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A Study Of Crizotinib Plus VEGF Inhibitor Combinations In Patients With Advanced Solid Tumors.

This study has been withdrawn prior to enrollment.
(Business/Operational issues)
Sponsor:
ClinicalTrials.gov Identifier:
NCT01441388
First Posted: September 27, 2011
Last Update Posted: December 20, 2011
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Pfizer
  Purpose
Despite the success of anti-angiogenic therapy in multiple treatment settings, a fraction of patients are refractory to vascular endothelial growth factor (VEGF) inhibitor treatment while the majority of patients will eventually develop evasive resistance and exhibit disease progression while on therapy. It is proposed that mesenchymal-epithelial transition factor (c-MET) and its ligand hepatocyte growth factor (HGF or scatter factor) contribute significantly to VEGF inhibitor resistance such that combining a c-MET inhibitor with a VEGF inhibitor will provide additional clinical activity compared to VEGF inhibitor alone. This hypothesis will be tested using the cMET/ALK inhibitor, crizotinib, in combination with individual VEGF inhibitors. Three combinations will be prioritized, namely crizotinib plus axitinib, crizotinib plus sunitinib and crizotinib plus bevacizumab, with a fourth combination, crizotinib plus sorafenib to be tested only if crizotinib does not combine with either axitinib and/or sunitinib.

Condition Intervention Phase
Carcinoma, Renal Cell Glioblastoma Carcinoma, Hepatocellular Drug: Crizotinib plus VEGF inhibitor combinations Drug: Crizotinib plus axitinib Drug: Crizotinib plus sunitinib Drug: Crizotinib plus bevacizumab Drug: Crizotinib plus sorafenib Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1B, Open-Label, Dose Escalation Study To Evaluate Safety, Pharmacokinetics And Pharmacodynamics Of Crizotinib (PF-02341066) Plus VEGF Inhibitor Combinations In Patients With Advanced Solid Tumors.

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Dose Limiting Toxicities (DLTs). [ Time Frame: 12 months ]

Secondary Outcome Measures:
  • Duration of Response (DR) [ Time Frame: 24 months ]
  • Progression free survival (PFS) [ Time Frame: 24 months ]
  • Area under the plasma concentration versus time curve (AUC) of crizotinib and each VEGF inhibitor [ Time Frame: 24 months ]
  • Best overall response, as assessed using the Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 or , in the case of GBM (glioblastoma multiforme , RANO (Response Assessment in Neuro-Oncology) criteria. [ Time Frame: 24 months ]
  • Overall survival (OS) up to 12 months [ Time Frame: 24 months ]
  • Pre- and post-dose levels of soluble peripheral blood biomarkers. [ Time Frame: 24 months ]
  • Tumor tissue biomarkers. [ Time Frame: 18 months ]
  • 6-month progression free survival proportion (PFS6) for glioblastoma patients [ Time Frame: 24 months ]
  • Peak plasma concentration (Cmax) of crizotinib and each VEGF inhibitor [ Time Frame: 24 months ]

Enrollment: 0
Study Start Date: December 2011
Estimated Study Completion Date: November 2013
Estimated Primary Completion Date: November 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dose Escalation
Histological or cytological diagnosis of advanced/metastatic solid tumor that is resistant to standard therapy or for which no standard therapy is available.
Drug: Crizotinib plus VEGF inhibitor combinations
Three combinations will be prioritized, namely crizotinib plus axitinib, crizotinib plus sunitinib and crizotinib plus bevacizumab, with a fourth combination, crizotinib plus sorafenib to be tested only if crizotinib does not combine with either axitinib and/or sunitinib. All study drugs are tablets or capsules except for bevacizumab which is parenteral (intravenous). Dosage, frequency and duration to be determined.
Experimental: Expansion Population 1
Patients with histologically confirmed metastatic renal cell cancer with no prior systemic therapy directed at the malignant tumor.
Drug: Crizotinib plus axitinib
Study drugs are tablets or capsules; dosage, frequency and duration to be determined.
Drug: Crizotinib plus sunitinib
Study drugs are tablets or capsules; dosage, frequency and duration to be determined.
Experimental: Expansion Population 2
Patients with histologically confirmed metastatic renal cell cancer whose prior systemic therapy directed at the malignant tumor was single agent VEGF inhibitor and who now have acquired resistance to this treatment.
Drug: Crizotinib plus axitinib
Study drugs are tablets or capsules; dosage, frequency and duration to be determined.
Drug: Crizotinib plus sunitinib
Study drugs are tablets or capsules; dosage, frequency and duration to be determined.
Experimental: Expansion Population 3
Patients with histologically confirmed glioblastoma whose disease has failed on previous therapy, and which must have included treatment with external beam radiation and temozolomide chemotherapy, and who now have radiographically recurrent or progressive disease.
Drug: Crizotinib plus bevacizumab
Study drugs are tablets or capsules except for bevacizumab which is parenteral (intravenous). Dosage, frequency and duration to be determined.
Experimental: Expansion Population 4
Patients with histologically confirmed advanced-stage (unresectable or metastatic) hepatocellular carcinoma who have not received previous systemic therapy directed at the malignant tumor will be eligible to receive crizotinib plus sorafenib, should this combination be tested.
Drug: Crizotinib plus sorafenib
Study drugs are tablets or capsules; dosage, frequency and duration to be determined.

  Eligibility

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Dose Escalation Population: Histological or cytological diagnosis of advanced/metastatic solid tumor that is resistant to standard therapy or for which no standard therapy is available. Lesions may be measurable or non measurable.
  • Expansion Population 1: Patients with histologically confirmed metastatic renal cell cancer with no prior systemic therapy directed at the malignant tumor.
  • Expansion Population 2: Patients with histologically confirmed metastatic renal cell cancer whose prior systemic therapy directed at the malignant tumor was single agent VEGF inhibitor and who now have acquired resistance to this treatment. Resistance is defined as progression following an initial response (complete or partial), or stable disease for at least 6 months on single agent VEGF inhibitor.
  • Expansion Population 3: Patients with histologically confirmed glioblastoma whose disease has failed on previous therapy, and which must have included treatment with external beam radiation and temozolomide chemotherapy, and who now have radiographically recurrent or progressive disease.
  • Expansion Population 4: Patients with histologically confirmed advanced-stage (unresectable or metastatic) hepatocellular carcinoma who have not received previous systemic therapy directed at the malignant tumor will be eligible to receive crizotinib plus sorafenib, should this combination be tested. Eligibility criteria also include normal hepatic function or Child-Pugh hepatic function class A.

Exclusion Criteria:

  • Patients with hemorrhagic brain metastases or with known symptomatic brain metastases requiring steroids.
  • Major surgery within 4 weeks of starting study treatment.
  • Radiation therapy within 2 weeks of starting study treatment.
  • Hypertension that cannot be controlled with medications (>150/90 mmHg despite optimal medical therapy).
  • For glioblastoma patients: Prior treatment of glioblastoma with Gliadel wafers, stereotactic radiation, or brachytherapy unless there is pathological or definitive radiological evidence (PET scan or perfusion MRI) of recurrent tumor or unless there is new enhancement outside of the radiation field. History of Grade 2 or greater acute intracranial hemorrhage. Radiation therapy (RT) for glioblastoma within 3 months unless there is either: a) histopathologic confirmation of recurrent tumor, or b) new enhancement on MRI outside of the RT treatment field.Concomitant treatment with therapeutic doses of anticoagulants (low dose warfarin (Coumadin) up to 2 mg PO daily for deep vein thrombosis prophylaxis is allowed).
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01441388


Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01441388     History of Changes
Other Study ID Numbers: A8081030
First Submitted: September 23, 2011
First Posted: September 27, 2011
Last Update Posted: December 20, 2011
Last Verified: December 2011

Keywords provided by Pfizer:
Phase 1b
crizotinib
sunitinib
axitinib
sorafenib
bevacizumab
cMET inhibitor
VEGF inhibitor
crizotinib combination

Additional relevant MeSH terms:
Carcinoma
Glioblastoma
Carcinoma, Hepatocellular
Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Kidney Diseases
Urologic Diseases
Bevacizumab
Sunitinib
Sorafenib
Axitinib
Crizotinib
Angiogenesis Inhibitors