Clinical trial NCT01347866: Clinical Study Of PI3K/mTOR Inhibitors In Combination With An Oral MEK Inhibitor Or Irinotecan In Patients With Advanced Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Advanced Cancer
Keywords: Advanced metastatic cancer (solid tumors)
PI3K
mTOR
MEK
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2011-05-04
Enrollment: 105
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Primary purpose: BASIC_SCIENCE

Brief summary: 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: 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.

Eligibility criteria: 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:

  1. 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
  2. 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

Primary outcomes:
measure: Percentage of Participants With Dose-Limiting Toxicities (DLTs) in First Cycle (28 Days)
timeFrame: Baseline up to 28 days
Secondary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline up to End of Treatment (EOT) (within 28 days after last treatment administration)
measure: Number of Participants With Treatment-Emergent AEs (TEAEs) by National Cancer Institute (NCI) Common Terminology Criteria (CTC) for AEs (CTCAE) (Version 4.0) Grade
timeFrame: Baseline up to End of Treatment (EOT) (within 28 days after last treatment administration)
measure: Number of Participants With Laboratory Test Abnormalities (Hematology)
timeFrame: 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)
measure: Number of Participants With Laboratory Test Abnormalities (Coagulation)
timeFrame: 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)
measure: Number of Participants With Laboratory Test Abnormalities (Chemistry)
timeFrame: 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)
measure: Number of Participants With Laboratory Test Abnormalities (Urinalysis)
timeFrame: 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)
measure: Number of Participants With Vital Signs Values Meeting Prespecified Criteria
timeFrame: 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)
measure: Maximum Plasma Concentrations (Cmax) for PF-05212384 on Cycle 1 Day 2 and Day 16 for Arm C
timeFrame: 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.
measure: Maximum Plasma Concentrations (Cmax) for PF-05212384 on Cycle 0 Day -14 and Cycle 1 Day 15 for Arm D
timeFrame: 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.
measure: Maximum Plasma Concentrations (Cmax) for PD-0325901 on Cycle 0 Day -1 and Cycle 1 Day 1 for Arm D
timeFrame: Cycle 0 Day -1 and Cycle 1 Day 1: Pre-dose and 1, 2, 4, 6 and 8 hours post-dose.
measure: Maximum Plasma Concentrations (Cmax) for PD-0325901 on Cycle 0 Day -7 and Cycle 1 Day 12 for Arm A
timeFrame: 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.
measure: Maximum Plasma Concentrations (Cmax) for PF-04691502 on Cycle 0 Day -7 and Cycle 1 Day 12 for Arm A
timeFrame: 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.
measure: Maximum Plasma Concentrations (Cmax) for PF-04691502 on Cycle 0 Day -7 and Cycle 1 Day 12 for Arm B
timeFrame: 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.
measure: Time to Reach Maximum Plasma Concentration (Tmax) for PF-05212384 on Cycle 1 Day 2 and Day 16 for Arm C
timeFrame: 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.
measure: Time to Reach Maximum Plasma Concentration (Tmax) for PF-05212384 on Cycle 0 Day -14 and Cycle 1 Day 15 for Arm D
timeFrame: Day -14 and Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 4, 6, 8, 24, 72, and 120 hours post-dose.
measure: Time to Reach Maximum Plasma Concentration (Tmax) for PD-0325901 on Cycle 0 Day -1 and Cycle 1 Day 1 for Arm D
timeFrame: Cycle 0 Day -1 and Cycle 1 Day 1: Pre-dose and 1, 2, 4, 6 and 8 hours post-dose.
measure: Time to Reach Maximum Plasma Concentration (Tmax) for PD-0325901 on Cycle 0 Day -7 and Cycle 1 Day 12 for Arm A
timeFrame: 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.
measure: Time to Reach Maximum Plasma Concentration (Tmax) for PF-04691502 on Cycle 0 Day -7 and Cycle 1 Day 12 for Arm A
timeFrame: 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.
measure: Time to Reach Maximum Plasma Concentration (Tmax) for PF-04691502 on Cycle 0 Day -7 and Cycle 1 Day 12 for Arm B
timeFrame: 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.
measure: Terminal Elimination Half Life (t½) for PF-05212384 on Cycle 1 Day 2 and Day 16 for Arm C
timeFrame: 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.
measure: Terminal Elimination Half Life (t½) for PF-05212384 on Cycle 0 Day -14 and Cycle 1 Day 15 for Arm D
timeFrame: Day -14 and Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 4, 6, 8, 24, 72, and 120 hours post-dose.
measure: Terminal Elimination Half Life (t½) for PD-0325901 on Cycle 0 Day -7 for Arm A
timeFrame: Cycle 0 Day -7: Pre-dose and 1, 2, 4, 6, 8, 24, and 72 hours post-dose.
measure: Terminal Elimination Half Life (t1/2) for PF-04691502 on Cycle 0 Day -7 and Cycle 1 Day 12 for Arm A
timeFrame: 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.
measure: Terminal Elimination Half Life (t1/2) for PF-04691502 on Cycle 0 Day -7 and Cycle 1 Day 12 for Arm B
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for PD-0325901 on Cycle 0 Day -7 for Arm A
timeFrame: Cycle 0 Day -7: Pre-dose and 1, 2, 4, 6, 8, 24, and 72 hours post-dose.
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for PF-04691502 on Cycle 0 Day -7 for Arm A
timeFrame: 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.
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for PF-04691502 on Cycle 0 Day -7 for Arm B
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) for PD-0325901 on Cycle 0 Day -7 for Arm A
timeFrame: Cycle 0 Day -7: Pre-dose and 1, 2, 4, 6, 8, 24, and 72 hours post-dose.
measure: Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) for PF-04691502 on Cycle 0 Day -7 for Arm A
timeFrame: 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.
measure: Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) for PF-04691502 on Cycle 0 Day -7 for Arm B
timeFrame: 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.
measure: Number of Participants With Increase From Baseline in QT Interval
timeFrame: 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)
measure: Number of Participants With Maximum Post-dose QT Interval Corrected
timeFrame: 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)
measure: Percentage of Participants With Complete Response (CR) or Partial Response (PR)
timeFrame: Baseline, every 8 weeks in Cycle 3 and subsequent cycles, until progression of disease was documented.
measure: Progression-Free Survival (PFS) (Stage 2)
timeFrame: Baseline, every 8 weeks in Cycle 3 and subsequent cycles, until progression of disease was documented.
measure: Ratio to Baseline in Serum Glucose Level at End of Treatment for Arm B, Arm C, and Arm D
timeFrame: 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)
measure: Ratio to Baseline in Serum Insulin Level at End of Treatment for Arm B, Arm C, and Arm D
timeFrame: 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)
measure: Ratio to Baseline in Serum Glucose Level at Cycle 2 Day 16 for Arm A
timeFrame: 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)
measure: Ratio to Baseline in Serum Insulin Level at Cycle 2 Day 16 for Arm A
timeFrame: 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)
measure: 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
timeFrame: Baseline and Cycle 1 Day 23.
measure: Duration of Response (Stage 2)
timeFrame: Baseline, every 8 weeks in Cycle 3 and subsequent cycles, until until progression of disease was documented.
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center
state: California
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center
state: California
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Los Angeles
country: United States
facility: UCLA Oncology Center
state: California
city: Santa Monica
country: United States
facility: Santa Monica - UCLA Medical Center and Orthopaedic Hospital
state: California
city: Santa Monica
country: United States
facility: UCLA Santa Monica Hematology Oncology
state: California
city: Aurora
country: United States
facility: Anschutz Cancer Pavilion
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Denver (CTRC)
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Hospital Anschutz Inpatient Pavilion
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Hospital
state: Colorado
city: Charleston
country: United States
facility: Medical University of South Carolina, Hollings Cancer Center
state: South Carolina
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Charleston
country: United States
facility: MUSC, Investigational Drug Services
state: South Carolina
city: Mount Pleasant
country: United States
facility: MUSC Health East Cooper
state: South Carolina
city: North Charleston
country: United States
facility: MUSC Specialty Care-North
state: South Carolina
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Milano
country: Italy
facility: Ospedale San Raffaele
city: Barcelona
country: Spain
facility: Hospital General Vall d'Hebron
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: