Clinical Study Of PI3K/mTOR Inhibitors In Combination With An Oral MEK Inhibitor Or Irinotecan In Patients With Advanced Cancer
Condition: Advanced Cancer
MeSH terms: Neoplasms
Intervention: PF-05212384; PD-0325901; PF-05212384; irinotecan
Intervention description: 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)
Intervention MeSH terms: Irinotecan; Gedatolisib
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Non-Randomized
Masking: None (Open Label)
Enrollment: 105.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Advanced metastatic cancer (solid tumors); PI3K; mTOR; MEK

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.
    

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