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

This study has been terminated.
(Refer to Detailed Description for documentaion of Termination Statement.)
Information provided by (Responsible Party):
Pfizer Identifier:
First received: May 2, 2011
Last updated: November 4, 2015
Last verified: November 2015
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.

Condition Intervention Phase
Advanced Cancer
Drug: PF-05212384
Drug: PD-0325901
Drug: irinotecan
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Basic Science
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

Resource links provided by NLM:

Further study details as provided by Pfizer:

Primary Outcome Measures:
  • First cycle Dose Limiting Toxicities (DLTs) [ Time Frame: up to 28 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Adverse Events as characterized by type, frequency, severity (as graded by NCI CTCAE v.4.0), timing , seriousness and relationship to study therapy [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
  • Area under the plasma concentration versus time curve (AUC) of PF-04691502, PF-05212384 and PD-0325901 [ Time Frame: 0, 1, 2, 8 and 24 hours post dose ] [ Designated as safety issue: No ]
  • Objective Tumor Response Rate (ORR) [ Time Frame: 15 months ] [ Designated as safety issue: No ]
  • Expression and/or phosphorylation in biopsied tumor tissue of PI3K pathway proteins and markers of cell cycle and survival [ Time Frame: at baseline and at 2 weeks ] [ Designated as safety issue: No ]
  • Gene and/or protein expression in biopsied tumor tissue relating to PI3K and/or MAPK pathway signaling [ Time Frame: at baseline ] [ Designated as safety issue: No ]

Estimated Enrollment: 165
Study Start Date: October 2011
Estimated Study Completion Date: November 2015
Estimated Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm D: PF-05212384 + PD-0325901 Drug: PF-05212384
PF-05212384 intravenous infusion weekly starting at 110 mg.
Drug: PD-0325901
PD-0325901 Oral twice daily (BID) dosing 2 mg BID 3 weeks on 1 week off
Experimental: Arm C: PF-05212384 + irinotecan Drug: PF-05212384
PF-05212384 intravenous infusion weekly starting at 95 mg.
Drug: irinotecan
Irinotecan by intravenous infusion at 180 mg/m2 every two weeks (Q x 2 week)

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.

Ages Eligible for Study:   18 Years to 150 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01347866

United States, California
Ronald Reagan UCLA Medical Center
Los Angeles, California, United States, 90095
Ronald Reagan UCLA Medical Center
Los Angeles, California, United States, 90095-6984
UCLA Medical Center
Los Angeles, California, United States, 90095
UCLA Oncology Center
Los Angeles, California, United States, 90095
Santa Monica - UCLA Medical Center and Orthopaedic Hospital
Santa Monica, California, United States, 90404
UCLA Santa Monica Hematology Oncology
Santa Monica, California, United States, 90404
United States, Colorado
University of Colorado Hospital
Aurora, Colorado, United States, 80045
University of Colorado Denver (CTRC)
Aurora, Colorado, United States, 80045
University of Colorado Hospital Anschutz Inpatient Pavilion
Aurora, Colorado, United States, 80045
Anschutz Cancer Pavilion
Aurora, Colorado, United States, 80045
United States, South Carolina
Medical University of South Carolina, Hollings Cancer Center
Charleston, South Carolina, United States, 29425
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
MUSC, Investigational Drug Services
Charleston, South Carolina, United States, 29425
MUSC Health East Cooper
Mt. Pleasant, South Carolina, United States, 29464
MUSC Specialty Care-North
North Charleston, South Carolina, United States, 29406
Canada, Ontario
Princess Margaret Hospital
Toronto, Ontario, Canada, M5G 2M9
Ospedale San Raffaele
Milano, Italy, 20132
Hospital General Vall d'Hebron
Barcelona, Spain, 08035
Sponsors and Collaborators
Study Director: Pfizer Call Center Pfizer
  More Information

Additional Information:
No publications provided

Responsible Party: Pfizer Identifier: NCT01347866     History of Changes
Other Study ID Numbers: B1271002, 2011-001671-39
Study First Received: May 2, 2011
Last Updated: November 4, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Pfizer:
Advanced metastatic cancer (solid tumors)

Additional relevant MeSH terms:
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Radiation-Sensitizing Agents
Therapeutic Uses
Topoisomerase I Inhibitors
Topoisomerase Inhibitors processed this record on November 25, 2015