, 8, and 24 hours.
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for PF-04691502 on Cycle 0 Day -7 for Arm B
Time frame: Cycle 0 Day -7 at 0 hours (pre-dose), 1, 2, 4, 6, 8, 24, and 72 hours, and at Cycle 1 Day 12 at 0 hours (pre-dose), 1, 2, 4, 6, 8, and 24 hours.
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) for PF-05212384 on Cycle 1 Day 2 and Cycle 1 Day 16 for Arm C
Time frame: Cycle 1 Day 2 and Cycle 1 Day 16: Pre-dose and 0.5, 1, 2, 4, 6, 8, 24, 72, and 120 hours post-dose.
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) for PF-05212384 on Cycle 0 Day -14 and Cycle 1 Day 15 for Arm D
Time frame: Cycle 0 Day -14 and Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 4, 6, 8, 24, 72, and 120 hours post-dose.
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) for PD-0325901 on Cycle 0 Day -7 for Arm A
Time frame: Cycle 0 Day -7: Pre-dose and 1, 2, 4, 6, 8, 24, and 72 hours post-dose.
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) for PF-04691502 on Cycle 0 Day -7 for Arm A
Time frame: Cycle 0 Day -7 at 0 hours (pre-dose), 1, 2, 4, 6, 8, 24, and 72 hours, and at Cycle 1 Day 12 at 0 hours (pre-dose), 1, 2, 4, 6, 8, and 24 hours.
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) for PF-04691502 on Cycle 0 Day -7 for Arm B
Time frame: Cycle 0 Day -7 at 0 hours (pre-dose), 1, 2, 4, 6, 8, 24, and 72 hours, and at Cycle 1 Day 12 at 0 hours (pre-dose), 1, 2, 4, 6, 8, and 24 hours.
Number of Participants With Increase From Baseline in QT Interval
Electrocardiogram (ECG) measurements (an average of the triplicate measurements) were used for the statistical analysis and all data presentations. QT intervals were corrected for heart rate (QTc) using Bazett's Formula (QTcB) and Fridericia's Formula (QTcF) .
Time frame: Baseline, Cycle 1 Day 2 for Arms C and D, Cycle 1 Day 15 for Arm D, and Cycle 1 Day 16 for Arm C, Day 2 in Arm C and Day 1 in Arm D for subsequent cycles, up to End of Treatment (within 28 days of last treatment administration)
Number of Participants With Maximum Post-dose QT Interval Corrected
Electrocardiogram (ECG) measurements (an average of the triplicate measurements) were used for the statistical analysis and all data presentations. QT intervals were corrected for heart rate (QTc) using Bazett's Formula (QTcB) and Fridericia's Formula (QTcF).
Time frame: Baseline, Cycle 1 Day 2 for Arms C and D, Cycle 1 Day 15 for Arm D, and Cycle 1 Day 16 for Arm C, Day 2 in Arm C and Day 1 in Arm D for subsequent cycles, up to End of Treatment (within 28 days of last treatment administration)
Percentage of Participants With Complete Response (CR) or Partial Response (PR)
CR was defined as the disappearance of all target lesions with the exception of nodal disease and all target nodes must decrease to normal size (short axis \<10 mm). PR was defined as at least a 30% decrease in the sum of the longest diameters of the targeted lesions.
Time frame: Baseline, every 8 weeks in Cycle 3 and subsequent cycles, until progression of disease was documented.
Progression-Free Survival (PFS) (Stage 2)
Progression-free survival (PFS) was the time from first dose to date of first documentation of progression or death due to any cause.
Time frame: Baseline, every 8 weeks in Cycle 3 and subsequent cycles, until progression of disease was documented.
Ratio to Baseline in Serum Glucose Level at End of Treatment for Arm B, Arm C, and Arm D
Time frame: Baseline, Cycle 1 Days 2, 15, 22, and 23, Cycle 2 Days 1 and 16, Day 1 in Cycle 3 and subsequent cycles, and EOT (within 28 days after last treatment administration)
Ratio to Baseline in Serum Insulin Level at End of Treatment for Arm B, Arm C, and Arm D
Time frame: Baseline, Cycle 1 Days 2, 15, 22, and 23, Cycle 2 Days 1 and 16, Day 1 in Cycle 3 and subsequent cycles, and EOT (within 28 days after last treatment administration)
Ratio to Baseline in Serum Glucose Level at Cycle 2 Day 16 for Arm A
Time frame: Baseline, Cycle 1 Days 2, 15, 22, and 23, Cycle 2 Days 1 and 16, Day 1 in Cycle 3 and subsequent cycles, and EOT (within 28 days after last treatment administration)
Ratio to Baseline in Serum Insulin Level at Cycle 2 Day 16 for Arm A
Time frame: Baseline, Cycle 1 Days 2, 15, 22, and 23, Cycle 2 Days 1 and 16, Day 1 in Cycle 3 and subsequent cycles, and EOT (within 28 days after last treatment administration)
Number of Participants With Expression of Genes Relating to Phosphatidylinositol 3 Kinase (PI3K), Mitogen Activated Protein Kinase (MAPK) and/or Wingless-Type Mouse Mammary Tumor Virus Integration Site Family Member (Wnt) Pathway Signaling
Number of participants with expression of genes relating to PI3K, MAPK and/or Wnt pathway signaling (kirsten rat sarcoma 2 viral oncogene homolog \[KRAS\] and PTEN protein). Biopsies were obtained at baseline and Cycle 1 Day 23. Biomarker evaluation was performed on these biopsies.
Time frame: Baseline and Cycle 1 Day 23.
Duration of Response (Stage 2)
Duration of response was to be calculated for participants with an objective response. Duration of PR or CR was the time from start date (date of first documentation of PR or CR) to date of first documentation of objective progression or death. CR: disappearance of a target lesions. PR: at least 30% decrease in the sum of diameters of target lesions.
Time frame: Baseline, every 8 weeks in Cycle 3 and subsequent cycles, until until progression of disease was documented.
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