Clinical Study Of PI3K/mTOR Inhibitors In Combination With An Oral MEK Inhibitor Or Irinotecan In Patients With Advanced Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Multi-arm Phase 1 Dose Escalation Study Of The Safety, Pharmacokinetics, And Pharmacodynamics Of The Dual Pi3k/Mtor Inhibitors Pf-04691502 And Pf-05212384 In Combination With Experimental Or Approved Anticancer Agents In Patients With Advanced Cancer

Conditions
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Advanced Cancer

Intervention / Treatment
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* Drug: PF-05212384
* Drug: PD-0325901
* Drug: PF-05212384
* Drug: irinotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological diagnosis of advanced/metastatic solid tumor for which there is no currently clinically effective treatment. All tumor types for patients enrolled in Stage 1 of Arm C. For patients enrolled in Stage 2 of Arm C, advanced colorectal cancer (both KRAS mutated and KRAS wild type), which has progressed on irinotecan-based regimens, and pancreatic ductal adenocarcinoma after progression on first line treatment for metastatic/advanced disease. For patients enrolled in Stage 1 of Arm D, tumors with KRAS or BRAF mutation (archived or fresh biopsy). Patients with tumors harboring other mutations that activate the MAPK pathway may be enrolled upon agreement with the Sponsor. For patients enrolled in Stage 2 of Arm D, ovarian cancer which has progressed on prior platinum containing regimen or KRAS mutated non small cell lung cancer which has progressed on one prior regimen. Patients with colorectal cancer enrolled to both Arms must: have received at least 6 weeks of irinotecan-based therapy (either as single agent or in combination with cytotoxic drugs or in combination with targeted therapies) as the last prior treatment have progressed on or within 1 month of completing this irinotecan-based regimen All patients must provide an archived or fresh tumor sample. For a subset of patients fresh tumor biopsies are mandatory: a. All patients with CRC enrolled to Stage 2 of Arm C must provide a fresh tumor biopsy at baseline. A subset of patients (10 or more) with at least 5 evaluable patients with CRC KRAS wild type must also provide tumor biopsy during treatment. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) must be 0 or 1 Adequate Bone Marrow, Renal, Cardiac, and Liver Function Exclusion Criteria: -Patients with known active brain metastases -Chemotherapy, radiotherapy (other than palliative radiotherapy to lesions that will not be followed for tumor assessment on this study, ie, non target lesions), biological or investigational agents within 4 weeks of the start of the study treatment (6 weeks for mitomycin C or nitrosoureas). -Any surgery (not including minor procedures such as lymph node biopsy, needle biopsy, and/or placement of port-a-cath) within 4 weeks of start of the study treatment; or not fully recovered from any side effects of previous procedures. -In Arm D only: Patients with glaucoma, intraocular pressure > 21 mmHg, history of retinal vein occlusions, ocular ischemia or any other clinically significant abnormality in the ophthalmologic exam which would make the patient inappropriate for entry into this study -For patients enrolling in Stage 2 prior therapy with an agent that is known or proposed to be active by action on PI3K and/or mTOR. -Prior high dose chemotherapy requiring hematopoietic stem cell transplantation within 12 months of study treatment start. -Known impaired pulmonary function or demonstrated to be impaired by Pulmonary Function Test (PFT) for patients who present with clinical suggestion of impairment. -Uncontrolled or significant cardiovascular disease -Current use or anticipated need for food or drugs that are known potent CYP3A4 inhibitors - Current or anticipated need for food or drugs that are known potent CYP3A4 inducers

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: Basic Science
Allocation: Non-Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm D: PF-05212384 + PD-0325901<br> | Drug: PF-05212384<br>* PF-05212384 intravenous infusion weekly starting at 110 mg.<br>Drug: PD-0325901<br>* PD-0325901 Oral twice daily (BID) dosing 2 mg BID 3 weeks on 1 week off<br>|
| Experimental: Arm C: PF-05212384 + irinotecan<br> | Drug: PF-05212384<br>* PF-05212384 intravenous infusion weekly starting at 95 mg.<br>Drug: irinotecan<br>* Irinotecan by intravenous infusion at 180 mg/m2 every two weeks (Q x 2 week)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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). | 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. | 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). | 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. | 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. | 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. | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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) . | 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). | 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. | 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. | 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 |  | 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 |  | 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 |  | 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 |  | 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. | 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. | Baseline, every 8 weeks in Cycle 3 and subsequent cycles, until until progression of disease was documented. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced metastatic cancer (solid tumors), PI3K, mTOR, MEK